AU2016273912B2 - High-purity production of multi-subunit proteins such as antibodies in transformed microbes such as Pichia pastoris - Google Patents

Abstract

Methods for producing heterologous multi-subunit proteins in transformed cells are disclosed. In particular, the present disclosure provides improved methods of producing multi-subunit proteins, including antibodies and other multi-subunit proteins, which may or may not be secreted, with a higher yield and decreased production of undesired side-products. In exemplary embodiments, the transformed cells are a yeast, e.g., methylotrophic yeast such as Pichia pastoris.

Description

The present invention contemplates the use of haploid yeast, as well as diploid or other polyploid yeast cells produced, for example, by mating or fusion (e.g., spheroplast fusion).

[00186] In one embodiment of the invention, the mating competent yeast is a member of the Saccharomycetaceae family, which includes the genera Arxiozyma', Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera; Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea; Lodderomyces; Pachysolen; Pichia', Saccharomyces', Saturnispora', Tetrapisispora', Torulaspora', Williopsis', and Zy go saccharomyces. Other types of yeast potentially useful in the invention include Yarrowia; Rhodosporidiunv, Candida', Hansenula', Filobasiunv, Sporidiobolus', Bullera', Leucosporidium and Filobasidella.

[00187] In a preferred embodiment of the invention, the mating competent yeast is a member of the genus Pichia or is another methylotroph. In a further preferred embodiment of the invention, the mating competent yeast of the genus Pichia is one of the following species: Pichia pastoris, Pichia methanolica, and Hansenula polymorpha (Pichia angusta). In a particularly preferred embodiment of the invention, the mating competent yeast of the genus Pichia is the species Pichia pastoris.

2016273912 14 Dec 2016 [00188] Haploid Yeast Cell·. A cell having a single copy of each gene of its normal genomic (chromosomal) complement.

[00189] Polyploid Yeast Cell· A cell having more than one copy of its normal genomic (chromosomal) complement.

[00190] Diploid Yeast Cell· A cell having two copies (alleles) of essentially every gene of its normal genomic complement, typically formed by the process of fusion (mating) of two haploid cells.

[00191] Tetraploid Yeast Cell· A cell having four copies (alleles) of essentially every gene of its normal genomic complement, typically formed by the process of fusion (mating) of two diploid cells. Tetraploids may carry two, three, four, or more different expression cassettes. Such tetraploids might be obtained in S. cerevisiae by selective mating homozygotic heterothallic a/a and alpha/alpha diploids and in Pichia by sequential mating of haploids to obtain auxotrophic diploids. For example, a [met his] haploid can be mated with [ade his] haploid to obtain diploid [his]; and a [met arg] haploid can be mated with [ade arg] haploid to obtain diploid [arg]; then the diploid [his] can be mated with the diploid [arg] to obtain a tetraploid prototroph. It will be understood by those of skill in the art that reference to the benefits and uses of diploid cells may also apply to tetraploid cells.

[00192] Yeast Mating·. The process by which two yeast cells fuse to form a single yeast cell. The fused cells may be haploid cells or cells of higher ploidy (e.g., mating two diploid cells to produce a tetraploid cell).

[00193] Meiosis'. The process by which a diploid yeast cell undergoes reductive division to form four haploid spore products. Each spore may then germinate and form a haploid vegetatively growing cell line.

[00194] Selectable Marker. A selectable marker is a gene or gene fragment that confers a growth phenotype (physical growth characteristic) on a cell receiving that gene as, for example through a transformation event. The selectable marker allows that cell to survive and grow in a selective growth medium under conditions in which cells that do not receive that selectable marker gene cannot grow. Selectable marker genes generally fall into several types, including

2016273912 14 Dec 2016 positive selectable marker genes such as a gene that confers on a cell resistance to an antibiotic or other drug, temperature when two temperature sensitive (“ts”) mutants are crossed or a ts mutant is transformed; negative selectable marker genes such as a biosynthetic gene that confers on a cell the ability to grow in a medium without a specific nutrient needed by all cells that do not have that biosynthetic gene, or a mutagenized biosynthetic gene that confers on a cell inability to grow by cells that do not have the wild type gene; and the like. Suitable markers include but are not limited to: ZEO; NEO (G418); LYS3; MET1; MET3a; ADE1; ADE3; URA3; and the like.

[00195] Integrated'. A genetic element (typically a heterologous genetic element) that are covalently joined into a chromosome of an organism.

[00196] Tandemly integrated'. Two or more copies of a genetic element that are integrated in adjacent locations in a chromosome. The two or more copies do not necessarily have the orientation; e.g., for transcribed genes, some copies may be transcribed from the Watson strand and others from the Crick strand.

[00197] Host cell: In the context of the present disclosure, the term host cell refers to a cell (e.g., a eukaryotic cell, such as a Pichia cell) which contains a heterologous gene. For example, the heterologous gene may provide for the expression of a subunit of a desired multisubunit complex, a gene involved in protein folding (e.g., a chaperone), expression, or secretion, and/or another desired gene. The heterologous gene may be integrated into the genome of the eukaryotic cell or contained in extrachromosomal element such as a plasmid or artificial chromosome.

[00198] Expression Vector. These DNA vectors contain elements that facilitate manipulation for the expression of a foreign protein within the target host cell. Conveniently, manipulation of sequences and production of DNA for transformation is first performed in a bacterial host, e.g. E. coli, and usually vectors will include sequences to facilitate such manipulations, including a bacterial origin of replication and appropriate bacterial selection marker. Selection markers encode proteins necessary for the survival or growth of transformed host cells grown in a selective culture medium. Host cells not transformed with the vector containing the selection gene will not survive in the culture medium. Typical selection genes

2016273912 14 Dec 2016 encode proteins that (a) confer resistance to antibiotics or other toxins, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media. Exemplary vectors and methods for transformation of yeast are described, for example, in Burke, D., Dawson, D., & Steams, T. (2000). Methods in yeast genetics: a Cold Spring Harbor Laboratory course manual. Plainview, N.Y.: Cold Spring Harbor Laboratory Press, which is incorporated by reference herein in its entirety.

[00199] Expression vectors for use in the methods of the invention may further include yeast specific sequences, including a selectable auxotrophic or drug marker for identifying transformed yeast strains. A drug marker may further be used to select for amplification of copy number of the vector in a yeast host cell.

[00200] The polypeptide coding sequence of interest is typically operably linked to transcriptional and translational regulatory sequences that provide for expression of the polypeptide in yeast cells. These vector components may include, but are not limited to, one or more of the following: an enhancer element, a promoter, and a transcription termination sequence. Sequences for the secretion of the polypeptide may also be included, e.g. a signal sequence, and the like. A yeast origin of replication is optional, as expression vectors are often integrated into the yeast genome.

[00201] Though optional, in one embodiment of the invention, one or more subunit of the multi-subunit complex is operably linked, or fused, to a secretion sequence that provides for secretion of the expressed polypeptide into the culture media, which can facilitate harvesting and purification of the heterologous multi-subunit complex. Even more preferably, the secretion sequences provide for optimized secretion of the polypeptide from the host cells (e.g., yeast diploid cells), such as through selecting preferred codons and/or altering the percentage AT through codon selection. It is known in the art that secretion efficiency and / or stability can be affected by the choice of secretion sequence and the optimal secretion sequence can vary between different proteins (see, e.g., Koganesawa et al., Protein Eng. 2001 Sep;14(9):705-10, which is incorporated by reference herein in its entirety). Many potentially suitable secretion signals are known in the art and can readily be tested for their effect upon yield and/or purity of a particular heterologous multi-subunit complex. Any secretion sequences may potentially be

2016273912 14 Dec 2016 used, including those present in secreted proteins of yeasts and other species, as well as engineered secretion sequences. Exemplary secretion sequences that may be utilized include: chicken lysozyme (CLY) signal peptide (MRSLLILVLCFLPLAALG (SEQ ID NO:414)), CLYL8 (MRLLLLLLLLPLAALG (SEQ ID NO:415)), S. cerevisiae invertase (SUC2) signal peptide (MLLQAFLFLLAGFAAKISA (SEQ ID NO:416)), MF-alpha (Prepro) (MRFPSIFTAVLFAASSALA-APVNTTTE-EGVSLEKR (SEQ ID NO:417)), MF-alpha (Pre)apv (MRFPSIFTAVLFAASSALA-APV (SEQ ID NO:418)), MF-alpha (Pre)-apv-SLEKR (MRFPSIFTAVLFAASSALA-APVSLEKR (SEQ ID NO:419)), MF-alpha (Prepro)-(EA)3 (MRFPSIFTAVLFAASSALA-APVNTTTE-EGVSLEKR-EAEAEA (SEQ ID NO:420)), aF signal peptide (MRFPSIFTAVLFAASSALA-APVNTTTEDETAQIPAEAVIGYSDLEGDFDVAVLPFSNSTNNGLLFINTTIASIAAKE-EGVSLEKR (SEQ ID NO:421)), KILM1 signal peptide (MTKPTQVLVRSVSILFFITLLHLVVALNDVAGPAETAPVSLLPR (SEQ ID NO :422)), repressible acid phosphatase (PHO1) signal peptide (MFSPILSLEIILALATLQSVFA (SEQ ID NO:423)), A. niger GOX signal peptide (MQTLLVSSLVVSLAAALPHYIR (SEQ ID NO:424)), Schwanniomyces occidentalis glucoamylase gene (GAM1) signal peptide (MIFLKLIKSIVIGLGLVSAIQA (SEQ ID NO:425)), human serum albumin (HSA) signal peptide with pro-sequence (MKWVTFISLLFLFSSAYSRGVFRR (SEQ ID NO:426)), human serum albumin (HSA) signal peptide without pro-sequence (MKWVTFISLLFLFSSAYS (SEQ ID NO:427)), ISN signal peptide (MALWMRLLPLLALLALWGPDPAAA (SEQ ID NO:428)), IFN signal peptide (MKYTSYILAFQLCIVLGSLGCDLP (SEQ ID NO:429)), HGH signal peptide (MAADSQTPWLLTFSLLCLLWPQEPGA (SEQ ID NO:430)), phytohaemagglutinin (PHA) (MKKNRMMMMIWSVGVVWMLLLVGGSYG (SEQ ID NO:431)), Silkworm lysozyme (MQKLIIFALVVLCVGSEA (SEQ ID NO:432)), Human lysozyme (LYZ1) (MKALIVLGLVLLSVTVQG (SEQ ID NO:433)), activin receptor type-1 (MVDGVMILPVLIMIALPSPS (SEQ ID NO:434)), activin type II receptor (MGAAAKLAFAVFLISCSSG (SEQ ID NO:435)), P. pastoris immunoglobulin binding protein (PpBiP) (MLSLKPSWLTLAALMYAMLLVVVPFAKPVRA (SEQ ID NO:436)), and human antibody 3D6 light chain leader (MDMRVPAQLLGLLLLWLPGAKC (SEQ ID NO:437)). See Hashimoto et al., Protein Engineering vol. 11 no. 2 pp.75-77, 1998; Oka et al., Biosci Biotechnol Biochem. 1999 Nov; 63(11): 1977-83; Gellissen et al., FEMS Yeast Research 5 (2005) 107940

2016273912 14 Dec 2016

1096; Ma et al., Hepatology. 2005 Dec;42(6): 1355-63; Raemaekers et al., Eur J Biochem. 1999 Oct l;265(l):394-403; Koganesawa et al., Protein Eng. (2001) 14 (9): 705-710; Daly et al., Protein Expr Purif. 2006 Apr;46(2):456-67 ; Damasceno et al., Appl Microbiol Biotechnol (2007) 74:381-389; and Felgenhauer et al., Nucleic Acids Res. 1990 Aug 25;18(16):4927, each of which is incorporated by reference herein in its entirety). The multi-subunit complex may also be secreted into the culture media without being operably linked or fused to a secretion signal. For example, it has been demonstrated that some heterologous polypeptides are secreted into the culture media when expressed in P. pastoris even without being linked or fused to a secretion signal. Additionally, the multi-subunit complex may be purified from host cells (which, for example, may be preferable if the complex is poorly secreted) using methods known in the art.

[00202] Media or cells comprising a desired multi-subunit complex may be recovered from the culture. Optionally, the secreted proteins may be purified. For example, cells comprising a desired multi-subunit complex may be lysed using mechanical, chemical, enzymatic, and/or osmotic methods (e.g., freezing with liquid nitrogen, using a homogenizer, spheroplasting, sonication, agitation in the presence of glass beads, using detergents, etc.). The desired multi-subunit complex may be concentrated, filtered, dialyzed, etc., using methods known in the art. The desired multi-subunit complex may be purified based on, for example, its molecular mass (e.g., size exclusion chromatography), isoelectric point (e.g., isoelectric focusing), electrophoretic mobility (e.g., gel electrophoresis), hydrophobic interaction chromatography (e.g., HPLC), charge (e.g., ion exchange chromatography), affinity (e.g., in the case of an antibody, binding to protein A, protein G, and/or an epitope to which the desired antibody binds), and/or glycosylation state (e.g., detected by lectin binding affinity). Multiple purification steps may be performed to obtain the desired level of purity. In an exemplary embodiment, the desired multi-subunit complex may be comprise an immunoglobulin constant domain and may be purified using protein A or protein G affinity, size exclusion chromatography, and lack of binding to lectin (to remove glycosylated forms). Optionally the A protease inhibitor, such as phenyl methyl sulfonyl fluoride (PMSF) may be added to inhibit proteolytic degradation during purification.

2016273912 14 Dec 2016 [00203] Nucleic acids are operably linked when placed into a functional relationship with another nucleic acid sequence. For example, DNA for a signal sequence is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence. Generally, operably linked means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking may be accomplished by ligation at convenient restriction sites or alternatively via a PCR/recombination method familiar to those skilled in the art (Gateway® Technology; Invitrogen, Carlsbad Calif.). If such sites do not exist, the synthetic oligonucleotide adapters or linkers may be used in accordance with conventional practice. Desired nucleic acids (including nucleic acids comprising operably linked sequences) may also be produced by chemical synthesis.

[00204] Promoters are untranslated sequences located upstream (5') to the start codon of a structural gene (generally within about 100 to 1000 bp) that control the transcription and translation of particular nucleic acid sequences to which they are operably linked. Such promoters fall into several classes: inducible, constitutive, and repressible promoters (that increase levels of transcription in response to absence of a repressor). Inducible promoters may initiate increased levels of transcription from DNA under their control in response to some change in culture conditions, e.g., the presence or absence of a nutrient or a change in temperature.

[00205] The yeast promoter fragment may also serve as the site for homologous recombination and integration of the expression vector into the same site in the yeast genome; alternatively a selectable marker is used as the site for homologous recombination. Pichia transformation is described in Cregg et al. (1985) Mol. Cell. Biol. 5:3376-3385, which is incorporated by reference herein in its entirety.

[00206] Examples of suitable promoters from Pichia include the CUP1 (induced by the level of copper in the medium), tetracycline inducible promoters, thiamine inducible promoters, AOX1 promoter (Cregg et al. (1989) Mol. Cell. Biol. 9:1316-1323); ICL1 promoter (Menendez et al. (2003) Yeast 20(13): 1097-108); glyceraldehyde-3-phosphate dehydrogenase promoter

2016273912 14 Dec 2016 (GAP) (Waterham et al. (1997) Gene 186(l):37-44); and FLD1 promoter (Shen et al. (1998)

Gene 216(1):93-102). The GAP promoter is a strong constitutive promoter and the CUP1, AOX and FLD1 promoters are inducible. Each foregoing reference is incorporated by reference herein in its entirety.

[00207] Other yeast promoters include ADH1, alcohol dehydrogenase II, GAL4, PHO3, PHO5, Pyk, and chimeric promoters derived therefrom. Additionally, non-yeast promoters may be used in the invention such as mammalian, insect, plant, reptile, amphibian, viral, and avian promoters. Most typically the promoter will comprise a mammalian promoter (potentially endogenous to the expressed genes) or will comprise a yeast or viral promoter that provides for efficient transcription in yeast systems.

[00208] The polypeptides of interest may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, e.g. a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the polypeptide coding sequence that is inserted into the vector. The heterologous signal sequence selected preferably is one that is recognized and processed through one of the standard pathways available within the host cell. The S. cerevisiae alpha factor pre-pro signal has proven effective in the secretion of a variety of recombinant proteins from P. pastoris. Other yeast signal sequences include the alpha mating factor signal sequence, the invertase signal sequence, and signal sequences derived from other secreted yeast polypeptides. Additionally, these signal peptide sequences may be engineered to provide for enhanced secretion in diploid yeast expression systems. Other secretion signals of interest also include mammalian signal sequences, which may be heterologous to the protein being secreted, or may be a native sequence for the protein being secreted. Signal sequences include pre-peptide sequences, and in some instances may include propeptide sequences. Many such signal sequences are known in the art, including the signal sequences found on immunoglobulin chains, e.g., K28 preprotoxin sequence, PHA-E, FACE, human MCP-1, human serum albumin signal sequences, human Ig heavy chain, human Ig light chain, and the like. For example, see Hashimoto et. al. Protein Eng 11(2) 75 (1998); and Kobayashi et. al. Therapeutic Apheresis 2(4) 257 (1998), each of which is incorporated by reference herein in its entirety.

2016273912 14 Dec 2016 [00209] Transcription may be increased by inserting a transcriptional activator sequence into the vector. These activators are cis-acting elements of DNA, usually about from 10 to 300 bp, which act on a promoter to increase its transcription. Transcriptional enhancers are relatively orientation and position independent, having been found 5' and 3' to the transcription unit, within an intron, as well as within the coding sequence itself. The enhancer may be spliced into the expression vector at a position 5' or 3' to the coding sequence, but is preferably located at a site 5' from the promoter.

[00210] Expression vectors used in eukaryotic host cells may also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from 3’ to the translation termination codon, in untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA.

[00211] Construction of suitable vectors containing one or more of the above-listed components employs standard ligation techniques or PCR/recombination methods. Isolated plasmids or DNA fragments are cleaved, tailored, and re-ligated in the form desired to generate the plasmids required or via recombination methods. For analysis to confirm correct sequences in plasmids constructed, the ligation mixtures are used to transform host cells, and successful transformants selected by antibiotic resistance (e.g. ampicillin or Zeocin) where appropriate. Plasmids from the transformants are prepared, analyzed by restriction endonuclease digestion and/or sequenced.

[00212] As an alternative to restriction and ligation of fragments, recombination methods based on att sites and recombination enzymes may be used to insert DNA sequences into a vector. Such methods are described, for example, by Landy (1989) Ann. Rev. Biochem. 58:913949; and are known to those of skill in the art. Such methods utilize intermolecular DNA recombination that is mediated by a mixture of lambda and E. coli-encoded recombination proteins. Recombination occurs between specific attachment (att) sites on the interacting DNA molecules. For a description of att sites see Weisberg and Landy (1983) Site-Specific Recombination in Phage Lambda, in Lambda II, Weisberg, ed. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Press), pp. 211-250. The DNA segments flanking the recombination sites are

2016273912 14 Dec 2016 switched, such that after recombination, the att sites are hybrid sequences comprised of sequences donated by each parental vector. The recombination can occur between DNAs of any topology. Each foregoing reference is incorporated by reference herein in its entirety.

[00213] Att sites may be introduced into a sequence of interest by ligating the sequence of interest into an appropriate vector; generating a PCR product containing att B sites through the use of specific primers; generating a cDNA library cloned into an appropriate vector containing att sites; and the like.

[00214] Monocistronic andpolycistronic genes. A monocistronic gene encodes an RNA that contains the genetic information to translate only a single protein. A polycistronic gene encodes an mRNA that contains the genetic information to translate more than one protein. The proteins encoded in a polycistronic gene may have the same or different sequences or a combination thereof. Dicistronic or bicistronic refers to a polycistronic gene that encodes two proteins. Polycistronic genes optionally include one or more internal ribosome entry site (IRES) elements to facilitate cap-independent initiation of translation, which may be situated at a location that can drive translation of the downstream protein coding region independently of the 5'-cap structure bound to the 5' end of the mRNA molecule. Any known IRES sequence (e.g., viral, eukaryotic, or artificial in origin) may be used. For example, the cricket paralysis virus IRES sequence in the intergenic region (IGR) may be used, as described in Thompson et al. (2001) PNAS 98:12972-12977. Optionally, IRES function may be potentiated by genetic alteration, e.g., by causing constitutive expression of eIF2 kinase GCN2 or disrupting two initiator tRNA(met) genes disrupted (id.).

[00215] Folding, as used herein, refers to the three-dimensional structure of polypeptides and proteins, where interactions between amino acid residues act to stabilize the structure. While non-covalent interactions are important in determining structure, usually the proteins of interest will have intra- and/or intermolecular covalent disulfide bonds formed by two cysteine residues. For naturally occurring proteins and polypeptides or derivatives and variants thereof, the proper folding is typically the arrangement that results in optimal biological activity, and can conveniently be monitored by assays for activity, e.g. ligand binding, enzymatic activity, etc.

2016273912 14 Dec 2016 [00216] In some instances, for example where the desired product is of synthetic origin, assays based on biological activity will be less meaningful. The proper folding of such molecules may be determined on the basis of physical properties, energetic considerations, modeling studies, and the like.

[00217] The expression host may be further modified by the introduction of sequences encoding one or more enzymes that enhance folding and disulfide bond formation, i.e. foldases, chaperoning, etc. Such sequences may be constitutively or inducibly expressed in the yeast host cell, using vectors, markers, etc. as known in the art. Preferably the sequences, including transcriptional regulatory elements sufficient for the desired pattern of expression, are stably integrated in the yeast genome through a targeted methodology.

[00218] For example, the eukaryotic PDI is not only an efficient catalyst of protein cysteine oxidation and disulfide bond isomerization, but also exhibits chaperone activity. Coexpression of PDI can facilitate the production of active proteins having multiple disulfide bonds. Also of interest is the expression of BIP (immunoglobulin heavy chain binding protein); cyclophilin; and the like. In one embodiment of the invention, the multi-subunit complex may be expressed from a yeast strain produced by mating, wherein each of the haploid parental strains expresses a distinct folding enzyme, e.g. one strain may express BIP, and the other strain may express PDI or combinations thereof.

[00219] The terms desired protein or target protein are used interchangeably and refer generally to a heterologous multi-subunit protein such as an antibody (e.g., a humanized antibody) or a binding portion thereof described herein.

[00220] The term antibody includes any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more noncovalent binding interactions stabilize the complex between the molecular structure and the epitope. The archetypal antibody molecule is the immunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA, IgE, IgD, etc., from all sources, e.g. human, rodent, rabbit, cow, sheep, pig, dog, other mammals, chicken, other avians, etc., are considered to be antibodies. A preferred source for producing antibodies useful as starting material according to the invention is rabbits. Numerous antibody coding sequences have been described; and others

2016273912 14 Dec 2016 may be raised by methods well-known in the art. Examples thereof include chimeric antibodies, human antibodies and other non-human mammalian antibodies, humanized antibodies, single chain antibodies such as scFvs, camelbodies, nanobodies, IgNAR (single-chain antibodies derived from sharks), small-modular immunopharmaceuticals (SMIPs), and antibody fragments such as Fabs, Fab', F(ab')2 and the like. See Streltsov V A, et al., Structure of a shark IgNAR antibody variable domain and modeling of an early-developmental isotype, Protein Sci. 2005 November; 14(11):2901-9. Epub 2005 Sep. 30; Greenberg A S, et al., A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks,

Nature. 1995 Mar. 9; 374(6518): 168-73; Nuttall S D, et al., Isolation of the new antigen receptor from wobbegong sharks, and use as a scaffold for the display of protein loop libraries, Mol Immunol. 2001 August; 38(4):313-26; Hamers-Casterman C, et al., Naturally occurring antibodies devoid of light chains, Nature. 1993 Jun. 3; 363(6428):446-8; Gill D S, et al., Biopharmaceutical drug discovery using novel protein scaffolds, Curr Opin Biotechnol. 2006 December; 17(6):653-8. Epub 2006 Oct. 19. Each foregoing reference is incorporated by reference herein in its entirety.

[00221] For example, antibodies or antigen binding fragments may be produced by genetic engineering. In this technique, as with other methods, antibody-producing cells are sensitized to the desired antigen or immunogen. The messenger RNA isolated from antibody producing cells is used as a template to make cDNA using PCR amplification. A library of vectors, each containing one heavy chain gene and one light chain gene retaining the initial antigen specificity, is produced by insertion of appropriate sections of the amplified immunoglobulin cDNA into the expression vectors. A combinatorial library is constructed by combining the heavy chain gene library with the light chain gene library. This results in a library of clones which co-express a heavy and light chain (resembling the Fab fragment or antigen binding fragment of an antibody molecule). The vectors that carry these genes are co-transfected into a host cell. When antibody gene synthesis is induced in the transfected host, the heavy and light chain proteins self-assemble to produce active antibodies that can be detected by screening with the antigen or immunogen.

[00222] Antibody coding sequences of interest include those encoded by native sequences, as well as nucleic acids that, by virtue of the degeneracy of the genetic code, are not identical in sequence to the disclosed nucleic acids, and variants thereof. Variant polypeptides can include

2016273912 14 Dec 2016 amino acid (aa) substitutions, additions or deletions. The amino acid substitutions can be conservative amino acid substitutions or substitutions to eliminate non-essential amino acids, such as to alter a glycosylation site, or to minimize misfolding by substitution or deletion of one or more cysteine residues that are not necessary for function. Variants can be designed so as to retain or have enhanced biological activity of a particular region of the protein (e.g., a functional domain, catalytic amino acid residues, etc). Variants also include fragments of the polypeptides disclosed herein, particularly biologically active fragments and/or fragments corresponding to functional domains. Techniques for in vitro mutagenesis of cloned genes are known. Also included in the subject invention are polypeptides that have been modified using ordinary molecular biological techniques so as to improve their resistance to proteolytic degradation or to optimize solubility properties or to render them more suitable as a therapeutic agent.

[00223] Chimeric antibodies may be made by recombinant means by combining the variable light and heavy chain regions (Vl and Vh), obtained from antibody producing cells of one species with the constant light and heavy chain regions from another. Typically chimeric antibodies utilize rodent or rabbit variable regions and human constant regions, in order to produce an antibody with predominantly human domains. The production of such chimeric antibodies is well known in the art, and may be achieved by standard means (as described, e.g., in U.S. Pat. No. 5,624,659, incorporated herein by reference in its entirety). It is further contemplated that the human constant regions of chimeric antibodies of the invention may be selected from IgGl, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgGlO, IgGl 1, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19 constant regions.

[00224] Humanized antibodies are engineered to contain even more human-like immunoglobulin domains, and incorporate only the complementarity-determining regions of the animal-derived antibody. This is accomplished by carefully examining the sequence of the hyper-variable loops of the variable regions of the monoclonal antibody, and fitting them to the structure of the human antibody chains. Although facially complex, the process is straightforward in practice. See, e.g., U.S. Pat. No. 6,187,287, incorporated fully herein by reference. Methods of humanizing antibodies have been described previously in issued U.S. Patent No. 7935340, the disclosure of which is incorporated herein by reference in its entirety.

In some instances, a determination of whether additional rabbit framework residues are required

2016273912 14 Dec 2016 to maintain activity is necessary. In some instances the humanized antibodies still requires some critical rabbit framework residues to be retained to minimize loss of affinity or activity. In these cases, it is necessary to change single or multiple framework amino acids from human germline sequences back to the original rabbit amino acids in order to have desired activity. These changes are determined experimentally to identify which rabbit residues are necessary to preserve affinity and activity.

[00225] In addition to entire immunoglobulins (or their recombinant counterparts), immunoglobulin fragments comprising the epitope binding site (e.g., Fab', F(ab')2, or other fragments) may be synthesized. Fragment, or minimal immunoglobulins may be designed utilizing recombinant immunoglobulin techniques. For instance Fv immunoglobulins for use in the present invention may be produced by synthesizing a fused variable light chain region and a variable heavy chain region. Combinations of antibodies are also of interest, e.g. diabodies, which comprise two distinct Fv specificities. In another embodiment of the invention, SMIPs (small molecule immunopharmaceuticals), camelbodies, nanobodies, and IgNAR are encompassed by immunoglobulin fragments.

[00226] Immunoglobulins and fragments thereof may be modified post-translationally, e.g. to add effector moieties such as chemical linkers, detectable moieties, such as fluorescent dyes, enzymes, toxins, substrates, bioluminescent materials, radioactive materials, chemiluminescent moieties and the like, or specific binding moieties, such as streptavidin, avidin, or biotin, and the like may be utilized in the methods and compositions of the present invention. Examples of additional effector molecules are provided infra.

[00227] Product-associated variant', a product other than the desired product (e.g., the desired multi-subunit complex) which is present in a preparation of the desired product and related to the desired product. Exemplary product-associated variants include truncated or elongated peptides, products having different glycosylation than the desired glycosylation (e.g., if an aglycosylated product is desired then any glycosylated product would be considered to be a product-associated variant), complexes having abnormal stoichiometry, improper assembly, abnormal disulfide linkages, abnormal or incomplete folding, aggregation, protease cleavage, or other abnormalities. Exemplary product-associated variants may exhibit alterations in one or

2016273912 14 Dec 2016 more of molecular mass (e.g., detected by size exclusion chromatography), isoelectric point (e.g., detected by isoelectric focusing), electrophoretic mobility (e.g., detected by gel electrophoresis), phosphorylation state (e.g., detected by mass spectrometry), charge to mass ratio (e.g., detected by mass spectrometry), mass or identity of proteolytic fragments (e.g., detected by mass spectrometry or gel electrophoresis), hydrophobicity (e.g., detected by HPLC) , charge (e.g., detected by ion exchange chromatography), affinity (e.g., in the case of an antibody, detected by binding to protein A, protein G, and/or an epitope to which the desired antibody binds), and glycosylation state (e.g., detected by lectin binding affinity). Where the desired protein is an antibody, the term product-associate variant may include a glyco-heavy variant and/or half antibody species (described below).

[00228] Exemplary product-associated variants include variant forms that contain aberrant disulfide bonds. For example, most IgGl antibody molecules are stabilized by a total of 16 intrachain and inter-chain disulfide bridges, which stabilize the folding of the IgG domains in both heavy and light chains, while the inter-chain disulfide bridges stabilize the association between heavy and light chains. Other antibody types likewise contain characteristic stabilizing intrachain and inter-chain disulfide bonds. Further, some antibodies (including Ab-A and Ab-B disclosed herein) contain additional disulfide bonds referred to as non-canonical disulfide bonds. Thus, aberrant inter-chain disulfide bonds may result in abnormal complex stoichiometry, due to the absence of a stabilizing covalent linkage, and/or disulfide linkages to additional subunits. Additionally, aberrant disulfide bonds (whether inter-chain or intra-chain) may decrease structural stability of the antibody, which may result in decreased activity, decreased stability, increased propensity to form aggregates, and/or increased immunogenicity. Product-associated variants containing aberrant disulfide bonds may be detected in a variety of ways, including nonreduced denaturing SDS-PAGE, capillary electrophoresis, cIEX, mass spectrometry (optionally with chemical modification to produce a mass shift in free cysteines), size exclusion chromatography, HPLC, changes in light scattering, and any other suitable methods known in the art. See, e.g., The Protein Protocols Handbook 2002, Part V, 581-583, DOE 10.1385/1-59259169-8:581;

[00229] Half antibody, half-antibody species, or HILI refer to a protein complex that includes a single heavy and single light antibody chain, but lacks a covalent linkage to a second

2016273912 14 Dec 2016 heavy and light antibody chain. Two half antibodies may remain non-covalently associated under some conditions (which may give behavior similar to a full antibody, e.g., apparent molecular weight determined by size exclusion chromatography). Similarly, H2L1 refers to a protein complex that includes two heavy antibody chains and single light antibody chain, but lacks a covalent linkage to a second light antibody chain; these complexes may also noncovalently associate with another light antibody chain (and likewise give similar behavior to a full antibody). Like full antibodies, half antibody species and H2L1 species can dissociate under reducing conditions into individual heavy and light chains. Half antibody species and H2L1 species can be detected on a non-reduced SDS-PAGE gel as a species migrating at a lower apparent molecular weight than the full antibody, e.g., HILI migrates at approximately half the apparent molecular weight of the full antibody (e.g., about 75 kDa).

[00230] Glyco-heavy variant refers to a glycosylated product-associated variant sometimes present in antibody preparations and which contains at least a partial Fc sequence. The glyco-heavy variant is characterized by decreased electrophoretic mobility observable by SDS-PAGE (relative to a normal heavy chain), lectin binding affinity, binding to an anti-Fc antibody, and apparent higher molecular weight of antibody complexes containing the glycoheavy variant as determined by size exclusion chromatography. See U.S. Provisional Application Ser. No. 61/525,307 (Atty. Docket No. 67858.730200), filed August 31, 2011 which is incorporated by reference herein in its entirety.

[00231] The term polyploid yeast that stably expresses or expresses a desired secreted heterologous polypeptide for prolonged time refers to a yeast culture that secretes said polypeptide for at least several days to a week, more preferably at least a month, still more preferably at least 1-6 months, and even more preferably for more than a year at threshold expression levels, typically at least 50-500 mg/liter (after about 90 hours in culture) and preferably substantially greater.

[00232] The term polyploidal yeast culture that secretes desired amounts of recombinant polypeptide refers to cultures that stably or for prolonged periods secrete at least at least 50-500 mg/liter, and most preferably 500-1000 mg/liter or more.

2016273912 14 Dec 2016 [00233] A polynucleotide sequence corresponds to a polypeptide sequence if translation of the polynucleotide sequence in accordance with the genetic code yields the polypeptide sequence (i.e., the polynucleotide sequence encodes the polypeptide sequence), one polynucleotide sequence corresponds to another polynucleotide sequence if the two sequences encode the same polypeptide sequence.

[00234] A heterologous region or domain of a DNA construct is an identifiable segment of DNA within a larger DNA molecule that is not found in association with the larger molecule in nature. Thus, when the heterologous region encodes a mammalian gene, the gene will usually be flanked by DNA that does not flank the mammalian genomic DNA in the genome of the source organism. Another example of a heterologous region is a construct where the coding sequence itself is not found in nature (e.g., a cDNA where the genomic coding sequence contains introns, or synthetic sequences having codons different than the native gene). Allelic variations or naturally-occurring mutational events do not give rise to a heterologous region of DNA as defined herein.

[00235] A coding sequence is an in-frame sequence of codons that (in view of the genetic code) correspond to or encode a protein or peptide sequence. Two coding sequences correspond to each other if the sequences or their complementary sequences encode the same amino acid sequences. A coding sequence in association with appropriate regulatory sequences may be transcribed and translated into a polypeptide. A polyadenylation signal and transcription termination sequence will usually be located 3' to the coding sequence. A promoter sequence is a DNA regulatory region capable of binding RNA polymerase in a cell and initiating transcription of a downstream (3' direction) coding sequence. Promoter sequences typically contain additional sites for binding of regulatory molecules (e.g., transcription factors) which affect the transcription of the coding sequence. A coding sequence is under the control of the promoter sequence or operatively linked to the promoter when RNA polymerase binds the promoter sequence in a cell and transcribes the coding sequence into mRNA, which is then in turn translated into the protein encoded by the coding sequence.

[00236] Vectors are used to introduce a foreign substance, such as DNA, RNA or protein, into an organism or host cell. Typical vectors include recombinant viruses (for polynucleotides)

2016273912 14 Dec 2016 and liposomes (for polypeptides). A DNA vector is a replicon, such as plasmid, phage or cosmid, to which another polynucleotide segment may be attached so as to bring about the replication of the attached segment. An expression vector is a DNA vector which contains regulatory sequences which will direct polypeptide synthesis by an appropriate host cell. This usually means a promoter to bind RNA polymerase and initiate transcription of mRNA, as well as ribosome binding sites and initiation signals to direct translation of the mRNA into a polypeptide(s). Incorporation of a polynucleotide sequence into an expression vector at the proper site and in correct reading frame, followed by transformation of an appropriate host cell by the vector, enables the production of a polypeptide encoded by said polynucleotide sequence.

[00237] Amplification of polynucleotide sequences is the in vitro production of multiple copies of a particular nucleic acid sequence. The amplified sequence is usually in the form of DNA. A variety of techniques for carrying out such amplification are described in the following review articles, each of which is incorporated by reference herein in its entirety: Van Brunt 1990, Bio/Technol., 8(4):291-294; and Gill and Ghaemi, Nucleosides Nucleotides Nucleic Acids. 2008 Mar;27(3):224-43. Polymerase chain reaction or PCR is a prototype of nucleic acid amplification, and use of PCR herein should be considered exemplary of other suitable amplification techniques.

[00238] The general structure of antibodies in most vertebrates (including mammals) is now well understood (Edelman, G. M., Ann. N.Y. Acad. Sci., 190: 5 (1971)). Conventional antibodies consist of two identical light polypeptide chains of molecular weight approximately 23,000 daltons (the light chain), and two identical heavy chains of molecular weight 53,00070,000 (the heavy chain). The four chains are joined by disulfide bonds in a Y configuration wherein the light chains bracket the heavy chains starting at the mouth of the Y configuration. The branch portion of the Y configuration is designated the F_ab region; the stem portion of the Y configuration is designated the Fc region. The amino acid sequence orientation runs from the N-terminal end at the top of the Y configuration to the C-terminal end at the bottom of each chain. The N-terminal end possesses the variable region having specificity for the antigen that elicited it, and is approximately 100 amino acids in length, there being slight variations between light and heavy chain and from antibody to antibody.

2016273912 14 Dec 2016 [00239] The variable region is linked in each chain to a constant region that extends the remaining length of the chain and that within a particular class of antibody does not vary with the specificity of the antibody (i.e., the antigen eliciting it). There are five known major classes of constant regions that determine the class of the immunoglobulin molecule (IgG, IgM, IgA, IgD, and IgE corresponding to gamma, mu, alpha, delta, and epsilon heavy chain constant regions). The constant region or class determines subsequent effector function of the antibody, including activation of complement (Kabat, E. A., Structural Concepts in Immunology and

Immunochemistry, 2nd Ed., p. 413-436, Holt, Rinehart, Winston (1976)), and other cellular responses (Andrews, D. W., et al., Clinical Immunobiology, pp 1-18, W. B. Sanders (1980);

Kohl, S., et al., Immunology, 48: 187 (1983)); while the variable region determines the antigen with which it will react. Light chains are classified as either kappa or lambda. Each heavy chain class can be paired with either kappa or lambda light chain. The light and heavy chains are covalently bonded to each other, and the tail portions of the two heavy chains are bonded to each other by covalent disulfide linkages when the immunoglobulins are generated either by hybridomas or by B cells.

[00240] The expression variable region or VR refers to the domains within each pair of light and heavy chains in an antibody that are involved directly in binding the antibody to the antigen. Each heavy chain has at one end a variable domain (Vh) followed by a number of constant domains. Each light chain has a variable domain (Vl) at one end and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

[00241] The expressions complementarity determining region, hypervariable region, or CDR refer to one or more of the hyper-variable or complementarity determining regions (CDRs) found in the variable regions of light or heavy chains of an antibody (See Kabat, E. A. et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987)). These expressions include the hypervariable regions as defined by Kabat et al. (Sequences of Proteins of Immunological Interest, Kabat E., et al., US Dept. of Health and Human Services, 1983) or the hypervariable loops in 3-dimensional structures of antibodies (Chothia and Lesk, J Mol. Biol. 196 901-917 (1987)). The CDRs in each chain are held in close

2016273912 14 Dec 2016 proximity by framework regions and, with the CDRs from the other chain, contribute to the formation of the antigen binding site. Within the CDRs there are select amino acids that have been described as the selectivity determining regions (SDRs) which represent the critical contact residues used by the CDR in the antibody-antigen interaction (Kashmiri, S., Methods, 36:25-34 (2005)).

[00242] The expressions framework region or FR refer to one or more of the framework regions within the variable regions of the light and heavy chains of an antibody (See Rabat, E. A. et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., (1987)). These expressions include those amino acid sequence regions interposed between the CDRs within the variable regions of the light and heavy chains of an antibody.

[00243] Anti-NGF Antibodies and Binding Fragments Thereof Having Binding Activity for NGF [00244] Antibody Abl [00245] The invention contemplates methods of treating pain and the specific pain associated disorders using antibody Abl or fragments thereof, or an antibody or antibody fragment that binds to the same or overlapping epitope as Abl, for example as set forth below, alone or is association with another active agent, e.g., an NSAID or opioid analgesic, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75 and/or inhibits or prevents pain. In one embodiment, the invention includes chimeric antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

ALVMTQTPSSVSAAVGGTVTINCQASQNIYSNLAWYQQRPGQRPKLLIYGASNLDAGV PSRFRGSGSGTEYTLTISDLECDDVGTYYCQSAFDSDSTENTFGGGTEVVVKR (SEQ ID NO: 1).

[00246] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or

2016273912 14 Dec 2016 opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: ALVMTQTPSSVSAAVGGTVTINCQASQNIYSNLAWYQQRPGQRPKLLIYGASNLDAGV PSRFRGSGSGTEYTLTISDLECDDVGTYYCQSAFDSDSTENTFGGGTEVVVKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 2).

[00247] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below:

[00248] QSLEESGGRLVTPGTPLTLTCTVSGFSLSSYAMSWVRQAPGKGLEWIGVI TSIGSTVYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARGYDDYDEMTYFNIWGQ GTLVTVSS (SEQ ID NO: 3).

[00249] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

[00250] QSLEESGGRLVTPGTPLTLTCTVSGFSLSSYAMSWVRQAPGKGLEWIGVI TSIGSTVYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARGYDDYDEMTYFNIWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 4).

[00251] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or

2016273912 14 Dec 2016 opioid analgesic, wherein the antibodies comprise one or more of the polypeptide sequences of SEQ ID NO: 5; SEQ ID NO: 6; and SEQ ID NO: 7 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 1 or the light chain sequence of SEQ ID NO: 2, and/or one or more of the polypeptide sequences of SEQ ID NO: 8; SEQ ID NO: 9; and SEQ ID NO: 10 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 3 or the heavy chain sequence of SEQ ID NO: 4, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00252] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibody is a fragment having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 1 or SEQ ID NO: 2. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 3 or SEQ ID NO: 4.

[00253] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 5; SEQ ID NO: 6; and SEQ ID NO: 7 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 1 or the light chain sequence of SEQ ID NO: 2.

[00254] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include fragments having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO:

8; SEQ ID NO: 9; and SEQ ID NO: 10 which correspond to the complementarity-determining

2016273912 14 Dec 2016 regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 3 or the heavy chain sequence of SEQ ID NO: 4.

[00255] The invention also optionally contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 1; the variable heavy chain region of SEQ ID NO: 3; the complementarity-determining regions (SEQ ID NO: 5; SEQ ID NO: 6; and SEQ ID NO: 7) of the variable light chain region of SEQ ID NO: 1; and the complementarity-determining regions (SEQ ID NO: 8; SEQ ID NO: 9; and SEQ ID NO: 10) of the variable heavy chain region of SEQ ID NO: 3.

[00256] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody is Abl, comprising, or alternatively consisting of, SEQ ID NO: 2 and SEQ ID NO: 4, and having at least one of the biological activities set forth herein.

[00257] In a further particularly preferred optional embodiment of the invention, antibody fragments for use herein comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Abl. With respect to antibody Abl, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 1 and the variable heavy chain sequence of SEQ ID NO: 3. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 1 and/or SEQ ID NO: 3 in said Fab while retaining binding specificity for NGF.

[00258] In one optional embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Abl. In another embodiment of the invention, anti-NGF antibodies such as Abl or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

2016273912 14 Dec 2016 [00259] Antibody Ab2 [00260] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric or humanized antibodies having binding specificity to NGF wherein the antibody is antibody Ab2 or fragments thereof, or an antibody or antibody fragment that binds to the same or overlapping epitope as Ab2, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

DIQMTQSPSTFSASVGDRVTITCQASQNIYSNFAWYQQKPGKAPKFFIYGASNFDAGVP SRFSGSGSGTEYTFTISSFQPDDFATYYCQSAFDSDSTENTFGGGTKVEIKR (SEQ ID NO:

[00261] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSTFSASVGDRVTITCQASQNIYSNFAWYQQKPGKAPKFFIYGASNFDAGVP SRFSGSGSGTEYTFTISSFQPDDFATYYCQSAFDSDSTENTFGGGTKVEIKRTVAAPSVFI FPPSDEQFKSGTASVVCFFNNFYPREAKVQWKVDNAFQSGNSQESVTEQDSKDSTYSFS STFTFSKADYEKHKVYACEVTHQGFSSPVTKSFNRGEC (SEQ ID NO: 12).

[00262] The invention further optionally includes chimeric or humanized antibodies having binding specificity to NGF for treatment or prevention of pain and pain associated conditions and possessing a variable heavy chain sequence comprising the sequence set forth below:

EVQFVESGGGFVQPGGSFRFSCAASGFTVSSYAMSWVRQAPGKGFEWVGVITSIGSTV YASSAKGRFTISRDNSKNTFYFQMNSFRAEDTAVYYCARGYDDYDEMTYFNIWGQGT FVTVSS (SEQ ID NO: 13).

[00263] The invention also optionally includes chimeric or humanized antibodies having binding specificity to NGF for treatment or prevention of pain and pain associated conditions and

2016273912 14 Dec 2016 possessing a heavy chain sequence comprising the sequence set forth below:

EVQLVESGGGLVQPGGSLRLSCAASGFTVSSYAMSWVRQAPGKGLEWVGVITSIGSTV

YASSAKGRFTISRDNSKNTFYFQMNSFRAEDTAVYYCARGYDDYDEMTYFNIWGQGT

FVTVSSASTKGPSVFPFAPSSKSTSGGTAAFGCFVKDYFPEPVTVSWNSGAFTSGVHTFP

AVFQSSGFYSFSSVVTVPSSSFGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA

PEFFGGPSVFFFPPKPKDTFMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYASTYRVVSVFTVFHQDWFNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQV

YTFPPSREEMTKNQVSFTCFVKGFYPSDIAVEWESNGQPENNYKTTPPVFDSDGSFFFYS

KFTVDKSRWQQGNVFSCSVMHEAFHNHYTQKSFSFSPGK (SEQIDNO: 14).

[00264] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 11 or the light chain sequence of SEQ ID NO: 12, and/or one or more of the polypeptide sequences of SEQ ID NO: 18; SEQ ID NO: 19; and SEQ ID NO: 20 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 13 or the heavy chain sequence of SEQ ID NO: 14, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00265] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 11 or SEQ ID NO: 12. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 13 or SEQ ID NO: 14.

[00266] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions

2016273912 14 Dec 2016 optionally comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 11 or the light chain sequence of SEQ ID NO: 12.

[00267] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 18; SEQ ID NO: 19; and SEQ ID NO: 20 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 13 or the heavy chain sequence of SEQ ID NO: 14.

[00268] The invention also optionally contemplates antibody fragments which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 11; the variable heavy chain region of SEQ ID NO: 13; the complementarity-determining regions (SEQ ID NO: 15; SEQ ID NO: 16; and SEQ ID NO: 17) of the variable light chain region of SEQ ID NO: 11; and the complementarity-determining regions (SEQ ID NO: 18; SEQ ID NO:

19; and SEQ ID NO: 20) of the variable heavy chain region of SEQ ID NO: 13.

[00269] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions optionally is Ab2, comprising, or alternatively consisting of, SEQ ID NO: 12 and SEQ ID NO:

14, and having at least one of the biological activities set forth herein.

[00270] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF or a Fab or other monovalent antibody fragment that binds to the same or overlapping epitope as Ab2,. With respect to antibody Ab2, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 11 and the variable heavy chain sequence of SEQ ID NO: 13.

2016273912 14 Dec 2016

This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 11 and/or SEQ ID NO: 13 in said Fab while retaining binding specificity for NGF.

[00271] In one optional embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab2. In another embodiment of the invention, anti-NGF antibodies such as Ab2 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00272] Antibody Ab3 [00273] The invention contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric or humanized antibodies having binding specificity to NGF wherein the antibody is Ab3 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab3, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75. In one embodiment, the invention includes chimeric antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AVFTQTPSPVSAAMGDTVTIKCQSSQSVYKNNYFSWYQQKPGQPPRFFIYDASNFPSGV PSRFSGSGSGTQFTFTISGVQCDDAATYYCFGDYDDDADNAFGGGTEVVVKR (SEQ ID NO: 21).

[00274] The invention also includes chimeric antibodies or treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

AVFTQTPSPVSAAMGDTVTIKCQSSQSVYKNNYFSWYQQKPGQPPRFFIYDASNFPSGV PSRFSGSGSGTQFTFTISGVQCDDAATYYCFGDYDDDADNAFGGGTEVVVKRTVAAPS VFIFPPSDEQFKSGTASVVCFFNNFYPREAKVQWKVDNAFQSGNSQESVTEQDSKDSTY SFSSTFTFSKADYEKHKVYACEVTHQGFSSPVTKSFNRGEC (SEQ ID NO: 22).

2016273912 14 Dec 2016 [00275] The invention further includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below:

QSVEESGGRFVTPGTPFTFTCTVSGFSFSSYVMIWVRQAPGKGFEYIGITWSAGTYYAS WAKGRFTISKTSSTTVDLKITSPTTEDTATYFCAGGGGSIYDIWGPGTLVTVSS (SEQ ID NO: 23).

[00276] The invention also includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

QSVEESGGRLVTPGTPLTLTCTVSGFSLSSYVMIWVRQAPGKGLEYIGITWSAGTYYAS

WAKGRFTISKTSSTTVDLKITSPTTEDTATYFCAGGGGSIYDIWGPGTLVTVSSASTKGPS

VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS

VVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFP

PKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRV

VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN

QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 24).

[00277] The invention further contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 25; SEQ ID NO: 26; and SEQ ID NO: 27 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 21 or the light chain sequence of SEQ ID NO: 22, and/or one or more of the polypeptide sequences of SEQ ID NO: 28; SEQ ID NO: 29; and SEQ ID NO: 30 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 23 or the heavy chain sequence of SEQ ID NO: 24, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

2016273912 14 Dec 2016 [00278] The invention also contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 21 or SEQ ID NO: 22. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 23 or SEQ ID NO: 24.

[00279] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 25; SEQ ID NO: 26; and SEQ ID NO: 27 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 21 or the light chain sequence of SEQ ID NO: 22.

[00280] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 28; SEQ ID NO: 29; and SEQ ID NO: 30 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:

or the heavy chain sequence of SEQ ID NO: 24.

[00281] The invention also optionally contemplates antibody fragments which include one or more of the antibody fragments described herein for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 21; the variable heavy chain region of SEQ ID NO: 23; the complementarity-determining regions (SEQ ID NO: 25; SEQ ID NO: 26; and SEQ ID NO: 27) of the variable light chain region of SEQ ID NO: 21; and the complementarity-determining regions (SEQ ID NO: 28; SEQ ID NO: 29; and SEQ ID NO: 30) of the variable heavy chain region of SEQ ID NO: 23.

[00282] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab3,

2016273912 14 Dec 2016 comprising, or alternatively consisting of, SEQ ID NO: 22 and SEQ ID NO: 24, and having at least one of the biological activities set forth herein.

[00283] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Ab3. With respect to antibody Ab3, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 21 and the variable heavy chain sequence of SEQ ID NO: 23. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 21 and/or SEQ ID NO: 23 in said Fab while retaining binding specificity for NGF.

[00284] In one optional embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab3. In another embodiment of the invention, anti-NGF antibodies such as Ab3 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00285] Antibody Ab4 [00286] The invention contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric or humanized antibodies having binding specificity to NGF wherein the antibody is antibody Ab4 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab4, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75 and/or for preventing or effectively treating pain. In one embodiment, the invention includes humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

2016273912 14 Dec 2016 [00287] DIQMTQSPSTLSASVGDRVTITCQSSQSVYKNNYLSWYQQKPGKAPKLLI YDASNLPSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCLGDYDDDADNAFGGGTKVEI KR (SEQ ID NO: 31).

[00288] The invention also includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: DIQMTQSPSTFSASVGDRVTITCQSSQSVYKNNYFSWYQQKPGKAPKFFIYDASNFPSG VPSRFSGSGSGTEFTFTISSFQPDDFATYYCFGDYDDDADNAFGGGTKVEIKRTVAAPSV FIFPPSDEQFKSGTASVVCFFNNFYPREAKVQWKVDNAFQSGNSQESVTEQDSKDSTYS FSSTFTFSKADYEKHKVYACEVTHQGFSSPVTKSFNRGEC (SEQ ID NO: 32).

[00289] The invention further includes humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below:

EVQLVESGGGLVQPGGSLRLSCAASGFTVSSYVMIWVRQAPGKGLEYIGITWSAGTYY ASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGGGSIYDIWGQGTLVTVSS (SEQ ID NO: 33).

[00290] The invention also includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAASGFTVSSYVMIWVRQAPGKGLEYIGITWSAGTYY ASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGGGSIYDIWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 34).

[00291] The invention further contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID

2016273912 14 Dec 2016

NO: 35; SEQ ID NO: 36; and SEQ ID NO: 37 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 31 or the light chain sequence of SEQ ID NO: 32, and/or one or more of the polypeptide sequences of SEQ ID NO: 38; SEQ ID NO: 39; and SEQ ID NO: 40 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 33 or the heavy chain sequence of SEQ ID NO: 34, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00292] The invention also contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 31 or SEQ ID NO: 32. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 33 or SEQ ID NO: 34.

[00293] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 35; SEQ ID NO: 36; and SEQ ID NO: 37 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 31 or the light chain sequence of SEQ ID NO: 32.

[00294] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 38; SEQ ID NO: 39; and SEQ ID NO: 40 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 33 or the heavy chain sequence of SEQ ID NO: 34.

2016273912 14 Dec 2016 [00295] The invention also optional contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 31; the variable heavy chain region of SEQ ID NO: 33; the complementarity-determining regions (SEQ ID NO: 35; SEQ ID NO: 36; and SEQ ID NO: 37) of the variable light chain region of SEQ ID NO: 31; and the complementarity-determining regions (SEQ ID NO: 38; SEQ ID NO: 39; and SEQ ID NO: 40) of the variable heavy chain region of SEQ ID NO: 33.

[00296] In a particularly preferred embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab4, comprising, or alternatively consisting of, SEQ ID NO: 32 and SEQ ID NO: 34, and having at least one of the biological activities set forth herein.

[00297] In a further particularly preferred embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Abl4. With respect to antibody Ab4, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 31 and the variable heavy chain sequence of SEQ ID NO: 33. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 31 and/or SEQ ID NO: 33 in said Fab while retaining binding specificity for NGF.

[00298] In one embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab4. In another embodiment of the invention, anti-NGF antibodies such as Ab4 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00299] Antibody Ab5

2016273912 14 Dec 2016 [00300] The invention contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies optionally include Ab5 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab5, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AYDMTQTPASVEVAVGGTVTIKCQASQSIYSNFAWYQQRPGQPPKFFIYDASTFESGVP SRFKGSGSGTEYTFTISGVECADAASYYCQQGFTVSDIDNAFGGGTEVVVKR (SEQ ID NO: 41).

[00301] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: AYDMTQTPASVEVAVGGTVTIKCQASQSIYSNFAWYQQRPGQPPKFFIYDASTFESGVP SRFKGSGSGTEYTFTISGVECADAASYYCQQGFTVSDIDNAFGGGTEVVVKRTVAAPSV FIFPPSDEQFKSGTASVVCFFNNFYPREAKVQWKVDNAFQSGNSQESVTEQDSKDSTYS FSSTFTFSKADYEKHKVYACEVTHQGFSSPVTKSFNRGEC (SEQ ID NO: 42).

[00302] The invention further optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QSVEESGGRFVTPGTPFTFTCTVSGFSFSNYAVGWVRQAPGKGFEWIGIIGRNGNTWYA SWARGRFTISKTSTTVDFKITSPTSEDTATYFCARGYGRSVAYYVFNIWGPGTFVTVSS (SEQ ID NO: 43).

[00303] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QSVEESGGRFVTPGTPFTFTCTVSGFSFSNYAVGWVRQAPGKGFEWIGIIGRNGNTWYA SWARGRFTISKTSTTVDFKITSPTSEDTATYFCARGYGRSVAYYVFNIWGPGTFVTVSSA

2016273912 14 Dec 2016

STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG

LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP

SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY

ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK

SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 44).

[00304] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 45; SEQ ID NO: 46; and SEQ ID NO: 47 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 41 or the light chain sequence of SEQ ID NO: 42, and/or one or more of the polypeptide sequences of SEQ ID NO: 48; SEQ ID NO: 49; and SEQ ID NO: 50 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 43 or the heavy chain sequence of SEQ ID NO: 44, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof optionally comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00305] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 41 or SEQ ID NO: 42. In another optional embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 43 or SEQ ID NO: 44.

[00306] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 45; SEQ ID NO: 46; and SEQ ID NO: 47 which correspond to the

2016273912 14 Dec 2016 complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 41 or the light chain sequence of SEQ ID NO: 42.

[00307] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions optionally comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 48; SEQ ID NO: 49; and SEQ ID NO: 50 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 43 or the heavy chain sequence of SEQ ID NO: 44.

[00308] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 41; the variable heavy chain region of SEQ ID NO: 43; the complementarity-determining regions (SEQ ID NO: 45; SEQ ID NO: 46; and SEQ ID NO: 47) of the variable light chain region of SEQ ID NO: 41; and the complementarity-determining regions (SEQ ID NO: 48; SEQ ID NO: 49; and SEQ ID NO: 50) of the variable heavy chain region of SEQ ID NO: 43.

[00309] In a particularly preferred optional embodiment of the invention, the optionally included chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab5, comprising, or alternatively consisting of, SEQ ID NO: 42 and SEQ ID NO: 44, and having at least one of the biological activities set forth herein.

[00310] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF or another Fab or antibody fragment that binds to the same or overlapping epitope as Ab5. With respect to antibody Ab5, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 41 and the variable heavy chain sequence of SEQ ID NO: 43. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 41 and/or SEQ ID NO: 43 in said Fab while retaining binding specificity for NGF.

2016273912 14 Dec 2016 [00311] In one embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab5. In another embodiment of the invention, anti-NGF antibodies such as Ab5 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00312] Antibody Ab6 [00313] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include Ab6 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab6, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

DIQMTQSPSTFSASVGDRVTITCQASQSIYSNFAWYQQKPGKAPKFFIYDASTFESGVPS RFSGSGSGTEYTFTISSFQPDDFATYYCQQGFTVSDIDNAFGGGTKVEIKR (SEQ ID NO: 51).

[00314] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSTFSASVGDRVTITCQASQSIYSNFAWYQQKPGKAPKFFIYDASTFESGVPS RFSGSGSGTEYTFTISSFQPDDFATYYCQQGFTVSDIDNAFGGGTKVEIKRTVAAPSVFIF PPSDEQFKSGTASVVCFFNNFYPREAKVQWKVDNAFQSGNSQESVTEQDSKDSTYSFSS TFTFSKADYEKHKVYACEVTHQGFSSPVTKSFNRGEC (SEQ ID NO: 52).

[00315] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below:

2016273912 14 Dec 2016

EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYAVGWVRQAPGKGLEWVGIIGRNGNT WYASSARGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYGRSVAYYVFNIWGPGT LVTVSS (SEQ ID NO: 53).

[00316] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYAVGWVRQAPGKGLEWVGIIGRNGNT

WYASSARGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYGRSVAYYVFNIWGPGT

LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP

AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA

PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 54).

[00317] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 52, and/or one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 54, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00318] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or

2016273912 14 Dec 2016 alternatively consist of, the polypeptide sequence of SEQ ID NO: 51 or SEQ ID NO: 52. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 53 or SEQ ID NO: 54.

[00319] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 52.

[00320] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 54.

[00321] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 51; the variable heavy chain region of SEQ ID NO: 53; the complementarity-determining regions (SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57) of the variable light chain region of SEQ ID NO: 51; and the complementarity-determining regions (SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60) of the variable heavy chain region of SEQ ID NO: 53.

[00322] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab6, comprising, or alternatively consisting of, SEQ ID NO: 52 and SEQ ID NO: 54, and having at least one of the biological activities set forth herein.

2016273912 14 Dec 2016 [00323] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Ab6. With respect to antibody Ab6, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 51 and the variable heavy chain sequence of SEQ ID NO: 53. This optional embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 51 and/or SEQ ID NO: 53 in said Fab while retaining binding specificity for NGF.

[00324] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab6. In another embodiment of the invention, anti-NGF antibodies such as Ab6 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00325] Antibody Ab7 [00326] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include Ab7 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab7, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

ADVVMTQTPASVSQPVGGTVTIKCQASEDIYNLLAWYQQKPGQPPKLLIYSASTLASGV PSRFKGSGSGTEYTLTISGLECADAATYYCQNNYLVTTYGVAFGGGTEVVVKR (SEQ ID NO: 61).

2016273912 14 Dec 2016 [00327] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: ADVVMTQTPASVSQPVGGTVTIKCQASEDIYNLLAWYQQKPGQPPKLLIYSASTLASGV PSRFKGSGSGTEYTLTISGLECADAATYYCQNNYLVTTYGVAFGGGTEVVVKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 62).

[00328] The invention further optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QEQLKESGGRLVTPGTPLTLTCTVSGFSLSSYAMIWVRQAPGKGLEYIGYIDTDTSAYYA SWVKGRFTISRTSTTVDLKITSPTTEDTATYFCARSYAAYGGYPATFDPWGPGTLVTVSS (SEQ ID NO: 63).

[00329] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QEQLKESGGRLVTPGTPLTLTCTVSGFSLSSYAMIWVRQAPGKGLEYIGYIDTDTSAYYA SWVKGRFTISRTSTTVDLKITSPTTEDTATYFCARSYAAYGGYPATFDPWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 64).

[00330] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 65; SEQ ID NO: 66; and SEQ ID NO: 67 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 61 or the light chain sequence of SEQ ID NO: 62, and/or one or

2016273912 14 Dec 2016 more of the polypeptide sequences of SEQ ID NO: 68; SEQ ID NO: 69; and SEQ ID NO: 70 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 63 or the heavy chain sequence of SEQ ID NO: 64, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00331] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 61 or SEQ ID NO: 62. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 63 or SEQ ID NO: 64.

[00332] In a further optional embodiment of the invention, fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 65; SEQ ID NO: 66; and SEQ ID NO: 67 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 61 or the light chain sequence of SEQ ID NO: 62.

[00333] In a further optional embodiment of the invention, fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 68; SEQ ID NO: 69; and SEQ ID NO: 70 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 63 or the heavy chain sequence of SEQ ID NO: 64.

[00334] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more,

2016273912 14 Dec 2016 including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 61; the variable heavy chain region of SEQ ID NO: 63; the complementarity-determining regions (SEQ ID NO: 65; SEQ ID NO: 66; and SEQ ID NO: 67) of the variable light chain region of SEQ ID NO: 61; and the complementarity-determining regions (SEQ ID NO: 68; SEQ ID NO: 69; and SEQ ID NO: 70) of the variable heavy chain region of SEQ ID NO: 63.

[00335] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab7, comprising, or alternatively consisting of, SEQ ID NO: 62 and SEQ ID NO: 64, and having at least one of the biological activities set forth herein.

[00336] In a further particularly optionally preferred embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Ab7. With respect to antibody Ab7, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 61 and the variable heavy chain sequence of SEQ ID NO: 63. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 61 and/or SEQ ID NO: 63 in said Fab while retaining binding specificity for NGF.

[00337] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab7. In another embodiment of the invention, anti-NGF antibodies such as Ab7 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00338] Antibody Ab8 [00339] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include Ab8 or fragments thereof, or another antibody

2016273912 14 Dec 2016 or fragment that binds to the same or overlapping epitope as Ab8, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

DIQMTQSPSSLSASVGDRVTITCQASEDIYNLLAWYQQKPGKVPKLLIYSASTLASGVPS RFSGSGSGTDYTLTISSLQPEDVATYYCQNNYLVTTYGVAFGGGTKVEIKR (SEQ ID NO: 71).

[00340] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSSLSASVGDRVTITCQASEDIYNLLAWYQQKPGKVPKLLIYSASTLASGVPS RFSGSGSGTDYTLTISSLQPEDVATYYCQNNYLVTTYGVAFGGGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 72).

[00341] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMIWVRQAPGKGLEYIGYIDTDTSAYY ASSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYCARSYAAYGGYPATFDPWGQGTL VTVSS (SEQ ID NO: 73).

[00342] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMIWVRQAPGKGLEYIGYIDTDTSAYY

ASSVKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYCARSYAAYGGYPATFDPWGQGTL

VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAP

ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP

2016273912 14 Dec 2016

REEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 74).

[00343] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 75; SEQ ID NO: 76; and SEQ ID NO: 77 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 71 or the light chain sequence of SEQ ID NO: 72, and/or one or more of the polypeptide sequences of SEQ ID NO: 78; SEQ ID NO: 79; and SEQ ID NO: 80 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 73 or the heavy chain sequence of SEQ ID NO: 74, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00344] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 71 or SEQ ID NO: 72. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 73 or SEQ ID NO: 74.

[00345] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 75; SEQ ID NO: 76; and SEQ ID NO: 77 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 71 or the light chain sequence of SEQ ID NO: 72.

[00346] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated

2016273912 14 Dec 2016 conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 78; SEQ ID NO: 79; and SEQ ID NO: 80 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 73 or the heavy chain sequence of SEQ ID NO: 74.

[00347] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 71; the variable heavy chain region of SEQ ID NO: 73; the complementarity-determining regions (SEQ ID NO: 75; SEQ ID NO: 76; and SEQ ID NO: 77) of the variable light chain region of SEQ ID NO: 71; and the complementarity-determining regions (SEQ ID NO: 78; SEQ ID NO: 79; and SEQ ID NO: 80) of the variable heavy chain region of SEQ ID NO: 73.

[00348] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab8, comprising, or alternatively consisting of, SEQ ID NO: 72 and SEQ ID NO: 74, and having at least one of the biological activities set forth herein.

[00349] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab8, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 71 and the variable heavy chain sequence of SEQ ID NO: 73 or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Ab8. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 71 and/or SEQ ID NO: 73 in said Fab while retaining binding specificity for NGF.

[00350] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab8. In another embodiment of the invention, anti-NGF antibodies such as Ab8 or Fab fragments thereof may be produced via expression in mammalian

2016273912 14 Dec 2016 cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00351] Antibody Ab9 [00352] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include Ab9 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab9, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one optional embodiment, the invention includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AYDMTQTPASVSAAVGGTVTIKCQASENIGSYLAWYQQKPGQPPELLIYRASTLASGVP SRFKGSGSGTQFTLTISGVECADAATYYCQQGYNSENLDNAFGGGTEVVVKR (SEQ ID NO: 81).

[00353] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: AYDMTQTPASVSAAVGGTVTIKCQASENIGSYLAWYQQKPGQPPELLIYRASTLASGVP SRFKGSGSGTQFTLTISGVECADAATYYCQQGYNSENLDNAFGGGTEVVVKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 82).

[00354] The invention further optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QSVEESGGRLVTPGTPLTLTCTVSGIDLSMYSMGWVRQAPGKGLEYIGWISYGGTAYYA SWAKGRFTISKTSTTVELKITSPTIEDTATYFCARETPVNYYLDIWGQGTLVTVSS (SEQ ID NO: 83).

2016273912 14 Dec 2016 [00355] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QSVEESGGRFVTPGTPFTFTCTVSGIDFSMYSMGWVRQAPGKGFEYIGWISYGGTAYYA SWAKGRFTISKTSTTVELKITSPTIEDTATYFCARETPVNYYLDIWGQGTLVTVSSASTKG PSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 84).

[00356] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 85; SEQ ID NO: 86; and SEQ ID NO: 87 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 81 or the light chain sequence of SEQ ID NO: 82, and/or one or more of the polypeptide sequences of SEQ ID NO: 88; SEQ ID NO: 89; and SEQ ID NO: 90 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 83 or the heavy chain sequence of SEQ ID NO: 84, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00357] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 81 or SEQ ID NO: 82. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 83 or SEQ ID NO: 84.

2016273912 14 Dec 2016 [00358] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 85; SEQ ID NO: 86; and SEQ ID NO: 87 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 81 or the light chain sequence of SEQ ID NO: 82.

[00359] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 88; SEQ ID NO: 89; and SEQ ID NO: 90 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 83 or the heavy chain sequence of SEQ ID NO: 84.

[00360] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 81; the variable heavy chain region of SEQ ID NO: 83; the complementarity-determining regions (SEQ ID NO: 85; SEQ ID NO: 86; and SEQ ID NO: 87) of the variable light chain region of SEQ ID NO: 81; and the complementarity-determining regions (SEQ ID NO: 88; SEQ ID NO: 89; and SEQ ID NO: 90) of the variable heavy chain region of SEQ ID NO: 83.

[00361] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab9, comprising, or alternatively consisting of, SEQ ID NO: 82 and SEQ ID NO: 84, and having at least one of the biological activities set forth herein.

[00362] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab9, the Fab fragment includes the variable light chain sequence

2016273912 14 Dec 2016 of SEQ ID NO: 81 and the variable heavy chain sequence of SEQ ID NO: 83 or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Ab9. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 81 and/or SEQ ID NO: 83 in said Fab while retaining binding specificity for NGF.

[00363] In one embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab9. In another optional embodiment of the invention, anti-NGF antibodies such as Ab9 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00364] Antibody AblO [00365] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include AblO or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as AblO, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AYDMTQSPSSFSASVGDRVTITCQASENIGSYFAWYQQKPGKVPKFFIYRASTFASGVPS RFSGSGSGTDFTFTISSFQPEDVATYYCQQGYNSENFDNAFGGGTKVEIKR (SEQ ID NO: 91).

[00366] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

AYDMTQSPSSFSASVGDRVTITCQASENIGSYFAWYQQKPGKVPKFFIYRASTFASGVPS

RFSGSGSGTDFTFTISSFQPEDVATYYCQQGYNSENFDNAFGGGTKVEIKRTVAAPSVFI

2016273912 14 Dec 2016

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STFTFSKADYEKHKVYACEVTHQGFSSPVTKSFNRGEC (SEQ ID NO: 92).

[00367] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QVQFVESGGGVVQPGRSFRFSCAASGFTFSMYSMGWVRQAPGKGFEYIGWISYGGTAY YASSAKGRFTISRDNSKNTFYFQMSSFRAEDTAVYYCARETPVNYYFDIWGQGTFVTV SS (SEQ ID NO: 93).

[00368] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

QVQFVESGGGVVQPGRSFRFSCAASGFTFSMYSMGWVRQAPGKGFEYIGWISYGGTAY

YASSAKGRFTISRDNSKNTFYFQMSSFRAEDTAVYYCARETPVNYYFDIWGQGTFVTV

SSASTKGPSVFPFAPSSKSTSGGTAAFGCFVKDYFPEPVTVSWNSGAFTSGVHTFPAVFQ

SSGFYSFSSVVTVPSSSFGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFF

GGPSVFFFPPKPKDTFMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE

QYASTYRVVSVFTVFHQDWFNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTFPP

SREEMTKNQVSFTCFVKGFYPSDIAVEWESNGQPENNYKTTPPVFDSDGSFFFYSKFTV

DKSRWQQGNVFSCSVMHEAFHNHYTQKSFSFSPGK (SEQ ID NO: 94).

[00369] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 95; SEQ ID NO: 96; and SEQ ID NO: 97 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 91 or the light chain sequence of SEQ ID NO: 92, and/or one or more of the polypeptide sequences of SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 93 or the heavy chain sequence of SEQ ID NO: 94, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist

2016273912 14 Dec 2016 of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00370] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 91 or SEQ ID NO: 92. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 93 or SEQ ID NO: 94.

[00371] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions optionally comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 95; SEQ ID NO: 96; and SEQ ID NO: 97 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 91 or the light chain sequence of SEQ ID NO: 92.

[00372] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 93 or the heavy chain sequence of SEQ ID NO: 94.

[00373] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 91; the variable heavy chain region of SEQ ID NO: 93; the complementarity-determining regions (SEQ ID NO: 95; SEQ ID NO: 96; and SEQ ID NO: 97) of the variable light chain region of SEQ ID NO: 91; and the

2016273912 14 Dec 2016 complementarity-determining regions (SEQ ID NO: 98; SEQ ID NO: 99; and SEQ ID NO: 100) of the variable heavy chain region of SEQ ID NO: 93.

[00374] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 10, comprising, or alternatively consisting of, SEQ ID NO: 92 and SEQ ID NO: 94, and having at least one of the biological activities set forth herein.

[00375] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 10, the Fab fragment for treatment or prevention of pain and pain associated conditions includes the variable light chain sequence of SEQ ID NO: 91 and the variable heavy chain sequence of SEQ ID NO: 93 or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Ab 10. This embodiment of the invention further optionally contemplates additions, deletions, and variants of SEQ ID NO: 91 and/or SEQ ID NO: 93 in said Fab while retaining binding specificity for NGF.

[00376] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of AblO. In another embodiment of the invention, anti-NGF antibodies such as AblO or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00377] Antibody Abl 1 [00378] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include Abl 1 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Abl 1, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with

2016273912 14 Dec 2016

TrkA and the association of NGF with p75. In one optional embodiment, the invention includes chimeric antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AFELTQTPSSVEAAVGGTVTIKCQASQNIVTNLAWYQQKPGQPPKLLIYGASTLASGVSS RFKGSGSGTQFTLTISDLECADAATYFCQSYDGFNSAGFGGGTEVVVKR (SEQ ID NO: 101).

[00379] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: AFELTQTPSSVEAAVGGTVTIKCQASQNIVTNLAWYQQKPGQPPKLLIYGASTLASGVSS RFKGSGSGTQFTLTISDLECADAATYFCQSYDGFNSAGFGGGTEVVVKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 102).

[00380] The invention further optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCTASGFSLSGYDMSWVRQAPGKGLEYIGLISYDGNTYYA TWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSLYAGPNAGIGPFNIWGQGTLVTVSS (SEQ ID NO: 103).

[00381] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGTPLTLTCTASGFSLSGYDMSWVRQAPGKGLEYIGLISYDGNTYYA TWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARSLYAGPNAGIGPFNIWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR

2016273912 14 Dec 2016

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 104).

[00382] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 105; SEQ ID NO: 106; and SEQ ID NO: 107 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101 or the light chain sequence of SEQ ID NO: 102, and/or one or more of the polypeptide sequences of SEQ ID NO: 108; SEQ ID NO: 109; and SEQ ID NO: 110 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 103 or the heavy chain sequence of SEQ ID NO: 104, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof optionally comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00383] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 101 or SEQ ID NO: 102. In another optional embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 103 or SEQ ID NO: 104.

[00384] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 105; SEQ ID NO: 106; and SEQ ID NO: 107 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 101 or the light chain sequence of SEQ ID NO: 102.

[00385] In a further optional embodiment of the invention, fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF

2016273912 14 Dec 2016 comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 108; SEQ ID NO: 109; and SEQ ID NO: 110 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 103 or the heavy chain sequence of SEQ ID NO: 104.

[00386] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 101; the variable heavy chain region of SEQ ID NO: 103; the complementarity-determining regions (SEQ ID NO: 105; SEQ ID NO: 106; and SEQ ID NO: 107) of the variable light chain region of SEQ ID NO: 101; and the complementarity-determining regions (SEQ ID NO: 108; SEQ ID NO: 109; and SEQ ID NO: 110) of the variable heavy chain region of SEQ ID NO: 103.

[00387] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Abl 1, comprising, or alternatively consisting of, SEQ ID NO: 102 and SEQ ID NO: 104, and having at least one of the biological activities set forth herein.

[00388] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl 1, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 101 and the variable heavy chain sequence of SEQ ID NO: 103 or comprises another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Abl 1. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 101 and/or SEQ ID NO: 103 in said Fab while retaining binding specificity for NGF.

[00389] In one optional embodiment of the invention described herein (infra), Fab fragments may for treatment or prevention of pain and pain associated conditions be produced by enzymatic digestion (e.g., papain) of Abl 1. In another optional embodiment of the invention,

2016273912 14 Dec 2016 anti-NGF antibodies such as Abl 1 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00390] Antibody Ab 12 [00391] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include Ab 12 or fragments thereof, f or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab 12, or example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AFQMTQSPSSLSASVGDRVTITCQASQNIVTNLAWYQQKPGKVPKLLIYGASTLASGVP SRFSGSGSGTDFTLTISSLQPEDVATYYCQSYDGFNSAGFGGGTKVEIKR (SEQ ID NO: 111).

[00392] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

AFQMTQSPSSLSASVGDRVTITCQASQNIVTNLAWYQQKPGKVPKLLIYGASTLASGVP SRFSGSGSGTDFTLTISSLQPEDVATYYCQSYDGFNSAGFGGGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 112).

[00393] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QVQLVESGGGVVQPGRSLRLSCAASGFSLSGYDMSWVRQAPGKGLEWVGLISYDGNT

2016273912 14 Dec 2016

YYATSAKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYCARSLYAGPNAGIGPFNIWGQG TLVTVSS (SEQ ID NO: 113).

[00394] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

QVQLVESGGGVVQPGRSLRLSCAASGFSLSGYDMSWVRQAPGKGLEWVGLISYDGNT

YYATSAKGRFTISRDNSKNTLYLQMSSLRAEDTAVYYCARSLYAGPNAGIGPFNIWGQG

TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF

PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCP

APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT

KPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ

VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL

YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 114).

[00395] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 115; SEQ ID NO: 116; and SEQ ID NO: 117 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 111 or the light chain sequence of SEQ ID NO: 112, and/or one or more of the polypeptide sequences of SEQ ID NO: 118; SEQ ID NO: 119; and SEQ ID NO: 120 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 113 or the heavy chain sequence of SEQ ID NO: 114, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00396] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one optional embodiment of the invention, antibody fragments of the invention comprise, or

2016273912 14 Dec 2016 alternatively consist of, the polypeptide sequence of SEQ ID NO: 111 or SEQ ID NO: 112. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 113 or SEQ ID NO: 114.

[00397] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 115; SEQ ID NO: 116; and SEQ ID NO: 117 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 111 or the light chain sequence of SEQ ID NO: 112.

[00398] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 118; SEQ ID NO: 119; and SEQ ID NO: 120 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 113 or the heavy chain sequence of SEQ ID NO: 114.

[00399] The invention also optionally contemplates antibody fragments which include one or more of the antibody fragments described herein. In one optional embodiment of the invention, fragments of the antibodies having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 111; the variable heavy chain region of SEQ ID NO: 113; the complementaritydetermining regions (SEQ ID NO: 115; SEQ ID NO: 116; and SEQ ID NO: 117) of the variable light chain region of SEQ ID NO: 111; and the complementarity-determining regions (SEQ ID NO: 118; SEQ ID NO: 119; and SEQ ID NO: 120) of the variable heavy chain region of SEQ ID NO: 113.

[00400] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 12, comprising, or alternatively consisting of, SEQ ID NO: 112 and SEQ ID NO: 114, and having at least one of the biological activities set forth herein.

2016273912 14 Dec 2016 [00401] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl2, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 111 and the variable heavy chain sequence of SEQ ID NO: 113 or comprises another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Abl2. This optional embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 111 and/or SEQ ID NO: 113 in said Fab while retaining binding specificity for NGF.

[00402] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl2. In another embodiment of the invention, anti-NGF antibodies such as Ab 12 or Fab fragments thereof for treatment or prevention of pain and pain associated conditions may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00403] Antibody Abl3 [00404] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include Ab 13 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab 13, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AAVLTQTPSPVSAAVGGTVSISCQSSQNVYKNNYLSWYQQKPGQPPKLLIYKASTLASG

2016273912 14 Dec 2016

VPSRFKGGGSGTDFTLTISDVQCDAAATYYCAGGYTSSSDNAFGGGTEVVVKR (SEQ ID NO: 121).

[00405] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: AAVFTQTPSPVSAAVGGTVSISCQSSQNVYKNNYFSWYQQKPGQPPKFFIYKASTFASG VPSRFKGGGSGTDFTFTISDVQCDAAATYYCAGGYTSSSDNAFGGGTEVVVKRTVAAP SVFIFPPSDEQFKSGTASVVCFFNNFYPREAKVQWKVDNAFQSGNSQESVTEQDSKDST YSFSSTFTFSKADYEKHKVYACEVTHQGFSSPVTKSFNRGEC (SEQ ID NO: 122).

[00406] The invention further optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QSVEASGGRFVTPGTPFTFTCTASGFSFSTYWMSWVRQAPGKGFEWIGDIYFSNEETNY ASWAKGRFTISKTSTTVDFNVISPTTEDTATYFCARGSPDVDIGIDMWGPGTFVTVSS (SEQ ID NO: 123).

[00407] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QSVEASGGRFVTPGTPFTFTCTASGFSFSTYWMSWVRQAPGKGFEWIGDIYFSNEETNY ASWAKGRFTISKTSTTVDFNVISPTTEDTATYFCARGSPDVDIGIDMWGPGTFVTVSSAS TKGPSVFPFAPSSKSTSGGTAAFGCFVKDYFPEPVTVSWNSGAFTSGVHTFPAVFQSSGF YSFSSVVTVPSSSFGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFFGGPS VFFFPPKPKDTFMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYA STYRVVSVFTVFHQDWFNGKEYKCKVSNKAFPAPIEKTISKAKGQPREPQVYTFPPSRE EMTKNQVSFTCFVKGFYPSDIAVEWESNGQPENNYKTTPPVFDSDGSFFFYSKFTVDKS RWQQGNVFSCSVMHEAFHNHYTQKSFSFSPGK (SEQ ID NO: 124).

[00408] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 125; SEQ ID NO: 126; and SEQ ID NO: 127 which correspond to the

2016273912 14 Dec 2016 complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 121 or the light chain sequence of SEQ ID NO: 122, and/or one or more of the polypeptide sequences of SEQ ID NO: 128; SEQ ID NO: 129; and SEQ ID NO: 130 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123 or the heavy chain sequence of SEQ ID NO: 124, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00409] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 121 or SEQ ID NO: 122. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 123 or SEQ ID NO: 124.

[00410] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 125; SEQ ID NO: 126; and SEQ ID NO: 127 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 121 or the light chain sequence of SEQ ID NO: 122.

[00411] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 128; SEQ ID NO: 129; and SEQ ID NO: 130 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 123 or the heavy chain sequence of SEQ ID NO: 124.

2016273912 14 Dec 2016 [00412] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 121; the variable heavy chain region of SEQ ID NO: 123; the complementarity-determining regions (SEQ ID NO: 125; SEQ ID NO: 126; and SEQ ID NO: 127) of the variable light chain region of SEQ ID NO: 121; and the complementarity-determining regions (SEQ ID NO: 128; SEQ ID NO: 129; and SEQ ID NO: 130) of the variable heavy chain region of SEQ ID NO: 123.

[00413] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 13, comprising, or alternatively consisting of, SEQ ID NO: 122 and SEQ ID NO: 124, and having at least one of the biological activities set forth herein.

[00414] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl3, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 121 and the variable heavy chain sequence of SEQ ID NO: 123 or comprises another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as Abl3. This optional embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 121 and/or SEQ ID NO: 123 in said Fab while retaining binding specificity for NGF.

[00415] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl3. In another embodiment of the invention, anti-NGF antibodies such as Ab 13 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

2016273912 14 Dec 2016 [00416] Antibody Ab 14 [00417] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab 14 or fragments thereof, or another antibody or fragment that binds to the same or overlapping epitope as Ab 14, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one optional embodiment, the invention includes chimeric or humanized antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

DIQMTQSPSSLSASVGDRVTITCQSSQNVYKNNYLSWYQQKPGKVPKLLIYKASTLASG VPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYTSSSDNAFGGGTKVEIKR (SEQ ID NO: 131).

[00418] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSSLSASVGDRVTITCQSSQNVYKNNYLSWYQQKPGKVPKLLIYKASTLASG VPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYTSSSDNAFGGGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQIDNO: 132).

[00419] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAASGFTVSTYWMSWVRQAPGKGLEWVGDIYFSNEET NYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSPDVDIGIDMWGPGTLV TVSS (SEQIDNO: 133).

[00420] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

2016273912 14 Dec 2016

EVQLVESGGGLVQPGGSLRLSCAASGFTVSTYWMSWVRQAPGKGLEWVGDIYFSNEET

NYASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSPDVDIGIDMWGPGTLV

TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV

LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE

LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR

EEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT

VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 134).

[00421] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 131 or the light chain sequence of SEQ ID NO: 132, and/or one or more of the polypeptide sequences of SEQ ID NO: 138; SEQ ID NO: 139; and SEQ ID NO: 140 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 133 or the heavy chain sequence of SEQ ID NO: 134, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00422] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 131 or SEQ ID NO: 132. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 133 or SEQ ID NO: 134.

[00423] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated

100

2016273912 14 Dec 2016 conditions optionally comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 131 or the light chain sequence of SEQ ID NO: 132.

[00424] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 138; SEQ ID NO: 139; and SEQ ID NO: 140 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 133 or the heavy chain sequence of SEQ ID NO: 134.

[00425] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 131; the variable heavy chain region of SEQ ID NO: 133; the complementarity-determining regions (SEQ ID NO: 135; SEQ ID NO: 136; and SEQ ID NO: 137) of the variable light chain region of SEQ ID NO: 131; and the complementarity-determining regions (SEQ ID NO: 138; SEQ ID NO: 139; and SEQ ID NO: 140) of the variable heavy chain region of SEQ ID NO: 133.

[00426] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 14, comprising, or alternatively consisting of, SEQ ID NO: 132 and SEQ ID NO: 134, and having at least one of the biological activities set forth herein.

[00427] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl4, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 131 and the variable heavy chain sequence of SEQ ID NO: 133 or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as

101

2016273912 14 Dec 2016

Abl4. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 131 and/or SEQ ID NO: 133 in said Fab while retaining binding specificity for NGF.

[00428] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl4. In another embodiment of the invention, anti-NGF antibodies such as Ab 14 or Fab fragments thereof for treatment or prevention of pain and pain associated conditions may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00429] Antibody Ab 15 [00430] The invention contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab 15 or fragments thereof, for example as set forth below, or comprises another antibody or antibody fragment that binds to the same or overlapping epitope as Ab 15, in a therapeutically effective amount which inhibits the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75. In one embodiment, the invention includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AAVLTQTPSPVSAAVGDTVTIKCQSSQSVYKNNYLSWYQQKPGQPPKLLIYDASNLPSG VPSRFSGSGSGTQFTLTISGVQCDDAATYYCLGDYDDDTDNGFGGGTEVVVKR (SEQ ID NO: 141).

[00431] The invention also includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

AAVLTQTPSPVSAAVGDTVTIKCQSSQSVYKNNYLSWYQQKPGQPPKLLIYDASNLPSG

102

2016273912 14 Dec 2016

VPSRFSGSGSGTQFTLTISGVQCDDAATYYCLGDYDDDTDNGFGGGTEVVVKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 142).

[00432] The invention further includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below:

QSVEESGGRLVTPGTPLTLTCTVSGIDLSSYAMIWVRQAPGKGLEYIGIIWSGGTYYATW AKGRFTISKTSTTVDLQITSPTTEDAATYFCAAGGGSIYDVWGPGTLVTVSS (SEQ ID NO: 143).

[00433] The invention also includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

QSVEESGGRLVTPGTPLTLTCTVSGIDLSSYAMIWVRQAPGKGLEYIGIIWSGGTYYATW

AKGRFTISKTSTTVDLQITSPTTEDAATYFCAAGGGSIYDVWGPGTLVTVSSASTKGPSV

FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV

VTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP

KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRV

VSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKN

QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG

NVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 144).

[00434] The invention further contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 145; SEQ ID NO: 146; and SEQ ID NO: 147 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 141 or the light chain sequence of SEQ ID NO: 142, and/or one or more of the polypeptide sequences of SEQ ID NO: 148; SEQ ID NO: 149; and SEQ ID NO: 150 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 143 or the heavy chain sequence of SEQ ID NO: 144, or combinations of these polypeptide sequences. In another embodiment of the invention,

103

2016273912 14 Dec 2016 the antibodies of the invention or fragments thereof for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00435] The invention also contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 141 or SEQ ID NO: 142. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 143 or SEQ ID NO: 144.

[00436] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 145; SEQ ID NO: 146; and SEQ ID NO: 147 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 141 or the light chain sequence of SEQ ID NO: 142.

[00437] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 148; SEQ ID NO: 149; and SEQ ID NO: 150 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 143 or the heavy chain sequence of SEQ ID NO: 144.

[00438] The invention also contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 141; the variable heavy chain region of SEQ ID NO: 143; the complementarity-determining regions (SEQ ID NO: 145; SEQ

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ID NO: 146; and SEQ ID NO: 147) of the variable light chain region of SEQ ID NO: 141; and the complementarity-determining regions (SEQ ID NO: 148; SEQ ID NO: 149; and SEQ ID NO: 150) of the variable heavy chain region of SEQ ID NO: 143.

[00439] In a particularly preferred embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 15, comprising, or alternatively consisting of, SEQ ID NO: 142 and SEQ ID NO: 144, and having at least one of the biological activities set forth herein.

[00440] In a further particularly preferred embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl5, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 141 and the variable heavy chain sequence of SEQ ID NO: 143 or comprises another Fab that binds to the same or overlapping epitope as Ab 15,. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 141 and/or SEQ ID NO: 143 in said Fab while retaining binding specificity for NGF.

[00441] In one embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl5. In another embodiment of the invention, anti-NGF antibodies for treatment or prevention of pain and pain associated conditions such as Ab 15 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00442] Antibody Abl6 [00443] The invention contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab 16 or fragments thereof, for example as set forth below, or comprises

105

2016273912 14 Dec 2016 another antibody or antibody fragment that binds to the same or overlapping epitope as Ab 16, in a therapeutically effective amount which inhibits the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

ALVMTQTPSSTSEPVGGTVTINCQASQNIGNDLSWYQQKPGQPPELLIYSTSKLATGVPK RFSGSRSGTQFTLTISDLECDDAATYYCLGVYSYISDDGNAFGGGTEVVVKR (SEQ ID NO: 151).

[00444] The invention also includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: ALVMTQTPSSTSEPVGGTVTINCQASQNIGNDLSWYQQKPGQPPELLIYSTSKLATGVPK RFSGSRSGTQFTLTISDLECDDAATYYCLGVYSYISDDGNAFGGGTEVVVKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 152).

[00445] The invention further includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QSVEEFGGRLVTPGTPLTLTCTVSGFSLNNYAMTWVRQAPGKGLEWIGIIGSIGTTYYAS WAKGRFFISKTSTTVDLKIISPTTEDTATYFCARDAGVTVDGYGYYFNIWGPGTLVTVSS (SEQ ID NO: 153).

[00446] The invention also includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QSVEEFGGRLVTPGTPLTLTCTVSGFSLNNYAMTWVRQAPGKGLEWIGIIGSIGTTYYAS WAKGRFFISKTSTTVDLKIISPTTEDTATYFCARDAGVTVDGYGYYFNIWGPGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG

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PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 154).

[00447] The invention further contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 155; SEQ ID NO: 156; and SEQ ID NO: 157 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 151 or the light chain sequence of SEQ ID NO: 152, and/or one or more of the polypeptide sequences of SEQ ID NO: 158; SEQ ID NO: 159; and SEQ ID NO: 160 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 153 or the heavy chain sequence of SEQ ID NO: 154, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00448] The invention also contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 151 or SEQ ID NO: 152. In another embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 153 or SEQ ID NO: 154.

[00449] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 155; SEQ ID NO: 156; and SEQ ID NO: 157 which correspond to the complementarity107

2016273912 14 Dec 2016 determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 151 or the light chain sequence of SEQ ID NO: 152.

[00450] In a further embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 158; SEQ ID NO: 159; and SEQ ID NO: 160 which correspond to the complementaritydetermining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 153 or the heavy chain sequence of SEQ ID NO: 154.

[00451] The invention also contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 151; the variable heavy chain region of SEQ ID NO: 153; the complementarity-determining regions (SEQ ID NO: 155; SEQ ID NO: 156; and SEQ ID NO: 157) of the variable light chain region of SEQ ID NO: 151; and the complementarity-determining regions (SEQ ID NO: 158; SEQ ID NO: 159; and SEQ ID NO: 160) of the variable heavy chain region of SEQ ID NO: 153.

[00452] In a particularly preferred embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 16, comprising, or alternatively consisting of, SEQ ID NO: 152 and SEQ ID NO: 154, and having at least one of the biological activities set forth herein.

[00453] In a further particularly preferred embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 16, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 151 and the variable heavy chain sequence of SEQ ID NO: 153 or comprises another Fab or another bivalent or monovalent antibody fragment that binds to the same or overlapping epitope as Ab 16. This embodiment of the invention further contemplates

108

2016273912 14 Dec 2016 additions, deletions, and variants of SEQ ID NO: 151 and/or SEQ ID NO: 153 in said Fab while retaining binding specificity for NGF.

[00454] In one embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl6. In another embodiment of the invention, anti-NGF antibodies for treatment or prevention of pain and pain associated conditions such as Ab 16 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00455] Antibody Ab 17 [00456] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab 17 or fragments thereof, for example as set forth below, or comprises another antibody or antibody fragment that binds to the same or overlapping epitope as Ab 17, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AIEMTQTPFSVSAAVGGTVTIKCQASQTISNYFAWYQQKPGQPPKFFIYGASNFESGVPS RFKGSGSGTQFTFTISDFECDDAATYYCQQGYTISNVDNNVFGGGTEVVVKR (SEQ ID NO: 161).

[00457] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

AIEMTQTPFSVSAAVGGTVTIKCQASQTISNYFAWYQQKPGQPPKFFIYGASNFESGVPS

RFKGSGSGTQFTFTISDFECDDAATYYCQQGYTISNVDNNVFGGGTEVVVKRTVAAPSV

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FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 162).

[00458] The invention further optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGGSLTLTCAASGFSLTGYNLVWVRQAPGKGLEWIGFISYGDTTYYA SWAKGRFTISKTSTTVTLTITDLQPSDTGTYFCARETANTYDYGIWGPGTLVTVSS (SEQ ID NO: 163).

[00459] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QSLEESGGRLVTPGGSLTLTCAASGFSLTGYNLVWVRQAPGKGLEWIGFISYGDTTYYA SWAKGRFTISKTSTTVTLTITDLQPSDTGTYFCARETANTYDYGIWGPGTLVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 164).

[00460] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 165; SEQ ID NO: 166; and SEQ ID NO: 167 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 161 or the light chain sequence of SEQ ID NO: 162, and/or one or more of the polypeptide sequences of SEQ ID NO: 168; SEQ ID NO: 169; and SEQ ID NO: 170 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 163 or the heavy chain sequence of SEQ ID NO: 164, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof for treatment

110

2016273912 14 Dec 2016 or prevention of pain and pain associated conditions comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00461] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 161 or SEQ ID NO: 162. In another optional embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 163 or SEQ ID NO: 164.

[00462] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 165; SEQ ID NO: 166; and SEQ ID NO: 167 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 161 or the light chain sequence of SEQ ID NO: 162.

[00463] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 168; SEQ ID NO: 169; and SEQ ID NO: 170 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 163 or the heavy chain sequence of SEQ ID NO: 164.

[00464] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 161; the variable heavy chain region of SEQ ID NO: 163; the complementarity-determining regions (SEQ ID NO: 165; SEQ ID NO: 166; and SEQ ID NO: 167) of the variable light chain region of SEQ ID NO: 161; and

111

2016273912 14 Dec 2016 the complementarity-determining regions (SEQ ID NO: 168; SEQ ID NO: 169; and SEQ ID NO: 170) of the variable heavy chain region of SEQ ID NO: 163.

[00465] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 17, comprising, or alternatively consisting of, SEQ ID NO: 162 and SEQ ID NO: 164, and having at least one of the biological activities set forth herein.

[00466] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 17, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 161 and the variable heavy chain sequence of SEQ ID NO: 163 or comprises another Fab or monovalent or bivalent antibody fragment that binds to the same or overlapping epitope as Ab 15,. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 161 and/or SEQ ID NO: 163 in said Fab while retaining binding specificity for NGF.

[00467] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl7. In another embodiment of the invention, anti-NGF antibodies such as Ab 17 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00468] Antibody Ab 18 [00469] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab 18 or fragments thereof, for example as set forth below, or comprises another antibody or antibody fragment that binds to the same or overlapping epitope

112

2016273912 14 Dec 2016 as Ab 18, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

DIQMTQSPSTLSASVGDRVTITCQASQTISNYLAWYQQKPGKAPKLLIYGASNLESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQGYTISNVDNNVFGGGTKVEIKR (SEQ ID NO: 171).

[00470] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSTLSASVGDRVTITCQASQTISNYLAWYQQKPGKAPKLLIYGASNLESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQGYTISNVDNNVFGGGTKVEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 172).

[00471] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAASGFTVSGYNLVWVRQAPGKGLEWVGFISYGDTTY YASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARETANTYDYGIWGQGTLVTV SS (SEQ ID NO: 173).

[00472] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

EVQLVESGGGLVQPGGSLRLSCAASGFTVSGYNLVWVRQAPGKGLEWVGFISYGDTTY

YASSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARETANTYDYGIWGQGTLVTV

SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ

SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL

GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE

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QYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 174).

[00473] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 171 or the light chain sequence of SEQ ID NO: 172, and/or one or more of the polypeptide sequences of SEQ ID NO: 178; SEQ ID NO: 179; and SEQ ID NO: 180 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 173 or the heavy chain sequence of SEQ ID NO: 174, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00474] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 171 or SEQ ID NO: 172. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 173 or SEQ ID NO: 174.

[00475] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 171 or the light chain sequence of SEQ ID NO: 172.

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2016273912 14 Dec 2016 [00476] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 178; SEQ ID NO: 179; and SEQ ID NO: 180 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 173 or the heavy chain sequence of SEQ ID NO: 174.

[00477] The invention also optional contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 171; the variable heavy chain region of SEQ ID NO: 173; the complementarity-determining regions (SEQ ID NO: 175; SEQ ID NO: 176; and SEQ ID NO: 177) of the variable light chain region of SEQ ID NO: 171; and the complementarity-determining regions (SEQ ID NO: 178; SEQ ID NO: 179; and SEQ ID NO: 180) of the variable heavy chain region of SEQ ID NO: 173.

[00478] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Abl8, comprising, or alternatively consisting of, SEQ ID NO: 172 and SEQ ID NO: 174, and having at least one of the biological activities set forth herein.

[00479] In a further particularly preferred optional embodiment of the invention, antibody fragments comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 18, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 171 and the variable heavy chain sequence of SEQ ID NO: 173 or comprise another Fab or antibody fragment that binds to the same or overlapping epitope as Ab 18. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 171 and/or SEQ ID NO: 173 in said Fab while retaining binding specificity for NGF.

115

2016273912 14 Dec 2016 [00480] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl8. In another embodiment of the invention, anti-NGF antibodies such as Ab 18 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00481] Antibody Ab 19 [00482] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab 19 or fragments thereof, for example as set forth below, or comprises another antibody or antibody fragment that binds to the same or overlapping epitope as Ab 19, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

AAVLTQTPSPVSAAVGGTVSISCQSSQNVYKNNYLSWYQQKPGQPPKLLIYKASTLASG VPSRFKGSGSGTDFTLTISDVQCDAAATYYCAGGYSSSSDNAFGGGTEVVVKR (SEQ ID NO: 181).

[00483] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below: AAVLTQTPSPVSAAVGGTVSISCQSSQNVYKNNYLSWYQQKPGQPPKLLIYKASTLASG VPSRFKGSGSGTDFTLTISDVQCDAAATYYCAGGYSSSSDNAFGGGTEVVVKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 182).

116

2016273912 14 Dec 2016 [00484] The invention further optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: QSVEASGGRLVMPGGSLTLTCTASGFSLSTYWMSWVRQAPGKGLEWIGDIYFSNEETN YATWAKGRFTISKTSTTVDLNVISPTTEDTATYFCARGSPDVEIAIDMWGQGTLVTVSS (SEQ ID NO: 183).

[00485] The invention also optionally includes chimeric antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: QSVEASGGRLVMPGGSLTLTCTASGFSLSTYWMSWVRQAPGKGLEWIGDIYFSNEETN YATWAKGRFTISKTSTTVDLNVISPTTEDTATYFCARGSPDVEIAIDMWGQGTLVTVSSA STKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY ASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 184).

[00486] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 185; SEQ ID NO: 186; and SEQ ID NO: 187 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 181 or the light chain sequence of SEQ ID NO: 182, and/or one or more of the polypeptide sequences of SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 183 or the heavy chain sequence of SEQ ID NO: 184, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

117

2016273912 14 Dec 2016 [00487] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 181 or SEQ ID NO: 182. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 183 or SEQ ID NO: 184.

[00488] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 185; SEQ ID NO: 186; and SEQ ID NO: 187 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 181 or the light chain sequence of SEQ ID NO: 182.

[00489] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 183 or the heavy chain sequence of SEQ ID NO: 184.

[00490] The invention also optionally contemplates antibody fragments which include one or more of the antibody fragments described herein for treatment or prevention of pain and pain associated conditions. In one optional embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 181; the variable heavy chain region of SEQ ID NO: 183; the complementarity-determining regions (SEQ ID NO: 185; SEQ ID NO: 186; and SEQ ID NO: 187) of the variable light chain region of SEQ ID NO: 181; and the complementarity-determining regions (SEQ ID NO: 188; SEQ ID NO: 189; and SEQ ID NO: 190) of the variable heavy chain region of SEQ ID NO: 183.

[00491] In a particularly preferred optional embodiment of the invention, the chimeric anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab 19,

118

2016273912 14 Dec 2016 comprising, or alternatively consisting of, SEQ ID NO: 182 and SEQ ID NO: 184, and having at least one of the biological activities set forth herein.

[00492] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 19, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 181 and the variable heavy chain sequence of SEQ ID NO: 183 or comprises another Fab or antibody fragment that binds to the same or overlapping epitope as Ab 19. This optional embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 181 and/or SEQ ID NO: 183 in said Fab while retaining binding specificity for NGF.

[00493] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl9. In another embodiment of the invention, anti-NGF antibodies such as Ab 19 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00494] Antibody Ab20 [00495] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab20 or fragments thereof, for example as set forth below, or comprises another antibody or antibody fragment that binds to the same or overlapping epitope as Ab20, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

119

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DIQMTQSPSSLSASVGDRVTITCQSSQNVYKNNYLSWYQQKPGKVPKLLIYKASTLASG VPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYTSSSDNAFGGGTKVEIKR (SEQ ID NO: 191).

[00496] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSSLSASVGDRVTITCQSSQNVYKNNYLSWYQQKPGKVPKLLIYKASTLASG VPSRFSGSGSGTDFTLTISSLQPEDVATYYCAGGYTSSSDNAFGGGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 192).

[00497] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAASGFTVSTYWMSWVRQAPGKGLEWVGDIYFSNEET NYATSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSPDVEIAIDMWGQGTLV TVSS (SEQ ID NO: 193).

[00498] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

EVQLVESGGGLVQPGGSLRLSCAASGFTVSTYWMSWVRQAPGKGLEWVGDIYFSNEET

NYATSAKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSPDVEIAIDMWGQGTLV

TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV

LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE

LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPR

EEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL

PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLT

VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 194).

[00499] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide

120

2016273912 14 Dec 2016 sequences of SEQ ID NO: 195; SEQ ID NO: 196; and SEQ ID NO: 197 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 191 or the light chain sequence of SEQ ID NO: 192, and/or one or more of the polypeptide sequences of SEQ ID NO: 198; SEQ ID NO: 199; and SEQ ID NO: 200 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 193 or the heavy chain sequence of SEQ ID NO: 194, or combinations of these polypeptide sequences. In another embodiment of the invention, the antibodies of the invention or fragments thereof for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00500] The invention also optionally contemplates fragments of the antibody having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 191 or SEQ ID NO: 192. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 193 or SEQ ID NO: 194.

[00501] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 195; SEQ ID NO: 196; and SEQ ID NO: 197 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 191 or the light chain sequence of SEQ ID NO: 192.

[00502] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 198; SEQ ID NO: 199; and SEQ ID NO: 200 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 193 or the heavy chain sequence of SEQ ID NO: 194.

121

2016273912 14 Dec 2016 [00503] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 191; the variable heavy chain region of SEQ ID NO: 193; the complementarity-determining regions (SEQ ID NO: 195; SEQ ID NO: 196; and SEQ ID NO: 197) of the variable light chain region of SEQ ID NO: 191; and the complementarity-determining regions (SEQ ID NO: 198; SEQ ID NO: 199; and SEQ ID NO: 200) of the variable heavy chain region of SEQ ID NO: 193.

[00504] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab20, comprising, or alternatively consisting of, SEQ ID NO: 192 and SEQ ID NO: 194, and having at least one of the biological activities set forth herein.

[00505] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab20, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 191 and the variable heavy chain sequence of SEQ ID NO: 193. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 191 and/or SEQ ID NO: 193 in said Fab while retaining binding specificity for NGF.

[00506] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab20. In another embodiment of the invention, anti-NGF antibodies for treatment or prevention of pain and pain associated conditions such as Ab20 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00507] Antibody Ab21

122

2016273912 14 Dec 2016 [00508] The invention optionally contemplates methods of treating pain and the specific pain associated disorders alone or is association with another active agent, e.g., an NSAID or opioid analgesic, wherein the antibodies include chimeric antibodies having binding specificity to NGF wherein the antibody is Ab21 or fragments thereof, or another antibody or antibody fragment that binds to the same or overlapping epitope as Ab5, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75. In one embodiment, the invention includes chimeric or humanized antibodies having binding specificity to NGF and possessing a variable light chain sequence comprising the sequence set forth below:

DIQMTQSPSTFSASVGDRVTITCQASQSIYSNFAWYQQKPGKAPKFFIYDASTFESGVPS RFSGSGSGTEYTLTISSLQPDDFATYYCQQGFTVSDIDNAFGGGTKVEIKR (SEQ ID NO: 51).

[00509] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSTLSASVGDRVTITCQASQSIYSNLAWYQQKPGKAPKLLIYDASTLESGVPS RFSGSGSGTEYTLTISSLQPDDFATYYCQQGFTVSDIDNAFGGGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 401).

[00510] The invention further optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a variable heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYAVGWVRQAPGKGLEWVGIIGRNGNT WYASSARGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYGRSVAYYVFNIWGPGT LVTVSS (SEQ ID NO: 53).

[00511] The invention also optionally includes chimeric or humanized antibodies for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below:

EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYAVGWVRQAPGKGLEWVGIIGRNGNT

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2016273912 14 Dec 2016

WYASSARGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYGRSVAYYVFNIWGPGT

LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP

AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTHTCPPCPA

PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTK

PREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQV

YTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS

KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 402).

[00512] The invention further optionally contemplates antibodies for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 401, and/or one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 402, or combinations of these polypeptide sequences. In another optional embodiment of the invention, the antibodies of the invention or fragments thereof comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00513] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 51 or SEQ ID NO: 401. In another embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 53 or SEQ ID NO: 402.

[00514] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated

124

2016273912 14 Dec 2016 conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 401.

[00515] In a further optional embodiment of the invention, fragments of the antibody having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 402.

[00516] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 51; the variable heavy chain region of SEQ ID NO: 53; the complementarity-determining regions (SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57) of the variable light chain region of SEQ ID NO: 51; and the complementarity-determining regions (SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60) of the variable heavy chain region of SEQ ID NO: 53.

[00517] In a particularly preferred optional embodiment of the invention, the chimeric or humanized anti-NGF antibody for treatment or prevention of pain and pain associated conditions is Ab21, comprising, or alternatively consisting of, SEQ ID NO: 401 and SEQ ID NO: 402, and having at least one of the biological activities set forth herein.

[00518] In a further particularly preferred optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab21, the Fab fragment includes the variable light chain sequence of SEQ ID NO: 51 and the variable heavy chain sequence of SEQ ID NO: 53 or another Fab or monovalent antibody fragment that binds to the same or overlapping epitope as

125

2016273912 14 Dec 2016

Ab5,. This embodiment of the invention further contemplates additions, deletions, and variants of SEQ ID NO: 51 and/or SEQ ID NO: 53 in said Fab while retaining binding specificity for NGF.

[00519] In one optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Ab21. In another embodiment of the invention, anti-NGF antibodies for treatment or prevention of pain and pain associated conditions such as Ab21 or Fab fragments thereof may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00520] Antibody fragment Fabl [00521] The invention optionally contemplates methods of treating pain using antibody fragment Fabl or fragments thereof, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75.

In one embodiment, the invention optionally includes Fab antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

[00522]

DIQMTQSPSTLSASVGDRVTITCQASQSIYSNLAWYQQKPGKAPKLLIYDASTLESGVPS RFSGSGSGTEYTLTISSLQPDDFATYYCQQGFTVSDIDNAFGGGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 405).

[00523] The invention further optionally includes Fab antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYAVGWVRQAPGKGLEWVGIIGRNGNT WYASSARGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYGRSVAYYVFNIWGPGT

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2016273912 14 Dec 2016

LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTH (SEQ ID NO: 406).

[00524] The invention further optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 405, and/or one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 406, or combinations of these polypeptide sequences. In another optional embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00525] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 51 or SEQ ID NO: 405. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 53 or SEQ ID NO: 406.

[00526] In a further optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 405.

127

2016273912 14 Dec 2016 [00527] In a further optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO:

or the heavy chain sequence of SEQ ID NO: 406.

[00528] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 51; the variable heavy chain region of SEQ ID NO: 53; the complementarity-determining regions (SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57) of the variable light chain region of SEQ ID NO: 51; and the complementarity-determining regions (SEQ ID NO: 58; SEQ ID NO:

59; and SEQ ID NO: 60) of the variable heavy chain region of SEQ ID NO: 53.

[00529] In a particularly preferred optional embodiment of the invention, the anti-NGF antibody fragment for treatment or prevention of pain and pain associated conditions is Fabl, comprising SEQ ID NO: 405 and SEQ ID NO: 406, or another Fab or antibody fragment that binds to the same or overlapping epitope as Fabl, and having at least one of the biological activities set forth herein. In one embodiment of the invention, antibody fragment Fabl may be produced by enzymatic digestion (e.g., papain) of Ab21.

[00530] Antibody fragment Fab2 [00531] The invention optionally contemplates methods of treating pain using antibody fragment Fab2 or fragments thereof, for example as set forth below, in a therapeutically effective amount which inhibits the association of NGF with TrkA and the association of NGF with p75.

In one embodiment, the invention includes Fab antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a light chain sequence comprising the sequence set forth below:

DIQMTQSPSTLSASVGDRVTITCQASQSIYSNLAWYQQKPGKAPKLLIYDASTLESGVPS

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2016273912 14 Dec 2016

RFSGSGSGTEYTLTISSLQPDDFATYYCQQGFTVSDIDNAFGGGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 407).

[00532] The invention further optionally includes Fab antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF and possessing a heavy chain sequence comprising the sequence set forth below: EVQLVESGGGLVQPGGSLRLSCAASGFTVSNYAVGWVRQAPGKGLEWVGIIGRNGNT WYASSARGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGYGRSVAYYVFNIWGPGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDARVEPKSCDKTH (SEQ ID NO: 408).

[00533] The invention further optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions comprising one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 407, and/or one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 408, or combinations of these polypeptide sequences. In another embodiment of the invention, antibody fragments of the invention comprise, or alternatively consist of, combinations of one or more of the CDRs, the variable heavy and variable light chain sequences, and the heavy and light chain sequences set forth above, including all of them.

[00534] The invention also optionally contemplates fragments of the antibody for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 51 or SEQ ID NO: 407. In another embodiment of the invention, antibody fragments of the invention for treatment or prevention of pain and pain

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2016273912 14 Dec 2016 associated conditions comprise, or alternatively consist of, the polypeptide sequence of SEQ ID NO: 53 or SEQ ID NO: 408.

[00535] In a further optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable light chain sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 407.

[00536] In a further optional embodiment of the invention, antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polypeptide sequences of SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60 which correspond to the complementarity-determining regions (CDRs, or hypervariable regions) of the variable heavy chain sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 408.

[00537] The invention also optionally contemplates antibody fragments for treatment or prevention of pain and pain associated conditions which include one or more of the antibody fragments described herein. In one embodiment of the invention, fragments of the antibodies having binding specificity to NGF for treatment or prevention of pain and pain associated conditions comprise, or alternatively consist of, one, two, three or more, including all of the following antibody fragments: the variable light chain region of SEQ ID NO: 51; the variable heavy chain region of SEQ ID NO: 53; the complementarity-determining regions (SEQ ID NO: 55; SEQ ID NO: 56; and SEQ ID NO: 57) of the variable light chain region of SEQ ID NO: 51; and the complementarity-determining regions (SEQ ID NO: 58; SEQ ID NO: 59; and SEQ ID NO: 60) of the variable heavy chain region of SEQ ID NO: 53.

[00538] In a particularly preferred optional embodiment of the invention, the anti-NGF antibody fragment for treatment or prevention of pain and pain associated conditions is Fab2, comprising SEQ ID NO: 407 and SEQ ID NO: 408, or another Fab or antibody fragment that binds to the same or overlapping epitope as Fab2, and having at least one of the biological activities set forth herein.

130

2016273912 14 Dec 2016 [00539] In another optional embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced via expression in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention, antibody fragment Fab2 may be produced by expression in Pichia pastoris using protocols set forth herein in the examples.

[00540] In another embodiment, antibody fragments may be present in one or more of the following non-limiting forms: Fab, Fab', F(ab')2, Fv and single chain Fv antibody forms. In a preferred embodiment, the anti-NGF antibodies described herein further comprises the kappa constant light chain sequence comprising the sequence set forth below:

[00541] VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 412).

[00542] In another preferred optional embodiment, the anti-NGF antibodies described herein for treatment or prevention of pain and pain associated conditions further comprises the gamma-1 constant heavy chain polypeptide sequence comprising the sequence set forth below:

[00543] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 413).

[00544] In another optional embodiment, the invention contemplates an isolated anti-NGF antibody for treatment or prevention of pain and pain associated conditions comprising a Vh polypeptide sequence selected from: SEQ ID NO: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123, 133, 143, 153, 163, 173, 183, 193, or 402, or a variant thereof; and further comprising a V_L polypeptide sequence selected from: SEQ ID NO: 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111,

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121, 131, 141, 151, 161, 171, 181, 191, or 401, or a variant thereof, wherein one or more of the framework residues (FR residues) in said V_H or V_L polypeptide has been substituted with another amino acid residue resulting in an anti-NGF antibody that specifically binds NGF. The invention contemplates humanized and chimeric forms of these antibodies for treatment or prevention of pain and pain associated conditions. The chimeric antibodies may include an Fc derived from IgGl, IgG2, IgG3, IgG4, IgG5, IgG6, IgG7, IgG8, IgG9, IgGlO, IgGl 1, IgG12, IgG13, IgG14, IgG15, IgG16, IgG17, IgG18 or IgG19 constant regions.

[00545] In one embodiment of the invention, the antibodies or Vh or Vl polypeptides originate or are selected from one or more rabbit B cell populations prior to initiation of the humanization process referenced herein.

[00546] In another embodiment of the invention, the anti-NGF antibodies and fragments thereof for treatment or prevention of pain and pain associated conditions do not have binding specificity for p75 or TrkA. In a further embodiment of the invention, there is contemplated methods for treating pain comprising using the anti-NGF antibodies and fragments thereof to inhibit the association of NGF with p75 and/or TrkA. In another embodiment of the invention, there is contemplated methods for treating pain comprising using anti-NGF antibodies and fragments thereof to inhibit the association of NGF with TrkA and/or multimers thereof and/or antagonizes the biological effects thereof. In another embodiment of the invention, there is contemplated methods for treating pain comprising using anti-NGF antibodies and fragments thereof to inhibit the association of NGF with p75 and/or multimers thereof and the association of NGF with TrkA and/or multimers thereof, and antagonizes the biological effects of p75 and TrkA.

[00547] As stated supra, antibodies and fragments thereof may be modified posttranslationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

[00548] Regarding detectable moieties, further exemplary enzymes include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase

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2016273912 14 Dec 2016 and luciferase. Further exemplary fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin and dansyl chloride. Further exemplary chemiluminescent moieties include, but are not limited to, luminol. Further exemplary bioluminescent materials include, but are not limited to, luciferin and aequorin. Further exemplary radioactive materials include, but are not limited to, Iodine 125 (¹²⁵I), Carbon 14 (¹⁴C), Sulfur 35 (³⁵S), Tritium (³H) and Phosphorus 32 (³²P).

[00549] Regarding functional moieties, exemplary cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimytotic agents such as the vinca alkaloids, vincristine and vinblastine. Other cytotoxic agents include paclitaxel (taxol), ricin, pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), interferons, and mixtures of these cytotoxic agents.

[00550] Further cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine and bleomycin. Toxic enzymes from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin may be conjugated to the humanized or chimeric antibodies, or binding fragments thereof, to generate cell-type-specific-killing reagents (Youle, et al., Proc. Nat! Acad. Sci. USA 77:5483 (1980); Gilliland, et al., Proc. Nat! Acad. Sci. USA 77:4539 (1980); Krolick, et al., Proc. Nat! Acad. Sci. USA 77:5419 (1980)).

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2016273912 14 Dec 2016 [00551] Other cytotoxic agents include cytotoxic ribonucleases as described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the invention also relate to radioimmunoconjugates where a radionuclide that emits alpha or beta particles is stably coupled to the antibody, or binding fragments thereof, with or without the use of a complex-forming agent. Such radionuclides include beta-emitters such asPhosphorus-32 (³²P), Scandium-47 (⁴⁷Sc), Copper-67 (⁶⁷Cu), Gallium-67 (⁶⁷Ga), Yttrium-88 (⁸⁸Y), Yttrium-90 (⁹⁰Y), Iodine-125 (¹²⁵I), Iodine-131 (¹³¹I), Samarium-153 (¹⁵³Sm), Lutetium-177 (¹⁷⁷Lu), Rhenium-186 (¹⁸⁶Re) or Rhenium-188 (¹⁸⁸Re), and alpha-emitters such as Astatine-211 (²¹¹At), Lead-212 (²¹²Pb), Bismuth-212 (²¹²Bi) or -213 (²¹³Bi) or Actinium-225 (²²⁵Ac).

[00552] Further exemplary radioactive materials include, but are not limited to, Iodine 125 (¹²⁵I), Carbon 14 (¹⁴C), Sulfur 35 (³⁵S), Tritium (³H) and Phosphorus 32 (³²P).

[00553] Regarding functional moieties, exemplary cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimytotic agents such as the vinca alkaloids, vincristine and vinblastine. Other cytotoxic agents include paclitaxel (taxol), ricin, pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), interferons, and mixtures of these cytotoxic agents.

[00554] Further cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine and bleomycin. Toxic

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2016273912 14 Dec 2016 enzymes from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin may be conjugated to the humanized or chimeric antibodies, or binding fragments thereof, to generate cell-type-specific-killing reagents (Youle, et al., Proc. Nat'l Acad. Sci. USA 77:5483 (1980); Gilliland, et al., Proc. Nat'l Acad. Sci. USA 77:4539 (1980); Krolick, et al., Proc. Nat'l Acad. Sci. USA 77:5419 (1980)).

[00555] Other cytotoxic agents include cytotoxic ribonucleases as described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the invention also relate to radioimmunoconjugates where a radionuclide that emits alpha or beta particles is stably coupled to the antibody, or binding fragments thereof, with or without the use of a complex-forming agent. Such radionuclides include beta-emitters such asPhosphorus-32 (³²P), Scandium-47 (⁴⁷Sc), Copper-67 (⁶⁷Cu), Gallium-67 (⁶⁷Ga), Yttrium-88 (⁸⁸Y), Yttrium-90 (⁹⁰Y), Iodine-125 (¹²⁵I), Iodine-131 (¹³¹I), Samarium-153 (¹⁵³Sm), Lutetium-177 (¹⁷⁷Lu), Rhenium-186 (¹⁸⁶Re) or Rhenium-188 (¹⁸⁸Re), and alpha-emitters such as Astatine-211 (²¹¹At), Lead-212 (²¹²Pb), Bismuth-212 (²¹²Bi) or -213 (²¹³Bi) or Actinium-225 (²²⁵Ac). .

[00556] Methods are known in the art for conjugating an antibody or binding fragment thereof to a detectable moiety and the like, such as for example those methods described by Hunter et al, Nature 144:945 (1962); David et al, Biochemistry 13:1014 (1974); Pain et al, J. Immunol. Meth. 40:219 (1981); andNygren, J., Histochem. and Cytochem. 30:407 (1982).

[00557] Embodiments described herein further include variants and equivalents that are substantially homologous to the antibodies, antibody fragments, diabodies, SMIPs, camelbodies, nanobodies, IgNAR, polypeptides, variable regions and CDRs set forth herein. These may contain, e.g., conservative substitution mutations, (i.e., the substitution of one or more amino acids by similar amino acids). For example, conservative substitution refers to the substitution of an amino acid with another within the same general class, e.g., one acidic amino acid with another acidic amino acid, one basic amino acid with another basic amino acid, or one neutral amino acid by another neutral amino acid. What is intended by a conservative amino acid substitution is well known in the art.

[00558] In another embodiment, the invention contemplates polypeptide sequences having at least 90% or greater sequence homology to any one or more of the polypeptide sequences of

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2016273912 14 Dec 2016 antibody fragments, variable regions and CDRs set forth herein. More preferably, the invention contemplates polypeptide sequences having at least 95% or greater sequence homology, even more preferably at least 98% or greater sequence homology, and still more preferably at least 99% or greater sequence homology to any one or more of the polypeptide sequences of antibody fragments, variable regions and CDRs set forth herein. Methods for determining homology between nucleic acid and amino acid sequences are well known to those of ordinary skill in the art.

[00559] In another embodiment, the invention further contemplates the above-recited polypeptide homologs of the antibody fragments, variable regions and CDRs set forth herein further having anti-NGF activity. Non-limiting examples of anti-NGF activity are set forth herein.

[00560] In another embodiment, the invention further contemplates the generation and use of anti-idiotypic antibodies that bind any of the foregoing sequences. In an exemplary embodiment, such an anti-idiotypic antibody could be administered to a subject who has received an anti-NGF antibody to modulate, reduce, or neutralize, the effect of the anti-NGF antibody. Such anti-idiotypic antibodies could also be useful for treatment of an autoimmune disease characterized by the presence of anti-NGF antibodies. A further exemplary use of such antiidiotypic antibodies is for detection of the anti-NGF antibodies of the present invention, for example to monitor the levels of the anti-NGF antibodies present in a subject’s blood or other bodily fluids.

[00561] The present invention also contemplates anti-NGF antibodies comprising any of the polypeptide or polynucleotide sequences described herein substituted for any of the other polynucleotide sequences described herein. For example, without limitation thereto, the present invention contemplates antibodies comprising the combination of any of the variable light chain and variable heavy chain sequences described herein, and further contemplates antibodies resulting from substitution of any of the CDR sequences described herein for any of the other CDR sequences described herein.

[00562]

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2016273912 14 Dec 2016 [00563] Polynucleotides Encoding Anti-NGF Antibody Polypeptides [00564] Antibody Ab 1 [00565] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Abl polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Abl polypeptides. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 1:

[00566] GCCCTTGTGATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGA GGCACAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTACAGCAATTTAGCCTGG TATCAACAGAGACCAGGGCAGCGTCCCAAGCTCCTGATCTATGGTGCATCCAATCTG GATGCTGGGGTCCCATCGCGGTTCAGAGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCGACCTGGAGTGTGACGATGTTGGCACTTACTACTGTCAAAGTGCTTT TGATAGTGATAGTACTGAAAATACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAC GT (SEQ ID NO: 201).

[00567] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 2:

[00568] GCCCTTGTGATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGA GGCACAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTACAGCAATTTAGCCTGG TATCAACAGAGACCAGGGCAGCGTCCCAAGCTCCTGATCTATGGTGCATCCAATCTG GATGCTGGGGTCCCATCGCGGTTCAGAGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCGACCTGGAGTGTGACGATGTTGGCACTTACTACTGTCAAAGTGCTTT TGATAGTGATAGTACTGAAAATACTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAC GTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG

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TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 202).

[00569] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 3:

[00570] CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGCTTCTCCCTCAGTAGCTATGCAATGAGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGTCATTACTAGTATTG GTAGCACAGTCTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTT CTGTGCCAGAGGCTACGATGACTATGATGAGATGACCTACTTTAACATCTGGGGCCA GGGGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 203).

[00571] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 4:

[00572] CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGCTTCTCCCTCAGTAGCTATGCAATGAGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGTCATTACTAGTATTG GTAGCACAGTCTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTT CTGTGCCAGAGGCTACGATGACTATGATGAGATGACCTACTTTAACATCTGGGGCCA

GGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT

GGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCA

AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC

GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC

GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAAT

CACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAA

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AACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTT

CCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCAC

ATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACG

TGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGC

CAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG

CAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA

CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA

TCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT

CTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACT

ACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC

TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG

CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA

TGA (SEQ ID NO: 204).

[00573] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 205; SEQ ID NO: 206; and SEQ ID NO: 207 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 1 or the light chain sequence of SEQ ID NO: 2.

[00574] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 208; SEQ ID NO: 209; and SEQ ID NO: 210 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 3 or the heavy chain sequence of SEQ ID NO: 4.

[00575] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or

139

2016273912 14 Dec 2016 prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 201 encoding the light chain variable sequence of SEQ ID NO: 1; the polynucleotide SEQ ID NO: 202 encoding the light chain sequence of SEQ ID NO: 2; the polynucleotide SEQ ID NO: 203 encoding the heavy chain variable sequence of SEQ ID NO: 3; the polynucleotide SEQ ID NO: 204 encoding the heavy chain sequence of SEQ ID NO: 4; polynucleotides encoding the complementaritydetermining regions (SEQ ID NO: 205; SEQ ID NO: 206; and SEQ ID NO: 207) of the light chain variable sequence of SEQ ID NO: 1 or the light chain sequence of SEQ ID NO: 2; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 208; SEQ ID NO: 209; and SEQ ID NO: 210) of the heavy chain variable sequence of SEQ ID NO: 3 or the heavy chain sequence of SEQ ID NO: 4.

[00576] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments for treatment or prevention of pain and pain associated conditions having binding specificity for NGF. With respect to antibody Abl, the polynucleotides encoding the full length Abl antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 202 encoding the light chain sequence of SEQ ID NO: 2 and the polynucleotide SEQ ID NO:

204 encoding the heavy chain sequence of SEQ ID NO: 4.

[00577] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments for treatment or prevention of pain and pain associated conditions may be produced by enzymatic digestion (e.g., papain) of Abl following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Abl or Fab fragments thereof may be produced via expression of Abl polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example

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2016273912 14 Dec 2016 diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00578] Antibody Ab2 [00579] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab2 polypeptides which inhibit the association of NGF with TrkA and the association of NGF with p75, for treatment or prevention of pain and pain associated conditions having binding specificity to NGF in methods of treating pain in an individual comprising administering to said individual antibody Ab2 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to NGF for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 11:

[00580] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAACATTTACAGCAACTTAGCCTG GTATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAATCT GGATGCTGGAGTCCCATCAAGGTTCTCTGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGCCAAAGTGCTTT TGATAGTGATAGTACTGAAAACACTTTCGGCGGAGGAACCAAGGTGGAAATCAAAC GT (SEQ ID NO: 211).

[00581] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 12:

[00582] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAACATTTACAGCAACTTAGCCTG GTATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAATCT GGATGCTGGAGTCCCATCAAGGTTCTCTGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGCCAAAGTGCTTT

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2016273912 14 Dec 2016

TGATAGTGATAGTACTGAAAACACTTTCGGCGGAGGAACCAAGGTGGAAATCAAAC

GTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT

CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG

TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA

GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA

AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA

GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 212).

[00583] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 13:

[00584] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAGCTATGCAATGAG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAGTCATTACTAGTA TTGGTAGCACAGTCTACGCGAGCAGCGCGAAAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCT GTGTATTACTGTGCTAGAGGCTACGATGACTATGATGAGATGACCTACTTTAACATC TGGGGCCAAGGGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 213).

[00585] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 14:

[00586] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAGCTATGCAATGAG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAGTCATTACTAGTA TTGGTAGCACAGTCTACGCGAGCAGCGCGAAAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCT GTGTATTACTGTGCTAGAGGCTACGATGACTATGATGAGATGACCTACTTTAACATC TGGGGCCAAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGT CTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTG CCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCT

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2016273912 14 Dec 2016

GACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCT

CAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCA

ACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCT

TGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACC

GTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCC

TGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCA

ACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGA

GCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTG

GCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCA

TCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC

CTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGT

CAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGG

AGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCT

ACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGC

TCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT

CCGGGTAAATGA (SEQ ID NO: 214).

[00587] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 215; SEQ ID NO: 216; and SEQ ID NO: 217 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 11 or the light chain sequence of SEQ ID NO: 12.

[00588] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 218; SEQ ID NO: 219; and SEQ ID NO: 220 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 13 or the heavy chain sequence of SEQ ID NO: 14.

143

2016273912 14 Dec 2016 [00589] The invention also optional contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 211 encoding the light chain variable sequence of SEQ ID NO: 11; the polynucleotide SEQ ID NO: 212 encoding the light chain sequence of SEQ ID NO: 12; the polynucleotide SEQ ID NO: 213 encoding the heavy chain variable sequence of SEQ ID NO: 13; the polynucleotide SEQ ID NO: 214 encoding the heavy chain sequence of SEQ ID NO: 14; polynucleotides encoding the complementaritydetermining regions (SEQ ID NO: 215; SEQ ID NO: 216; and SEQ ID NO: 217) of the light chain variable sequence of SEQ ID NO: 11 or the light chain sequence of SEQ ID NO: 12; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 218; SEQ ID NO: 219; and SEQ ID NO: 220) of the heavy chain variable sequence of SEQ ID NO: 13 or the heavy chain sequence of SEQ ID NO: 14.

[00590] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments for treatment or prevention of pain and pain associated conditions having binding specificity for NGF. With respect to antibody Ab2, the polynucleotides encoding the full length Ab2 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 212 encoding the light chain sequence of SEQ ID NO: 12 and the polynucleotide SEQ ID NO: 214 encoding the heavy chain sequence of SEQ ID NO: 14.

[00591] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab2 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab2 or Fab fragments thereof may be produced via expression of Ab2 polynucleotides in mammalian

144

2016273912 14 Dec 2016 cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00592] Antibody Ab3 [00593] The invention is further directed to the use of polynucleotides set forth below to produce antibody Ab3 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab3 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 21:

[00594] GCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCAGCTATGGGA GACACAGTCACCATCAAGTGCCAGTCCAGTCAGAGTGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAGGCTCCTGATCTATGATGCATCC AATCTGCCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTC ACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGC GATTATGATGATGATGCTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGT (SEQ ID NO: 221).

[00595] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 22:

[00596] GCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCAGCTATGGGA GACACAGTCACCATCAAGTGCCAGTCCAGTCAGAGTGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAGGCTCCTGATCTATGATGCATCC AATCTGCCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTC ACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGC

145

2016273912 14 Dec 2016

GATTATGATGATGATGCTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA

ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA

ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA

AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA

CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC

AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT

GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 222).

[00597] In another embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 23:

[00598] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGCTATGTAATGATCTGG GTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATCACTTGGAGTGCTGG TACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGA CCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTC TGTGCCGGAGGTGGTGGTAGTATTTATGATATTTGGGGCCCGGGCACCCTGGTCACC GTCTCGAGC (SEQ ID NO: 223).

[00599] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 24:

[00600] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGCTATGTAATGATCTGG GTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATCACTTGGAGTGCTGG TACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGA CCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTC TGTGCCGGAGGTGGTGGTAGTATTTATGATATTTGGGGCCCGGGCACCCTGGTCACC GTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGA ACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCC

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2016273912 14 Dec 2016

CGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCT

CCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC

ACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCC

ACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAA

ACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGG

ACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG

GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGT

GGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGT

GCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCC

AAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGAT

GACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACA

TCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCT

CCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAG

AGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC

AACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO:

224).

[00601] In a further embodiment of the invention, polynucleotides encoding antibody fragments having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 225; SEQ ID NO: 226; and SEQ ID NO: 227 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 21 or the light chain sequence of SEQ ID NO: 22.

[00602] In a further embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 228; SEQ ID NO: 229; and SEQ ID NO: 230 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 23 or the heavy chain sequence of SEQ ID NO: 24.

147

2016273912 14 Dec 2016 [00603] The invention also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein for treatment or prevention of pain and pain associated conditions. In one embodiment of the invention, polynucleotides encoding antibody fragments having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 221 encoding the light chain variable sequence of SEQ ID NO: 21; the polynucleotide SEQ ID NO: 222 encoding the light chain sequence of SEQ ID NO: 22; the polynucleotide SEQ ID NO: 223 encoding the heavy chain variable sequence of SEQ ID NO: 23; the polynucleotide SEQ ID NO: 224 encoding the heavy chain sequence of SEQ ID NO: 24; polynucleotides encoding the complementaritydetermining regions (SEQ ID NO: 225; SEQ ID NO: 226; and SEQ ID NO: 227) of the light chain variable sequence of SEQ ID NO: 21 or the light chain sequence of SEQ ID NO: 22; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 228; SEQ ID NO: 229; and SEQ ID NO: 230) of the heavy chain variable sequence of SEQ ID NO: 23 or the heavy chain sequence of SEQ ID NO: 24.

[00604] In a preferred embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments for treatment or prevention of pain and pain associated conditions having binding specificity for NGF. With respect to antibody Ab3, the polynucleotides encoding the full length Ab3 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 222 encoding the light chain sequence of SEQ ID NO: 22 and the polynucleotide SEQ ID NO: 224 encoding the heavy chain sequence of SEQ ID NO: 24.

[00605] Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab3 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab3 or Fab fragments thereof may be produced via expression of Ab3 polynucleotides in mammalian

148

2016273912 14 Dec 2016 cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00606] Antibody Ab4 [00607] The invention is further directed to the use of polynucleotides set forth below to produce antibody Ab4 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab4 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 31:

[00608] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAAGGCATCC ACTCTGGCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGC GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAA ACGT (SEQ ID NO: 231).

[00609] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 32:

[00610] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAAGGCATCC ACTCTGGCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGC

149

2016273912 14 Dec 2016

GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAA

ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA

ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA

AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA

CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC

AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT

GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 232).

[00611] In another embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 33:

[00612] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAGCTATGTAATGAT CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAATCACTTGGAGTG CTGGTACATACTACGCGAGCAGTGCGAAAGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCTGTG TATTACTGTGCTGGAGGTGGTGGTAGTATCTATGATATTTGGGGCCAAGGGACCCTC GTCACCGTCTCGAGC (SEQ ID NO: 233).

[00613] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 34:

[00614] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAGCTATGTAATGAT CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTACATCGGAATCACTTGGAGTG CTGGTACATACTACGCGAGCAGTGCGAAAGGCCGATTCACCATCTCCAGAGACAAT TCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCTGTG TATTACTGTGCTGGAGGTGGTGGTAGTATCTATGATATTTGGGGCCAAGGGACCCTC GTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCC TCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTT CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA

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2016273912 14 Dec 2016

CCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG

TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA

GCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA

TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC

CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT

GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG

TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTA

CCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGT

ACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC

AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGA

GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA

GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC

CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGT

GGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG

CTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ

ID NO: 234).

[00615] In a further embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 235; SEQ ID NO: 236; and SEQ ID NO: 237 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 31 or the light chain sequence of SEQ ID NO: 32.

[00616] In a further embodiment of the invention, polynucleotides encoding antibody fragments h for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 238; SEQ ID NO: 239; and SEQ ID NO: 240 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 33 or the heavy chain sequence of SEQ ID NO: 34.

151

2016273912 14 Dec 2016 [00617] The invention also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 231 encoding the light chain variable sequence of SEQ ID NO: 31; the polynucleotide SEQ ID NO: 232 encoding the light chain sequence of SEQ ID NO: 32; the polynucleotide SEQ ID NO: 233 encoding the heavy chain variable sequence of SEQ ID NO: 33; the polynucleotide SEQ ID NO: 234 encoding the heavy chain sequence of SEQ ID NO: 34; polynucleotides encoding the complementaritydetermining regions (SEQ ID NO: 235; SEQ ID NO: 236; and SEQ ID NO: 237) of the light chain variable sequence of SEQ ID NO: 31 or the light chain sequence of SEQ ID NO: 32; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 238; SEQ ID NO: 239; and SEQ ID NO: 240) of the heavy chain variable sequence of SEQ ID NO: 33 or the heavy chain sequence of SEQ ID NO: 34.

[00618] In a preferred embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments for treatment or prevention of pain and pain associated conditions having binding specificity for NGF. With respect to antibody Ab4, the polynucleotides encoding the full length Ab4 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 232 encoding the light chain sequence of SEQ ID NO: 32 and the polynucleotide SEQ ID NO: 234 encoding the heavy chain sequence of SEQ ID NO: 34.

[00619] Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab4 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies for treatment or prevention of pain and pain associated conditions such as Ab4 or Fab fragments thereof may be

152

2016273912 14 Dec 2016 produced via expression of Ab4 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00620] Antibody Ab5 [00621] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab5 polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab5 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 41:

[00622] GCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTTACAGCAATTTAGCCTG GTATCAGCAGAGACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATGCATCCACTCT GGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTC TCACCATCAGCGGCGTGGAGTGTGCCGATGCTGCCTCTTACTACTGTCAACAGGGTT TTACTGTTAGTGATATTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAC GT (SEQ ID NO: 241).

[00623] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 42:

[00624] GCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTTACAGCAATTTAGCCTG GTATCAGCAGAGACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATGCATCCACTCT

153

2016273912 14 Dec 2016

GGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTC

TCACCATCAGCGGCGTGGAGTGTGCCGATGCTGCCTCTTACTACTGTCAACAGGGTT

TTACTGTTAGTGATATTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAC

GTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT

CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG

TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA

GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA

AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA

GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 242).

[00625] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 43:

[00626] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAACTATGCAGTGGGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTGGTCGTAATG GTAACACATGGTACGCGAGCTGGGCAAGAGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGGATCTGAAAATCACCAGTCCGACAAGCGAGGACACGGCCACATATTT CTGTGCCAGAGGATATGGCCGTAGTGTTGCTTATTACGTCTTTAACATCTGGGGCCC AGGCACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 243).

[00627] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 44:

[00628] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAACTATGCAGTGGGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTGGTCGTAATG GTAACACATGGTACGCGAGCTGGGCAAGAGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGGATCTGAAAATCACCAGTCCGACAAGCGAGGACACGGCCACATATTT CTGTGCCAGAGGATATGGCCGTAGTGTTGCTTATTACGTCTTTAACATCTGGGGCCC AGGCACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCT

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GGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCA

AGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC

GGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC

GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAAT

CACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAA

AACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTT

CCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCAC

ATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACG

TGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGC

CAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG

CAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAA

CCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA

TCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTT

CTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACT

ACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGC

TCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATG

CATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA

TGA (SEQ ID NO: 244).

[00629] In a further optional embodiment of the invention, polynucleotides encoding for treatment or prevention of pain and pain associated conditions fragments having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 245; SEQ ID NO: 246; and SEQ ID NO: 247 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 41 or the light chain sequence of SEQ ID NO: 42.

[00630] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 248; SEQ ID NO: 249; and SEQ ID NO: 250 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or

155

2016273912 14 Dec 2016 hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 43 or the heavy chain sequence of SEQ ID NO: 44.

[00631] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 241 encoding the light chain variable sequence of SEQ ID NO: 41; the polynucleotide SEQ ID NO: 242 encoding the light chain sequence of SEQ ID NO: 42; the polynucleotide SEQ ID NO: 243 encoding the heavy chain variable sequence of SEQ ID NO: 43; the polynucleotide SEQ ID NO: 244 encoding the heavy chain sequence of SEQ ID NO: 44; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 245; SEQ ID NO: 246; and SEQ ID NO: 247) of the light chain variable sequence of SEQ ID NO: 41 or the light chain sequence of SEQ ID NO: 42; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 248; SEQ ID NO: 249; and SEQ ID NO: 250) of the heavy chain variable sequence of SEQ ID NO: 43 or the heavy chain sequence of SEQ ID NO: 44.

[00632] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab5, the polynucleotides encoding the full length Ab5 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 242 encoding the light chain sequence of SEQ ID NO: 42 and the polynucleotide SEQ ID NO: 244 encoding the heavy chain sequence of SEQ ID NO: 44.

[00633] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by

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2016273912 14 Dec 2016 enzymatic digestion (e.g., papain) of Ab5 following expression of the full-length polynucleotides in a suitable host. In another optional embodiment of the invention, anti-NGF antibodies such as Ab5 or Fab fragments thereof may be produced via expression of Ab5 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00634] Antibody Ab6 [00635] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab6 polypeptides having binding specificity to NGF, which inhibits the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab6 polypeptides.

The invention is further directed to polynucleotides encoding for treatment or prevention of pain and pain associated conditions polypeptides having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 51:

[00636] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTTACAGCAATCTTGCCTGG TATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGATGCATCCACTCTG

GAATCTGGAGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGCCAACAGGGTTT TACTGTTAGTGATATTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAAC GT (SEQ ID NO: 251).

[00637] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 52:

[00638] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTTACAGCAATCTTGCCTGG

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TATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGATGCATCCACTCTG

GAATCTGGAGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTACACTCT

CACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGCCAACAGGGTTT

TACTGTTAGTGATATTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAAC

GTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT

CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG

TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA

GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA

AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA

GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 252).

[00639] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 53:

[00640] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAACTATGCAGTGGG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAATCATTGGTCGTA ATGGTAACACATGGTACGCGAGCTCTGCAAGAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCT GTGTATTACTGTGCTAGAGGATATGGCCGTAGTGTTGCTTATTACGTCTTTAACATCT GGGGCCCAGGGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 253).

[00641] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 54:

[00642] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAACTATGCAGTGGG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAATCATTGGTCGTA ATGGTAACACATGGTACGCGAGCTCTGCAAGAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCT GTGTATTACTGTGCTAGAGGATATGGCCGTAGTGTTGCTTATTACGTCTTTAACATCT

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GGGGCCCAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCT

TCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCC

TGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG

ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC

AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAA

CGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTT

GTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCG

TCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCT

GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAA

CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC

AGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC

TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC

GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCT

GCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCA

AAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG

AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC

AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTC

CGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCC

GGGTAAATGA (SEQ ID NO: 254).

[00643] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 52.

[00644] In a further optional embodiment of the invention, polynucleotides encoding for treatment or prevention of pain and pain associated conditions fragments having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 258; SEQ ID NO: 259; and SEQ ID NO: 260 which correspond to

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2016273912 14 Dec 2016 polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 54.

[00645] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 251 encoding the light chain variable sequence of SEQ ID NO: 51; the polynucleotide SEQ ID NO: 252 encoding the light chain sequence of SEQ ID NO: 52; the polynucleotide SEQ ID NO: 253 encoding the heavy chain variable sequence of SEQ ID NO: 53; the polynucleotide SEQ ID NO: 254 encoding the heavy chain sequence of SEQ ID NO: 54; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257) of the light chain variable sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 52; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 258; SEQ ID NO: 259; and SEQ ID NO: 260) of the heavy chain variable sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 54.

[00646] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab6, the polynucleotides encoding the full length Ab6 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 252 encoding the light chain sequence of SEQ ID NO: 52 and the polynucleotide SEQ ID NO: 254 encoding the heavy chain sequence of SEQ ID NO: 54.

[00647] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

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In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab6 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab6 or Fab fragments thereof may be produced via expression of Ab6 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00648] Antibody Ab7 [00649] The invention optionally is further directed to the use of polynucleotides set forth below to produce antibody Ab7 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75. in methods of treating pain in an individual comprising administering to said individual antibody Ab7 polypeptides.

The invention is further directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 61:

[00650] GCCGATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTCAACCTGTG GGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGGACATTTATAACTTATTGGC CTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCAC TCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACA CTCTCACCATCAGCGGCCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAACA ATTATCTTGTTACTACTTATGGTGTTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCA AACGT (SEQ ID NO: 261).

[00651] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 62:

161

2016273912 14 Dec 2016 [00652] GCCGATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTCAACCTGTG GGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGGACATTTATAACTTATTGGC CTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCAC TCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACA CTCTCACCATCAGCGGCCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAACA ATTATCTTGTTACTACTTATGGTGTTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCA

AACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGA

AATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCA

AAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTC

ACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAG

CAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC

TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 262).

[00653] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 63:

[00654] CAGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGAC ACCCCTGACACTCACCTGTACAGTCTCTGGATTCTCCCTCAGTAGCTATGCAATGAT CTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATACATTGATACTG ATACTAGCGCATACTACGCGAGCTGGGTGAAAGGCCGATTCACCATCTCCAGAACC TCGACCACGGTGGATCTCAAAATCACTAGTCCGACAACCGAGGACACGGCCACCTA TTTCTGTGCCAGATCTTATGCTGCTTATGGTGGTTATCCTGCTACTTTTGATCCCTGG GGCCCAGGCACCCTGGTCACCGTCTCGAGC (SEQ ID NO: 263).

[00655] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 64:

[00656] CAGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGAC ACCCCTGACACTCACCTGTACAGTCTCTGGATTCTCCCTCAGTAGCTATGCAATGAT

CTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATACATTGATACTG

ATACTAGCGCATACTACGCGAGCTGGGTGAAAGGCCGATTCACCATCTCCAGAACC

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TCGACCACGGTGGATCTCAAAATCACTAGTCCGACAACCGAGGACACGGCCACCTA

TTTCTGTGCCAGATCTTATGCTGCTTATGGTGGTTATCCTGCTACTTTTGATCCCTGG

GGCCCAGGCACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTC

CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTG

GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC

CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG

CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT

GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG

ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA

GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG

GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG

GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAG

TACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTG

AATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGA

GAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC

CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA

GGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA

CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG

CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCG

TGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG

GTAAATGA (SEQ ID NO: 264).

[00657] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 265; SEQ ID NO: 266; and SEQ ID NO: 267 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 61 or the light chain sequence of SEQ ID NO: 62.

[00658] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

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2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 268; SEQ ID NO: 269; and SEQ ID NO: 270 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 63 or the heavy chain sequence of SEQ ID NO: 64.

[00659] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 261 encoding the light chain variable sequence of SEQ ID NO: 61; the polynucleotide SEQ ID NO: 262 encoding the light chain sequence of SEQ ID NO: 62; the polynucleotide SEQ ID NO: 263 encoding the heavy chain variable sequence of SEQ ID NO: 63; the polynucleotide SEQ ID NO: 264 encoding the heavy chain sequence of SEQ ID NO: 64; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 265; SEQ ID NO: 266; and SEQ ID NO: 267) of the light chain variable sequence of SEQ ID NO: 61 or the light chain sequence of SEQ ID NO: 62; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 268; SEQ ID NO: 269; and SEQ ID NO: 270) of the heavy chain variable sequence of SEQ ID NO: 63 or the heavy chain sequence of SEQ ID NO: 64.

[00660] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab7, the polynucleotides encoding the full length Ab7 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 262 encoding the light chain sequence of SEQ ID NO: 62 and the polynucleotide SEQ ID NO: 264 encoding the heavy chain sequence of SEQ ID NO: 64.

[00661] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

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2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab7 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab7 or Fab fragments thereof may be produced via expression of Ab7 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00662] Antibody Ab8 [00663] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab8 polypeptides having binding specificity to NGF, which inhibits the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab8 polypeptides.

The invention is further optionally directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 71:

[00664] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTGAGGACATTTACAACTTATTGGCCTGG TATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATTCTGCATCCACTCTG GCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTACACTCTC ACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAACAACTAT CTTGTTACTACTTATGGTGTTGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAACGT (SEQ ID NO: 271).

[00665] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 72:

165

2016273912 14 Dec 2016 [00666] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTGAGGACATTTACAACTTATTGGCCTGG TATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATTCTGCATCCACTCTG GCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTACACTCTC ACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAAAACAACTAT CTTGTTACTACTTATGGTGTTGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAACGT

ACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT

GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTA

CAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA

GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAG

CAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGC

TCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 272).

[00667] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 73:

[00668] CAGGTACAGCTGGTGGAGTCTGGTGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCTTCTGGATTCACCTTCAGTAGCTATGCAATGATC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATACATTGATACTGA TACTAGCGCATACTACGCAAGCAGTGTGAAAGGCCGATTCACCATCTCCAGAGACA ATTCCAAGAACACGCTGTACCTGCAAATGTCTAGCCTGAGAGCCGAGGACACGGCT GTGTATTACTGTGCTAGATCTTATGCTGCTTATGGTGGTTATCCTGCTACTTTTGATC CCTGGGGCCAAGGTACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 273).

[00669] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 74:

[00670] CAGGTACAGCTGGTGGAGTCTGGTGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCTTCTGGATTCACCTTCAGTAGCTATGCAATGATC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATACATTGATACTGA TACTAGCGCATACTACGCAAGCAGTGTGAAAGGCCGATTCACCATCTCCAGAGACA

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ATTCCAAGAACACGCTGTACCTGCAAATGTCTAGCCTGAGAGCCGAGGACACGGCT

GTGTATTACTGTGCTAGATCTTATGCTGCTTATGGTGGTTATCCTGCTACTTTTGATC

CCTGGGGCCAAGGTACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGG

TCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCT

GCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCC

CTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCC

CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGC

AACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATC

TTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGAC

CGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCC

CTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTC

AACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGG

AGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT

GGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCC

ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACAC

CCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGG

TCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG

GAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTC

TACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATG

CTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTC

TCCGGGTAAATGA (SEQ ID NO: 274).

[00671] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 275; SEQ ID NO: 276; and SEQ ID NO: 277 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 71 or the light chain sequence of SEQ ID NO: 72.

[00672] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

167

2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 278; SEQ ID NO: 279; and SEQ ID NO: 280 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 73 or the heavy chain sequence of SEQ ID NO: 74.

[00673] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 271 encoding the light chain variable sequence of SEQ ID NO: 71; the polynucleotide SEQ ID NO: 272 encoding the light chain sequence of SEQ ID NO: 72; the polynucleotide SEQ ID NO: 273 encoding the heavy chain variable sequence of SEQ ID NO: 73; the polynucleotide SEQ ID NO: 274 encoding the heavy chain sequence of SEQ ID NO: 74; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 275; SEQ ID NO: 276; and SEQ ID NO: 277) of the light chain variable sequence of SEQ ID NO: 71 or the light chain sequence of SEQ ID NO: 72; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 278; SEQ ID NO: 279; and SEQ ID NO: 280) of the heavy chain variable sequence of SEQ ID NO: 73 or the heavy chain sequence of SEQ ID NO: 74.

[00674] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab8, the polynucleotides encoding the full length Ab8 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 272 encoding the light chain sequence of SEQ ID NO: 72 and the polynucleotide SEQ ID NO: 274 encoding the heavy chain sequence of SEQ ID NO: 74.

[00675] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

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2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab8 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab8 or Fab fragments thereof may be produced via expression of Ab8 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00676] Antibody Ab9 [00677] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab9 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab9 polypeptides.

The invention is further optionally directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 81:

[00678] GCCTATGATATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAACATTGGTAGCTACTTAGCCTG GTATCAGCAGAAACCAGGGCAGCCTCCCGAACTCCTGATCTACAGGGCGTCCACTCT GGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTA TAATAGTGAGAATCTTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAC GT (SEQ ID NO: 281).

[00679] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 82:

169

2016273912 14 Dec 2016 [00680] GCCTATGATATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAACATTGGTAGCTACTTAGCCTG GTATCAGCAGAAACCAGGGCAGCCTCCCGAACTCCTGATCTACAGGGCGTCCACTCT GGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTA TAATAGTGAGAATCTTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAAC

GTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT

CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG

TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA

GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA

AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA

GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 282).

[00681] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 83:

[00682] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTATGTATTCAATGGGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATGGATTAGTTATGGTG GTACTGCATATTACGCGAGCTGGGCGAAGGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGGAGCTGAAGATCACCAGTCCGACAATCGAGGACACGGCCACCTATTT CTGTGCCAGAGAGACTCCTGTTAATTATTATTTGGACATTTGGGGCCAGGGGACCCT CGTCACCGTCTCGAGC (SEQ ID NO: 283).

[00683] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 84:

[00684] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTATGTATTCAATGGGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATGGATTAGTTATGGTG GTACTGCATATTACGCGAGCTGGGCGAAGGGCCGATTCACCATCTCCAAAACCTCG

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ACCACGGTGGAGCTGAAGATCACCAGTCCGACAATCGAGGACACGGCCACCTATTT

CTGTGCCAGAGAGACTCCTGTTAATTATTATTTGGACATTTGGGGCCAGGGGACCCT

CGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTC

CTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACT

TCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC

ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACC

GTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC

AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACAC

ATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCC

CCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT

GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG

TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTA

CCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGT

ACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC

AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGA

GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA

GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC

CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGT

GGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG

CTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ

ID NO: 284).

[00685] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 285; SEQ ID NO: 286; and SEQ ID NO: 287 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 81 or the light chain sequence of SEQ ID NO: 82.

[00686] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

171

2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 288; SEQ ID NO: 289; and SEQ ID NO: 290 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 83 or the heavy chain sequence of SEQ ID NO: 84.

[00687] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 281 encoding the light chain variable sequence of SEQ ID NO: 81; the polynucleotide SEQ ID NO: 282 encoding the light chain sequence of SEQ ID NO: 82; the polynucleotide SEQ ID NO: 283 encoding the heavy chain variable sequence of SEQ ID NO: 83; the polynucleotide SEQ ID NO: 284 encoding the heavy chain sequence of SEQ ID NO: 84; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 285; SEQ ID NO: 286; and SEQ ID NO: 287) of the light chain variable sequence of SEQ ID NO: 81 or the light chain sequence of SEQ ID NO: 82; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 288; SEQ ID NO: 289; and SEQ ID NO: 290) of the heavy chain variable sequence of SEQ ID NO: 83 or the heavy chain sequence of SEQ ID NO: 84.

[00688] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab9, the polynucleotides encoding the full length Ab9 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 282 encoding the light chain sequence of SEQ ID NO: 82 and the polynucleotide SEQ ID NO: 284 encoding the heavy chain sequence of SEQ ID NO: 84.

[00689] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

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2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab9 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab9 or Fab fragments thereof may be produced via expression of Ab9 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00690] Antibody AblO [00691] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody AblO polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody AblO polypeptides. The invention is further optionally directed to polynucleotides encoding antibody polypeptides having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 91:

[00692] GCCTATGATATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACAGAGTCACCATCACTTGCCAGGCCAGTGAGAACATTGGTAGCTACTTAGCCTGGT ATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAGGGCTTCCACTCTGG CATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCA CCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAACAGGGTTACA ATAGTGAGAATCTTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAACGT (SEQ ID NO: 291).

[00693] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 92:

173

2016273912 14 Dec 2016 [00694] GCCTATGATATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAG ACAGAGTCACCATCACTTGCCAGGCCAGTGAGAACATTGGTAGCTACTTAGCCTGGT ATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAGGGCTTCCACTCTGG CATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCA CCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAACAGGGTTACA ATAGTGAGAATCTTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAACGT

ACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCT

GGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTA

CAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGA

GCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAG

CAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGC

TCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 292).

[00695] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 93:

[00696] CAGGTACAGCTGGTGGAGTCTGGTGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCTTCTGGATTCACCTTCAGTATGTATTCAATGGGC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATGGATTAGTTATGG TGGTACTGCATACTACGCTAGCAGCGCTAAGGGCCGATTCACCATCTCCAGAGACA ATTCCAAGAACACGCTGTACCTGCAAATGTCTAGCCTGAGAGCCGAGGACACGGCT GTGTATTACTGTGCTAGAGAGACTCCTGTTAATTACTACTTGGACATTTGGGGCCAA GGTACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 293).

[00697] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 94:

[00698] CAGGTACAGCTGGTGGAGTCTGGTGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCTTCTGGATTCACCTTCAGTATGTATTCAATGGGC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATGGATTAGTTATGG TGGTACTGCATACTACGCTAGCAGCGCTAAGGGCCGATTCACCATCTCCAGAGACA

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2016273912 14 Dec 2016

ATTCCAAGAACACGCTGTACCTGCAAATGTCTAGCCTGAGAGCCGAGGACACGGCT

GTGTATTACTGTGCTAGAGAGACTCCTGTTAATTACTACTTGGACATTTGGGGCCAA

GGTACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTG

GCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA

GGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCG

GCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCG

TGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATC

ACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAA

ACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTC

CTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACA

TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT

GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCC

AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGC

AAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAAC

CATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCAT

CCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC

TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTA

CAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCT

CACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGC

ATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAT

GA (SEQ ID NO: 294).

[00699] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 295; SEQ ID NO: 296; and SEQ ID NO: 297 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 91 or the light chain sequence of SEQ ID NO: 92.

[00700] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

175

2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 298; SEQ ID NO: 299; and SEQ ID NO: 300 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 93 or the heavy chain sequence of SEQ ID NO: 94.

[00701] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 291 encoding the light chain variable sequence of SEQ ID NO: 91; the polynucleotide SEQ ID NO: 292 encoding the light chain sequence of SEQ ID NO: 92; the polynucleotide SEQ ID NO: 293 encoding the heavy chain variable sequence of SEQ ID NO: 93; the polynucleotide SEQ ID NO: 294 encoding the heavy chain sequence of SEQ ID NO: 94; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 295; SEQ ID NO: 296; and SEQ ID NO: 297) of the light chain variable sequence of SEQ ID NO: 91 or the light chain sequence of SEQ ID NO: 92; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 298; SEQ ID NO: 299; and SEQ ID NO: 300) of the heavy chain variable sequence of SEQ ID NO: 93 or the heavy chain sequence of SEQ ID NO: 94.

[00702] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 10, the polynucleotides encoding the full length Ab 10 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 292 encoding the light chain sequence of SEQ ID NO: 92 and the polynucleotide SEQ ID NO: 294 encoding the heavy chain sequence of SEQ ID NO: 94.

[00703] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

176

2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab 10 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 10 or Fab fragments thereof may be produced via expression of Ab 10 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00704] Antibody Abl 1 [00705] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Abl 1 polypeptides having binding specificity to NGF, which inhibits the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Abl 1 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 101:

[00706] GCATTCGAATTGACCCAGACTCCATCCTCCGTGGAGGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAACATTGTTACCAATTTAGCCTGG TATCAACAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTG GCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTC ACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTATTTCTGTCAGAGCTATGAT GGTTTTAATAGTGCTGGGTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGT (SEQ ID NO: 301).

[00707] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 102:

177

2016273912 14 Dec 2016 [00708] GCATTCGAATTGACCCAGACTCCATCCTCCGTGGAGGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAACATTGTTACCAATTTAGCCTGG TATCAACAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTG GCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTC ACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTATTTCTGTCAGAGCTATGAT GGTTTTAATAGTGCTGGGTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGT AGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAAC TGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTG GAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGG ACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCC CGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 302).

[00709] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 103:

[00710] CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTGGCTACGACATGAGCTG GGTCCGCCAGGCTCCAGGAAAGGGGCTGGAATACATCGGACTCATTAGTTATGATG GTAACACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTT CTGTGCCAGAAGTCTTTATGCTGGTCCTAATGCTGGTATCGGACCGTTTAACATCTG GGGCCAGGGGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 303).

[00711] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 104:

[00712] CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTGGCTACGACATGAGCTG GGTCCGCCAGGCTCCAGGAAAGGGGCTGGAATACATCGGACTCATTAGTTATGATG GTAACACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCG

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ACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTT

CTGTGCCAGAAGTCTTTATGCTGGTCCTAATGCTGGTATCGGACCGTTTAACATCTG

GGGCCAGGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTT

CCCCCTGGCAcCCTCCTCCaAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCT

GGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGA

CCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCA

GCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAAC

GTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTG

TGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGT

CAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTG

AGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAAC

TGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC

AGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC

TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC

GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCT

GCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCA

AAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG

AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC

AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTC

CGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCC

GGGTAAATGA (SEQ ID NO: 304).

[00713] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 305; SEQ ID NO: 306; and SEQ ID NO: 307 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 101 or the light chain sequence of SEQ ID NO: 102.

[00714] In a further optional embodiment of the invention, polynucleotides encoding for treatment or prevention of pain and pain associated conditions fragments having binding

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2016273912 14 Dec 2016 specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 308; SEQ ID NO: 309; and SEQ ID NO: 310 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 103 or the heavy chain sequence of SEQ ID NO: 104.

[00715] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 301 encoding the light chain variable sequence of SEQ ID NO: 101; the polynucleotide SEQ ID NO: 302 encoding the light chain sequence of SEQ ID NO: 102; the polynucleotide SEQ ID NO: 303 encoding the heavy chain variable sequence of SEQ ID NO: 103; the polynucleotide SEQ ID NO: 304 encoding the heavy chain sequence of SEQ ID NO: 104; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 305; SEQ ID NO: 306; and SEQ ID NO: 307) of the light chain variable sequence of SEQ ID NO: 101 or the light chain sequence of SEQ ID NO: 102; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 308; SEQ ID NO: 309; and SEQ ID NO: 310) of the heavy chain variable sequence of SEQ ID NO: 103 or the heavy chain sequence of SEQ ID NO: 104.

[00716] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl 1, the polynucleotides encoding the full length Abl 1 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 302 encoding the light chain sequence of SEQ ID NO: 102 and the polynucleotide SEQ ID NO: 304 encoding the heavy chain sequence of SEQ ID NO: 104.

[00717] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

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2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Abl 1 following expression of the full-length polynucleotides in a suitable host. In another optional embodiment of the invention, anti-NGF antibodies such as Abl 1 or Fab fragments thereof may be produced via expression of Abl 1 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00718] Antibody Ab 12 [00719] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab 12 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab 12 polypeptides. The invention is further optionally directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 111:

[00720] GCATTCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAACATTGTTACCAACTTAGCCTGG TATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATGGTGCATCCACTCTG GCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAGAGCTATGAT GGTTTCAATAGTGCTGGTTTCGGCGGAGGAACCAAGGTGGAAATCAAACGT (SEQ ID NO: 311).

[00721] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 112:

181

2016273912 14 Dec 2016 [00722] GCATTCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAACATTGTTACCAACTTAGCCTGG TATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATGGTGCATCCACTCTG GCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTC ACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTCAGAGCTATGAT GGTTTCAATAGTGCTGGTTTCGGCGGAGGAACCAAGGTGGAAATCAAACGTACGGT AGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAAC TGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTG GAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGG ACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGAC TACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCC CGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 312).

[00723] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 113:

[00724] CAGGTACAGCTGGTGGAGTCTGGTGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCTTCTGGATTCTCCCTCAGTGGCTACGACATGAG CTGGGTCCGTCAGGCTCCAGGCAAGGGACTGGAGTGGGTGGGACTCATTAGTTATG ATGGTAACACATACTACGCGACCTCCGCGAAAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACGCTGTACCTGCAAATGTCTAGCCTGAGAGCCGAGGACACGGC TGTGTATTACTGTGCTAGAAGTCTTTATGCTGGTCCTAATGCTGGTATCGGACCGTTT AACATCTGGGGCCAAGGTACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 313).

[00725] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 114:

[00726] CAGGTACAGCTGGTGGAGTCTGGTGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCTTCTGGATTCTCCCTCAGTGGCTACGACATGAG CTGGGTCCGTCAGGCTCCAGGCAAGGGACTGGAGTGGGTGGGACTCATTAGTTATG ATGGTAACACATACTACGCGACCTCCGCGAAAGGCCGATTCACCATCTCCAGAGAC

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AATTCCAAGAACACGCTGTACCTGCAAATGTCTAGCCTGAGAGCCGAGGACACGGC

TGTGTATTACTGTGCTAGAAGTCTTTATGCTGGTCCTAATGCTGGTATCGGACCGTTT

AACATCTGGGGCCAAGGTACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCC

ATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCT

GGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAG

GCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCT

ACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA

TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCC

AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGG

GGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGG

ACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAA

GTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGG

AGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG

GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGC

CCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGT

ACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGC

CTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCA

GCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTT

CCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCT

CATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCC

TGTCTCCGGGTAAATGA (SEQ ID NO: 314).

[00727] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 315; SEQ ID NO: 316; and SEQ ID NO: 317 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 111 or the light chain sequence of SEQ ID NO: 112.

[00728] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

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2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 318; SEQ ID NO: 319; and SEQ ID NO: 320 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 113 or the heavy chain sequence of SEQ ID NO: 114.

[00729] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 311 encoding the light chain variable sequence of SEQ ID NO: 111; the polynucleotide SEQ ID NO: 312 encoding the light chain sequence of SEQ ID NO: 112; the polynucleotide SEQ ID NO: 313 encoding the heavy chain variable sequence of SEQ ID NO: 113; the polynucleotide SEQ ID NO: 314 encoding the heavy chain sequence of SEQ ID NO: 114; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 315; SEQ ID NO: 316; and SEQ ID NO: 317) of the light chain variable sequence of SEQ ID NO: 111 or the light chain sequence of SEQ ID NO: 112; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 318; SEQ ID NO: 319; and SEQ ID NO: 320) of the heavy chain variable sequence of SEQ ID NO: 113 or the heavy chain sequence of SEQ ID NO: 114.

[00730] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl2, the polynucleotides encoding the full length Ab 12 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 312 encoding the light chain sequence of SEQ ID NO: 112 and the polynucleotide SEQ ID NO: 314 encoding the heavy chain sequence of SEQ ID NO: 114.

[00731] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

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2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Abl2 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 12 or Fab fragments thereof may be produced via expression of Ab 12 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00732] Antibody Abl3 [00733] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab 13 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab 13 polypeptides. The invention is further optionally directed to polynucleotides encoding antibody polypeptides having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 121:

[00734] GCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGA GGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCC ACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCGGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCGACGTGCAGTGTGACGCTGCTGCCACTTACTACTGTGCAGGC GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGT (SEQ ID NO: 321).

[00735] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 122:

185

2016273912 14 Dec 2016 [00736] GCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGA GGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA

TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCC

ACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCGGTGGATCTGGGACAGATTTC

ACTCTCACCATCAGCGACGTGCAGTGTGACGCTGCTGCCACTTACTACTGTGCAGGC

GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA

ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA

ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA

AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA

CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC

AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT

GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTA (SEQ ID NO: 322).

[00737] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 123:

[00738] CAGTCGGTGGAGGCGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTACCTACTGGATGAGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGACATTTATTTTAGTA ATGAAGAAACAAACTACGCGAGCTGGGCGAAAGGCCGATTTACCATCTCCAAAACC

TCGACCACGGTGGATCTGAATGTCATCAGTCCGACAACCGAGGACACGGCCACCTA TTTCTGTGCCAGAGGTTCTCCTGATGTTGATATTGGTATAGATATGTGGGGCCCGGG CACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 323).

[00739] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 124:

[00740] CAGTCGGTGGAGGCGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTACCTACTGGATGAGCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGACATTTATTTTAGTA ATGAAGAAACAAACTACGCGAGCTGGGCGAAAGGCCGATTTACCATCTCCAAAACC

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2016273912 14 Dec 2016

TCGACCACGGTGGATCTGAATGTCATCAGTCCGACAACCGAGGACACGGCCACCTA

TTTCTGTGCCAGAGGTTCTCCTGATGTTGATATTGGTATAGATATGTGGGGCCCGGG

CACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGC

ACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGG

ACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGC

GTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG

GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCAC

AAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAAC

TCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCT

CTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATG

CGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGG

ACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAG

CACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAA

GGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCA

TCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCC

CGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA

TCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACA

AGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCA

CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCAT

GAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATG

A (SEQ ID NO: 324).

[00741] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 325; SEQ ID NO: 326; and SEQ ID NO: 327 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 121 or the light chain sequence of SEQ ID NO: 122.

[00742] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

187

2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 328; SEQ ID NO: 329; and SEQ ID NO: 330 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 123 or the heavy chain sequence of SEQ ID NO: 124.

[00743] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 321 encoding the light chain variable sequence of SEQ ID NO: 121; the polynucleotide SEQ ID NO: 322 encoding the light chain sequence of SEQ ID NO: 122; the polynucleotide SEQ ID NO: 323 encoding the heavy chain variable sequence of SEQ ID NO: 123; the polynucleotide SEQ ID NO: 324 encoding the heavy chain sequence of SEQ ID NO: 124; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 325; SEQ ID NO: 326; and SEQ ID NO: 327) of the light chain variable sequence of SEQ ID NO: 121 or the light chain sequence of SEQ ID NO: 122; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 328; SEQ ID NO: 329; and SEQ ID NO: 330) of the heavy chain variable sequence of SEQ ID NO: 123 or the heavy chain sequence of SEQ ID NO: 124.

[00744] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl3, the polynucleotides encoding the full length Ab 13 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 322 encoding the light chain sequence of SEQ ID NO: 122 and the polynucleotide SEQ ID NO: 324 encoding the heavy chain sequence of SEQ ID NO: 124.

[00745] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

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2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab 13 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 13 or Fab fragments thereof may be produced via expression of Ab 13 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00746] Antibody Ab 14 [00747] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab 14 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab 14 polypeptides. The invention is further optionally directed to polynucleotides encoding antibody polypeptides having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 131:

[00748] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAAGGCATCC ACTCTGGCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGC GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAA ACGT (SEQIDNO: 331).

[00749] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 132:

189

2016273912 14 Dec 2016 [00750] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAAGGCATCC ACTCTGGCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGC GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAA

ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA

ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA

AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA

CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC

AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT

GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 332).

[00751] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 133:

[00752] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTACCTACTGGATGAG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAGACATTTACTTTA GTAATGAAGAAACAAACTACGCGAGCAGCGCGAAAGGCCGATTCACCATCTCCAGA GACAATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACAC TGCTGTGTATTACTGTGCTAGAGGTTCTCCTGATGTTGATATTGGTATAGATATGTGG GGCCCAGGGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 333).

[00753] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 134:

[00754] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTACCTACTGGATGAG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAGACATTTACTTTA GTAATGAAGAAACAAACTACGCGAGCAGCGCGAAAGGCCGATTCACCATCTCCAGA

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2016273912 14 Dec 2016

GACAATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACAC

TGCTGTGTATTACTGTGCTAGAGGTTCTCCTGATGTTGATATTGGTATAGATATGTGG

GGCCCAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTC

CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTG

GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC

CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG

CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT

GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG

ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA

GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG

GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG

GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAG

TACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTG

AATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGA

GAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC

CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA

GGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA

CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG

CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCG

TGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG

GTAAATGA (SEQ ID NO: 334).

[00755] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 335; SEQ ID NO: 336; and SEQ ID NO: 337 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 131 or the light chain sequence of SEQ ID NO: 132.

[00756] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

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2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 338; SEQ ID NO: 339; and SEQ ID NO: 340 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 133 or the heavy chain sequence of SEQ ID NO: 134.

[00757] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 331 encoding the light chain variable sequence of SEQ ID NO: 131; the polynucleotide SEQ ID NO: 332 encoding the light chain sequence of SEQ ID NO: 132; the polynucleotide SEQ ID NO: 333 encoding the heavy chain variable sequence of SEQ ID NO: 133; the polynucleotide SEQ ID NO: 334 encoding the heavy chain sequence of SEQ ID NO: 134; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 335; SEQ ID NO: 336; and SEQ ID NO: 337) of the light chain variable sequence of SEQ ID NO: 131 or the light chain sequence of SEQ ID NO: 132; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 338; SEQ ID NO: 339; and SEQ ID NO: 340) of the heavy chain variable sequence of SEQ ID NO: 133 or the heavy chain sequence of SEQ ID NO: 134.

[00758] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl4, the polynucleotides encoding the full length Ab 14 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 332 encoding the light chain sequence of SEQ ID NO: 132 and the polynucleotide SEQ ID NO: 334 encoding the heavy chain sequence of SEQ ID NO: 134.

[00759] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such

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2016273912 14 Dec 2016 as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Abl4 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 14 or Fab fragments thereof may be produced via expression of Ab 14 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00760] Antibody Abl5 [00761] The invention is further directed to the use of polynucleotides set forth below to produce antibody Ab 15 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab 15 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 141:

[00762] GCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCAGCTGTGGGA GACACAGTCACCATCAAGTGCCAGTCCAGTCAGAGTGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATGCATCC AATCTGCCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTC ACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGC GATTATGATGATGATACTGATAATGGTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGT (SEQ ID NO: 341).

[00763] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 142:

193

2016273912 14 Dec 2016 [00764] GCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCAGCTGTGGGA GACACAGTCACCATCAAGTGCCAGTCCAGTCAGAGTGTTTATAAGAACAACTACTTA

TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATGCATCC

AATCTGCCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTC

ACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGC

GATTATGATGATGATACTGATAATGGTTTCGGCGGAGGGACCGAGGTGGTGGTCAA

ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA

ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA

AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA

CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC

AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT

GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 342).

[00765] In another embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 143:

[00766] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCTATGCAATGATCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATCATTTGGAGTGGTG GCACCTACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACC ACGGTGGATCTGCAAATCACCAGTCCGACAACCGAGGACGCGGCCACCTATTTCTGT GCCGCAGGTGGTGGTAGTATTTATGATGTTTGGGGCCCGGGCACCCTGGTCACCGTC TCGAGC (SEQ ID NO: 343).

[00767] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 144:

[00768] CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCTATGCAATGATCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATCATTTGGAGTGGTG GCACCTACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACC

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ACGGTGGATCTGCAAATCACCAGTCCGACAACCGAGGACGCGGCCACCTATTTCTGT

GCCGCAGGTGGTGGTAGTATTTATGATGTTTGGGGCCCGGGCACCCTGGTCACCGTC

TCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC

ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACC

GGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGG

CTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCA

GCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACC

AAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACC

GTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACC

CAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT

GAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGC

ATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTC

AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAA

GGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAG

GGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACC

AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCC

GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT

GCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAG

GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA

CTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 344).

[00769] In a further embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 345; SEQ ID NO: 346; and SEQ ID NO: 347 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 141 or the light chain sequence of SEQ ID NO: 142.

[00770] In a further embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide

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2016273912 14 Dec 2016 sequences of SEQ ID NO: 348; SEQ ID NO: 349; and SEQ ID NO: 350 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 143 or the heavy chain sequence of SEQ ID NO: 144.

[00771] The invention also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 341 encoding the light chain variable sequence of SEQ ID NO: 141; the polynucleotide SEQ ID NO: 342 encoding the light chain sequence of SEQ ID NO: 142; the polynucleotide SEQ ID NO: 343 encoding the heavy chain variable sequence of SEQ ID NO: 143; the polynucleotide SEQ ID NO: 344 encoding the heavy chain sequence of SEQ ID NO: 144; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 345; SEQ ID NO: 346; and SEQ ID NO: 347) of the light chain variable sequence of SEQ ID NO: 141 or the light chain sequence of SEQ ID NO: 142; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 348; SEQ ID NO: 349; and SEQ ID NO: 350) of the heavy chain variable sequence of SEQ ID NO: 143 or the heavy chain sequence of SEQ ID NO: 144.

[00772] In a preferred embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Abl5, the polynucleotides encoding the full length Ab 15 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 342 encoding the light chain sequence of SEQ ID NO: 142 and the polynucleotide SEQ ID NO: 344 encoding the heavy chain sequence of SEQ ID NO: 144.

[00773] Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast

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Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab 15 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 15 or Fab fragments thereof may be produced via expression of Ab 15 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00774] Antibody Abl6 [00775] The invention is further directed to the use of polynucleotides set forth below to produce antibody Ab 16 polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF, which inhibit the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab 16 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 151:

[00776] GCCCTGGTGATGACCCAGACTCCATCCTCCACGTCTGAACCAGTGGGA GGCACAGTCACCATCAATTGCCAGGCTAGTCAGAATATTGGTAACGACCTATCCTGG TATCAGCAGAAACCAGGGCAGCCTCCCGAGCTCCTAATCTATTCTACATCCAAACTG GCAACTGGGGTCCCAAAGCGGTTCAGTGGCAGCAGATCTGGGACACAGTTCACTCT CACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCTAGGTGTTTA TAGTTATATTAGTGATGATGGTAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGT (SEQ ID NO: 351).

[00777] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 152:

197

2016273912 14 Dec 2016 [00778] GCCCTGGTGATGACCCAGACTCCATCCTCCACGTCTGAACCAGTGGGA GGCACAGTCACCATCAATTGCCAGGCTAGTCAGAATATTGGTAACGACCTATCCTGG TATCAGCAGAAACCAGGGCAGCCTCCCGAGCTCCTAATCTATTCTACATCCAAACTG GCAACTGGGGTCCCAAAGCGGTTCAGTGGCAGCAGATCTGGGACACAGTTCACTCT CACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCTAGGTGTTTA TAGTTATATTAGTGATGATGGTAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA

ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA

ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA

AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA

CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC

AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT

GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 352).

[00779] In another embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 153:

[00780] CAGTCGGTGGAGGAGTTCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACCGTCTCTGGATTCTCCCTCAATAACTATGCAATGACCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGGATCATTGGTAGTATTG GTACCACATACTACGCGAGCTGGGCGAAAGGCCGATTCTTCATCTCCAAAACCTCGA CCACTGTGGATCTGAAAATCATTAGTCCGACAACCGAGGACACGGCCACCTATTTCT GTGCCAGAGATGCTGGCGTTACTGTTGATGGTTATGGCTACTACTTTAACATCTGGG GCCCAGGCACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 353).

[00781] In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 154:

[00782] CAGTCGGTGGAGGAGTTCGGGGGTCGCCTGGTCACGCCTGGGACACC CCTGACACTCACCTGCACCGTCTCTGGATTCTCCCTCAATAACTATGCAATGACCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGGATCATTGGTAGTATTG GTACCACATACTACGCGAGCTGGGCGAAAGGCCGATTCTTCATCTCCAAAACCTCGA

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2016273912 14 Dec 2016

CCACTGTGGATCTGAAAATCATTAGTCCGACAACCGAGGACACGGCCACCTATTTCT

GTGCCAGAGATGCTGGCGTTACTGTTGATGGTTATGGCTACTACTTTAACATCTGGG

GCCCAGGCACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCC

CCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGG

TCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACC

AGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGC

AGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTG

AATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGA

CAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAG

TCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGG

TCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGG

TACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGT

ACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA

ATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG

AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC

CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAG

GCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC

AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC

AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT

GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGG

TAAATGA (SEQ ID NO: 354).

[00783] In a further embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 355; SEQ ID NO: 356; and SEQ ID NO: 357 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 151 or the light chain sequence of SEQ ID NO: 152.

[00784] In a further embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding

199

2016273912 14 Dec 2016 specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 358; SEQ ID NO: 359; and SEQ ID NO: 360 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 153 or the heavy chain sequence of SEQ ID NO: 154.

[00785] The invention also contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 351 encoding the light chain variable sequence of SEQ ID NO: 151; the polynucleotide SEQ ID NO: 352 encoding the light chain sequence of SEQ ID NO: 152; the polynucleotide SEQ ID NO: 353 encoding the heavy chain variable sequence of SEQ ID NO: 153; the polynucleotide SEQ ID NO: 354 encoding the heavy chain sequence of SEQ ID NO: 154; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 355; SEQ ID NO: 356; and SEQ ID NO: 357) of the light chain variable sequence of SEQ ID NO: 151 or the light chain sequence of SEQ ID NO: 152; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 358; SEQ ID NO: 359; and SEQ ID NO: 360) of the heavy chain variable sequence of SEQ ID NO: 153 or the heavy chain sequence of SEQ ID NO: 154.

[00786] In a preferred embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 16, the polynucleotides encoding the full length Ab 16 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 352 encoding the light chain sequence of SEQ ID NO: 152 and the polynucleotide SEQ ID NO: 354 encoding the heavy chain sequence of SEQ ID NO: 154.

[00787] Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO,

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2016273912 14 Dec 2016

HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab 16 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 16 or Fab fragments thereof may be produced via expression of Ab 16 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00788] Antibody Ab 17 [00789] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab 17 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA without appreciably inhibiting the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab 17 polypeptides. The invention is further optionally directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 161:

[00790] GCCATCGAAATGACCCAGACTCCATTCTCCGTGTCTGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTCAGACCATTAGCAACTACTTAGCCTG GTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATCT GGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTTA TACTATCAGTAATGTTGATAACAATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGT (SEQ ID NO: 361).

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2016273912 14 Dec 2016 [00791] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 162:

[00792] GCCATCGAAATGACCCAGACTCCATTCTCCGTGTCTGCAGCTGTGGGA GGCACAGTCACCATCAAGTGCCAGGCCAGTCAGACCATTAGCAACTACTTAGCCTG GTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATCT GGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCT CACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTTA TACTATCAGTAATGTTGATAACAATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 362).

[00793] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 163:

[00794] CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGGGATC CCTGACACTCACCTGCGCAGCCTCTGGATTCTCCCTCACTGGCTACAACTTGGTCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGATTCATTAGTTATGGTG ATACCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGACTCTGACGATCACCGATCTGCAACCTTCAGACACGGGCACCTATTTC TGTGCCAGAGAGACTGCTAATACTTATGATTATGGCATCTGGGGCCCAGGCACCCTC GTCACCGTCTCGAGC (SEQ ID NO: 363).

[00795] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 164:

202

2016273912 14 Dec 2016 [00796] CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGGGATC CCTGACACTCACCTGCGCAGCCTCTGGATTCTCCCTCACTGGCTACAACTTGGTCTG GGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGATTCATTAGTTATGGTG ATACCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCG ACCACGGTGACTCTGACGATCACCGATCTGCAACCTTCAGACACGGGCACCTATTTC TGTGCCAGAGAGACTGCTAATACTTATGATTATGGCATCTGGGGCCCAGGCACCCTC GTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCC TCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTT CCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACA CCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCG TGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCA GCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACA TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGT GGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCG TGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTA CCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGT ACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCC AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGA GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGT GGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGG CTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 364).

[00797] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 365; SEQ ID NO: 366; and SEQ ID NO: 367 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or

203

2016273912 14 Dec 2016 hypervariable regions) of the light chain variable sequence of SEQ ID NO: 161 or the light chain sequence of SEQ ID NO: 162.

[00798] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 368; SEQ ID NO: 369; and SEQ ID NO: 370 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 163 or the heavy chain sequence of SEQ ID NO: 164.

[00799] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 361 encoding the light chain variable sequence of SEQ ID NO: 161; the polynucleotide SEQ ID NO: 362 encoding the light chain sequence of SEQ ID NO: 162; the polynucleotide SEQ ID NO: 363 encoding the heavy chain variable sequence of SEQ ID NO: 163; the polynucleotide SEQ ID NO: 364 encoding the heavy chain sequence of SEQ ID NO: 164; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 365; SEQ ID NO: 366; and SEQ ID NO: 367) of the light chain variable sequence of SEQ ID NO: 161 or the light chain sequence of SEQ ID NO: 162; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 368; SEQ ID NO: 369; and SEQ ID NO: 370) of the heavy chain variable sequence of SEQ ID NO: 163 or the heavy chain sequence of SEQ ID NO: 164.

[00800] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 17, the polynucleotides encoding the full length Ab 17 antibody comprise, or alternatively consist of, the

204

2016273912 14 Dec 2016 polynucleotide SEQ ID NO: 362 encoding the light chain sequence of SEQ ID NO: 162 and the polynucleotide SEQ ID NO: 364 encoding the heavy chain sequence of SEQ ID NO: 164.

[00801] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris.

In one optional embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab 17 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 17 or Fab fragments thereof may be produced via expression of Ab 17 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00802] Antibody Ab 18 [00803] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab 18 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab 18 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 171:

[00804] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGTCAGGCTAGTCAGACCATTAGCAACTACTTAGCCTGG TATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAATCTG GAATCTGGAGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGAACAGAATTCACTCTC ACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGTCAACAGGGTTAT

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2016273912 14 Dec 2016

ACTATCAGTAATGTTGATAACAATGTTTTCGGCGGAGGAACCAAGGTGGAAATCAA ACGT (SEQ ID NO: 371).

[00805] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 172:

[00806] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGTCAGGCTAGTCAGACCATTAGCAACTACTTAGCCTGG TATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAATCTG GAATCTGGAGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGAACAGAATTCACTCTC ACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGTCAACAGGGTTAT ACTATCAGTAATGTTGATAACAATGTTTTCGGCGGAGGAACCAAGGTGGAAATCAA ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 372).

[00807] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 173:

[00808] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTGGCTACAACTTGGT CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGATTCATTAGTTATG GTGATACCACATACTACGCTAGCTCTGCTAAAGGCCGATTCACCATCTCCAGAGACA ATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCTG TGTATTACTGTGCTAGAGAGACTGCTAATACTTATGATTATGGCATCTGGGGCCAAG GGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 373).

206

2016273912 14 Dec 2016 [00809] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 174:

[00810] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTGGCTACAACTTGGT CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGATTCATTAGTTATG GTGATACCACATACTACGCTAGCTCTGCTAAAGGCCGATTCACCATCTCCAGAGACA ATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCTG TGTATTACTGTGCTAGAGAGACTGCTAATACTTATGATTATGGCATCTGGGGCCAAG GGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGG CACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAG GACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGG CGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGT GGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCA CAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAA CTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC TCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACAT GCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTG GACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCA GCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCA AGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACC ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATC CCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCT ATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTC ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCA TGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATG A (SEQ ID NO: 374).

[00811] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having

207

2016273912 14 Dec 2016 binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 375; SEQ ID NO: 376; and SEQ ID NO: 377 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 171 or the light chain sequence of SEQ ID NO: 172.

[00812] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 378; SEQ ID NO: 379; and SEQ ID NO: 380 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 173 or the heavy chain sequence of SEQ ID NO: 174.

[00813] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 371 encoding the light chain variable sequence of SEQ ID NO: 171; the polynucleotide SEQ ID NO: 372 encoding the light chain sequence of SEQ ID NO: 172; the polynucleotide SEQ ID NO: 373 encoding the heavy chain variable sequence of SEQ ID NO: 173; the polynucleotide SEQ ID NO: 374 encoding the heavy chain sequence of SEQ ID NO: 174; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 375; SEQ ID NO: 376; and SEQ ID NO: 377) of the light chain variable sequence of SEQ ID NO: 171 or the light chain sequence of SEQ ID NO: 172; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 378; SEQ ID NO: 379; and SEQ ID NO: 380) of the heavy chain variable sequence of SEQ ID NO: 173 or the heavy chain sequence of SEQ ID NO: 174.

208

2016273912 14 Dec 2016 [00814] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments for treatment or prevention of pain and pain associated conditions having binding specificity for NGF. With respect to antibody Ab 18, the polynucleotides encoding the full length Ab 18 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 372 encoding the light chain sequence of SEQ ID NO: 172 and the polynucleotide SEQ ID NO: 374 encoding the heavy chain sequence of SEQ ID NO: 174.

[00815] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab 18 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 18 or Fab fragments thereof may be produced via expression of Ab 18 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00816] Antibody Ab 19 [00817] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab 19 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75. in methods of treating pain in an individual comprising administering to said individual antibody Ab 19 polypeptides. The invention is further optionally directed to polynucleotides encoding antibody polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 181:

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2016273912 14 Dec 2016 [00818] GCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGA GGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTATTTA

TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCTTCC ACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCGACGTGCAGTGTGACGCTGCTGCCACTTACTACTGTGCAGGC GGTTATAGTAGTAGTAGTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGT (SEQ ID NO: 381).

[00819] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 182:

[00820] GCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGA GGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTATTTA TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCTTCC ACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCGACGTGCAGTGTGACGCTGCTGCCACTTACTACTGTGCAGGC GGTTATAGTAGTAGTAGTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAA ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 382).

[00821] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 183:

[00822] CAGTCGGTGGAGGCGTCCGGGGGTCGTCTGGTCATGCCTGGAGGATCC CTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTACCTACTGGATGTCCTGG GTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGACATTTATTTTAGTAA TGAGGAAACAAACTACGCGACCTGGGCGAAAGGCCGATTTACCATCTCCAAAACCT

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2016273912 14 Dec 2016

CGACCACGGTGGATCTGAATGTCATCAGTCCGACAACCGAGGACACGGCCACCTAT TTCTGTGCAAGAGGTTCTCCTGATGTTGAGATTGCTATAGATATGTGGGGCCAGGGC ACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 383).

[00823] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 184:

[00824] CAGTCGGTGGAGGCGTCCGGGGGTCGTCTGGTCATGCCTGGAGGATCC CTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTACCTACTGGATGTCCTGG GTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGACATTTATTTTAGTAA TGAGGAAACAAACTACGCGACCTGGGCGAAAGGCCGATTTACCATCTCCAAAACCT CGACCACGGTGGATCTGAATGTCATCAGTCCGACAACCGAGGACACGGCCACCTAT TTCTGTGCAAGAGGTTCTCCTGATGTTGAGATTGCTATAGATATGTGGGGCCAGGGC ACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCA CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGA CTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGT GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACA AGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTC TTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGA CGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGC ACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCAT CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCC GGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACA AGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCA CCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCAT

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2016273912 14 Dec 2016

GAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATG A (SEQ ID NO: 384).

[00825] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 385; SEQ ID NO: 386; and SEQ ID NO: 387 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 181 or the light chain sequence of SEQ ID NO: 182.

[00826] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 388; SEQ ID NO: 389; and SEQ ID NO: 390 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 183 or the heavy chain sequence of SEQ ID NO: 184.

[00827] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 381 encoding the light chain variable sequence of SEQ ID NO: 181; the polynucleotide SEQ ID NO: 382 encoding the light chain sequence of SEQ ID NO: 182; the polynucleotide SEQ ID NO: 383 encoding the heavy chain variable sequence of SEQ ID NO: 183; the polynucleotide SEQ ID NO: 384 encoding the heavy chain sequence of SEQ ID NO: 184; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 385; SEQ ID NO: 386; and SEQ ID NO: 387) of the light chain variable sequence of SEQ ID NO: 181 or the light chain sequence of SEQ ID NO: 182; and

212

2016273912 14 Dec 2016 polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 388; SEQ ID NO: 389; and SEQ ID NO: 390) of the heavy chain variable sequence of SEQ ID NO: 183 or the heavy chain sequence of SEQ ID NO: 184.

[00828] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab 19, the polynucleotides encoding the full length Ab 19 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 382 encoding the light chain sequence of SEQ ID NO: 182 and the polynucleotide SEQ ID NO: 384 encoding the heavy chain sequence of SEQ ID NO: 184.

[00829] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one optional embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab 19 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab 19 or Fab fragments thereof may be produced via expression of Ab 19 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00830] Antibody Ab20 [00831] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab20 polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF, which inhibits the association of NGF with TrkA and the association of NGF with p75, in methods of treating pain in an individual comprising administering to said individual antibody Ab20 polypeptides. The invention is further directed to polynucleotides encoding antibody polypeptides having binding specificity to NGF. In one optional embodiment of the invention, polynucleotides of the invention comprise,

213

2016273912 14 Dec 2016 or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 191:

[00832] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAAGGCATCC ACTCTGGCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGC GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAA ACGT (SEQ ID NO: 391).

[00833] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 192:

[00834] GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGTCCAGTCAGAATGTTTATAAGAACAACTACTTA TCCTGGTATCAGCAGAAACCAGGGAAAGTCCCTAAGCTCCTGATCTATAAGGCATCC ACTCTGGCATCTGGGGTCCCATCTCGTTTCAGTGGCAGTGGATCTGGGACAGATTTC ACTCTCACCATCAGCAGCCTGCAGCCTGAAGATGTTGCAACTTATTACTGTGCAGGC GGTTATACCAGTAGTAGTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAA ACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAA ATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAA AGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCA CAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGC AAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCT GAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 392).

[00835] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 193:

214

2016273912 14 Dec 2016 [00836] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTACCTACTGGATGAG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAGACATTTACTTTA GTAATGAAGAAACAAACTACGCGACCAGCGCGAAAGGCCGATTCACCATCTCCAGA GACAATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACAC TGCTGTGTATTACTGTGCTAGAGGTTCTCCTGATGTTGAGATTGCTATAGATATGTGG GGCCAAGGGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 393).

[00837] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 194:

[00838] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTACCTACTGGATGAG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAGACATTTACTTTA GTAATGAAGAAACAAACTACGCGACCAGCGCGAAAGGCCGATTCACCATCTCCAGA GACAATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACAC TGCTGTGTATTACTGTGCTAGAGGTTCTCCTGATGTTGAGATTGCTATAGATATGTGG GGCCAAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTC CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTG GTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGAC CAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAG CAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGT GAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTG ACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAG GTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTG GTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAG TACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTG AATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGA GAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGC CCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA

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2016273912 14 Dec 2016

GGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAA CAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAG CAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCG TGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAATGA (SEQ ID NO: 394).

[00839] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 395; SEQ ID NO: 396; and SEQ ID NO: 397 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 191 or the light chain sequence of SEQ ID NO: 192.

[00840] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 398; SEQ ID NO: 399; and SEQ ID NO: 400 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 193 or the heavy chain sequence of SEQ ID NO: 194.

[00841] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 391 encoding the light chain variable sequence of SEQ ID NO: 191; the polynucleotide SEQ ID NO: 392 encoding the light chain sequence of SEQ ID NO: 192; the polynucleotide SEQ ID NO: 393 encoding the heavy chain variable sequence of SEQ ID NO: 193; the polynucleotide SEQ ID NO: 394 encoding the heavy chain

216

2016273912 14 Dec 2016 sequence of SEQ ID NO: 194; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 395; SEQ ID NO: 396; and SEQ ID NO: 397) of the light chain variable sequence of SEQ ID NO: 191 or the light chain sequence of SEQ ID NO: 192; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 398; SEQ ID NO: 399; and SEQ ID NO: 400) of the heavy chain variable sequence of SEQ ID NO: 193 or the heavy chain sequence of SEQ ID NO: 194.

[00842] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab20, the polynucleotides encoding the full length Ab20 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 392 encoding the light chain sequence of SEQ ID NO: 192 and the polynucleotide SEQ ID NO: 394 encoding the heavy chain sequence of SEQ ID NO: 194.

[00843] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab20 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab20 or Fab fragments thereof may be produced via expression of Ab20 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00844] Antibody Ab21 [00845] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody Ab21 polypeptides having binding specificity to NGF, which inhibit the association of NGF with TrkA and the association of NGF with p75 in methods of treating pain in an individual comprising administering to said individual antibody Ab21 polypeptides. The invention is further optionally directed to polynucleotides encoding antibody polypeptides

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2016273912 14 Dec 2016 for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable light chain polypeptide sequence of SEQ ID NO: 51:

[00846] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTTACAGCAATCTTGCCTGG TATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGATGCATCCACTCTG GAATCTGGAGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGCCAACAGGGTTT TACTGTTAGTGATATTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAAC GT (SEQ ID NO: 251).

[00847] In one embodiment of the invention, polynucleotides of the invention optionally comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 401:

[00848] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTTACAGCAATCTTGCCTGG TATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGATGCATCCACTCTG GAATCTGGAGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGCCAACAGGGTTT TACTGTTAGTGATATTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAAC GTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 403).

[00849] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the variable heavy chain polypeptide sequence of SEQ ID NO: 53:

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2016273912 14 Dec 2016 [00850] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAACTATGCAGTGGG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAATCATTGGTCGTA ATGGTAACACATGGTACGCGAGCTCTGCAAGAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCT GTGTATTACTGTGCTAGAGGATATGGCCGTAGTGTTGCTTATTACGTCTTTAACATCT GGGGCCCAGGGACCCTCGTCACCGTCTCGAGC (SEQ ID NO: 253).

[00851] In one optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 402:

[00852] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAACTATGCAGTGGG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAATCATTGGTCGTA ATGGTAACACATGGTACGCGAGCTCTGCAAGAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCT GTGTATTACTGTGCTAGAGGATATGGCCGTAGTGTTGCTTACTACGTCTTTAACATCT GGGGCCCAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCT TCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCC TGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAA CGTGAATCACAAGCCCAGCAACACCAAGGTGGACGCGAGAGTTGAGCCCAAATCTT GTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCG TCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCT GAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAA CTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGC AGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGC TGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCT GCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCA

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AAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTAC AGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTC CGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCC GGGTAAATGA (SEQ ID NO: 404).

[00853] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 401.

[00854] In a further optional embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one or more of the polynucleotide sequences of SEQ ID NO: 258; SEQ ID NO: 259; and SEQ ID NO: 260 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 402.

[00855] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 251 encoding the light chain variable sequence of SEQ ID NO: 51; the polynucleotide SEQ ID NO: 403 encoding the light chain sequence of SEQ ID NO: 401; the polynucleotide SEQ ID NO: 253 encoding the heavy chain variable sequence of SEQ ID NO: 53; the polynucleotide SEQ ID NO: 404 encoding the heavy chain sequence of

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SEQ ID NO: 402; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257) of the light chain variable sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 401; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 258; SEQ ID NO: 259; and SEQ ID NO: 260) of the heavy chain variable sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 402.

[00856] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody Ab21, the polynucleotides encoding the full length Ab21 antibody comprise, or alternatively consist of, the polynucleotide SEQ ID NO: 403 encoding the light chain sequence of SEQ ID NO: 401 and the polynucleotide SEQ ID NO: 404 encoding the heavy chain sequence of SEQ ID NO: 402.

[00857] Another optional embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one optional embodiment of the invention described herein (infra), Fab fragments may be produced by enzymatic digestion (e.g., papain) of Ab21 following expression of the full-length polynucleotides in a suitable host. In another embodiment of the invention, anti-NGF antibodies such as Ab21 or Fab fragments thereof may be produced via expression of Ab21 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00858] Antibody fragment Fab2 [00859] The invention is further optionally directed to the use of polynucleotides set forth below to produce antibody fragment Fab2 polypeptides that inhibit the association of NGF with TrkA and p75 for treatment or prevention of pain and pain associated conditions having binding specificity to NGF in methods of treating pain in an individual comprising administering to said individual antibody Abl polypeptides . The invention is further directed to polynucleotides

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2016273912 14 Dec 2016 encoding antibody fragment polypeptides for treatment or prevention of pain and pain associated conditions having binding specificity to NGF. In one embodiment of the invention, Fab polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the light chain polypeptide sequence of SEQ ID NO: 407:

[00860] GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGA GACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTTACAGCAATCTTGCCTGG TATCAGCAGAAACCAGGAAAAGCCCCTAAGCTCCTGATCTATGATGCATCCACTCTG GAATCTGGAGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAGTACACTCT CACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTACTACTGCCAACAGGGTTT TACTGTTAGTGATATTGATAATGCTTTCGGCGGAGGAACCAAGGTGGAAATCAAAC

GTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAAT

CTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAG

TACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACA

GAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAA

AGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGA

GCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG (SEQ ID NO: 409).

[00861] In another optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, the following polynucleotide sequence encoding the heavy chain polypeptide sequence of SEQ ID NO: 408:

[00862] GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCGTCAGTAACTATGCAGTGGG CTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGAATCATTGGTCGTA ATGGTAACACATGGTACGCGAGCTCTGCAAGAGGCCGATTCACCATCTCCAGAGAC AATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCT GTGTATTACTGTGCTAGAGGATATGGCCGTAGTGTTGCTTACTACGTCTTTAACATCT GGGGCCCAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCT TCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCC TGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTC

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AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAA CGTGAATCACAAGCCCAGCAACACCAAGGTGGACGCGAGAGTTGAGCCCAAATCTT GTGACAAAACTCACTAG (SEQ ID NO: 410).

[00863] In a further optional embodiment of the invention, polynucleotides encoding Fab antibody fragments having binding specificity to NGF comprise one or more of the polynucleotide sequences of SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the light chain variable sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 409.

[00864] In a further optional embodiment of the invention, polynucleotides encoding Fab antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise one or more of the polynucleotide sequences of SEQ ID NO: 258; SEQ ID NO: 259; and SEQ ID NO: 260 which correspond to polynucleotides encoding the complementarity-determining regions (CDRs, or hypervariable regions) of the heavy chain variable sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 410.

[00865] The invention also optionally contemplates polynucleotide sequences including one or more of the polynucleotide sequences encoding antibody fragments for treatment or prevention of pain and pain associated conditions described herein. In one embodiment of the invention, polynucleotides encoding antibody fragments for treatment or prevention of pain and pain associated conditions having binding specificity to NGF comprise, or alternatively consist of, one, two, three or more, including all of the following polynucleotides encoding antibody fragments: the polynucleotide SEQ ID NO: 251 encoding the light chain variable sequence of SEQ ID NO: 51; the polynucleotide SEQ ID NO: 409 encoding the light chain sequence of SEQ ID NO: 407; the polynucleotide SEQ ID NO: 253 encoding the heavy chain variable sequence of SEQ ID NO: 53; the polynucleotide SEQ ID NO: 410 encoding the heavy chain sequence of SEQ ID NO: 408; polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 255; SEQ ID NO: 256; and SEQ ID NO: 257) of the light chain variable sequence of SEQ ID NO: 51 or the light chain sequence of SEQ ID NO: 407; and polynucleotides encoding the complementarity-determining regions (SEQ ID NO: 258; SEQ ID NO: 259; and SEQ ID NO:

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260) of the heavy chain variable sequence of SEQ ID NO: 53 or the heavy chain sequence of SEQ ID NO: 408.

[00866] In a preferred optional embodiment of the invention, polynucleotides of the invention comprise, or alternatively consist of, polynucleotides encoding Fab (fragment antigen binding) fragments having binding specificity for NGF. With respect to antibody fragment Fab2, the polynucleotides encoding the Fab fragment include the polynucleotide SEQ ID NO: 409 encoding the light chain sequence of SEQ ID NO: 407 and the polynucleotide SEQ ID NO: 410 encoding the heavy chain sequence of SEQ ID NO: 408.

[00867] Another embodiment of the invention contemplates these polynucleotides incorporated into an expression vector for expression in mammalian cells such as CHO, NSO, HEK-293, or in fungal, insect, plant or microbial systems such as yeast cells such as the yeast Pichia. Suitable Pichia species include, but are not limited to, Pichia pastoris. In one embodiment of the invention described herein (infra), Fab fragments may be produced via expression of Fab2 polynucleotides in mammalian cells such as CHO, NSO or HEK 293 cells, fungal, insect, plant or microbial systems such as yeast cells (for example diploid yeast such as diploid Pichia) and other yeast strains. Suitable Pichia species include, but are not limited to, Pichia pastoris.

[00868] In one embodiment, the invention is optionally directed to an isolated polynucleotide comprising a polynucleotide encoding an anti-NGF Vh antibody amino acid sequence selected from SEQ ID NO: 3, 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123, 133,

143, 153, 163, 173, 183, 193, or 402, or encoding a variant thereof wherein at least one framework residue (FR residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-NGF antibody Vh polypeptide or a conservative amino acid substitution.

[00869] In another optional embodiment, the invention is directed to an isolated polynucleotide comprising the polynucleotide sequence encoding an anti-NGF Vl antibody amino acid sequence of 1, 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, 171, 181, 191, or 401, or encoding a variant thereof wherein at least one framework residue (FR

224

2016273912 14 Dec 2016 residue) has been substituted with an amino acid present at the corresponding position in a rabbit anti-NGF antibody Vl polypeptide or a conservative amino acid substitution.

[00870] In yet another optional embodiment, the invention is directed to one or more heterologous polynucleotides comprising a sequence encoding the polypeptides contained in SEQ IDNO:1 and SEQ ID NOG; SEQ ID NO: 11 and SEQ ID NO: 13; SEQ IDNO:21 and SEQ IDNO:23; SEQ ID NO:31 and SEQ IDNO:33; SEQ ID NO:411 and SEQ IDNO:43; SEQ ID NO:51 and SEQ IDNO:53, SEQ IDNO:61 and SEQ IDNO:63; SEQ IDNO:71 and SEQ ID NO:73; SEQ ID NO:81 and SEQ ID NO:83; SEQ ID NO:91 and SEQ ID NO:93; SEQ ID ΝΟΤΟΙ and SEQ IDNO:103; SEQ ID NOTH and SEQ IDNO:113; SEQ IDNO:121 and SEQ ID NO: 123; SEQ ID NO: 131 and SEQ ID NO: 133; SEQ ID NO: 141 and SEQ ID NO: 143; SEQ IDNOT51 and SEQ IDNO:153; SEQ IDNO:161 and SEQ IDNO:163; SEQ IDNO:171 and SEQ IDNOT73; SEQ IDNOT81 and SEQ IDNO:183; SEQ IDNO:191 and SEQ IDNO:193; or SEQ ID NO:401 and SEQ ID NO:403.

[00871] In another embodiment, the invention is optionally directed to an isolated polynucleotide that expresses a polypeptide containing at least one CDR polypeptide derived from an anti-NGF antibody wherein said expressed polypeptide alone specifically binds NGF or specifically binds NGF when expressed in association with another polynucleotide sequence that expresses a polypeptide containing at least one CDR polypeptide derived from an anti-NGF antibody for treatment or prevention of pain and pain associated conditions wherein said at least one CDR is selected from those contained in the Vl or Vh polypeptides of SEQ ID NO: 1,3, 11, 13, 21, 23, 31, 33, 41, 43, 51, 53, 61, 63, 71, 73, 81, 83, 91, 93, 101, 103, 111, 113, 121, 123,

131, 133, 141, 143, 151, 153, 161, 163, 171, 173, 181, 183, 191, 193, 401 or SEQ ID NO:403.

[00872] Host cells and vectors comprising said polynucleotides are also contemplated.

[00873] The invention further optionally contemplates vectors comprising the polynucleotide sequences encoding the variable heavy and light chain polypeptide sequences, as well as the individual complementarity-determining regions (CDRs, or hypervariable regions), as set forth herein, as well as host cells comprising said vector sequences. In one embodiment of the invention, the host cell is a yeast cell. In another embodiment of the invention, the yeast host cell belongs to the genus Pichia.

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EXAMPLES [00874] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the subject invention, and are not intended to limit the scope of what is regarded as the invention. Efforts have been made to ensure accuracy with respect to the numbers used (e.g. amounts, temperature, concentrations, etc.) but some experimental errors and deviations should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees centigrade; and pressure is at or near atmospheric.

[00875] EXAMPLE 1 [00876] This example describes culture methods that improved the purity of recombinant antibodies produced from cultured P. pastoris cells. When a bolus of ethanol was added during culturing, the resulting antibodies exhibited a great decrease in the concentration of an undesired product-associated variant.

[00877] Methods [00878] To generate the inoculum, diploid P. pastoris was grown using a medium composed of the following nutrients (percentages are given as w/v): yeast extract 3%, anhydrous dextrose 2%, YNB 1.34%, Biotin 0.004% and 100 mM potassium phosphate (pH 6.0). The inoculum medium for runs L355, L357, L358, L359 and L360 was composed of the following nutrients (percentages are given as w/v): yeast extract 3%, glycerol 2%, YNB 1.34%, Biotin 0.004%, 200 mM potassium phosphate (pH 6.0) The inoculum was grown for approximately 24 hours to 29 hours in a shaking incubator at 30°C and 300 rpm. A 10% inoculum was then added to Labfors 2.5L working volume vessels containing 1 L sterile growth medium. The growth medium was composed of the following nutrients: potassium sulfate 18.2 g/L, ammonium phosphate monobasic 36.4 g/L, potassium phosphate dibasic 12.8 g/L, magnesium sulfate heptahydrate 3.72 g/L, sodium citrate dihydrate 10 g/L, glycerol 40 g/L, yeast extract 30 g/L, PTM1 trace metals 4.35 mL/L, and antifoam 204 1.67 mL/L. The PTM1 trace metal solution was comprised of the following components: cupric sulfate pentahydrate 6 g/L, sodium iodide

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0.08 g/L, manganese sulfate hydrate 3 g/L, sodium molybdate dihyrate 0.2 g/L, boric acid 0.02 g/L, cobalt chloride 0.5 g/L, zinc chloride 20 g/L, ferrous sulfate heptahydrate 65 g/L, biotin 0.2 g/L, and sulfuric acid 5 mL/L. The yeast strain was engineered to express Ab-A antibody from four integrated genomic copies of the heavy chain coding sequence (SEQ ID NO: 441) and 3 copies of the light chain coding sequence (SEQ ID NO: 440). The heavy chain gene copies were integrated into the pGAP locus (3 copies) and HIS4 TT locus (1 copy) while the 3 light chain gene copies were integrated into the pGAP locus. The antibody chain gene copies were each under the control of the GAP promoter. The bioreactor process control parameters were set as follows: Agitation 1000 rpm, airflow 1.35 standard liter per minute, temperature 28°C and pH was controlled (at 6) using ammonium hydroxide. No oxygen supplementation was provided.

[00879] Following addition of the inoculum, fermentation cultures were grown for approximately 12 to 16 hours (the “growth phase”). The growth phase ended when the initial glycerol in the medium was consumed, as which was detected by a dissolved oxygen (“DO”) spike (a sudden increase in the dissolved oxygen concentration). The cultures were then starved for approximately three hours after the dissolved oxygen spike (“starvation phase”) for run L306. For other runs, the ethanol bolus was added immediately after DO spike. A bolus of ethanol was then added to the reactor to give a final concentration of 1% ethanol (w/v). Control cultures were treated identically, except that the bolus addition of ethanol was omitted. The fermentation cultures were allowed to equilibrate for 15 to 30 minutes (“equilibration phase”). After the equilibration phase, feed was added at a constant rate of 30 g/L/hr for 40 minutes (“transition phase”). For the remainder of the culture (“production phase”) the ethanol concentration was detected using an ethanol sensing probe (Raven Biotech) which was used to control the feed rate, with the feed rate being set at 15 g/L/hr when the ethanol concentration was below the set point, or 7.5 g/L/hr when the ethanol concentration was above the set point. In instances in which the high feed rate of 15 g/L/hr was not high enough to maintain ethanol at set point (which occurred in the L315 fermentation run), the high feed rate was set to 22.5 g/L/hr while the low feed rate was set to 15 g/L/hr. The same set point was maintained whether or not an ethanol bolus had been added to the culture (production of ethanol by the yeast caused the set point to be reached without the bolus addition of ethanol). The feed was composed of the following components: yeast extract 50 g/L, anhydrous dextrose 500 g/L, magnesium sulfate heptahydrate 3 g/L, PTM1 trace metals 12 mL/L, and sodium citrate dihydrate 0.5g/L The total fermentation time was

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2016273912 14 Dec 2016 typically 85 hours to 97 hours in these experiments, though longer and shorter times can also be used.

[00880] After the production phase, fermentation cultures had PEI (polyethyleneimine) and EDTA (ethylenediaminetetraacetic acid) added to 0.05% w/v and 3 mM final concentrations respectively. The cultures were then spun in a centrifuge and antibodies were purified from the culture supernatant by Protein A affinity. Briefly, approximately 20 mL of 0.2μ clarified supernatants from harvested fermentation broth were diluted with the same volume of equilibration buffer (20 mM Histidine pH6). From this diluted broth, 20 mL were then loaded onto a pre-equilibrated 1 mL HiTrap MabSelect Sure column (GE, Piscataway, NJ). The column was subsequently washed using 40 column volumes of equilibration buffer. The antibody bound onto the column was eluted using a step gradient into 100% elution buffer (100 mM Citric Acid pH 3.0). One mL fractions were collected and immediately neutralized using 100pL of 2M Tris buffer pH 8.0. Protein containing fractions were determined by measuring absorbance at 280nM and protein-containing fractions were pooled.

[00881] Protein A purified antibodies were analyzed for purity by SDS-PAGE. For nonreduced samples, SDS-PAGE was carried out using precast polyacrylamide gels (NuPAGE® Bis-Tris Gels) containing a 4%-12% polyacrylamide gradient, using NuPAGE® MES SDS running buffer and NuPAGE® LDS Sample Buffer (all from Invitrogen, Carlsbad, Ca.) in accord with the manufacturer’s instructions. Proteins were then visualized by Coomassie blue staining. Reduced samples were processed in the same manner except that samples were reduced prior to loading using the NuPAGE® Sample Reducing Agent (Invitrogen, Carlsbad, Ca.) in accord with the manufacturer’s instructions.

[00882] Results [00883] To determine the effect of a bolus addition of ethanol during culture on antibody purity, the antibody Ab-A was produced from yeast cultures with or without the addition of a bolus of ethanol to a final concentration of 1% (10 g/L) at the end of the growth phase and prior to the production phase. The production phase was continued for 97 hours (FIG. 1), 87 hours (FIG. 2), or 86 hours (FIG. 3). The antibody produced by each culture was then harvested from the culture media, purified by Protein A affinity chromatography.

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2016273912 14 Dec 2016 [00884] SDS-PAGE was used to detect the relative abundance of the full antibody, the “half antibody” or HILI complex (containing one heavy and one light chain) and the H2L1 complex (containing two heavy chains and one light chain). The abundance of the HILI and H2L1 complexes was greatly decreased in the cultures that were produced with the bolus addition of ethanol. This improvement was reproduced in three experiments shown in FIG. 1 A, compare lanes 2 and 3 (with bolus) to 5 (no bolus); FIG. 2A, compare lane 2 (with bolus) to 3 (no bolus); FIG. 3A, compare lanes 2 and 4 (with bolus) to lanes 5-7 (no bolus). Under reducing conditions, the HILI, H2L1, and full antibody species were each separated into individual heavy and light chains, confirming the identity of the 75 kDa band as consisting of one light and one heavy chain joined by a disulfide-linkage (FIGS. IB and 2B; lane order is the same as FIGS. 1A and IB, respectively).

[00885] The decrease in abundance of the HILI species was then quantified using Image J to plot the gel band density along the length of the non-reduced gels (FIGS. 1C-E and 2C-D, respectively corresponding to FIG. 1A, lanes 2, 3, and 5, and FIG. 2A, lanes 2 and 3, and FIG. 3B, corresponding to lanes 2 and 4-6 of FIG. 3A). The area under the HILI peak was quantified and results are tabulated in FIGS. IF, 2E, and 3B. Based on these measurements, the addition of an ethanol bolus prior to antibody production decreased the relative abundance of the 75 kDa band by about 90% in FIG. 1 A, by about 85% in FIG. 2A, and by about 87% in FIG. 3A.

[00886] In summary, these results demonstrate that the concentration of the HILI species was greatly decreased by the bolus addition of ethanol to the culture, resulting in decreased production of the HILI species between about 85% to 90%.

[00887] EXAMPLE 2 [00888] This example extends the results obtained in Example 1 by demonstrating that the same methods produced a similar improvement in antibody purity when used during production of two additional antibodies.

[00889] Methods [00890] Antibodies Ab-B and Ab-C were recombinantly produced using the methods described in Example 1. Antibody Ab-C was expressed from a yeast strain engineered contain

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2016273912 14 Dec 2016 four copies of the heavy chain coding sequence (SEQ ID NO: 439) and three copies of the light chain coding sequence (SEQ ID NO: 438). Samples were taken from the reactors and culture supernatant containing antibodies was collected after a total fermentation time of 67 hours (T67) or 87 hours (T87) for the Ab-B antibody and for 86 hours (T86) for the Ab-C antibody, purified by Protein A affinity, and analyzed by SDS-PAGE as described in Example 1.

[00891] Results [00892] Antibodies Ab-B (FIG. 4) and Ab-C (FIG. 5) were produced with or without a bolus addition of ethanol to a final concentration of 1% at the end of the growth phase and prior to the production phase. For the antibodies produced without the bolus addition of ethanol, the HILI or half antibody species, and the H2L1 species were each observed as a prominent band (FIG. 4A, lines 6 and 7; FIG. 4C, lanes 6 and 7; FIG. 5 A, lanes 5 and 6). The intensity of these bands were greatly decreased for the culture produced with a bolus addition of ethanol (FIG. 4A, lanes 2-3; FIG. 4C, lanes 2-3; FIG. 5A, lane 3). Under reducing conditions, the HILI and H2L1 bands were separated into individual heavy and light chains, confirming the identity of these species as consisting full length heavy and light chains (FIGS. 4B, 4D, and 5B; lane order is the same as in FIGS. 4A, 4D, and 5A, respectively).

[00893] The decrease in abundance of the HILI species was then quantified using Image J to plot the gel band density along the length of the non-reduced gels. FIGS. 4E and 4F tabulate the area contained in the HILI peaks shown in FIGS. 4A (T67) and 4C (T87), respectively, demonstrating that the bolus addition of ethanol produced about a 73% reduction in the relative abundance of HILI complexes at the earlier time point shown FIG. 4A and about a 34% average reduction in the relative abundance of HILI complexes at the later time point shown in FIG. 4C. Similarly, FIG. 5C tabulates the area contained in the HILI peaks shown in FIGS. 5A, demonstrating about a 61% average reduction in the relative abundance of HILI complexes by the bolus addition of ethanol.

[00894] In summary, these results demonstrate that the concentration of the HILI and H2L1 species were decreased by between about 61% and 73% by the bolus addition of ethanol to the culture for two additional antibodies having binding specificity for different targets.

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2016273912 14 Dec 2016 [00895] EXAMPLE 3 [00896] This example further describes the improved purity of recombinant antibodies produced from cultured P. pastoris cells through addition of a bolus of ethanol during culturing. In addition to greatly decreasing the abundance of the HILI and H2L1 species, this example further demonstrates a decrease in the concentration of other product-associated variants.

[00897] Methods [00898] Recombinant antibodies Ab-A, Ab-B, and Ab-C were prepared and purified from P. pastoris cultures as described in Examples 1 and 2. Antibodies were produced either with or without a bolus addition of ethanol to a final concentration of 1% (w/v) at the end of the growth phase and prior to the production phase. To analyze the purity of protein A purified antibody preparations, size exclusion high-performance liquid chromatography (SE-HPLC) was used. Briefly, an Agilent (Santa Clara, CA) 1200 Series HPLC with UV detection instrument was used. For sample separation, a TSKgel 3000SWxl 7.8x300 mm column connected with a TSKgel Guard SW_XL 6x40 mm from Tosoh Bioscience (King of Prussia, PA) was used. A solution of 100 mM sodium phosphate, 200 mM sodium chloride pH 6.5 was used as mobile phase with a flow rate of 0.5 mL/min in isocratic mode and absorbance at UV 215nm was monitored. Before injection of samples the column was equilibrated until a stable baseline was achieved. Samples were diluted to a concentration of 1 mg/mL using mobile phase and a 30 uL volume was injected. To monitor column performance, BioRad (Hercules, CA) gel filtration standards were used.

[00899] Results [00900] The Ab-A antibody preparations described in Example 1 and additional preparations produced using the same methods were expressed in yeast, purified by protein A affinity, and then analyzed for purity using size exclusion chromatography (SEC). Under the condition used, the half antibody (HILI) species co-elutes with the full antibody, which is thought to be due to non-covalent association between pairs of half antibodies. However, this method allows purity to be assessed with respect to other product-associated variants, such complexes having aberrant stoichiometry, fragments, glycosylated forms, and aggregates.

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2016273912 14 Dec 2016 [00901] SE-HPLC data are shown for Ab-A samples produced without (FIGS. 6A, 6C, and 6E) or with (FIGS. 6B, 6D, and 6F) a bolus addition of ethanol. A product-associated variant consisting of an aggregate of two full antibodies (containing four heavy and four light chains) was detected (arrow), and the abundance thereof was reduced on average in the samples prepared with the bolus addition. FIG. 7 shows quantification of the purity of Ab-A by determining the percentage of the antibody preparation contained in the main peak (containing the full antibody). The bolus addition of ethanol increased the average percentage contained in the main peak from 80.3% up to 90.6%.

[00902] Similar analysis was performed for the Ab-B and Ab-C antibody preparations described in Example 2, quantified in FIGS. 8 and 9, respectively. Overall purity of the Ab-B antibody was improved, with the average fraction in the main peak increasing from 76% to 79% at T67 and from 60% to 73% at T87. For the Ab-C antibody, there was little detectable difference in antibody purity assessed by this method, apparently due to the high initial purity of the Ab-C antibody even without the bolus addition.

[00903] In summary, these results demonstrate that a bolus addition of ethanol to the culture can decrease the concentration of other product-associated variants in addition to the half-antibody species.

[00904] EXAMPLE 4 [00905] This example describes the further confirmation of the identity of the 75 kDa product associated variant as a half antibody species containing only one antibody heavy chain and only one antibody light chain. This hypothesis was based on several observations. First, the 75 kDa band was present in protein A purified samples (see Example 1) indicating that it contained at least the protein A binding portion of an antibody heavy chain. Second, the 75 kDa band was prominent in non-reduced samples analyzed by SDS-PAGE (see, e.g., FIG. 1 A, lanes 2-3), but under reducing conditions the same samples did not contain any bands of comparable intensity (other than the expected light and heavy chains), indicating that the 75 kDa band does not include any components other than antibody heavy and light chains (or other species having the same electrophoretic mobility). Third, disappearance of the 75 kDa band from the reduced samples also indicates that its constituents are linked by at least one disulfide bond. Fourth, SEC

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2016273912 14 Dec 2016 analysis had demonstrated co-elution of the 75 kDa species with the full antibody, strongly suggesting that the 75 kDa species can non-covalently self-associate to form a full antibody (or another complex of the same apparent hydrodynamic radius). Finally, the apparent molecular weight of about 75 kDa (determined by reference to electrophoresis standards), taken together with the observation (from denaturing gels) that this complex was only made up of full-length antibody chains, was consistent with complex containing only one heavy chain and only one light chain, but was inconsistent with other complexes.

[00906] Methods [00907] Mass spectrometry was used to detect the relative abundance of heavy chains lacking the inter-heavy chain disulfide bonds (normally found at amino acids 220 and 223) in different samples. Two-hundred and fifty micrograms of each sample was added into an Eppendorf tube. An appropriate amount (~450 pL) of denaturing buffer (6 M Guanidine-HCl, 1 mM EDTA, 0.25 M Tris, pH 7.5) was added to the tube to obtain a final volume of 500 pL and a sample concentration of 0.5 mg/mL. Twelve and a half microliters of 2 M Iodoacetamide was added into each sample to alkylate any free cysteine. The samples were vortexed then incubated at room temperature, in the dark, for 30 ± 5 minutes. The samples were then desalted using NAP5 columns pre-equilibrated with digestion buffer (0.1 M Tris-HCl, pH 7.5). Each sample solution was added to separate (pre-equilibrated) columns and allowed to enter the column bed. One milliliter of digestion buffer was added to each column and the eluent was collected into Eppendorf tubes. The samples were divided into equal aliquots containing approximately 50 pg of material (five 200 pL aliquots). The alkylated and desalted aliquots were stored at -20 °C until needed. One aliquot of each sample (alkylated, and desalted) was used for each digestion.

Trypsin solution at 0.5 mg/mL was added to each sample aliquot at a 1:25 w:w ratio of trypsimprotein (4 pL). All trypsin tubes were incubated at 37 ± 2 °C for 4 hours. After incubation, the enzymatic digestion was quenched by adding 1 pL of Trifluoroacetic acid to each tube. The samples were then divided into two equal portions, reduced and non-reduced. Half the samples were reduced in the presence of 1 M DTT for 1 hour at 37 ± 2 °C. The contents of both reduced and nonreduced samples were transferred to HPLC vials and placed in the autosampler for analysis.

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2016273912 14 Dec 2016 [00908] MS and MS/MS data was collected on a Micromass Q-TOF Ultima mass spectrometer using electrospray ionization (ESI) in positive ion mode. Data was acquired from m/z 200-1950 in MS mode. Prior to analysis, the mass spectrometer was calibrated using a 5th order fit on fragment ions of [Glu'j-Fibrinopcptidc covering a range from m/z 175 to 1285. The injections volumes were adjusted to achieve an on-column load of approximately 20 pmoles of protein.

[00909] Results [00910] Based on the observations discussed above, Applicants hypothesized that the 75 kDa band was a “half antibody” species containing one heavy antibody chain and one light antibody chain covalently linked to one another through disulfide bonds, and that pairs of half antibody complexes could non-covalently associate to form a complex having the same stoichiometry as a full antibody (two heavy chains and two light chains) but lacking the disulfide linkages between the two heavy chains (“unlinked heavy chains”). Based thereon, it was predicted the relative abundance of the 75 kDa band would correlate with the relative proportion of unlinked heavy chains, which was determined using mass spectrometry analysis of trypsin digested antibody samples.

[00911] The peptide fragments of interest for this study were the T17 trypsin fragment of the heavy chain (T17H) which is composed of amino acids 217-242, respectively. Amino acids 220 and 223 are responsible for disulfide bonding between antibody heavy chains. Typically, free cysteine analysis can be conducted by determining a ratio of alkylated cysteine residues to non-alkylated residues in reduced samples after a tryptic digestion. However, alkylated species were not present in either lot of material. It was hypothesized the two cysteine residues of the peptide fragment of interest, T17H, were bonding to each other, or the cysteines were protected by the antibody’s quaternary structure. In either case, the cysteine residues would not be accessible for alkylation. Instead, the analytical approach was to utilize the ratio of non-reduced species to reduced species in both lots to calculate a percent difference. It was observed that the non-reduced samples had a 2 Da decrease in molecular weight, indicative of disulfide bonding. This behavior was exploited to calculate the percent free T17H. The theoretical mass of the non234

2016273912 14 Dec 2016 reduced T17H species is 2727.41 Da (disulfide bonding between Cys220 & Cys223) and 2729.41 Da for reduced peptide.

[00912] The extracted ion chromatograms of reduced and non-reduced samples were analyzed for representative charge states, ratio of counts between the non-reduced to reduced samples calculates the free T17H species to be 2.3% in the antibody produced with a bolus addition of ethanol, and 26.1% in the sample produced without a bolus addition of ethanol.

These results are presented in tabular form in Fig. 9.

[00913] Thus, the abundance of heavy chains lacking the inter-heavy chain disulfide bond was greatly increased in the sample produced without the bolus addition of ethanol, further confirming the identity of this species as containing one heavy chain and one light chain but lacking an inter-heavy chain disulfide bond. Moreover, the detection of a species 2 Da lighter than the expected mass indicated that heavy chain in the HILI species may contain an extra disulfide bond to itself which may interfere with the formation of the normal inter-heavy chain disulfide bond.

[00914] EXAMPLE 5 [00915] This example demonstrates a correlation between cell viability and antibody purity. The addition of an ethanol bolus generally improved cell viability and antibody purity for Ab-A and the Ab-B antibody. Further, the Ab-C antibody, which already exhibited high purity even without the bolus addition, also exhibited higher culture viability. Taken together, these results suggest that the improvement in antibody purity resulting from a bolus addition of ethanol is at least partially attributable to increased culture viability.

[00916] Methods [00917] Culture viability was determined using a Cellometer (Nexcelom). Culture samples were diluted with PBS so that the final cell count was within 1 x 10⁷ to 5 x 10⁷ cells/mL. One half of the sample was then treated to heat conditions of 75°C for 10 minutes as positive control for propidium iodide (PI) staining. The untreated sample and treated sample were then mixed with PI (20 uL of sample plus 20 uL of PI). The sample was then placed in a slide cassette and viability was determined by counting the number of non-fluorescing cells then dividing by the

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2016273912 14 Dec 2016 total number of cells. Cells that are dead have taken up the propidium iodide and are fluorescing so the positive control heat killed sample should show less than 1% cells alive.

[00918] Results [00919] Cell viability was determined for antibody-producing cultures grown with or without a bolus addition of ethanol as described in Examples 1 and 2. As described above, purity of the Ab-A and Ab-B antibodies were greatly improved by a bolus addition of ethanol to the yeast culture (see Examples 1-2 and FIGS. 1-4). The addition of an ethanol bolus improved cell viability for these cultures as well. For the Ab-A antibody, viability improved from 91.9% to 97.2% on average (FIG. 11), while for the Ab-B antibody, viability improved from 84.8% to 95.1% on average (FIG. 12). Due to the already high purity of the Ab-C antibody produced even without the bolus addition of ethanol, the improvements in the purity of this antibody resulting from the bolus addition of ethanol were more modest (see Example 3 and FIG. 5). Consistent with the observation that high cell viability correlated with higher antibody purity, the Ab-C antibody cultures exhibited high cell viability (95.8%% on average) in the absence of a bolus addition of ethanol, which was little changed by the bolus addition of ethanol (96.8%).

[00920] Taken together, these results indicate that the improvement in antibody purity resulting from the addition of an ethanol bolus may be in part caused by (or at least correlates with) an improvement in cell viability.

[00921] EXAMPLE 6 [00922] This example demonstrates that a similar improvement in antibody purity can be attained with varying ethanol bolus concentrations.

[00923] Methods [00924] The Ab-A antibody was produced as in Example 1, except that the bolus addition of ethanol was 5 g/L (0.5% w/v), 10 g/L (1% w/v), or 15 g/L (1.5% w/v). Antibodies samples were purified from the culture media at 63 and 86 hours and purified by protein A affinity, then the purity was analyzed by non-reduced SDS-PAGE as in Example 1.

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2016273912 14 Dec 2016 [00925] Results [00926] Antibody purity was similarly high irrespective of the bolus concentration added (between 0.5% and 1.5% w/v), at both time points tested, 63 hours (FIG. 14A) and 86 hours (FIG, 14B). Detected levels of the HILI and H2L1 species were similarly low in each culture.

[00927] These results indicate that the improvement in antibody purity can be attained while varying the ethanol bolus concentration.

[00928] EXAMPLE 7 [00929] This example demonstrates that similar improvements in antibody purity can be attained while varying the duration of the “starvation period” between the dissolved oxygen spike and the addition of the ethanol bolus to the cultures.

[00930] Methods [00931] The Ab-A antibody was produced as in Example 1, except that the duration of the starvation period, the time between the dissolved oxygen spike (indicating exhaustion of the carbon source in the culture) and the bolus addition of ethanol, was either 0 hours or 3 hours. Antibodies samples were purified from the culture media and purified by protein A affinity, then the purity was analyzed by non-reduced SDS-PAGE as in Example 1.

[00932] Results [00933] Antibody purity was similarly high irrespective of the variation of the starvation period between 0 and 3 hours (FIG. 15 A, compare lanes 5 (0 hours starvation) and 6 (3 hours starvation)). Detected levels of the HILI and H2L1 species were similarly low in each culture.

[00934] These results indicate that the improvement in antibody purity can be attained with a varying the duration of the starvation period.

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2016273912 14 Dec 2016 [00935] EXAMPLE 8 [00936] This example tests the effect on antibody purity from varying the duration of the “equilibration period” between the addition of the ethanol bolus and commencement of adding the feed to the cultures.

[00937] Methods [00938] The Ab-B antibody was produced as in Example 2, except that the duration of the equilibration period, the time between addition of the ethanol bolus and the commencement of feeding the culture, was 0, 30, or 60 minutes. Additionally, the yeast strain from which the Ab-B antibody was produced contained three copies of the light chain gene instead of four. Antibodies samples were purified from the culture media and purified by protein A affinity, then the purity was analyzed by non-reduced SDS-PAGE as in Example 1. Viability was also assessed using the methods described in Example 5.

[00939] Results [00940] Antibody purity was similarly high for an equilibration period of 0 or 30 minutes (FIG. 16A, lanes 7 and 8 (0 minutes equilibration time) and lane 3 (30 minutes equilibration time). However, detected levels of the HILI and H2L1 species were increased in the culture with the 60 minute equilibration period (FIG. 16A, lanes 5 and 6).

[00941] Viability was also assessed for each culture at the 23 hour and 85 hour time points. For the 60 minute equilibration period, viability was between 75% and 80% at 23 hours, while at the same time point viability was approximately 88-90% for the 0 and 30 minute equilibration periods (FIG. 16B). Subsequently, at 85 hours, viability had improved but remained somewhat reduced for the 60 minute equilibration period relative to the 0 and 30 minute equilibration periods (FIG. 16C).

[00942] These results indicate that the improvement in antibody purity can be attained while varying the equilibration period at least between 0 and 30 minutes, while some loss of viability and purity may occur for an equilibration period of 60 minutes or longer (though purity may still be improved relative to a control culture without a bolus addition of ethanol).

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2016273912 14 Dec 2016 [00943] The above description of various illustrated embodiments of the invention is not intended to be exhaustive or to limit the invention to the precise form disclosed. While specific embodiments of, and examples for, the invention are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the invention, as those skilled in the relevant art will recognize. The teachings provided herein of the invention can be applied to other purposes, other than the examples described above.

[00944] The invention may be practiced in ways other than those particularly described in the foregoing description and examples. Numerous modifications and variations of the invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.

[00945] These and other changes can be made to the invention in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the invention to the specific embodiments disclosed in the specification and the claims. Accordingly, the invention is not limited by the disclosure, but instead the scope of the invention is to be determined entirely by the following claims.

[00946] Certain teachings related to methods for obtaining a clonal population of antigenspecific B cells were disclosed in U.S. Provisional patent application no. 60/801,412, filed May 19, 2006, the disclosure of which is herein incorporated by reference in its entirety.

[00947] Certain teachings related to humanization of rabbit-derived monoclonal antibodies and preferred sequence modifications to maintain antigen binding affinity were disclosed in International Application No. PCT/US2008/064421, corresponding to International Publication No. WO/2008/144757, entitled “Novel Rabbit Antibody Humanization Methods and Humanized Rabbit Antibodies”, filed May 21, 2008, the disclosure of which is herein incorporated by reference in its entirety.

[00948] Certain teachings related to producing antibodies or fragments thereof using mating competent yeast and corresponding methods were disclosed in U.S. Patent application no.

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2016273912 14 Dec 2016

11/429,053, filed May 8, 2006, (U.S. Patent Application Publication No. US2006/0270045), the disclosure of which is herein incorporated by reference in its entirety.

[00949] The entire disclosure of each document cited herein (including patents, patent applications, journal articles, abstracts, manuals, books, or other disclosures), including each document cited in the Background, Summary, Detailed Description, and Examples, is hereby incorporated by reference herein in its entirety.

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2016273912 06Jul2018

Claims (22)

1. Claims

   1. A method of producing a multi-subunit complex, comprising:

   (a) providing a culture comprising yeast cells comprising genes that provide for the expression of the subunits of said multi-subunit complex;

   (b) adding a bolus of ethanol to said culture, resulting in an ethanol concentration between 0.1% and 3%; and (c) adding a feed comprising at least one fermentable carbon source to said culture, and culturing said culture to produce said multi-subunit complex, wherein said multi-subunit complex: (i) is not an anti-NGF antibody or antigen-binding fragment thereof, (ii) is not an anti-NGF Fab antibody fragment containing the polypeptide sequence SEQ ID NO: 407 and SEQ ID NO: 408 and is not an anti-NGF antibody containing the polypeptide sequences SEQ ID NO: 401 and SEQ ID NO: 402; or (iii) does not contain all six CDR sequences of SEQ ID NOs: 5-10, does not contain all six CDR sequences of SEQ ID NOs: 15-20, does not contain all six CDR sequences of SEQ ID NOs: 25-30, does not contain all six CDR sequences of SEQ ID NOs: 35-40, does not contain all six CDR sequences of SEQ ID NOs: 45-50, does not contain all six CDR sequences of SEQ ID NOs: 55-60, does not contain all six CDR sequences of SEQ ID NOs: 65-70, does not contain all six CDR sequences of SEQ ID NOs: 75-80, does not contain all six CDR sequences of SEQ ID NOs: 85-90, does not contain all six CDR sequences of SEQ ID NOs: 95-100, does not contain all six CDR sequences of SEQ ID NOs: 105-110, does not contain all six CDR sequences of SEQ ID NOs: 115-120, does not contain all six CDR sequences of SEQ ID NOs: 125-130, does not contain all six CDR sequences of SEQ ID NOs: 135-140, does not contain all six CDR sequences of SEQ ID NOs: 145-150, does not contain all six CDR sequences of SEQ ID NOs: 155160, does not contain all six CDR sequences of SEQ ID NOs: 165-170, does not contain all six CDR sequences of SEQ ID NOs: 175-180, does not contain all six CDR sequences of SEQ ID NOs: 185-190, does not contain all six CDR sequences of SEQ ID NOs: 195200.

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   2016273912 06Jul2018
2. 2. The method of claim 1, wherein the method provides at least one of the following:

   (i) the ethanol bolus enhances the formation of stable disulfide bonds relative to the same method effected in the absence of the bolus of ethanol;

   (ii) the multi-subunit complex contains one or more polypeptides comprising at least one disulfide bond;

   (iii) the multi-subunit complex comprises an antibody;

   (iv) the culture method decreases the relative abundance of one or more productassociated variants relative to the same method effected in the absence of the bolus of ethanol;

   (v) the culture method decreases the relative abundance of complexes having aberrant stoichiometry relative to the same method effected in the absence of the bolus of ethanol;

   (vi) the culture method decreases the relative abundance of complexes having reduced cysteines relative to the same method effected in the absence of the bolus of ethanol;

   (vii) the culture method decreases the relative abundance of complexes having aberrant glycosylation relative to the same method effected in the absence of the bolus of ethanol; and/or (viii) the culture method increases the purity of said multi-subunit complex relative to said method effected in the absence of said bolus of ethanol;

   and wherein:

   step (b) is effected prior to step (c);

   step (b) is effected subsequent to addition of a feed comprising at least one fermentable carbon source to said culture but not after said culturing of the culture of step (c); or step (b) is effected concurrently with step (c).

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3. 3. The method of claim 1 or 2, wherein step (b) (i) results in a concentration of ethanol in said culture of at least about 0.01 % (w/v), at most about 4% (w/v) or between about 0.2% and about 2.75%;

   and/or (ii) comprises adding ethanol to said culture, adding a carrier comprising ethanol to said culture, adding said cells to a medium or carrier comprising ethanol, or replacing part of the culture medium, preferably wherein the bolus of ethanol is added to the culture medium over a period of time between 1 and 20 minutes;

   and/or wherein step (c):

   (i) comprises providing oxygen to said cells, preferably by agitating the culture or contacting said culture with a gas mixture comprising oxygen;

   (ii) comprises adding a feed comprising one or more of glucose, ethanol, citrate, sorbitol, xylose, trehalose, arabinose, galactose, fructose, melibiose, lactose, maltose, rhamnose, ribose, mannose, mannitol, and raffinose; and/or (iii) comprises maintaining the concentration of ethanol between an upper set point and a lower set point during step (c), preferably wherein said lower set point is about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.2%, 0.3%, 0.4%, 0.6%, 0.6%, 0.7%, 0.8% or 0.9% (w/v); or said upper set point is about 4%, 3.5%, 3%, 2.5%, 2%, 1.8%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.35%, 0.3%, 0.25%, 0.2%, or 0.15% (w/v).
4. 4. The method of any one of claims 1 to 3, wherein:

   (i) the concentration of ethanol in the culture is maintained by controlling production of ethanol by said cells or by addition of ethanol to said culture, preferably by controlling one or more of the concentration of glucose, availability of oxygen, intensity of agitation, gas pressure, flow rate of supplied air or other gas mixture, viscosity of the culture, culture density, concentration of oxygen in the supplied air or other gas mixture, and temperature;

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   2016273912 06Jul2018 (ii) the time between step (a) and step (b) is less than about 72 hours;

   (iii) the time between step (b) and step (c) is less than about 10 hours; and/or (iv) the culture of step (a) is produced by adding a carbon source to said culture, and culturing said culture until the carbon source is depleted, preferably wherein the depletion of the carbon source is determined by detecting a decrease in the metabolic activity of said yeast cells.
5. 5. The method of any one of claims 1 to 4, wherein:

   (i) the yeast cells comprise diploid yeast cells;

   (ii) the yeast cells comprise methylotrophic yeast;

   (iii) the yeast cells comprise Pichia cells;

   (iv) the yeast cells comprise Pichia pastoris cells;

   (v) the yeast cells comprise methylotrophic yeast of the genus Pichia selected from the group consisting of: Pichia angusta, Pichia guillermordii, Pichia methanolica, and Pichia inositovera;

   (vi) the yeast cells comprise genes integrated into their genome that provide for expression of said multi-subunit complex, wherein said genes are integrated into one or more genomic loci;

   (vii) the yeast cells are Pichia pastoris cells that comprise genes integrated into their genome at loci selected from the group consisting of the pGAP locus, 3' AOX TT locus; PpURA5; OCH1; A0X1; HIS4; GAP; pGAP; 3' AOX TT; ARG; and the HIS4 TT locus;

   (viii) the genes encoding the subunits of the multi-subunit complex are expressed under control of an inducible or constitutive promoter;

   (ix) the genes encoding the subunits of the multi-subunit complex are expressed under control of an inducible promoter selected from the group consisting of the A0X1, CUP1, tetracycline inducible, thiamine inducible, and FLD1 promoters;

   (x) at least one of the genes encoding said subunits of the multi-subunit complex are expressed under control of a promoter selected from the group consisting of: the CUP1, A0X1, ICL1, glyceraldehyde-3 -phosphate dehydrogenase (GAP), FLD1, ADH1, alcohol dehydrogenase II, GAL4, PH03, PH05, and Pyk

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   2016273912 06Jul2018 promoters, tetracycline inducible promoters, thiamine inducible promoters, chimeric promoters derived therefrom, yeast promoters, mammalian promoters, insect promoters, plant promoters, reptile promoters, amphibian promoters, viral promoters, and avian promoters; and/or (xi) the yeast cell is a diploid, tetraploid cell, or polyploid.
6. 6. The method of any one of claims 1 to 5, further comprising at least one of the following:

   (i) purifying said multi-subunit complex from said yeast cells or from the culture medium;

   (ii) the multi-subunit complex is purified from an intracellular component, cytoplasm, nucleoplasm, or a membrane of said yeast cells;

   (iii) the yeast cells secrete said multi-subunit complex into the culture medium;

   (iv) the multi-subunit complex is purified from said culture medium;

   (v) the multi-subunit complex comprises a monospecific or bispecific antibody;

   (vi) the said multi-subunit complex comprises a human antibody or a humanized antibody or fragment thereof;

   (vii) the said multi-subunit complex comprises a humanized antibody wherein said humanized antibody is of mouse, rat, rabbit, goat, sheep, or cow origin;

   (viii) the said multi-subunit complex comprises a humanized antibody of rabbit origin;

   (ix) the said multi-subunit complex comprises a monovalent, bivalent, or multivalent antibody;

   (x) the multi-subunit complex is an antibody wherein said antibody is purified from said culture by protein A and/or protein G affinity;

   (xi) at least one of the genes that provide for expression of a subunit of said multisubunit complex in at least one of said yeast cells in said panel is optimized for expression in said yeast cell;

   (xii) the multi-subunit complex comprises an antibody and the purity of said antibody is assessed by measuring the fraction of the antibody produced by said yeast cell that is contained in antibody complexes having the expected apparent

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   2016273912 06Jul2018 hydrodynamic radius, is contained in antibody complexes having the expected molecular weight, and / or specifically binds a target of said antibody;

   (xiii) said multi-subunit complex comprises an antibody and the yield of said antibody is assessed by determining the amount of antibody produced by said yeast cell discounting any product-associated variants that are abnormally glycosylated, contained in antibody complexes other than complexes having the expected apparent hydrodynamic radius, contained in antibody complexes having the expected molecular weight, and / or that fail to specifically bind to the target of said antibody and the molecular weight of said antibody complexes is optionally determined by non-reducing SDS-PAGE;

   (xiv) the multi-subunit complex comprises an antibody, said method further comprising purifying said antibody;

   (xv) the culture cells produce a supernatant antibody titer of at least 100 mg / L, at least 150 mg / L, at least 200 mg / L, at least 250 mg / L, at least 300 mg / L, between 100 and 300 mg / L, between 100 and 500 mg / L, between 100 and 1000 mg / L, at least 1000 mg / L, at least 1250 mg/liter, at least 1500 mg/liter, at least about 1750 mg/liter, at least about 2000 mg/liter, at least about 10000 mg/liter, or more;

   (xvi) one or more subunits of said multi-subunit complex are expressed from more than one gene copy;

   (xvii) the multi-subunit complex comprises an antibody which is expressed from between 1-10 copies of a gene encoding the light chain of said antibody and from 1-10 copies of a gene encoding the heavy chain of said antibody, optionally integrated into the genome of said cells;

   (xviii) the genes that provide for expression of said multi-subunit complex are contained on an extrachromosomal element, plasmid, or artificial chromosome;

   (xix) the cultured cells comprise more copies of the gene that provide for the expression of the light chain of said antibody than copies of the gene that provide for expression of the heavy chain of said antibody;

   (xx) the cultured cells comprise more copies of the gene that provides for the expression of the light chain of said antibody than copies of the gene that

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   2016273912 06Jul2018 provides for expression of the heavy chain of said antibody, wherein the respective number of copies of the gene encoding the heavy chain of said antibody and the number of copies of the gene encoding the light chain of said antibody in said cells are: 2 and 2, 2 and 3, 3 and 3, 3 and 4, 3 and 5, 4 and 3, 4 and 4, 4 and 5, 4 and 6, 5 and 4, 5 and 5, 5 and 6, or 5 and 7; or (xxi) the cultured cells comprise more copies of the gene that provides for the expression of the light chain of said antibody than copies of the gene that provide for expression of the heavy chain of said antibody, and further wherein the respective number of copies of the gene encoding the heavy chain of said antibody and the number of copies of the gene encoding the light chain of said antibody in said cells are: 2 and 1, 3 and 1, 4 and 1, 5 and 1, 6 and 1, 7 and 1, 8 and 1, 9 and 1,10 and 1, 1 and 2, 2 and 2, 3 and 2, 4 and 2, 5 and 2, 6 and 2, 7 and 2, 8 and 2, 9 and 2, 10 and 2, 1 and 3, 2 and 3, 3 and 3, 4 and 3, 5 and 3, 6 and 3, 7 and 3, 8 and 3, 9 and 3, 10 and 3, 1 and 4, 2 and 4, 3 and 4, 4 and 4, 5 and 4, 6 and 4, 7 and 4, 8 and 4, 9 and 4, 10 and 4, 1 and 5, 2 and 5, 3 and 5, 4 and 5, 5 and 5, 6 and 5, 7 and 5, 8 and 5, 9 and 5, 10 and 5, 1 and 6, 2 and 6, 3 and 6, 4 and 6, 5 and 6, 6 and 6, 7 and 6, 8 and 6, 9 and 6, 10 and 6, 1 and 7, 2 and 7, 3 and 7, 4 and 7, 5 and 7, 6 and 7, 7 and 7, 8 and 7, 9 and 7, 10 and 7, 1 and 8, 2 and 8, 3 and 8, 4 and 8, 5 and 8, 6 and 8, 7 and 8, 8 and 8, 9 and 8, 10 and 8, 1 and 9, 2 and 9, 3 and 9, 4 and 9, 5 and 9, 6 and 9, 7 and 9, 8 and 9, 9 and 9, 10 and 9, 1 and 10, 2 and 10, 3 and 10, 4 and 10, 5 and 10, 6 and 10, 7 and 10, 8 and 10, 9 and 10, 10 and 10.
7. 7. The method of any one of claims 1 to 6, wherein:

   (i) the culture of step (c) is grown in a production medium;

   (ii) the culture of step (c) is grown to a high cell density, preferably of a cell density which is at least 50 g/L; and/or (iii) the cultured cells are yeast cells which are cultured for at least 20 doublings and maintain high levels of expression of said multi-subunit complex after said at least 20 doublings.

   247

   2016273912 06Jul2018
8. 8. The method of any one claims 1 to 7, wherein:

   (i) at least one subunit of said multi-subunit complex is encoded by a gene that comprises a secretion signal;

   (ii) the multi-subunit complex comprises an antibody; and/or (iii) at least one subunit of said multi-subunit complex is encoded by a gene that comprises a secretion signal wherein the secretion signal comprises one or more polypeptides selected from the group consisting of: SEQ ID NOS: 414 to 437 and any combination thereof.

   ALDERBIO HOLDINGS LLC

   WATERMARK INTELLECTUAL PROPERTY PTY LTD

   P38218AU01

   248

   2016273912 14 Dec 2016

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   2016273912 14 Dec 2016

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   L301 No Bolus

   FIG. 1C

   FIG. 1D

   2016273912 14 Dec 2016

   3/22

   L30510 g/L Bolus

   FIG. 1E

   H1L1 Abundance

   Run Bolus H1L1 Band L301 None 8034 L302 None 7993 L305 10 g/L 798

   FIG.1F

   2016273912 14 Dec 2016

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   2016273912 14 Dec 2016

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   L315 No Bolus

   FIG. 2C

   L31410 g/L Bolus

   FIG. 2D

   H1L1 Abundance

   Run Bolus H1L1 Band L314 10 g/L 9417 L315 None 1371

   FIG. 2E

   2016273912 14 Dec 2016

   6/22

   Non-reduced Gel

   Full Ab (H2L2)

   H2L1

   H1L1

   HG. 3A

   H1L1 Abundance

   Run Time Point Ethanol Bolus H1L1 Band L399 T86 10 g/L 917 L401 T86 10 g/L 647 L402 T86 None 3089 L403 T86 None 7597 L404 T86 None 7574

   FIG 5IR

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   2016273912 14 Dec 2016

   H1L1 Abundance (T67)

   Run Time Point Ethanol Bolus H1L1 Band L437 T67 None 9427 L441 T67 None 7283 L440 T67 10 g/L 1220 L442 T67 10g/L 3269

   FIG. 4E

   H1L1 Abundance (T87)

   Run Time Point Ethanol Bolus H1L1Band L437 T86 None 10360 L441 T86 None 12022 L440 T86 10 g/L 6140 L442 T86 10 g/L 8726

   FIG. 4F
10. 10/22

    2016273912 14 Dec 2016 _Q
11. 11/22

    2016273912 14 Dec 2016

    H1L1 Abundance

    Run Time Point Ethanol Bolus H1L1 Band L412 T86 10 g/L 1177 L414 T86 None 3770 L415 T86 None 2219

    FIG. 5C
12. 12/22

    2016273912 14 Dec 2016

    L301 (No Bolus)

    L305 (with Bolus)

    FIG. 6B
13. 13/22

    2016273912 14 Dec 2016

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    2016273912 14 Dec 2016
14. 14/22

    L315(No Bolus)

    L314 (with Bolus)

    FIG. 6F
15. 15/22

    2016273912 14 Dec 2016

    Run Number Run Set Ethanol Bolus Sampled Elapsed Fermentation Time SEC Main Peak % {Desired Antibody) L301 1 None T97 78% L302 1 None T97 79% L305 1 10 g/L T97 90% L311 2 10 g/L T97 94% L315 3 None T87 87% L314 3 10 g/L T87 91% L399 4 10 g/L T86 91% L401 4 10 g/L T86 87% L402 4 None T86 93% L403 4 None T86 74% L404 4 None T86 71%

    FIG. 7
16. 16/22

    2016273912 14 Dec 2016

    Run Number Ethanol Bolus Sampled Elapsed Fermentation Time SEC Main Peak % (Desired Antibody) L437 None T67 71% L441 None T67 81% L440 10 g/L T67 80% L442 10 g/L T67 80% L437 None T87 59% L441 None T87 61% L440 10 g/L T87 77% L442 10 g/L T87 68%

    FIG. 8

    Run Number Ethanol Bolus Sampled Elapsed Fermentation Time SEC Main Peak % (Desired Antibody) L412 10 g/L T85 89% L414 None T85 88% L415 None T85 89%

    FIG. 9

    Observed H1L1 Band Relative Half Antibody (T17H Peptide) Percentage + 2.3% ++++ 26.1%

    FIG. 10
17. 17/22

    2016273912 14 Dec 2016

    No Bolus With EtOH Bolus

    FIG. 11

    FIG. 12
18. 18/22

    2016273912 14 Dec 20

    FIG. 13
19. 19/22

    2016273912 14 Dec 2016 _Q < -5 CM 'ΓΙΑ- 3= ΞΕ co

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20. 20/22

    2016273912 14 Dec 2016

    -Ο <C T— -c—

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    Starvation Period (Hrs) Starvation Period (Hrs)

    FIG. 15A FIG. 1SB
21. 21/22

    2016273912 14 Dec 2016

    Equilibration period:

    Non-reduced Gel

    30’ 60’ 60' 0' 0'

    M L355 L357^L358L359^L36°

    Full Ab

    H2L1

    H1L1

    FIG. 16A

    2016273912 14 Dec 2016
22. 22/22

    Viability at 23 Hours

    Equilibration

    Period: 0' 0’ 30' 60' 60'

    FIG. 16B

    Viability at 85 Hours

    FIG. 16C

    2016273912 14 Dec 2016

    Sequence Listing <110> Patti McNeill

    Leon F. Garcia-Martinez Nicole Janson Gary Lesnicki

    Pei Qi John Latham <120> HIGH-PURITY PRODUCTION OF MULTI-SUBUNIT PROTEINS SUCH AS ANTIBODIES IN TRANSFORMED MICROBES SUCH AS PICHIA PASTORIS <130> 67858.711002 <150> 61/525,307 <151> 2011-08-19 <150> 61/496,860 <151> 2011-06-14 <150> 61/496,873 <151> 2011-06-14 <150> 61/418,832 <151> 2010-12-01 <160> 441 <170> Patentln version 3.5 <210> 1 <211> 111 <212> PRT <213> Oryctolagus cunicuius <400> 1

    Al a 1 Leu Val Met Thr Gin 5 Thr Pro Ser Ser 10 Val Ser Al a Al a Val 15 Gly Gly Thr Val Thr lie Asn cys Gin Al a Ser Gin Asn lie Tyr Ser Asn 20 25 30 Leu Al a T rp Tyr Gin Gin Arg Pro Gly Gin Arg Pro Lys Leu Leu lie 35 40 45 Tyr Gly Al a Ser Asn Leu Asp Al a Gly Val Pro Ser Arg Phe Arg Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Asp Leu Glu cys 65 70 75 80 Asp Asp Val Gly Thr Tyr Tyr cys Gin Ser Al a Phe Asp Ser Asp Ser 85 90 95 Thr Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg

    100 105 110 <210> 2

    Page 1

    2016273912 14 Dec 2016 <211> 217 <212> PRT <213> Synthetic <400> 2

    Ala Leu Val 1 Met Thr Gin 5 Thr Pro Ser Ser Val 10 Ser Al a Al a Val 15 Gly Gly Thr Val Thr lie Asn cys Gin Al a Ser Gin Asn lie Tyr Ser Asn 20 25 30 Leu Al a T rp Tyr Gin Gin Arg Pro Gly Gin Arg Pro Lys Leu Leu lie 35 40 45 Tyr Gly Al a Ser Asn Leu Asp Al a Gly Val Pro Ser Arg Phe Arg Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Asp Leu Glu cys 65 70 75 80 Asp Asp Val Gly Thr Tyr Tyr cys Gin Ser Al a Phe Asp Ser Asp Ser 85 90 95 Thr Glu Asn Thr Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190 Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215

    <210> 3 <211> 118 <212> PRT <213> Oryctolagus cunicuius <400> 3

    Page 2

    2016273912 14 Dec 2016

    Gin Ser 1 Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr 15 Pro 5 10 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Al a 20 25 30 Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 Val lie Thr Ser lie Gly Ser Thr Val Tyr Al a Ser T rp Al a Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe cys Al a Arg Gly Tyr 85 90 95 Asp Asp Tyr Asp Glu Met Thr Tyr Phe Asn lie T rp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 4 <211> 448 <212> PRT <213> : Syntheti c <400> 4 Gin Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr Al a 20 25 30 Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 Val lie Thr Ser lie Gly Ser Thr Val Tyr Al a Ser T rp Al a Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe cys Al a Arg Gly Tyr 85 90 95 Asp Asp Tyr Asp Glu Met Thr Tyr Phe Asn lie T rp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125

    Page 3

    2016273912 14 Dec 2016

    Leu Al a 130 Pro Ser Ser Lys Ser Thr Ser Gly 135 Gly Thr 140 Al a Al a Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn 145 150 155 160 Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr 210 215 220 Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255 Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr 325 330 335 lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser 370 375 380 Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp

    385 390 395 400

    Page 4

    2016273912 14 Dec 2016

    Ser Asp Gly Ser Phe 405 Phe Leu Tyr Ser Lys 410 Leu Thr Val Asp Lys 415 Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a 420 425 430 Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys

    435 440 445 <210> 5 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 5

    Gin Ala Ser Gin Asn lie Tyr Ser Asn Leu Ala 15 10 <210> 6 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 6

    Gly Ala Ser Asn Leu Asp Ala 1 5 <210> 7 <211> 12 <212> PRT <213> Oryctolagus cunicuius <400> 7

    Gin Ser Ala Phe Asp Ser Asp Ser Thr Glu Asn Thr 15 10 <210> 8 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 8

    Ser Tyr Ala Met Ser 1 5 <210> 9 <211> 16 <212> PRT <213> Oryctolagus cunicuius <400> 9

    Val lie Thr Ser lie Gly Ser Thr Val Tyr Ala Ser Trp Ala Lys Gly 15 10 15 <210> 10

    Page 5

    2016273912 14 Dec 2016 <211> 13 <212> PRT <213> Oryctolagus curricuius <400> 10

    Gly Tyr Asp Asp Tyr Asp Glu Met Thr Tyr Phe Asn lie 1 5 10 <210> 11 <211> 111 <212> PRT <213> Synthetic <400> 11 Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Al a Ser Gin Asn lie Tyr Ser Asn 20 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu Leu lie 35 40 45 Tyr Gly Ala Ser Asn Leu Asp Al a Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr cys Gin Ser Al a Phe Asp Ser Asp Ser 85 90 95 Thr Glu Asn Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg

    100 105 110 <210> 12 <211> 217 <212> PRT <213> Synthetic <400> 12

    Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Al a Ser Gin Asn lie Tyr Ser Asn 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu Leu lie 35 40 45 Tyr Gly Al a Ser Asn Leu Asp Al a Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro

    Page 6

    2016273912 14 Dec 2016

    65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr cys Gin Ser Al a Phe Asp Ser Asp Ser 85 90 95 Thr Glu Asn Thr Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190 Lys Val Tyr Al a Cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 13 <211> 121 <212> PRT <213> : Syntheti c <400> 13 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Val Ser Ser Tyr 20 25 30 Al a Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Val lie Thr Ser lie Gly Ser Thr Val Tyr Al a Ser Ser Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95

    Page 7

    2016273912 14 Dec 2016

    Arg Gly Tyr Asp Asp Tyr Asp Glu Met Thr Tyr Phe Asn lie Trp Gly 100 105 110

    Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 14 <211> 451 <212> PRT <213> Synthetic <400> 14

    Glu 1 Val Gin Leu Val 5 Glu Ser Gly Gly Gly 10 Leu Val Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Val Ser Ser Tyr 20 25 30 Al a Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Val lie Thr Ser lie Gly Ser Thr Val Tyr Al a Ser Ser Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Gly Tyr Asp Asp Tyr Asp Glu Met Thr Tyr Phe Asn lie T rp Gly 100 105 110 Gin Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a 130 135 140 Al a Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys

    Page 8

    2016273912 14 Dec 2016

    210

    215

    220

    Asp 225 Lys Thr Hi s Thr cys 230 Pro Pro Cys Pro Al a 235 Pro Glu Leu Leu Gly 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val 275 280 285 Hi s Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie 325 330 335 Glu Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365 Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu 370 375 380 T rp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met 420 425 430 Hi s Glu Al a Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser

    435 440 445

    Pro Gly Lys 450

    <210> 15 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 15

    Page 9

    2016273912 14 Dec 2016

    Gin Ala Ser Gin Asn lie Tyr Ser Asn Leu Ala 15 10 <210> 16 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 16

    Gly Ala Ser Asn Leu Asp Ala 1 5 <210> 17 <211> 12 <212> PRT <213> Oryctolagus cunicuius <400> 17

    Gin Ser Ala Phe Asp Ser Asp Ser Thr Glu Asn Thr 15 10 <210> 18 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 18

    Ser Tyr Ala Met Ser 1 5 <210> 19 <211> 16 <212> PRT <213> Synthetic <400> 19

    Val lie Thr Ser lie Gly Ser Thr Val Tyr Ala Ser Ser Ala Lys Gly 15 10 15 <210> 20 <211> 13 <212> PRT <213> Oryctolagus cunicuius <400> 20

    Gly Tyr Asp Asp Tyr Asp Glu Met Thr Tyr Phe Asn lie 15 10 <210> 21 <211> 111 <212> PRT <213> Oryctolagus cunicuius <400> 21

    Ala Val Leu Thr Gin Thr Pro Ser Pro Val Ser Ala Ala Met Gly Asp 15 10 15

    Page 10

    2016273912 14 Dec 2016

    Thr Val Thr lie 20 Lys cys Gin Ser Ser 25 Gin Ser Val Tyr Lys 30 Asn Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Arg Leu Leu 35 40 45 lie Tyr Asp Al a Ser Asn Leu Pro Ser Gly Val Pro Ser Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Gly Val Gin 65 70 75 80 Cys Asp Asp Al a Al a Thr Tyr Tyr Cys Leu Gly Asp Tyr Asp Asp Asp 85 90 95 Ala Asp Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 <210> 22 <211> 217 <212> PRT <213> : Syntheti c <400> 22 Ala Val Leu Thr Gin Thr Pro Ser Pro Val Ser Al a Al a Met Gly Asp 1 5 10 15 Thr Val Thr lie Lys cys Gin Ser Ser Gin Ser Val Tyr Lys Asn Asn 20 25 30 Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Arg Leu Leu 35 40 45 lie Tyr Asp Al a Ser Asn Leu Pro Ser Gly Val Pro Ser Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Gly Val Gin 65 70 75 80 Cys Asp Asp Al a Al a Thr Tyr Tyr Cys Leu Gly Asp Tyr Asp Asp Asp 85 90 95 Ala Asp Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Thr 100 105 110 Val Ala Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140

    Page 11

    2016273912 14 Dec 2016

    Arg 145 Glu Ala Lys Val Gin 150 Trp Lys Val Asp Asn Ala Leu Gin Ser Gly 155 160 Asn Ser Gin Glu Ser 165 Val Thr Glu Gin Asp Ser 170 Lys Asp Ser Thr Tyr 175 Ser Leu Ser Ser Thr 180 Leu Thr Leu Ser 185 Lys Ala Asp Tyr Glu Lys His 190 Lys Val Tyr Ala Cys Glu Val Thr His 195 200 Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 23 <211> 113 <212> PRT <213> Oryctolagus cunicuius <400> 23 Gin Gly Leu Ser Ser Pro Val 205 Gin 1 Ser Val Glu Glu 5 Ser Gly Gly Arg Leu Val 10 Thr Pro Gly Thr Pro 15 Leu Thr Leu Thr Cys 20 Thr Val Ser Gly 25 Phe Ser Leu Ser Ser Tyr Val 30 Met lie Trp Val Arg 35 Gin Ala Pro Gly 40 Lys Gly Leu Glu Tyr lie Gly 45 lie Thr Trp Ser Ala 50 Gly Thr Tyr Tyr 55 Ala Ser Trp Ala Lys Gly Arg 60 Phe 65 Thr lie Ser Lys Thr 70 Ser Ser Thr Thr Val 75 Asp Leu Lys lie Thr 80 Ser Pro Thr Thr Glu 85 Asp Thr Ala Thr Tyr Phe 90 Cys Ala Gly Gly Gly 95 Gly Ser lie Tyr Asp 100 Ser <210> 24 <211> 443 <212> PRT <213> Synthetic <400> 24 lie Trp Gly Pro 105 Gly Thr Leu Val Thr Val Ser 110 Gin 1 Ser Val Glu Glu 5 Ser Gly Gly Arg Leu Val 10 Thr Pro Gly Thr Pro 15

    Page 12

    2016273912 14 Dec 2016

    Leu Thr Leu Thr 20 cys Thr Val Ser Met lie T rp 35 Val Arg Gin Al a Pro 40 lie Thr 50 T rp Ser Al a Gly Thr 55 Tyr Phe 65 Thr lie Ser Lys Thr 70 Ser Ser Ser Pro Thr Thr Glu 85 Asp Thr Al a Gly Ser lie Tyr 100 Asp lie T rp Gly Ser Al a Ser 115 Thr Lys Gly Pro Ser 120 Lys Ser 130 Thr Ser Gly Gly Thr 135 Al a Tyr 145 Phe Pro Glu Pro Val 150 Thr Val Ser Gly Val Hi s Thr 165 Phe Pro Al a Ser Leu Ser Ser 180 Val Val Thr Val Thr Tyr lie 195 cys Asn Val Asn Hi s 200 Lys Arg 210 Val Glu Pro Lys Ser 215 cys Cys 225 Pro Al a Pro Glu Leu 230 Leu Gly Pro Lys Pro Lys Asp 245 Thr Leu Met cys Val Val Val 260 Asp Val Ser Hi s T rp Tyr Val 275 Asp Gly Val Glu Val 280

    Gly 25 Phe Ser Leu Ser Ser 30 Tyr Val Gly Lys Gly Leu Glu 45 Tyr lie Gly Tyr Al a Ser T rp 60 Al a Lys Gly Arg Thr Thr Val 75 Asp Leu Lys lie Thr 80 Thr Tyr 90 Phe cys Al a Gly Gly 95 Gly Pro 105 Gly Thr Leu Val Thr 110 Val Ser Val Phe Pro Leu Al a 125 Pro Ser Ser Al a Leu Gly cys 140 Leu Val Lys Asp Ser T rp Asn 155 Ser Gly Al a Leu Thr 160 Val Leu 170 Gin Ser Ser Gly Leu 175 Tyr Pro 185 Ser Ser Ser Leu Gly 190 Thr Gin Lys Pro Ser Asn Thr 205 Lys Val Asp Asp Lys Thr Hi s 220 Thr cys Pro Pro Gly Pro Ser 235 Val Phe Leu Phe Pro 240 lie Ser 250 Arg Thr Pro Glu Val 255 Thr Glu 265 Asp Pro Glu Val Lys 270 Phe Asn Hi s Asn Al a Lys Thr Lys Pro Arg

    285

    Page 13

    2016273912 14 Dec 2016

    Glu Glu 290 Gin Tyr Ala Ser Thr Tyr Arg Val 295 Val Ser Val 300 Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr Lys cys Lys Val Ser 305 310 315 320 Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr lie Ser Lys Al a Lys 325 330 335 Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu 340 345 350 Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser Asn Gly Gin Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg T rp Gin Gin Gly 405 410 415 Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a Leu Hi s Asn Hi s Tyr 420 425 430 Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <210> 25 <211> 13 <212> PRT <213> i Oryctolagus cunicuius <400> 25 Gin Ser Ser Gin Ser Val Tyr Lys Asn Asn Tyr Leu Ser

    15 10 <210> 26 <211> 7 <212> PRT <213> Oryctolagus curricuius <400> 26

    Asp Ala Ser Asn Leu Pro Ser

    1 5 <210> 27 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 27

    Page 14

    2016273912 14 Dec 2016

    Leu Gly Asp Tyr Asp Asp Asp Ala Asp Asn Ala 15 10 <210> 28 <211> 5 <212> PRT <213> Oryctolagus curricuius <400> 28

    Ser Tyr Val Met lie 1 5 <210> 29 <211> 15 <212> PRT <213> Oryctolagus curri cuius <400> 29 lie Thr Trp Ser Ala Gly Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 15 10 15 <210> 30 <211> 8 <212> PRT <213> Oryctolagus curri cuius <400> 30

    Gly Gly Gly Ser lie Tyr Asp lie 1 5 <210> 31 <211> 112 <212> PRT <213> Synthetic

    <4oo> : 31 Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Ser Ser Gin Ser Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu 35 40 45 Leu lie Tyr Asp Al a Ser Asn Leu Pro Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu 65 70 75 80 Gin Pro Asp Asp Phe Al a Thr Tyr Tyr cys Leu Gly Asp Tyr Asp Asp 85 90 95 Asp Al a Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg

    Page 15

    2016273912 14 Dec 2016

    100 105 110 <210> 32 <2ii> ; 218 <212> PRT <213> : Syntheti c <400> 32 Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Ser Ser Gin Ser Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu 35 40 45 Leu lie Tyr Asp Al a Ser Asn Leu Pro Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu 65 70 75 80 Gin Pro Asp Asp Phe Al a Thr Tyr Tyr cys Leu Gly Asp Tyr Asp Asp 85 90 95 Asp Al a Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 Thr Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys 180 185 190 Hi s Lys Val Tyr Al a Cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215

    <210> 33 <211> 115 <212> PRT

    Page 16

    2016273912 14 Dec 2016 <213> Synthetic <400> 33

    Glu Val 1 Gin Leu Val 5 Glu Ser Gly Gly Gly Leu 10 Val Gin Pro Gly Gly 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Tyr 20 25 30 Val Met lie Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Tyr lie 35 40 45 Gly lie Thr Trp Ser Al a Gly Thr Tyr Tyr Ala Ser Ser Ala Lys Gly 50 55 60 Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 65 70 75 80 Met Asn Ser Leu Arg Al a Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gly 85 90 95 Gly Gly Gly Ser lie Tyr Asp lie Trp Gly Gin Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 34 <211> 445 <212> PRT <213> : Syntheti c <400> 34 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Ala Ala Ser Gly Phe Thr Val Ser Ser Tyr 20 25 30 Val Met lie Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Tyr lie 35 40 45 Gly lie Thr Trp Ser Al a Gly Thr Tyr Tyr Ala Ser Ser Ala Lys Gly 50 55 60 Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gin 65 70 75 80 Met Asn Ser Leu Arg Al a Glu Asp Thr Ala Val Tyr Tyr Cys Ala Gly 85 90 95 Gly Gly Gly Ser lie Tyr Asp lie Trp Gly Gin Gly Thr Leu Val Thr 100 105 110

    Page 17

    2016273912 14 Dec 2016

    Val Ser Ser Ala Ser Thr 115 Lys Gly 120 Pro Ser Val Phe Pro 125 Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn Ser Gly Al a 145 150 155 160 Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr Hi s Thr cys 210 215 220 Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu 245 250 255 Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr Lys cys Lys 305 310 315 320 Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr lie Ser Lys 325 330 335 Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser Asn Gly Gin

    370 375 380

    Page 18

    2016273912 14 Dec 2016

    Pro Glu Asn Asn Tyr 385 Lys Thr 390 Thr Pro Pro Val 395 Leu Asp Ser Asp Gly 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg T rp Gin 405 410 415 Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a Leu Hi s Asn 420 425 430 Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys

    435 440 445 <210> 35 <211> 13 <212> PRT <213> Oryctolagus curricuius <400> 35

    Gin Ser Ser Gin Ser Val Tyr Lys Asn Asn Tyr Leu Ser 15 10 <210> 36 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 36

    Asp Ala Ser Asn Leu Pro Ser 1 5 <210> 37 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 37

    Leu Gly Asp Tyr Asp Asp Asp Ala Asp Asn Ala 15 10 <210> 38 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 38

    Ser Tyr Val Met lie 1 5 <210> 39 <211> 15 <212> PRT <213> Synthetic <400> 39 lie Thr Trp Ser Ala Gly Thr Tyr Tyr Ala Ser Ser Ala Lys Gly Page 19

    2016273912 14 Dec 2016

    1 5 <210> 40 <211> 8 <212> PRT <213> Oryctolagus cunicuius

    <400> 40

    Gly Gly Gly Ser lie Tyr Asp lie 1 5 <210> 41 <211> 111 <212> PRT <213> Oryctolagus cunicuius <400> 41

    Ala Tyr Asp Met Thr Gin Thr Pro Al a Ser Val Glu Val Al a Val Gly 1 5 10 15 Gly Thr Val Thr lie Lys cys Gin Al a Ser Gin Ser lie Tyr Ser Asn 20 25 30 Leu Ala T rp Tyr Gin Gin Arg Pro Gly Gin Pro Pro Lys Leu Leu lie 35 40 45 Tyr Asp Al a Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Gly Val Glu cys 65 70 75 80 Ala Asp Al a Al a Ser Tyr Tyr cys Gin Gin Gly Phe Thr Val Ser Asp 85 90 95 lie Asp Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 <210> 42 <211> : 217 <212> PRT <213> : Syntheti c <400> 42 Ala Tyr Asp Met Thr Gin Thr Pro Al a Ser Val Glu Val Al a Val Gly 1 5 10 15 Gly Thr Val Thr lie Lys cys Gin Al a Ser Gin Ser lie Tyr Ser Asn 20 25 30 Leu Ala T rp Tyr Gin Gin Arg Pro Gly Gin Pro Pro Lys Leu Leu lie 35 40 45 Tyr Asp Al a Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly

    Page 20

    2016273912 14 Dec 2016

    Ser 65 Gly Ser Gly Thr Glu Tyr Thr 70 Leu Thr lie 75 Ser Gly Val Glu cys 80 Al a Asp Al a Al a Ser Tyr Tyr cys Gin Gin Gly Phe Thr Val Ser Asp 85 90 95 lie Asp Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190 Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys

    210 215 <210> 43 <211> 118 <212> PRT <213> Oryctolagus cunicuius

    <400> 43 Gin Ser Val 1 Glu Glu 5 Ser Gly Gly Arg Leu 10 Val Thr Pro Gly Thr 15 Pro Leu Thr Leu Thr cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Al a 20 25 30 Val Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 lie lie Gly Arg Asn Gly Asn Thr T rp Tyr Al a Ser T rp Al a Arg Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie Thr 65 70 75 80

    Page 21

    2016273912 14 Dec 2016

    Ser Pro Thr Ser Glu 85 Asp Thr Ala Thr Tyr 90 Phe Cys Al a Arg Gly 95 Tyr Gly Arg Ser Val Al a Tyr Tyr Val Phe Asn lie T rp Gly Pro Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> ‘ 44 <211> ‘ 448 <212> 1 PRT <213> : Syntheti c <400> ‘ 44 Gin Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr cys Thr Val Ser Gly Phe Ser Leu Ser Asn Tyr Al a 20 25 30 Val Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 lie lie Gly Arg Asn Gly Asn Thr T rp Tyr Al a Ser T rp Al a Arg Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie Thr 65 70 75 80 Ser Pro Thr Ser Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Gly Tyr 85 90 95 Gly Arg Ser Val Al a Tyr Tyr Val Phe Asn lie T rp Gly Pro Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly 130 135 140 cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn 145 150 155 160 Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser

    Page 22

    2016273912 14 Dec 2016

    195 200 205

    Asn Thr 210 Lys Val Asp Lys Arg 215 Val Glu Pro Lys Ser 220 cys Asp Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255 Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr 325 330 335 lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser 370 375 380 Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a 420 425 430 Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

    <210> 45 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 45

    Page 23

    2016273912 14 Dec 2016

    Gin Ala Ser Gin Ser lie Tyr Ser Asn Leu Ala 15 10 <210> 46 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 46

    Asp Ala Ser Thr Leu Glu Ser 1 5 <210> 47 <211> 12 <212> PRT <213> Oryctolagus cunicuius <400> 47

    Gin Gin Gly Phe Thr Val Ser Asp lie Asp Asn Ala 15 10 <210> 48 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 48

    Asn Tyr Ala Val Gly 1 5 <210> 49 <211> 16 <212> PRT <213> Oryctolagus cunicuius <400> 49 lie lie Gly Arg Asn Gly Asn Thr Trp Tyr Ala Ser Trp Ala Arg Gly 15 10 15 <210> 50 <211> 13 <212> PRT <213> Oryctolagus cunicuius <400> 50

    Gly Tyr Gly Arg Ser Val Ala Tyr Tyr Val Phe Asn lie 15 10 <210> 51 <211> 111 <212> PRT <213> Synthetic <400> 51

    Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 15 10 15

    Page 24

    2016273912 14 Dec 2016

    Asp Arg Val Thr 20 lie Thr Cys Gin Ala Ser Gin Ser 25 lie Tyr 30 Ser Asn Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu Leu lie 35 40 45 Tyr Asp Al a Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr cys Gin Gin Gly Phe Thr Val Ser Asp 85 90 95 lie Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 <210> ! 52 <211> ; 217 <212> 1 PRT <213> : Syntheti c <400> ! 52 Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Al a Ser Gin Ser lie Tyr Ser Asn 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu Leu lie 35 40 45 Tyr Asp Al a Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr cys Gin Gin Gly Phe Thr Val Ser Asp 85 90 95 lie Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140

    Page 25

    2016273912 14 Dec 2016

    Arg Glu 145 Ala Lys Val Gin Trp Lys Val 150 Asp Asn 155 Al a Leu Gin Ser Gly 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190 Lys Val Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 53 <211> 121 <212> PRT <213> Syntheti c <400> 53 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asn Tyr 20 25 30 Ala Val Gly Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly lie lie Gly Arg Asn Gly Asn Thr T rp Tyr Al a Ser Ser Al a Arg 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Gly Tyr Gly Arg Ser Val Ala Tyr Tyr Val Phe Asn lie T rp Gly 100 105 110 Pro Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 54 <211> 451 <212> PRT <213> Syntheti c <400> 54 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15

    Page 26

    2016273912 14 Dec 2016

    Ser Leu Arg Leu Ser Cys Ala Ala 20 Ser 25 Gly Phe Thr Val Ser 30 Asn Tyr Al a Val Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly lie lie Gly Arg Asn Gly Asn Thr T rp Tyr Al a Ser Ser Al a Arg 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Gly Tyr Gly Arg Ser Val Al a Tyr Tyr Val Phe Asn lie T rp Gly 100 105 110 Pro Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a 130 135 140 Al a Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys 210 215 220 Asp Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val 275 280 285

    Page 27

    2016273912 14 Dec 2016

    Hi s Asn Ala Lys Thr 290 Lys Pro Arg Glu Glu Gin Tyr Ala Ser Thr Tyr 295 300 Arg Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie 325 330 335 Glu Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365 Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu 370 375 380 T rp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met 420 425 430 Hi s Glu Al a Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser

    435 440 445

    Pro Gly Lys 450

    <210> 55 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 55 Gin Ala Ser Gin Ser lie Tyr Ser Asn 1 5 <210> 56 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 56 Asp Ala Ser Thr Leu Glu Ser 1 5 <210> 57 <211> 12 <212> PRT

    Page 28

    2016273912 14 Dec 2016 <213> Oryctolagus cunicuius <400> 57

    Gin Gin Gly Phe Thr Val Ser Asp lie Asp Asn Ala 15 10 <210> 58 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 58

    Asn Tyr Ala Val Gly 1 5 <210> 59 <211> 16 <212> PRT <213> Synthetic <400> 59 lie lie Gly Arg Asn Gly Asn Thr Trp Tyr Ala Ser Ser Ala Arg Gly 15 10 15 <210> 60 <211> 13 <212> PRT <213> Oryctolagus cunicuius <400> 60

    Gly Tyr Gly Arg Ser Val Ala Tyr Tyr Val Phe Asn lie 15 10 <210> 61 <211> 112 <212> PRT <213> Oryctolagus cunicuius <400> 61

    Ala Asp 1 Val Val Met 5 Thr Gin Thr Pro Al a 10 Ser Val Ser Gin Pro 15 Val Gly Gly Thr Val Thr lie Lys cys Gin Al a Ser Glu Asp lie Tyr Asn 20 25 30 Leu Leu Al a T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu 35 40 45 lie Tyr Ser Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe Lys 50 55 60 Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Gly Leu Glu 65 70 75 80 cys Al a Asp Al a Al a Thr Tyr Tyr cys Gin Asn Asn Tyr Leu Val Thr

    Page 29

    2016273912 14 Dec 2016

    85 90 95

    Thr Tyr Gly Val 100 Ala Phe Gly Gly Gly 105 Thr Glu Val Val Val 110 Lys Arg <210> i 62 <211> ; 218 <212> PRT <213> : Syntheti c <400> i 62 Al a Asp Val Val Met Thr Gin Thr Pro Al a Ser Val Ser Gin Pro Val 1 5 10 15 Gly Gly Thr Val Thr lie Lys cys Gin Al a Ser Glu Asp lie Tyr Asn 20 25 30 Leu Leu Al a T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu 35 40 45 lie Tyr Ser Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe Lys 50 55 60 Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Gly Leu Glu 65 70 75 80 cys Al a Asp Al a Al a Thr Tyr Tyr cys Gin Asn Asn Tyr Leu Val Thr 85 90 95 Thr Tyr Gly Val Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 Thr Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys 180 185 190 Hi s Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215

    Page 30

    2016273912 14 Dec 2016 <210> 63 <211> 120 <212> PRT <213> Oryctolagus curricuius <400> 63

    Gin 1 Glu Gin Leu Lys Glu 5 Ser Gly Gly Arg 10 Leu Val Thr Pro Gly Thr 15 Pro Leu Thr Leu Thr cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Al a Met lie T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Tyr lie 35 40 45 Gly Tyr lie Asp Thr Asp Thr Ser Al a Tyr Tyr Al a Ser T rp Val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Thr Ser Thr Thr Val Asp Leu Lys lie 65 70 75 80 Thr Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Ser 85 90 95 Tyr Al a Al a Tyr Gly Gly Tyr Pro Al a Thr Phe Asp Pro T rp Gly Pro 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> i 64 <211> 450 <212> PRT <213> : Syntheti c <400> i 64 Gin Glu Gin Leu Lys Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr 1 5 10 15 Pro Leu Thr Leu Thr cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30 Al a Met lie T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Tyr lie 35 40 45 Gly Tyr lie Asp Thr Asp Thr Ser Al a Tyr Tyr Al a Ser T rp Val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Thr Ser Thr Thr Val Asp Leu Lys lie 65 70 75 80 Thr Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Ser

    85 90 95

    Page 31

    2016273912 14 Dec 2016

    Tyr Ala Ala Tyr Gly Gly Tyr Pro Ala 105 Thr Phe Asp Pro T rp 110 Gly Pro 100 Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a 130 135 140 Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val 165 170 175 Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp 210 215 220 Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255 Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s 275 280 285 Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu 325 330 335 Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu

    355 360 365

    Page 32

    2016273912 14 Dec 2016

    Thr Cys 370 Leu Val Lys Gly Phe Tyr 375 Pro Ser Asp lie Ala 380 Val Glu T rp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met Hi s 420 425 430 Gl u Al a Leu His Asn Hi s Tyr Thr Gl n Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 65 <211> 11 <212> PRT <213> i Oryctolagus cunicuius <400> 65 Gl n Al a Ser Glu Asp lie Tyr Asn Leu Leu Al a

    15 10 <210> 66 <211> 7 <212> PRT <213> Oryctolagus curri cuius <400> 66

    Ser Ala Ser Thr Leu Ala Ser 1 5 <210> 67 <211> 12 <212> PRT <213> Oryctolagus curri cuius <400> 67

    Gin Asn Asn Tyr Leu Val Thr Thr Tyr Gly Val Ala 15 10 <210> 68 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 68

    Ser Tyr Ala Met lie 1 5

    Page 33

    2016273912 14 Dec 2016 <210> 69 <211> 16 <212> PRT <213> Oryctolagus cunicuius <400> 69

    Tyr lie Asp Thr Asp Thr Ser Ala Tyr Tyr Ala Ser Trp Val Lys Gly 15 10 15 <210> 70 <211> 14 <212> PRT <213> Oryctolagus cunicuius <400> 70

    Ser Tyr Ala Ala Tyr Gly Gly Tyr Pro Ala Thr Phe Asp Pro 15 10 <210> 71 <211> 111 <212> PRT <213> Synthetic <400> 71

    Asp 1 lie Gin Met Thr Gin 5 Ser Pro Ser Ser 10 Leu Ser Ala Ser Val 15 Gly Asp Arg Val Thr lie Thr cys Gin Al a Ser Glu Asp lie Tyr Asn Leu 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45 Tyr Ser Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Glu Asp Val Al a Thr Tyr Tyr cys Gin Asn Asn Tyr Leu Val Thr Thr 85 90 95 Tyr Gly Val Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg

    100 105 110 <210> 72 <211> 217 <212> PRT <213> Synthetic

    <400> 72 Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Al a Ser Glu Asp lie Tyr Asn Leu

    Page 34

    2016273912 14 Dec 2016

    20 25 30

    Leu Ala Trp Tyr Gin Gin Lys Pro 40 Gly Lys Val Pro Lys 45 Leu Leu lie 35 Tyr Ser Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Glu Asp Val Al a Thr Tyr Tyr cys Gin Asn Asn Tyr Leu Val Thr Thr 85 90 95 Tyr Gly Val Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190 Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 73 <211> : 122 <212> PRT <213> : Syntheti c <400> 73 Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Al a Met lie T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Tyr lie

    35 40 45

    Page 35

    2016273912 14 Dec 2016

    Gly Tyr lie Asp Thr 50 Asp Thr Ser Ala Tyr Tyr Ala Ser Ser Val Lys 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Al a 85 90 95 Arg Ser Tyr Ala Ala Tyr Gly Gly Tyr Pro Ala Thr Phe Asp Pro T rp 100 105 110 Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 74 <211> 452 <212> PRT <213> Synthetic <400> 74 Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met lie Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Tyr lie 35 40 45 Gly Tyr lie Asp Thr Asp Thr Ser Ala Tyr Tyr Ala Ser Ser Val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Al a 85 90 95 Arg Ser Tyr Ala Ala Tyr Gly Gly Tyr Pro Ala Thr Phe Asp Pro T rp 100 105 110 Gly Gin Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro

    Page 36

    2016273912 14 Dec 2016

    165 170 175

    Ala Val Leu Gin 180 Ser Ser Gly Leu Tyr Ser 185 Leu Ser Ser Val 190 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn 195 200 205 Hi s Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser 210 215 220 cys Asp Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met lie Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser 260 265 270 Hi s Glu Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu 275 280 285 Val Hi s Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro 325 330 335 lie Glu Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin 340 345 350 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val 355 360 365 Ser Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val 370 375 380 Glu T rp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 405 410 415 Val Asp Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val 420 425 430 Met Hi s Glu Al a Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu

    435 440 445

    Page 37

    2016273912 14 Dec 2016

    Ser Pro Gly Lys 450

    <210> <211> <212> <213> 75 11 PRT Oryctolagus cuni culus <400> 75 Gin Ala Ser Glu Asp 1 5 i lie Tyr <210> <211> <212> <213> 76 7 PRT Oryctolagus cuni culus

    <400> 76

    Ser Ala Ser Thr Leu Ala Ser 1 5 <210> 77 <211> 12 <212> PRT <213> Oryctolagus cunicuius <400> 77

    Gin Asn Asn Tyr Leu Val Thr Thr Tyr Gly Val Ala 15 10 <210> 78 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 78

    Ser Tyr Ala Met lie 1 5 <210> 79 <211> 16 <212> PRT <213> Synthetic <400> 79

    Tyr lie Asp Thr Asp Thr Ser Ala Tyr Tyr Ala Ser Ser Val Lys Gly 15 10 15 <210> 80 <211> 14 <212> PRT <213> Oryctolagus cunicuius <400> 80

    Ser Tyr Ala Ala Tyr Gly Gly Tyr Pro Ala Thr Phe Asp Pro Page 38

    2016273912 14 Dec 2016

    15 10 <210> 81 <211> 111 <212> PRT <213> Oryctolagus cunicuius <400> 81

    Ala Tyr Asp Met 1 Thr 5 Gin Thr Pro Ala Ser Val 10 Ser Ala Ala Val 15 Gly Gly Thr Val Thr lie Lys Cys Gl n Al a Ser Glu Asn lie Gly Ser Tyr 20 25 30 Leu Ala Trp Tyr Gin Gl n Lys Pro Gly Gin Pro Pro Glu Leu Leu lie 35 40 45 Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Gly Val Glu cys 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gin Gly Tyr Asn Ser Glu Asn 85 90 95 Leu Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 <210> 82 <211> 217 <212> PRT <213> Synthetic <400> 82 Ala Tyr Asp Met Thr Gin Thr Pro Ala Ser Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Thr lie Lys Cys Gl n Al a Ser Glu Asn lie Gly Ser Tyr 20 25 30 Leu Ala Trp Tyr Gin Gl n Lys Pro Gly Gin Pro Pro Glu Leu Leu lie 35 40 45 Tyr Arg Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Gly Val Glu cys 65 70 75 80 Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gin Gly Tyr Asn Ser Glu Asn 85 90 95

    Page 39

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    Leu Asp Asn Ala 100 Phe Gly Gly Gly Thr 105 Glu Val Val Val Lys Arg 110 Thr Val Ala Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Ala Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Gl u Al a Lys Val Gin Trp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Gl u Lys Hi s 180 185 190 Lys Val Tyr Ala Cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 83 <211> 115 <212> PRT <213> Oryctolagus cunicuius <400> 83 Gin Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly lie Asp Leu Ser Met Tyr Ser 20 25 30 Met Gly Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Tyr lie Gly 35 40 45 T rp lie Ser Tyr Gly Gly Thr Al a Tyr Tyr Ala Ser T rp Ala Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Glu Leu Lys lie Thr 65 70 75 80 Ser Pro Thr lie Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Glu Thr 85 90 95 Pro Val Asn Tyr Tyr Leu Asp lie T rp Gly Gin Gly Thr Leu Val Thr 100 105 110

    Val Ser Ser 115

    Page 40

    2016273912 14 Dec 2016 <210> 84 <211> 445 <212> PRT <213> Synthetic <400> 84

    Gin Ser 1 Val Glu Glu 5 Ser Gly Gly Arg Leu 10 Val Thr Pro Gly Thr 15 Pro Leu Thr Leu Thr cys Thr Val Ser Gly lie Asp Leu Ser Met Tyr Ser 20 25 30 Met Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Tyr lie Gly 35 40 45 T rp lie Ser Tyr Gly Gly Thr Al a Tyr Tyr Al a Ser T rp Al a Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Glu Leu Lys lie Thr 65 70 75 80 Ser Pro Thr lie Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Glu Thr 85 90 95 Pro Val Asn Tyr Tyr Leu Asp lie T rp Gly Gin Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Al a Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn Ser Gly Al a 145 150 155 160 Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr Hi s Thr cys 210 215 220 Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

    225 230 235 240

    Page 41

    2016273912 14 Dec 2016

    Phe Pro Pro Lys Pro 245 Lys Asp Thr Leu Met 250 lie Ser Arg Thr Pro 255 Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr Lys cys Lys 305 310 315 320 Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr lie Ser Lys 325 330 335 Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350 Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys Leu Val Lys 355 360 365 Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser Asn Gly Gin 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg T rp Gin 405 410 415 Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a Leu Hi s Asn 420 425 430 Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

    <210> 85 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 85

    Gin Ala Ser Glu Asn lie Gly Ser Tyr Leu Ala

    1 5 <210> 86 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 86

    Page 42

    2016273912 14 Dec 2016

    Arg Ala Ser Thr Leu Ala Ser 1 5 <210> 87 <211> 12 <212> PRT <213> Oryctolagus cunicuius <400> 87

    Gin Gin Gly Tyr Asn Ser Glu Asn Leu Asp Asn Ala 15 10 <210> 88 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 88

    Met Tyr Ser Met Gly 1 5 <210> 89 <211> 16 <212> PRT <213> Oryctolagus cunicuius <400> 89

    Trp lie Ser Tyr Gly Gly Thr Ala Tyr Tyr Ala Ser Trp Ala Lys Gly 15 10 15 <210> 90 <211> 10 <212> PRT <213> Oryctolagus cunicuius <400> 90

    Glu Thr Pro 1 Val Asn 5 Tyr Tyr Leu Asp lie 10 <210> 91 <211> 111 <212> PRT <213> Synthetic <400> 91 Ala Tyr Asp 1 Met Thr 5 Gin Ser Pro Ser Ser 10 Leu Ser Al a Ser Val 15 Gly Asp Arg Val Thr 20 lie Thr cys Gin Al a 25 Ser Glu Asn lie Gly 30 Ser Tyr Leu Ala Trp 35 Tyr Gin Gin Lys Pro 40 Gly Lys Val Pro Lys 45 Leu Leu lie Tyr Arg Ala Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe Ser Gly

    Page 43

    2016273912 14 Dec 2016

    Ser 65 Gly Ser Gly Thr Asp 70 Phe Thr Leu Thr lie 75 Ser Ser Leu Gin Pro 80 Glu Asp Val Al a Thr Tyr Tyr cys Gin Gin Gly Tyr Asn Ser Glu Asn 85 90 95 Leu Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 <210> ! 92 <211> ; 217 <212> 1 PRT <213> : Syntheti c <400> ! 92 Al a Tyr Asp Met Thr Gin Ser Pro Ser Ser Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Al a Ser Glu Asn lie Gly Ser Tyr 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45 Tyr Arg Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Glu Asp Val Al a Thr Tyr Tyr cys Gin Gin Gly Tyr Asn Ser Glu Asn 85 90 95 Leu Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190

    Page 44

    2016273912 14 Dec 2016

    Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 93 <211> 118 <212> PRT <213> Syntheti c <400> 93 Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Ser Met Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Tyr lie 35 40 45 Gly Trp lie Ser Tyr Gly Gly Thr Al a Tyr Tyr Al a Ser Ser Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Ser Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Glu Thr Pro Val Asn Tyr Tyr Leu Asp lie T rp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 94 <211> 448 <212> PRT <213> Syntheti c <400> 94 Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Phe Ser Met Tyr 20 25 30 Ser Met Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Tyr lie 35 40 45 Gly Trp lie Ser Tyr Gly Gly Thr Al a Tyr Tyr Al a Ser Ser Al a Lys 50 55 60

    Page 45

    2016273912 14 Dec 2016

    Gly 65 Arg Phe Thr lie Ser Arg Asp Asn Ser 70 Lys Asn 75 Thr Leu Tyr Leu 80 Gin Met Ser Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Glu Thr Pro Val Asn Tyr Tyr Leu Asp lie T rp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly 130 135 140 cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn 145 150 155 160 Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr 210 215 220 Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255 Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr

    325 330 335

    Page 46

    2016273912 14 Dec 2016

    lie Ser Lys Al a 340 Lys Gly Gin Pro Arg 345 Glu Pro Gin Val Tyr 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser 370 375 380 Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a 420 425 430 Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

    <210> 95 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 95

    Gin Ala Ser Glu Asn lie Gly Ser Tyr Leu Ala 15 10 <210> 96 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 96

    Arg Ala Ser Thr Leu Ala Ser 1 5 <210> 97 <211> 12 <212> PRT <213> Oryctolagus cunicuius <400> 97

    Gin Gin Gly Tyr Asn Ser Glu Asn Leu Asp Asn Ala

    1 5 <210> 98 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 98

    Page 47

    2016273912 14 Dec 2016

    Met Tyr Ser Met Gly 1 5

    <210> 99 <211> 16 <212> PRT <213> Syntheti c <400> 99 Trp lie Ser Tyr Gly Gly Thr Ala Tyr Tyr Ala Ser Ser Ala Lys Gly 1 5 10 15 <210> 100 <211> 10 <212> PRT <213> Oryctolagus cunicuius <400> 100 Glu Thr Pro Val Asn Tyr Tyr Leu Asp lie 1 5 10 <210> 101 <211> 109 <212> PRT <213> Oryctolagus cunicuius

    <400> 101

    Ala Phe Glu Leu Thr Gin Thr Pro Ser Ser Val Glu Al a Al a Val Gly 1 5 10 15 Gly Thr Val Thr lie Lys cys Gin Al a Ser Gin Asn lie Val Thr Asn 20 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie 35 40 45 Tyr Gly Ala Ser Thr Leu Al a Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Asp Leu Glu cys 65 70 75 80 Ala Asp Ala Al a Thr Tyr Phe cys Gin Ser Tyr Asp Gly Phe Asn Ser 85 90 95 Ala Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 <210> 102 <211> 215 <212> PRT <213> Synthetic <400> 102 Ala Phe Glu Leu Thr Gin Thr Pro Ser Ser Val Glu Al a Al a Val Gly

    Page 48

    2016273912 14 Dec 2016

    1 5 10 15 Gly Thr Val Thr lie Lys cys Gin Al a Ser Gin Asn lie Val Thr Asn 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie 35 40 45 Tyr Gly Al a Ser Thr Leu Al a Ser Gly Val Ser Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Asp Leu Glu cys 65 70 75 80 Al a Asp Al a Al a Thr Tyr Phe cys Gin Ser Tyr Asp Gly Phe Asn Ser 85 90 95 Al a Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Thr Val Al a 100 105 110 Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser 115 120 125 Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly Asn Ser 145 150 155 160 Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s Lys Val 180 185 190 Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu cys

    210 215 <210> 103 <211> 120 <212> PRT <213> Oryctolagus cunicuius <400> 103

    Gin Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr cys Thr Al a Ser Gly Phe Ser Leu Ser Gly Tyr Asp

    20 25 30

    Page 49

    2016273912 14 Dec 2016

    Met Ser Trp Val Arg Gin Ala Pro Gly 40 Lys Gly Leu Glu Tyr 45 lie Gly 35 Leu lie Ser Tyr Asp Gly Asn Thr Tyr Tyr Ala Thr Trp Ala Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe cys Ala Arg Ser Leu 85 90 95 Tyr Ala Gly Pro Asn Ala Gly lie Gly Pro Phe Asn lie Trp Gly Gin 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> : 104 <211> ‘ 450 <212> 1 PRT <213> : Syntheti c <400> : 104 Gin Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr cys Thr Ala Ser Gly Phe Ser Leu Ser Gly Tyr Asp 20 25 30 Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Tyr lie Gly 35 40 45 Leu lie Ser Tyr Asp Gly Asn Thr Tyr Tyr Ala Thr Trp Ala Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie Thr 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Ala Thr Tyr Phe cys Ala Arg Ser Leu 85 90 95 Tyr Ala Gly Pro Asn Ala Gly lie Gly Pro Phe Asn lie Trp Gly Gin 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

    Page 50

    2016273912 14 Dec 2016

    145 150 155 160

    Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 170 Hi s Thr Phe Pro Al a 175 Val 165 Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp 210 215 220 Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255 Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s 275 280 285 Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu 325 330 335 Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu 355 360 365 Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp 370 375 380 Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s

    420 425 430

    Page 51

    2016273912 14 Dec 2016

    Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445

    Gly Lys 450 <210> 105 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 105

    Gin Ala Ser Gin Asn lie Val Thr Asn Leu Ala 15 10 <210> 106 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 106

    Gly Ala Ser Thr Leu Ala Ser 1 5 <210> 107 <211> 10 <212> PRT <213> Oryctolagus cunicuius <400> 107

    Gin Ser Tyr Asp Gly Phe Asn Ser Ala Gly 15 10 <210> 108 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 108

    Gly Tyr Asp Met Ser 1 5 <210> 109 <211> 16 <212> PRT <213> Oryctolagus cunicuius <400> 109

    Leu lie Ser Tyr Asp Gly Asn Thr Tyr Tyr Ala Thr Trp Ala Lys Gly

    1 5 <210> 110 <211> 15 <212> PRT <213> Oryctolagus cunicuius

    Page 52

    2016273912 14 Dec 2016 <400> 110

    Ser 1 Leu Tyr Ala Gly Pro Asn Ala Gly lie Gly Pro Phe Asn lie 15 5 10 <210> 111 <211> 109 <212> PRT <213> Synthetic <400> 111 Al a Phe Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asn lie Val Thr Asn 20 25 30 Leu Ala Trp Tyr Gl n Gln Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45 Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gin Ser Tyr Asp Gly Phe Asn Ser 85 90 95 Al a Gly Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 <210> 112 <211> 215 <212> PRT <213> Synthetic <400> 112 Al a Phe Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr Cys Gin Ala Ser Gin Asn lie Val Thr Asn 20 25 30 Leu Ala Trp Tyr Gl n Gln Lys Pro Gly Lys Val Pro Lys Leu Leu lie 35 40 45 Tyr Gly Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80

    Page 53

    2016273912 14 Dec 2016

    Glu Asp Val Al a Thr 85 Tyr Tyr cys Gin Ser Tyr Asp Gly Phe Asn Ser 90 95 Ala Gly Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gin T rp Lys Val Asp Asn Ala Leu Gin Ser Gly Asn Ser 145 150 155 160 Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 113 <211> 123 <212> PRT <213> Synthetic <400> 113 Gin Val Gin Leu Val Glu Ser Gly Gly Gly Val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Al a Ser Gly Phe Ser Leu Ser Gly Tyr 20 25 30 Asp Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Leu lie Ser Tyr Asp Gly Asn Thr Tyr Tyr Ala Thr Ser Ala Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Ser Leu Tyr Al a Gly Pro Asn Ala Gly lie Gly Pro Phe Asn lie 100 105 110

    Page 54

    2016273912 14 Dec 2016

    Trp Gly Gin Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 114 <211> 453 <212> PRT <213> Synthetic <400> 114

    Gin Val 1 Gin Leu Val 5 Glu Ser Gly Gly Gly Val 10 Val Gin Pro Gly 15 Arg Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Ser Leu Ser Gly Tyr 20 25 30 Asp Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Leu lie Ser Tyr Asp Gly Asn Thr Tyr Tyr Al a Thr Ser Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Ser Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Ser Leu Tyr Al a Gly Pro Asn Al a Gly lie Gly Pro Phe Asn lie 100 105 110 T rp Gly Gin Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly 115 120 125 Pro Ser Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly 130 135 140 Thr Al a Al a Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val 145 150 155 160 Thr Val Ser T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe 165 170 175 Pro Al a Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 180 185 190 Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val 195 200 205 Asn Hi s Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys 210 215 220

    Page 55

    2016273912 14 Dec 2016

    Ser Cys Asp 225 Lys Thr Hi s 230 Thr cys Pro Pro cys 235 Pro Ala Pro Glu Leu 240 Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 245 250 255 Leu Met lie Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val 260 265 270 Ser Hi s Glu Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val 275 280 285 Glu Val Hi s Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser 290 295 300 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu 305 310 315 320 Asn Gly Lys Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a 325 330 335 Pro lie Glu Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro 340 345 350 Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin 355 360 365 Val Ser Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a 370 375 380 Val Glu T rp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr 385 390 395 400 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu 405 410 415 Thr Val Asp Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser 420 425 430 Val Met Hi s Glu Al a Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser

    435 440 445

    Leu Ser Pro Gly Lys 450 <210> 115 <211> 11 <212> PRT <213> Oryctolagus cuniculus <400> 115

    Gin Ala Ser Gin Asn lie Val Thr Asn Leu Ala 15 10

    Page 56

    2016273912 14 Dec 2016

    <210> <211> <212> <213> 116 7 PRT Oryctolagus cuni culus <400> 116 Gly Ala Ser Thr Leu i Ala Ser 1 5 <210> 117 <211> 10 <212> PRT <213> Oryctolagus cuni culus <400> 117

    Gin Ser Tyr Asp Gly Phe Asn 1 5 <210> <211> <212> <213> 118 5 PRT Oryctolagus cuniculus

    <400> 118

    Gly Tyr Asp Met Ser 1 5 <210> 119 <211> 16 <212> PRT <213> Synthetic <400> 119

    Leu lie Ser Tyr Asp Gly Asn Thr Tyr Tyr Ala Thr Ser Ala Lys Gly 15 10 15 <210> 120 <211> 15 <212> PRT <213> Oryctolagus cunicuius <400> 120

    Ser Leu Tyr Ala Gly Pro Asn Ala Gly lie Gly Pro Phe Asn lie 15 10 15 <210> 121 <211> 112 <212> PRT <213> Oryctolagus cunicuius <400> 121

    Ala Ala Val Leu Thr Gin Thr Pro Ser Pro Val Ser Ala Ala Val Gly 15 10 15

    Gly Thr Val

    Ser lie Ser Cys Gin Ser

    Ser Gin Asn Val Page 57

    Tyr Lys Asn

    2016273912 14 Dec 2016

    20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu 35 40 45 Leu lie Tyr Lys Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe 50 55 60 Lys Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Asp Val 65 70 75 80 Gin cys Asp Al a Al a Al a Thr Tyr Tyr cys Al a Gly Gly Tyr Thr Ser 85 90 95 Ser Ser Asp Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 <210> : 122 <211> ; 218 <212> PRT <213> : Syntheti c <400> : 122 Al a Al a Val Leu Thr Gin Thr Pro Ser Pro Val Ser Al a Al a Val Gly 1 5 10 15 Gly Thr Val Ser lie Ser cys Gin Ser Ser Gin Asn Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu 35 40 45 Leu lie Tyr Lys Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe 50 55 60 Lys Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Asp Val 65 70 75 80 Gin cys Asp Al a Al a Al a Thr Tyr Tyr cys Al a Gly Gly Tyr Thr Ser 85 90 95 Ser Ser Asp Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 Thr Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160

    Page 58

    2016273912 14 Dec 2016

    Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys 180 185 190 Hi s Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu cys

    210 215 <210> 123 <211> 117 <212> PRT <213> Oryctolagus cunicuius

    <400> 123 Gin Ser Val 1 Glu Al a 5 Ser Gly Gly Arg Leu 10 Val Thr Pro Gly Thr 15 Pro Leu Thr Leu Thr cys Thr Al a Ser Gly Phe Ser Leu Ser Thr Tyr T rp 20 25 30 Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Ser T rp Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Asn Val 65 70 75 80 lie Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Gly 85 90 95 Ser Pro Asp Val Asp lie Gly lie Asp Met T rp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Ser

    115 <210> 124 <211> 447 <212> PRT <213> Synthetic

    <400> 124 Gin Ser Val Glu Al a Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr cys Thr Al a Ser Gly Phe Ser Leu Ser Thr Tyr T rp 20 25 30

    Page 59

    2016273912 14 Dec 2016

    Met Ser Trp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Trp lie Gly 35 40 45 Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Ser T rp Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Asn Val 65 70 75 80 lie Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Gly 85 90 95 Ser Pro Asp Val Asp lie Gly lie Asp Met T rp Gly Pro Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn Ser 145 150 155 160 Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr Hi s 210 215 220 Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255 Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val Ser

    290 295 300

    Page 60

    2016273912 14 Dec 2016

    Val 305 Leu Thr Val Leu Hi s 310 Gin Asp T rp Leu Asn Gly 315 Lys Glu Tyr Lys 320 cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335 Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu T rp Glu Ser Asn 370 375 380 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a Leu 420 425 430 Hi s Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 125 <211> 13 <212> PRT <213> Oryctolagus i cuni culus <400> 125 Gin Ser Ser Gin Asn Val Tyr Lys Asn Asn Tyr Leu Ser 1 5 10 <210> 126 <211> 7 <212> PRT <213> Oryctolagus i cuni culus <400> 126 Lys Ala Ser Thr Leu Al a Ser 1 5 <210> 127 <211> 11 <212> PRT <213> Oryctolagus i cuni culus <400> 127 Al a Gly Gly Tyr Thr Ser Ser Ser Asp Asn Ala 1 5 10

    Page 61

    2016273912 14 Dec 2016 <210> 128 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 128

    Thr Tyr Trp Met Ser 1 5 <210> 129 <211> 17 <212> PRT <213> Oryctolagus cunicuius <400> 129

    Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Ala Ser Trp Ala Lys 15 10 15

    Gly <210> 130 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 130

    Gly Ser Pro Asp Val Asp lie Gly lie Asp Met 15 10 <210> 131 <211> 112 <212> PRT <213> Synthetic

    <400> : L31 Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Ser Ser Gin Asn Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu 35 40 45 Leu lie Tyr Lys Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 65 70 75 80 Gin Pro Glu Asp Val Al a Thr Tyr Tyr cys Al a Gly Gly Tyr Thr Ser 85 90 95

    Page 62

    2016273912 14 Dec 2016

    Ser Ser Asp Asn Ala Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 <210> 132 <211> 218 <212> PRT <213> Synthetic <400> 132

    Asp lie Gin Met Thr Gin Ser Pro Ser Ser 10 Leu Ser Ala Ser Val 15 Gly 1 5 Asp Arg Val Thr lie Thr cys Gin Ser Ser Gin Asn Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu 35 40 45 Leu lie Tyr Lys Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 65 70 75 80 Gin Pro Glu Asp Val Al a Thr Tyr Tyr cys Al a Gly Gly Tyr Thr Ser 85 90 95 Ser Ser Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 Thr Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys 180 185 190 Hi s Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215

    <210> 133 <211> 120

    Page 63

    2016273912 14 Dec 2016 <212> PRT <213> Synthetic <400> 133

    Glu 1 Val Gin Leu Val 5 Glu Ser Gly Gly Gly Leu Val 10 Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Val Ser Thr Tyr 20 25 30 T rp Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Ser Ser Al a 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys 85 90 95 Al a Arg Gly Ser Pro Asp Val Asp lie Gly lie Asp Met T rp Gly Pro 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> : 134 <211> 450 <212> PRT <213> : Syntheti c <400> : 134 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Val Ser Thr Tyr 20 25 30 T rp Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Ser Ser Al a 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys 85 90 95 Al a Arg Gly Ser Pro Asp Val Asp lie Gly lie Asp Met T rp Gly Pro

    Page 64

    2016273912 14 Dec 2016

    100

    105 110

    Gly Thr Leu 115 Val Thr Val Ser Ser 120 Phe Pro 130 Leu Al a Pro Ser Ser 135 Lys Leu 145 Gly cys Leu Val Lys 150 Asp Tyr T rp Asn Ser Gly Al a 165 Leu Thr Ser Leu Gin Ser Ser 180 Gly Leu Tyr Ser Ser Ser Ser 195 Leu Gly Thr Gin Thr 200 Pro Ser 210 Asn Thr Lys Val Asp 215 Lys Lys 225 Thr Hi s Thr cys Pro 230 Pro cys Pro Ser Val Phe Leu 245 Phe Pro Pro Ser Arg Thr Pro 260 Glu Val Thr cys Asp Pro Glu 275 Val Lys Phe Asn T rp 280 Asn Al a 290 Lys Thr Lys Pro Arg 295 Glu Val 305 Val Ser Val Leu Thr 310 Val Leu Glu Tyr Lys cys Lys 325 Val Ser Asn Lys Thr lie Ser 340 Lys Al a Lys Gly Thr Leu Pro 355 Pro Ser Arg Glu Glu 360 Thr cys 370 Leu Val Lys Gly Phe 375 Tyr

    Al a Ser Thr Lys Gly 125 Pro Ser Val Ser Thr Ser Gly 140 Gly Thr Al a Al a Phe Pro Glu 155 Pro Val Thr Val Ser 160 Gly Val 170 Hi s Thr Phe Pro Al a 175 Val Leu 185 Ser Ser Val Val Thr 190 Val Pro Tyr lie cys Asn Val 205 Asn Hi s Lys Arg Val Glu Pro 220 Lys Ser cys Asp Pro Al a Pro 235 Glu Leu Leu Gly Gly 240 Lys Pro 250 Lys Asp Thr Leu Met 255 lie Val 265 Val Val Asp Val Ser 270 Hi s Glu Tyr Val Asp Gly Val 285 Glu Val Hi s Glu Gin Tyr Al a 300 Ser Thr Tyr Arg Hi s Gin Asp 315 T rp Leu Asn Gly Lys 320 Lys Al a 330 Leu Pro Al a Pro lie 335 Glu Gin 345 Pro Arg Glu Pro Gin 350 Val Tyr Met Thr Lys Asn Gin 365 Val Ser Leu Pro Ser Asp lie Al a Val Glu T rp

    380

    Page 65

    2016273912 14 Dec 2016

    Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s 420 425 430 Glu Al a Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro

    435 440 445

    Gly Lys 450

    <210> <211> <212> <213> 135 13 PRT Oryctolagus cuni culus <400> 135 Gin Ser Ser Gin Asn Val Tyr Lys Asn As 1 5 10

    <210> 136 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 136

    Lys Ala Ser Thr Leu Ala Ser

    1 5 <210> 137 <211> 11 <212> PRT <213> Oryctolagus cuniculus <400> 137 Ala Gly Gly Tyr Thr Ser Ser Ser Asp As 1 5 10 <210> 138 <211> 5 <212> PRT <213> Oryctolagus cuniculus <400> 138 Thr Tyr ’ Trp Met Ser 1 5 <210> 139 <211> 17 <212> PRT

    Page 66

    2016273912 14 Dec 2016 <213> Synthetic <400> 139

    Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Ala Ser Ser Ala Lys 15 10 15

    Gly <210> 140 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 140

    Gly Ser Pro Asp Val Asp lie Gly lie Asp Met 15 10 <210> 141 <211> 112 <212> PRT <213> Oryctolagus cunicuius <400> 141

    Ala Ala 1 Val Leu Thr Gin 5 Thr Pro Ser Pro Val 10 Ser Al a Al a Val 15 Gly Asp Thr Val Thr lie Lys cys Gin Ser Ser Gin Ser Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu 35 40 45 Leu lie Tyr Asp Al a Ser Asn Leu Pro Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Gly Val 65 70 75 80 Gin cys Asp Asp Al a Al a Thr Tyr Tyr cys Leu Gly Asp Tyr Asp Asp 85 90 95 Asp Thr Asp Asn Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg

    100 105 110 <210> 142 <211> 218 <212> PRT <213> Synthetic

    <400> 142 Ala Ala Val Leu Thr Gin Thr Pro Ser Pro Val Ser Ala Ala Val Gly 1 5 10 15

    Page 67

    2016273912 14 Dec 2016

    Asp Thr Val Thr 20 lie Lys Cys Gin Ser Ser Gin Ser 25 Val Tyr 30 Lys Asn Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu 35 40 45 Leu lie Tyr Asp Al a Ser Asn Leu Pro Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Gly Val 65 70 75 80 Gin Cys Asp Asp Al a Ala Thr Tyr Tyr Cys Leu Gly Asp Tyr Asp Asp 85 90 95 Asp Thr Asp Asn Gly Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 Thr Val Ala Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin Trp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Al a Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 143 <211> 112 <212> PRT <213> Oryctolagus cunicuius <400> 143 Gin Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr cys Thr Val Ser Gly lie Asp Leu Ser Ser Tyr Al a 20 25 30 Met lie Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Tyr lie Gly 35 40 45

    Page 68

    2016273912 14 Dec 2016

    lie lie Trp Ser Gly Gly Thr Tyr Tyr Ala Thr Trp Ala Lys Gly Arg 50 55 60 Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Gin lie Thr Ser 65 70 75 80 Pro Thr Thr Glu Asp Al a Al a Thr Tyr Phe cys Al a Al a Gly Gly Gly 85 90 95 Ser lie Tyr Asp Val T rp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 105 110 <210> 144 <211> 442 <212> PRT <213> : Syntheti c <400> 144 Gin Ser Val Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr cys Thr Val Ser Gly lie Asp Leu Ser Ser Tyr Al a 20 25 30 Met lie T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu Tyr lie Gly 35 40 45 lie lie T rp Ser Gly Gly Thr Tyr Tyr Al a Thr T rp Al a Lys Gly Arg 50 55 60 Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Gin lie Thr Ser 65 70 75 80 Pro Thr Thr Glu Asp Al a Al a Thr Tyr Phe cys Al a Al a Gly Gly Gly 85 90 95 Ser lie Tyr Asp Val T rp Gly Pro Gly Thr Leu Val Thr Val Ser Ser 100 105 110 Al a Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Al a Pro Ser Ser Lys 115 120 125 Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly cys Leu Val Lys Asp Tyr 130 135 140 Phe Pro Glu Pro Val Thr Val Ser T rp Asn Ser Gly Al a Leu Thr Ser 145 150 155 160 Gly Val Hi s Thr Phe Pro Al a Val Leu Gin Ser Ser Gly Leu Tyr Ser 165 170 175

    Page 69

    2016273912 14 Dec 2016

    Leu Ser Ser Val 180 Val Thr Val Pro Ser 185 Ser Ser Leu Gly Thr 190 Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser Asn Thr Lys Val Asp Lys 195 200 205 Arg Val Glu Pro Lys Ser cys Asp Lys Thr Hi s Thr cys Pro Pro cys 210 215 220 Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 225 230 235 240 Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr cys 245 250 255 Val Val Val Asp Val Ser Hi s Glu Asp Pro Glu Val Lys Phe Asn T rp 260 265 270 Tyr Val Asp Gly Val Glu Val Hi s Asn Al a Lys Thr Lys Pro Arg Glu 275 280 285 Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 290 295 300 Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr Lys cys Lys Val Ser Asn 305 310 315 320 Lys Al a Leu Pro Al a Pro lie Glu Lys Thr lie Ser Lys Al a Lys Gly 325 330 335 Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 340 345 350 Met Thr Lys Asn Gin Val Ser Leu Thr cys Leu Val Lys Gly Phe Tyr 355 360 365 Pro Ser Asp lie Al a Val Glu T rp Glu Ser Asn Gly Gin Pro Glu Asn 370 375 380 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 385 390 395 400 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg T rp Gin Gin Gly Asn 405 410 415 Val Phe Ser cys Ser Val Met Hi s Glu Al a Leu Hi s Asn Hi s Tyr Thr 420 425 430 Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys

    435 440 <210> 145

    Page 70

    2016273912 14 Dec 2016 <211> 13 <212> PRT <213> Oryctolagus cunicuius <400> 145

    Gin Ser Ser Gin Ser Val Tyr Lys Asn Asn Tyr Leu Ser 15 10 <210> 146 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 146

    Asp Ala Ser Asn Leu Pro Ser 1 5 <210> 147 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 147

    Leu Gly Asp Tyr Asp Asp Asp Thr Asp Asn Gly 15 10 <210> 148 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 148

    Ser Tyr Ala Met lie 1 5 <210> 149 <211> 15 <212> PRT <213> Oryctolagus cunicuius <400> 149 lie lie Trp Ser Gly Gly Thr Tyr Tyr Ala Thr Trp Ala Lys Gly 15 10 15 <210> 150 <211> 8 <212> PRT <213> Oryctolagus cunicuius <400> 150

    Gly Gly Gly Ser lie Tyr Asp Val 1 5 <210> 151 <211> 112 <212> PRT <213> Oryctolagus cunicuius

    Page 71

    2016273912 14 Dec 2016 <400> 151

    Al a 1 Leu Val Met Thr Gin 5 Thr Pro Ser Ser 10 Thr Ser Glu Pro Val 15 Gly Gly Thr Val Thr lie Asn cys Gin Al a Ser Gin Asn lie Gly Asn Asp 20 25 30 Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Glu Leu Leu lie 35 40 45 Tyr Ser Thr Ser Lys Leu Al a Thr Gly Val Pro Lys Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Asp Leu Glu cys 65 70 75 80 Asp Asp Al a Al a Thr Tyr Tyr cys Leu Gly Val Tyr Ser Tyr lie Ser 85 90 95 Asp Asp Gly Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 <210> 152 <211> 218 <212> PRT <213> : Syntheti c <400> 152 Al a Leu Val Met Thr Gin Thr Pro Ser Ser Thr Ser Glu Pro Val Gly 1 5 10 15 Gly Thr Val Thr lie Asn cys Gin Al a Ser Gin Asn lie Gly Asn Asp 20 25 30 Leu Ser T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Glu Leu Leu lie 35 40 45 Tyr Ser Thr Ser Lys Leu Al a Thr Gly Val Pro Lys Arg Phe Ser Gly 50 55 60 Ser Arg Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Asp Leu Glu cys 65 70 75 80 Asp Asp Al a Al a Thr Tyr Tyr cys Leu Gly Val Tyr Ser Tyr lie Ser 85 90 95 Asp Asp Gly Asn Al a Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 Thr Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125

    Page 72

    2016273912 14 Dec 2016

    Leu Lys 130 Ser Gly Thr Ala Ser 135 Val Val cys Leu Leu 140 Asn Asn Phe Tyr Pro Arg Gl u Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys 180 185 190 Hi s Lys Val Tyr Ala Cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 153 <211> 120 <212> PRT <213> i Oryctolagus cunicuius <400> 153 Gin Ser Val Glu Glu Phe Gly Gly Arg Leu Val Thr Pro Gly Thr Pro 1 5 10 15 Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Asn Asn Tyr Al a 20 25 30 Met Thr Trp Val Arg Gl n Al a Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 lie lie Gly Ser lie Gly Thr Thr Tyr Tyr Al a Ser T rp Al a Lys Gly 50 55 60 Arg Phe Phe lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie lie 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Asp Al a 85 90 95 Gly Val Thr Val Asp Gly Tyr Gly Tyr Tyr Phe Asn lie T rp Gly Pro 100 105 110 Gly Thr Leu Val Thr Val Ser Ser

    115 <210> 154 <211> 450 <212> PRT <213> Syntheti c

    Page 73

    2016273912 14 Dec 2016 <400> 154

    Gin Ser Val 1 Glu Glu 5 Phe Gly Gly Arg Leu 10 Val Thr Pro Gly Thr 15 Pro Leu Thr Leu Thr cys Thr Val Ser Gly Phe Ser Leu Asn Asn Tyr Al a 20 25 30 Met Thr T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 lie lie Gly Ser lie Gly Thr Thr Tyr Tyr Al a Ser T rp Al a Lys Gly 50 55 60 Arg Phe Phe lie Ser Lys Thr Ser Thr Thr Val Asp Leu Lys lie lie 65 70 75 80 Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Asp Al a 85 90 95 Gly Val Thr Val Asp Gly Tyr Gly Tyr Tyr Phe Asn lie T rp Gly Pro 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a 130 135 140 Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val 165 170 175 Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp 210 215 220 Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255 Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu 260 265 270

    Page 74

    2016273912 14 Dec 2016

    Asp Pro Glu Val 275 Lys Phe Asn T rp 280 Tyr Val Asp Gly Val 285 Glu Val Hi s Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu 325 330 335 Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu 355 360 365 Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp 370 375 380 Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s 420 425 430 Glu Al a Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro

    435 440 445

    Gly Lys 450 <210> 155 <211> 11 <212> PRT <213> Oryctolagus cuniculus <400> 155

    Gin Ala Ser Gin Asn lie Gly Asn Asp Leu Ser

    1 5 <210> 156 <211> 7 <212> PRT <213> Oryctolagus cuni culus <400> 156 Ser Thr Ser Lys Leu Ala Thr 1 5

    Page 75

    2016273912 14 Dec 2016 <210> 157 <211> 13 <212> PRT <213> Oryctolagus cuniculus <400> 157

    Leu Gly Val Tyr Ser Tyr lie Ser Asp Asp Gly Asn Ala

    1 5 <210> 158 <211> 5 <212> PRT <213> Oryctolagus cuniculus <400> 158 Asn Tyr Ala Met Thr

    1 5 <210> 159 <211> 16 <212> PRT <213> Oryctolagus cuniculus <400> 159 lie lie Gly Ser lie Gly Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 15 10 15 <210> 160 <211> 15 <212> PRT <213> Oryctolagus cuniculus <400> 160

    Asp Ala Gly Val Thr Val Asp Gly Tyr Gly Tyr Tyr Phe Asn lie 15 10 15 <210> 161 <211> 112 <212> PRT <213> Oryctolagus cuniculus <400> 161

    Al a lie Glu Met Thr Gin Thr Pro Phe Ser Val Ser Al a Al a Val Gly 1 5 10 15 Gly Thr Val Thr lie Lys cys Gin Al a Ser Gin Thr lie Ser Asn Tyr 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie 35 40 45 Tyr Gly Al a Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly

    50 55 60

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    2016273912 14 Dec 2016

    Ser Gly 65 Ser Gly Thr Gin 70 Phe Thr Leu Thr lie Ser 75 Asp Leu Glu cys 80 Asp Asp Al a Ala Thr Tyr Tyr Cys Gin Gin Gly Tyr Thr lie Ser Asn 85 90 95 Val Asp Asn Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 <210> : 162 <211> ; 218 <212> 1 PRT <213> : Syntheti c <400> : 162 Ala lie Glu Met Thr Gin Thr Pro Phe Ser Val Ser Al a Al a Val Gly 1 5 10 15 Gly Thr Val Thr lie Lys Cys Gln Al a Ser Gin Thr lie Ser Asn Tyr 20 25 30 Leu Ala T rp Tyr Gin Gin Lys Pro Gly Gin Pro Pro Lys Leu Leu lie 35 40 45 Tyr Gly Al a Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Lys Gly 50 55 60 Ser Gly Ser Gly Thr Gin Phe Thr Leu Thr lie Ser Asp Leu Glu cys 65 70 75 80 Asp Asp Al a Ala Thr Tyr Tyr Cys Gin Gin Gly Tyr Thr lie Ser Asn 85 90 95 Val Asp Asn Asn Val Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 Thr Val Al a Ala Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gin Trp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro 195 200 205

    Page 77

    2016273912 14 Dec 2016

    Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 163 <211> 115 <212> PRT <213> Oryctolagus cunicuius <400> 163

    Gin Ser 1 Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Gly Ser 15 5 10 Leu Thr Leu Thr Cys Ala Ala Ser Gly Phe Ser Leu Thr Gly Tyr Asn 20 25 30 Leu Val T rp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie Gly 35 40 45 Phe lie Ser Tyr Gly Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Thr Leu Thr lie Thr 65 70 75 80 Asp Leu Gin Pro Ser Asp Thr Gly Thr Tyr Phe cys Ala Arg Glu Thr 85 90 95 Ala Asn Thr Tyr Asp Tyr Gly lie Trp Gly Pro Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 164 <211> 445 <212> PRT <213> Syntheti c <400> 164 Gin Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Gly Ser 1 5 10 15 Leu Thr Leu Thr Cys Ala Ala Ser Gly Phe Ser Leu Thr Gly Tyr Asn 20 25 30 Leu Val T rp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp lie Gly 35 40 45 Phe lie Ser Tyr Gly Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 50 55 60 Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Thr Leu Thr lie Thr Page 78

    2016273912 14 Dec 2016

    65 70 75 80

    Asp Leu Gin Pro Ser Asp Thr Gly Thr Tyr Phe Cys Ala Arg Glu 95 Thr 85 90 Al a Asn Thr Tyr Asp Tyr Gly lie T rp Gly Pro Gly Thr Leu Val Thr 100 105 110 Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Al a Pro 115 120 125 Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly cys Leu Val 130 135 140 Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn Ser Gly Al a 145 150 155 160 Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin Ser Ser Gly 165 170 175 Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190 Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser Asn Thr Lys 195 200 205 Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr Hi s Thr cys 210 215 220 Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu 225 230 235 240 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu 245 250 255 Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro Glu Val Lys 260 265 270 Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a Lys Thr Lys 275 280 285 Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300 Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr Lys cys Lys 305 310 315 320 Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr lie Ser Lys 325 330 335 Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser 340 345 350

    Page 79

    2016273912 14 Dec 2016

    Arg Glu Glu Met Thr Lys Asn Gin Val 360 Ser Leu Thr cys 365 Leu Val Lys 355 Gly Phe Tyr Pro Ser Asp lie Ala Val Glu T rp Glu Ser Asn Gly Gin 370 375 380 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 385 390 395 400 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg T rp Gin 405 410 415 Gin Gly Asn Val Phe Ser Cys Ser Val Met Hi s Glu Al a Leu Hi s Asn 420 425 430 His Tyr Thr Gl n Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 165 <211> 11 <212> PRT <213> ' Oryctolagus ( suni culus <400> 165 Gl n Al a Ser Gin Thr lie Ser Asn Tyr Leu Al a

    1 5 <210> 166 <211> 7 <212> PRT <213> Oryctolagus cuni culus <400> 166 Gly Ala Ser Asn Leu i Glu Ser 1 5 <210> 167 <211> 13 <212> PRT <213> Oryctolagus cuni culus <400> 167

    Gin Gin Gly Tyr Thr lie Ser Asn Val Asp Asn Asn Val 15 10 <210> 168 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 168

    Gly Tyr Asn Leu Val 1 5

    Page 80

    2016273912 14 Dec 2016 <210> 169 <211> 16 <212> PRT <213> Oryctolagus cunicuius <400> 169

    Phe lie Ser Tyr Gly Asp Thr Thr Tyr Tyr Ala Ser Trp Ala Lys Gly 15 10 15 <210> 170 <211> 10 <212> PRT <213> Oryctolagus cunicuius <400> 170

    Glu Thr Ala Asn Thr Tyr Asp Tyr Gly lie 15 10 <210> 171 <211> 112 <212> PRT <213> Synthetic

    <400> 171 Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Al a Ser Gin Thr lie Ser Asn Tyr 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu Leu lie 35 40 45 Tyr Gly Al a Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr cys Gin Gin Gly Tyr Thr lie Ser Asn 85 90 95 Val Asp Asn Asn Val Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110

    <210> 172 <211> 218 <212> PRT <213> Synthetic <400> 172

    Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 15 10 15

    Page 81

    2016273912 14 Dec 2016

    Asp Arg Val Thr 20 lie Thr Cys Gin Ala 25 Ser Gin Thr lie Ser 30 Asn Tyr Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 Tyr Gly Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr Cys Gin Gin Gly Tyr Thr lie Ser Asn 85 90 95 Val Asp Asn Asn Val Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 Thr Val Ala Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin Trp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Al a Cys Glu Val Thr His Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 173 <211> 118 <212> PRT <213> Synthetic <400> 173 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Gly Tyr 20 25 30 Asn Leu Val T rp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu T rp Val 35 40 45

    Page 82

    2016273912 14 Dec 2016

    Gly Phe lie Ser Tyr Gly Asp Thr Thr Tyr Tyr Ala Ser Ser Ala Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Glu Thr Al a Asn Thr Tyr Asp Tyr Gly lie T rp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 174 <211> 448 <212> PRT <213> : Syntheti c <400> 174 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Val Ser Gly Tyr 20 25 30 Asn Leu Val T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Phe lie Ser Tyr Gly Asp Thr Thr Tyr Tyr Al a Ser Ser Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Glu Thr Al a Asn Thr Tyr Asp Tyr Gly lie T rp Gly Gin Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val Phe Pro 115 120 125 Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly 130 135 140 cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn 145 150 155 160

    Page 83

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    Ser Gly Al a Leu Thr 165 Ser Gly Val Hi s Thr 170 Phe Pro Al a Val Leu 175 Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 180 185 190 Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser 195 200 205 Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr 210 215 220 Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser 225 230 235 240 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg 245 250 255 Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu Asp Pro 260 265 270 Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val 290 295 300 Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr 325 330 335 lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys 355 360 365 Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser 370 375 380 Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 405 410 415 Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a 420 425 430 Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys

    Page 84

    2016273912 14 Dec 2016

    435

    440 <210> 175 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 175

    Gin Ala Ser Gin Thr lie Ser Asn Tyr Leu Ala 15 10 <210> 176 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 176

    Gly Ala Ser Asn Leu Glu Ser 1 5

    445 <210> 177 <211> 13 <212> PRT <213> Oryctolagus cunicuius <400> 177

    Gin Gin Gly Tyr Thr lie Ser Asn Val Asp Asn Asn Val 15 10 <210> 178 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 178

    Gly Tyr Asn Leu Val 1 5 <210> 179 <211> 16 <212> PRT <213> Synthetic <400> 179

    Phe lie Ser Tyr Gly Asp Thr Thr Tyr Tyr Ala Ser Ser Ala Lys Gly 15 10 15 <210> 180 <211> 10 <212> PRT <213> Oryctolagus cunicuius <400> 180

    Glu Thr Ala Asn Thr Tyr Asp Tyr Gly lie 15 10

    Page 85

    2016273912 14 Dec 2016 <210> 181 <211> 112 <212> PRT <213> Oryctolagus cunicuius <400> 181

    Ala Ala 1 Val Leu Thr 5 Gin Thr Pro Ser Pro 10 Val Ser Ala Ala Val 15 Gly Gly Thr Val Ser lie Ser Cys Gin Ser Ser Gin Asn Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser Trp Tyr Gin Gl n Lys Pro Gly Gin Pro Pro Lys Leu 35 40 45 Leu lie Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60 Lys Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Asp Val 65 70 75 80 Gln Cys Asp Ala Ala Ala Thr Tyr Tyr cys Al a Gly Gly Tyr Ser Ser 85 90 95 Ser Ser Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110 <210> : 182 <211> ; 218 <212> PRT <213> : Syntheti c <400> : 182 Ala Ala Val Leu Thr Gin Thr Pro Ser Pro Val Ser Ala Ala Val Gly 1 5 10 15 Gly Thr Val Ser lie Ser Cys Gin Ser Ser Gin Asn Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser Trp Tyr Gin Gl n Lys Pro Gly Gin Pro Pro Lys Leu 35 40 45 Leu lie Tyr Lys Ala Ser Thr Leu Ala Ser Gly Val Pro Ser Arg Phe 50 55 60 Lys Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Asp Val 65 70 75 80 Gln Cys Asp Ala Ala Ala Thr Tyr Tyr cys Al a Gly Gly Tyr Ser Ser 85 90 95 Ser Ser Asp Asn Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg 100 105 110

    Page 86

    2016273912 14 Dec 2016

    Thr Val Al a 115 Al a Pro Ser Val Phe 120 lie Phe Pro Pro Ser 125 Asp Glu Gin Leu Lys Ser Gly Thr Ala Ser Val Val cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 183 <211> 117 <212> PRT <213> i Oryctolagus cunicuius <400> 183 Gin Ser Val Glu Ala Ser Gly Gly Arg Leu Val Met Pro Gly Gly Ser 1 5 10 15 Leu Thr Leu Thr Cys Thr Al a Ser Gly Phe Ser Leu Ser Thr Tyr T rp 20 25 30 Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Thr T rp Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Asn Val 65 70 75 80 lie Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Gly 85 90 95 Ser Pro Asp Val Glu lie Al a lie Asp Met T rp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser

    <210> 184

    115

    Page 87

    2016273912 14 Dec 2016 <211> 447 <212> PRT <213> Synthetic <400> 184

    Gin Ser Val 1 Gl u Al a 5 Ser Gly Gly Arg Leu 10 Val Met Pro Gly Gly 15 Ser Leu Thr Leu Thr cys Thr Al a Ser Gly Phe Ser Leu Ser Thr Tyr T rp 20 25 30 Met Ser T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp lie Gly 35 40 45 Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Thr T rp Al a Lys 50 55 60 Gly Arg Phe Thr lie Ser Lys Thr Ser Thr Thr Val Asp Leu Asn Val 65 70 75 80 lie Ser Pro Thr Thr Glu Asp Thr Al a Thr Tyr Phe cys Al a Arg Gly 85 90 95 Ser Pro Asp Val Glu lie Al a lie Asp Met T rp Gly Gin Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser T rp Asn Ser 145 150 155 160 Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val Leu Gin Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr Hi s 210 215 220 Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr

    245 250 255

    Page 88

    2016273912 14 Dec 2016

    Pro Glu Val Thr 260 cys Val Val Val Asp 265 Val Ser Hi s Glu Asp 270 Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s Asn Al a Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu Lys Thr lie 325 330 335 Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp Glu Ser Asn 370 375 380 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s Glu Al a Leu 420 425 430 His Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 185 <211> 13 <212> PRT <213> i Oryctolagus cunicuius <400> 185 Gin Ser Ser Gin Asn Val Tyr Lys Asn Asn Tyr Leu Ser

    15 10 <210> 186 <211> 7 <212> PRT <213> Oryctolagus cunicuius <400> 186

    Lys Ala Ser Thr Leu Ala Ser 1 5

    Page 89

    2016273912 14 Dec 2016 <210> 187 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 187

    Ala Gly Gly Tyr Ser Ser Ser Ser Asp Asn Ala 15 10 <210> 188 <211> 5 <212> PRT <213> Oryctolagus cunicuius <400> 188

    Thr Tyr Trp Met Ser 1 5 <210> 189 <211> 17 <212> PRT <213> Oryctolagus cunicuius <400> 189

    Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Ala Thr Trp Ala Lys 15 10 15

    Gly <210> 190 <211> 11 <212> PRT <213> Oryctolagus cunicuius <400> 190

    Gly Ser Pro 1 Asp Val 5 Glu lie Al a lie Asp 10 Met <210> 191 <211> 112 <212> PRT <213> Synthetic <400> 191 Asp lie Gin 1 Met Thr 5 Gin Ser Pro Ser Ser 10 Leu Ser Al a Ser Val 15 Gly Asp Arg Val Thr 20 lie Thr cys Gin Ser 25 Ser Gin Asn Val Tyr 30 Lys Asn Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu

    35 40 45

    Page 90

    2016273912 14 Dec 2016

    Leu lie 50 Tyr Lys Al a Ser Thr 55 Leu Ala Ser Gly Val 60 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 65 70 75 80 Gin Pro Glu Asp Val Al a Thr Tyr Tyr cys Al a Gly Gly Tyr Thr Ser 85 90 95 Ser Ser Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 <210> : 192 <211> ; 218 <212> PRT <213> : Syntheti c <400> : 192 Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Ser Ser Gin Asn Val Tyr Lys Asn 20 25 30 Asn Tyr Leu Ser T rp Tyr Gin Gin Lys Pro Gly Lys Val Pro Lys Leu 35 40 45 Leu lie Tyr Lys Al a Ser Thr Leu Al a Ser Gly Val Pro Ser Arg Phe 50 55 60 Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu 65 70 75 80 Gin Pro Glu Asp Val Al a Thr Tyr Tyr cys Al a Gly Gly Tyr Thr Ser 85 90 95 Ser Ser Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg 100 105 110 Thr Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin 115 120 125 Leu Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser 145 150 155 160 Gly Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys 180 185 190

    Page 91

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    Hi s Lys Val 195 Tyr Ala Cys Glu Val 200 Thr Hi s Gin Gly Leu 205 Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu cys 210 215 <210> 193 <211> 120 <212> PRT <213> Syntheti c <400> 193 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Al a Al a Ser Gly Phe Thr Val Ser Thr Tyr 20 25 30 T rp Met Ser Trp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Thr Ser Al a 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys 85 90 95 Al a Arg Gly Ser Pro Asp Val Glu lie Al a lie Asp Met T rp Gly Gin 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 194 <211> 450 <212> PRT <213> Syntheti c <400> 194 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Al a Al a Ser Gly Phe Thr Val Ser Thr Tyr 20 25 30 T rp Met Ser Trp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Al a Thr Ser Al a

    Page 92

    2016273912 14 Dec 2016

    50 55 60

    Lys Gly Arg 65 Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 80 70 75 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys 85 90 95 Al a Arg Gly Ser Pro Asp Val Glu lie Al a lie Asp Met T rp Gly Gin 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a Al a 130 135 140 Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a Val 165 170 175 Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser cys Asp 210 215 220 Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255 Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp Val Ser Hi s Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val Hi s 275 280 285 Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie Glu

    325 330 335

    Page 93

    2016273912 14 Dec 2016

    Lys Thr lie Ser 340 Lys Ala Lys Gly Gin 345 Pro Arg Glu Pro Gin 350 Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu 355 360 365 Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu T rp 370 375 380 Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met Hi s 420 425 430 Glu Al a Leu Hi s Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 195 <211> 13 <212> PRT <213> i Oryctolagus cunicuius <400> 195 Gin Ser Ser Gin Asn Val Tyr Lys Asn Asn Tyr Leu Ser

    15 10 <210> 196 <211> 7 <212> PRT <213> Oryctolagus curricuius <400> 196

    Lys Ala Ser Thr Leu Ala Ser 1 5 <210> 197 <211> 11 <212> PRT <213> Oryctolagus curri cuius <400> 197

    Ala Gly Gly Tyr Thr Ser Ser Ser Asp Asn Ala 15 10 <210> 198 <211> 5

    Page 94

    2016273912 14 Dec 2016 <212> PRT <213> Oryctolagus cuniculus <400> 198

    Thr Tyr Trp Met Ser 1 5 <210> 199 <211> 17 <212> PRT <213> Synthetic <400> 199

    Asp lie Tyr Phe Ser Asn Glu Glu Thr Asn Tyr Ala Thr Ser Ala Lys 15 10 15

    Gly <210> 200 <211> 11 <212> PRT <213> Synthetic <400> 200

    Gly Ser Pro Asp Val Glu lie Ala lie Asp Met 15 10 <210> 201 <211> 333 <212> DNA <213> Oryctolagus cuniculus <400> 201 gcccttgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggagg cacagtcacc 60 atcaattgcc aggccagtca gaacatttac agcaatttag cctggtatca acagagacca 120 gggcagcgtc ccaagctcct gatctatggt gcatccaatc tggatgctgg ggtcccatcg 180 cggttcagag gcagtggatc tgggacagag tacactctca ccatcagcga cctggagtgt 240 gacgatgttg gcacttacta ctgtcaaagt gcttttgata gtgatagtac tgaaaatact 300 ttcggcggag ggaccgaggt ggtggtcaaa cgt 333 <210> 202 <211> 654 <212> DNA <213> Synthetic <400> 202 gcccttgtga tgacccagac tccatcctcc gtgtctgcag ctgtgggagg cacagtcacc 60 atcaattgcc aggccagtca gaacatttac agcaatttag cctggtatca acagagacca 120 gggcagcgtc ccaagctcct gatctatggt gcatccaatc tggatgctgg ggtcccatcg 180 cggttcagag gcagtggatc tgggacagag tacactctca ccatcagcga cctggagtgt 240 gacgatgttg gcacttacta ctgtcaaagt gcttttgata gtgatagtac tgaaaatact 300

    Page 95

    2016273912 14 Dec 2016 ttcggcggag ggaccgaggt ggtggtcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654 <210> 203 <211> 354 <212> DNA <213> Oryctolagus cunicuius <400> 203 cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggcttctc cctcagtagc tatgcaatga gctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggagtcatt actagtattg gtagcacagt ctacgcgagc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatcacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gaggctacga tgactatgat 300 gagatgacct actttaacat ctggggccag gggaccctcg tcaccgtctc gage 354 <210> 204 <211> 1347 <212> DNA <213> Synthetic <400> 204 cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggcttctc cctcagtagc tatgcaatga gctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggagtcatt actagtattg gtagcacagt ctacgcgagc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatcacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gaggctacga tgactatgat 300 gagatgacct actttaacat ctggggccag gggaccctcg tcaccgtctc gagcgcctcc 360 accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420 gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540 tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600 tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660 tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720 gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780 acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840 gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta cgccagcacg 900

    Page 96

    2016273912 14 Dec 2016

    taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960 aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020 aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080 aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140 gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200 tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260 gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320 agcctctccc tgtctccggg taaatga 1347 <210> 205 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 205 caggccagtc agaacattta cagcaattta gcc 33 <210> 206 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 206 ggtgcatcca atctggatgc t 21 <210> 207 <211> 36 <212> DNA <213> Oryctolagus cunicuius <400> 207 caaagtgctt ttgatagtga tagtactgaa aatact 36 <210> 208 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 208 agctatgcaa tgagc 15 <210> 209 <211> 48 <212> DNA <213> Oryctolagus cunicuius <400> 209 gtcattacta gtattggtag cacagtctac gcgagctggg cgaaaggc 48

    <210> 210 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 210 ggctacgatg actatgatga gatgacctac tttaacatc Page 97

    2016273912 14 Dec 2016 <210> 211 <211> 333 <212> DNA <213> Synthetic <400> 211

    gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gaacatttac agcaacttag cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatggt gcatccaatc tggatgctgg agtcccatca 180 aggttctctg gcagtggatc tgggacagag tacactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgccaaagt gcttttgata gtgatagtac tgaaaacact 300 ttcggcggag gaaccaaggt ggaaatcaaa cgt 333

    <210> 212 <211> 654 <212> DNA <213> Synthetic <400> 212 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gaacatttac agcaacttag cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatggt gcatccaatc tggatgctgg agtcccatca 180 aggttctctg gcagtggatc tgggacagag tacactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgccaaagt gcttttgata gtgatagtac tgaaaacact 300 ttcggcggag gaaccaaggt ggaaatcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654 <210> 213 <211> 363 <212> DNA <213> Synthetic <400> 213 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt agctatgcaa tgagctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggagtc attactagta ttggtagcac agtctacgcg 180 agcagcgcga aaggccgatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag aggctacgat 300 gactatgatg agatgaccta ctttaacatc tggggccaag ggaccctcgt caccgtctcg 360 age

    363

    Page 98

    2016273912 14 Dec 2016 <210> 214 <211> 1356 <212> DNA <213> Synthetic <400> 214

    gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt agctatgcaa tgagctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggagtc attactagta ttggtagcac agtctacgcg 180 agcagcgcga aaggccgatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag aggctacgat 300 gactatgatg agatgaccta ctttaacatc tggggccaag ggaccctcgt caccgtctcg 360 agcgcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900 gccagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320 acgcagaaga gcctctccct gtctccgggt aaatga 1356

    <210> 215 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 215 caggccagtc agaacattta cagcaactta gcc 33 <210> 216 <211> 21 <212> DNA <213> Oryctolagus cunicuius

    Page 99

    2016273912 14 Dec 2016 <400> 216 ggtgcatcca atctggatgc t <210> 217 <211>

    <212>

    DNA <213> Oryctolagus cuniculus <400> 217 caaagtgctt ttgatagtga tagtactgaa aacact <210> 218 <211> 15 <212> DNA <213> Oryctolagus cuniculus <400> 218 agctatgcaa tgagc <210> 219 <211>

    <212>

    DNA <213> Synthetic <400> 219 gtcattacta gtattggtag cacagtctac gcgagcagcg cgaaaggc <210> 220 <211>

    <212>

    DNA <213> Oryctolagus cuniculus <400> 220 ggctacgatg actatgatga gatgacctac tttaacatc <210> 221 <211> 336 <212> DNA <213> Oryctolagus cuniculus <400> 221

    gcagccgtgc tgacccagac accatcgccc gtgtctgcag ctatgggaga cacagtcacc 60 atcaagtgcc agtccagtca gagtgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccagggc agcctcccag gctcctgatc tatgatgcat ccaatctgcc atctggggtc 180 ccatcacggt tcagcggcag tggatctggg acacagttca ctctcaccat cagcggcgtg 240 cagtgtgacg atgctgccac ttactactgt ctaggcgatt atgatgatga tgctgataat 300 gctttcggcg gagggaccga ggtggtggtc aaacgt 336

    <210>

    <211>

    <212>

    <213>

    222

    657

    DNA

    Syntheti c <400> 222 gcagccgtgc tgacccagac accatcgccc gtgtctgcag ctatgggaga cacagtcacc atcaagtgcc agtccagtca gagtgtttat aagaacaact acttatcctg gtatcagcag

    Page 100

    120

    2016273912 14 Dec 2016 aaaccagggc agcctcccag gctcctgatc tatgatgcat ccaatctgcc atctggggtc 180 ccatcacggt tcagcggcag tggatctggg acacagttca ctctcaccat cagcggcgtg 240 cagtgtgacg atgctgccac ttactactgt ctaggcgatt atgatgatga tgctgataat 300 gctttcggcg gagggaccga ggtggtggtc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 223 <211> 339 <212> DNA <213> Oryctolagus cunicuius <400> 223 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggattctc cctcagtagc tatgtaatga tctgggtccg ccaggctcca 120 gggaaggggc tggaatacat cggaatcact tggagtgctg gtacatacta cgcgagctgg 180 gcgaaaggcc gattcaccat ctccaaaacc tcgtcgacca cggtggatct gaaaatcacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgccg gaggtggtgg tagtatttat 300 gatatttggg gcccgggcac cctggtcacc gtctcgagc 339 <210> 224 <211> 1332 <212> DNA <213> Synthetic <400> 224 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggattctc cctcagtagc tatgtaatga tctgggtccg ccaggctcca 120 gggaaggggc tggaatacat cggaatcact tggagtgctg gtacatacta cgcgagctgg 180 gcgaaaggcc gattcaccat ctccaaaacc tcgtcgacca cggtggatct gaaaatcacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgccg gaggtggtgg tagtatttat 300 gatatttggg gcccgggcac cctggtcacc gtctcgagcg cctccaccaa gggcccatcg 360 gtcttccccc tggcaccctc ctccaagagc acctctgggg gcacagcggc cctgggctgc 420 ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480 agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540 gtggtgaccg tgccctccag cagcttgggc acccagacct acatctgcaa cgtgaatcac 600 aagcccagca acaccaaggt ggacaagaga gttgagccca aatcttgtga caaaactcac 660 acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 720 ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg 780

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    2016273912 14 Dec 2016 gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg 840 cataatgcca agacaaagcc gcgggaggag cagtacgcca gcacgtaccg tgtggtcagc 900 gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc 960 aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga 1020 gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1080 ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat 1140 gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggctccttc 1200 ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca 1260 tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct 1320 ccgggtaaat ga 1332 <210> 225 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 225 cagtccagtc agagtgttta taagaacaac tacttatcc 39 <210> 226 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 226 gatgcatcca atctgccatc t 21 <210> 227 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 227 ctaggcgatt atgatgatga tgctgataat get 33 <210> 228 <211> 15 <212> DNA <213> Oryctolagus cunieulus <400> 228 agctatgtaa tgatc 15 <210> 229 <211> 45 <212> DNA <213> Oryctolagus cunieulus <400> 229 atcacttgga gtgctggtac atactacgcg agctgggcga aaggc 45 <210> 230 <211> 24

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    2016273912 14 Dec 2016 <212> DNA <213> Oryctolagus cunicuius <400> 230 ggtggtggta gtatttatga tatt 24 <210> 231 <211> 336 <212> DNA <213> Synthetic <400> 231 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc agtccagtca gagtgtctat aagaacaact acttatcctg gtatcagcag 120 aaaccaggaa aagcccctaa gctcctgatc tatgatgcat ccaatctgcc atctggagtc 180 ccatcaaggt tcagcggcag tggatctgga acagaattca ctctcaccat cagcagcctg 240 cagcctgatg attttgcaac ttattactgc ctaggcgatt atgatgatga tgctgataat 300 gctttcggcg gaggaaccaa ggtggaaatc aaacgt 336 <210> 232 <211> 657 <212> DNA <213> Synthetic <400> 232 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc agtccagtca gagtgtctat aagaacaact acttatcctg gtatcagcag 120 aaaccaggaa aagcccctaa gctcctgatc tatgatgcat ccaatctgcc atctggagtc 180 ccatcaaggt tcagcggcag tggatctgga acagaattca ctctcaccat cagcagcctg 240 cagcctgatg attttgcaac ttattactgc ctaggcgatt atgatgatga tgctgataat 300 gctttcggcg gaggaaccaa ggtggaaatc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 233 <211> 345 <212> DNA <213> Synthetic <400> 233 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt agctatgtaa tgatctgggt ccgtcaggct 120 ccagggaagg ggctggagta catcggaatc acttggagtg ctggtacata ctacgcgagc 180 agtgcgaaag gccgattcac catctccaga gacaattcca agaacaccct gtatcttcaa 240

    Page 103

    2016273912 14 Dec 2016

    atgaacagcc tgagagctga ggacactgct gtgtattact gtgctggagg tggtggtagt 300 atctatgata tttggggcca agggaccctc gtcaccgtct cgagc 345 <210> 234 <211> 1338 <212> DNA <213> Synthetic <400> 234 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt agctatgtaa tgatctgggt ccgtcaggct 120 ccagggaagg ggctggagta catcggaatc acttggagtg ctggtacata ctacgcgagc 180 agtgcgaaag gccgattcac catctccaga gacaattcca agaacaccct gtatcttcaa 240 atgaacagcc tgagagctga ggacactgct gtgtattact gtgctggagg tggtggtagt 300 atctatgata tttggggcca agggaccctc gtcaccgtct cgagcgcctc caccaagggc 360 ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480 ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540 agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600 aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 660 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acgccagcac gtaccgtgtg 900 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020 ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1080 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320 ctgtctccgg gtaaatga 1338

    <210> 235 <211> 39 <212> DNA <213> Oryctolagus cuniculus <400> 235 cagtccagtc agaatgttta taagaacaac tacttatcc 39 <210> 236 <211> 21

    Page 104

    2016273912 14 Dec 2016 <212> DNA <213> Oryctolagus cunicuius <400> 236 aaggcatcca ctctggcatc t 21 <210> 237 <211> 32 <212> DNA <213> Oryctolagus cunicuius <400> 237 gcaggcggtt ataccagtag tagtgataat gc 32 <210> 238 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 238 agctatgtaa tgatc 15 <210> 239 <211> 45 <212> DNA <213> Synthetic <400> 239 atcacttgga gtgctggtac atactacgcg agcagtgcga aaggc 45 <210> 240 <211> 24 <212> DNA <213> Oryctolagus cunicuius <400> 240 ggtggtggta gtatctatga tatt 24 <210> 241 <211> 333 <212> DNA <213> Oryctolagus cunicuius <400> 241 gcctatgata tgacccagac tccagcctct gtggaggtag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtca gagcatttac agcaatttag cctggtatca gcagagacca 120 gggcagcctc ccaagctcct gatctatgat gcatccactc tggaatctgg ggtcccatcg 180 cggttcaaag gcagtggatc tgggacagag tacactctca ccatcagcgg cgtggagtgt 240 gccgatgctg cctcttacta ctgtcaacag ggttttactg ttagtgatat tgataatgct 300 ttcggcggag ggaccgaggt ggtggtcaaa cgt 333 <210> 242 <211> 654 <212> DNA <213> Synthetic <400> 242 gcctatgata tgacccagac tccagcctct gtggaggtag ctgtgggagg cacagtcacc 60

    Page 105

    2016273912 14 Dec 2016 atcaagtgcc aggccagtca gagcatttac agcaatttag cctggtatca gcagagacca 120 gggcagcctc ccaagctcct gatctatgat gcatccactc tggaatctgg ggtcccatcg 180 cggttcaaag gcagtggatc tgggacagag tacactctca ccatcagcgg cgtggagtgt 240 gccgatgctg cctcttacta ctgtcaacag ggttttactg ttagtgatat tgataatgct 300 ttcggcggag ggaccgaggt ggtggtcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654 <210> 243 <211> 354 <212> DNA <213> Oryctolagus cunicuius <400> 243 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggattctc cctcagtaac tatgcagtgg gctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggaatcatt ggtcgtaatg gtaacacatg gtacgcgagc 180 tgggcaagag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatcacc 240 agtccgacaa gcgaggacac ggccacatat ttctgtgcca gaggatatgg ccgtagtgtt 300 gcttattacg tctttaacat ctggggccca ggcaccctcg tcaccgtctc gage 354 <210> 244 <211> 1347 <212> DNA <213> Synthetic <400> 244 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggattctc cctcagtaac tatgcagtgg gctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggaatcatt ggtcgtaatg gtaacacatg gtacgcgagc 180 tgggcaagag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatcacc 240 agtccgacaa gcgaggacac ggccacatat ttctgtgcca gaggatatgg ccgtagtgtt 300 gcttattacg tctttaacat ctggggccca ggcaccctcg tcaccgtctc gagcgcctcc 360 accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420 gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540 tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600 tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660

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    2016273912 14 Dec 2016 tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720 gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780 acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840 gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta cgccagcacg 900 taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960 aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020 aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080 aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140 gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200 tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260 gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320 agcctctccc tgtctccggg taaatga 1347 <210> 245 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 245 caggccagtc agagcattta cagcaattta gcc 33 <210> 246 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 246 gatgcatcca ctctggaatc t 21 <210> 247 <211> 36 <212> DNA <213> Oryctolagus cunicuius <400> 247 caacagggtt ttactgttag tgatattgat aatgct 36 <210> 248 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 248 aactatgcag tgggc 15 <210> 249 <211> 48 <212> DNA <213> Oryctolagus cunicuius <400> 249 atcattggtc gtaatggtaa cacatggtac gcgagctggg caagaggc 48

    Page 107

    2016273912 14 Dec 2016 <210> 250 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 250 ggatatggcc gtagtgttgc ttattacgtc tttaacatc 39 <210> 251 <211> 333 <212> DNA <213> Synthetic <400> 251 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gagcatttac agcaatcttg cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatgat gcatccactc tggaatctgg agtcccatca 180 aggttcagcg gcagtggatc tgggacagag tacactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgccaacag ggttttactg ttagtgatat tgataatgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgt 333 <210> 252 <211> 654 <212> DNA <213> Synthetic <400> 252 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gagcatttac agcaatcttg cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatgat gcatccactc tggaatctgg agtcccatca 180 aggttcagcg gcagtggatc tgggacagag tacactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgccaacag ggttttactg ttagtgatat tgataatgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654 <210> 253 <211> 363 <212> DNA <213> Synthetic

    <400> 253 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt aactatgcag tgggctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggaatc attggtcgta atggtaacac atggtacgcg 180

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    2016273912 14 Dec 2016

    agctctgcaa gaggeegatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag aggatatggc 300 cgtagtgttg ettattaegt ctttaacatc tggggcccag ggaccctcgt caccgtctcg 360 age 363

    <210> 254 <211> 1356 <212> DNA <213> Synthetic <400> 254

    gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt aactatgcag tgggctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggteggaate attggtcgta atggtaacac atggtacgcg 180 agctctgcaa gaggeegatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag aggatatggc 300 cgtagtgttg ettattaegt ctttaacatc tggggcccag ggaccctcgt caccgtctcg 360 agcgcctcca ccaagggccc ateggtette cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gagagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa ageegeggga ggagcagtac 900 gccagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggetteta tcccagcgac 1140 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260 tggcagcagg ggaaegtett ctcatgctcc gtgatgcatg aggetetgea caaccactac 1320 acgcagaaga gcctctccct gtctccgggt aaatga 1356

    <210> 255 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 255

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    2016273912 14 Dec 2016 caggccagtc agagcattta cagcaatctt gcc <210> 256 <211> 21 <212> DNA <213> Oryctolagus cuniculus <400> 256 gatgcatcca ctctggaatc t 21 <210> 257 <211> 36 <212> DNA <213> Oryctolagus cuniculus <400> 257 caacagggtt ttactgttag tgatattgat aatgct 36 <210> 258 <211> 15 <212> DNA <213> Oryctolagus cuniculus <400> 258 aactatgcag tgggc 15 <210> 259 <211> 48 <212> DNA <213> Synthetic <400> 259 atcattggtc gtaatggtaa cacatggtac gcgagctctg caagaggc 48 <210> 260 <211> 39 <212> DNA <213> Oryctolagus cuniculus <400> 260 ggatatggcc gtagtgttgc ttattacgtc tttaacatc 39 <210> 261 <211> 336 <212> DNA <213> Oryctolagus cuniculus <400> 261 gccgatgttg tgatgaccca gactccagcc tccgtgtctc aacctgtggg aggcacagtc 60 accatcaagt gccaggccag tgaggacatt tataacttat tggcctggta tcagcagaaa 120 ccagggcagc ctcccaagct cctgatctat tctgcatcca ctctggcatc tggggtccca 180 tcgcggttca aaggcagtgg atctgggaca gagtacactc tcaccatcag cggcctggag 240 tgtgccgatg ctgccactta ctactgtcaa aacaattatc ttgttactac ttatggtgtt 300 gctttcggcg gagggaccga ggtggtggtc aaacgt 336 <210> 262 <211> 657

    Page 110

    2016273912 14 Dec 2016 <212> DNA <213> Synthetic <400> 262 gccgatgttg tgatgaccca gactccagcc tccgtgtctc aacctgtggg aggcacagtc 60 accatcaagt gccaggccag tgaggacatt tataacttat tggcctggta tcagcagaaa 120 ccagggcagc ctcccaagct cctgatctat tctgcatcca ctctggcatc tggggtccca 180 tcgcggttca aaggcagtgg atctgggaca gagtacactc tcaccatcag cggcctggag 240 tgtgccgatg ctgccactta ctactgtcaa aacaattatc ttgttactac ttatggtgtt 300 gctttcggcg gagggaccga ggtggtggtc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 263 <211> 360 <212> DNA <213> Oryctolagus cunicuius <400> 263 caggagcagc tgaaggagtc cgggggtcgc ctggtcacgc ctgggacacc cctgacactc 60 acctgtacag tctctggatt ctccctcagt agctatgcaa tgatctgggt ccgccaggct 120 ccagggaagg ggctggaata catcggatac attgatactg atactagcgc atactacgcg 180 agctgggtga aaggccgatt caccatctcc agaacctcga ccacggtgga tctcaaaatc 240 actagtccga caaccgagga cacggccacc tatttctgtg ccagatctta tgctgcttat 300 ggtggttatc ctgctacttt tgatccctgg ggcccaggca ccctggtcac cgtctcgagc 360 <210> 264 <211> 1353 <212> DNA <213> Synthetic <400> 264 caggagcagc tgaaggagtc cgggggtcgc ctggtcacgc ctgggacacc cctgacactc 60 acctgtacag tctctggatt ctccctcagt agctatgcaa tgatctgggt ccgccaggct 120 ccagggaagg ggctggaata catcggatac attgatactg atactagcgc atactacgcg 180 agctgggtga aaggccgatt caccatctcc agaacctcga ccacggtgga tctcaaaatc 240 actagtccga caaccgagga cacggccacc tatttctgtg ccagatctta tgctgcttat 300 ggtggttatc ctgctacttt tgatccctgg ggcccaggca ccctggtcac cgtctcgagc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540

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    ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa tga 1353

    <210> 265 <211> 33 <212> DNA <213> Oryctolagus cunicuius

    <400> 265 caggccagtg aggacattta taacttattg gcc 33 <210> 266 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 266 tctgcatcca ctctggcatc t 21 <210> 267 <211> 36 <212> DNA <213> Oryctolagus cunicuius <400> 267 caaaacaatt atcttgttac tacttatggt gttgct 36 <210> 268 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 268 agctatgcaa tgatc 15 <210> 269 <211> 48 <212> DNA Page 112

    2016273912 14 Dec 2016 <213> Oryctolagus cuniculus <400> 269

    tacattgata ctgatactag cgcatactac gcgagctggg tgaaaggc 48 <210> 270 <211> 36 <212> DNA <213> Oryctolagus cuniculus <400> 270 tcttatgctg cttatggtgg ttatcctgct actttt 36

    <210> 271 <211> 333 <212> DNA <213> Synthetic <400> 271 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtga ggacatttac aacttattgg cctggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctattct gcatccactc tggcatctgg ggtcccatct 180 cgtttcagtg gcagtggatc tgggacagat tacactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcaaaac aactatcttg ttactactta tggtgttgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgt 333 <210> 272 <211> 654 <212> DNA <213> Synthetic

    <400> 272 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtga ggacatttac aacttattgg cctggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctattct gcatccactc tggcatctgg ggtcccatct 180 cgtttcagtg gcagtggatc tgggacagat tacactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcaaaac aactatcttg ttactactta tggtgttgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654

    <210> 273 <211> 366 <212> DNA <213> Synthetic <400> 273

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    2016273912 14 Dec 2016 caggtacagc tggtggagtc tggtggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cttctggatt caccttcagt agctatgcaa tgatctgggt ccgccaggct 120 ccagggaagg ggctggaata catcggatac attgatactg atactagcgc atactacgca 180 agcagtgtga aaggccgatt caccatctcc agagacaatt ccaagaacac gctgtacctg 240 caaatgtcta gcctgagagc cgaggacacg gctgtgtatt actgtgctag atcttatgct 300 gcttatggtg gttatcctgc tacttttgat ccctggggcc aaggtaccct cgtcaccgtc 360 tcgagc 366 <210> 274 <211> 1359 <212> DNA <213> Synthetic <400> 274 caggtacagc tggtggagtc tggtggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cttctggatt caccttcagt agctatgcaa tgatctgggt ccgccaggct 120 ccagggaagg ggctggaata catcggatac attgatactg atactagcgc atactacgca 180 agcagtgtga aaggccgatt caccatctcc agagacaatt ccaagaacac gctgtacctg 240 caaatgtcta gcctgagagc cgaggacacg gctgtgtatt actgtgctag atcttatgct 300 gcttatggtg gttatcctgc tacttttgat ccctggggcc aaggtaccct cgtcaccgtc 360 tcgagcgcct ccaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 420 tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 480 gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc tgtcctacag 540 tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacc 600 cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga caagagagtt 660 gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 720 gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 780 acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 840 aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 900 tacgccagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 960 ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1020 atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1080 gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1140 gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1200 cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1260 aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1320 tacacgcaga agagcctctc cctgtctccg ggtaaatga 1359 <210> 275

    Page 114

    2016273912 14 Dec 2016 <211> 33 <212> DNA <213> Oryctolagus curricuius <400> 275 caggccagtg aggacattta caacttattg gcc <210> 276 <211> 21 <212> DNA <213> Oryctolagus curri cuius <400> 276 tctgcatcca ctctggcatc t <210> 277 <211> 36 <212> DNA <213> Oryctolagus curri cuius <400> 277 caaaacaact atcttgttac tacttatggt gttgct <210> 278 <211> 15 <212> DNA <213> Oryctolagus curri cuius <400> 278 agctatgcaa tgatc <210> 279 <211> 48 <212> DNA <213> Synthetic <400> 279 tacattgata ctgatactag cgcatactac gcaagcagtg tgaaaggc <210> 280 <211> 42 <212> DNA <213> Oryctolagus cunicuius <400> 280 tcttatgctg cttatggtgg ttatcctgct acttttgatc cc <210> 281 <211> 333 <212> DNA <213> Oryctolagus cunicuius <400> 281 gcctatgata tgacccagac tccagcctcc gtgtctgcag ctgtgggagg cacagtcacc atcaagtgcc aggccagtga gaacattggt agctacttag cctggtatca gcagaaacca gggcagcctc ccgaactcct gatctacagg gcgtccactc tggcatctgg ggtcccatcg cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcgg cgtggagtgt gccgatgctg ccacttacta ctgtcaacag ggttataata gtgagaatct tgataatgct

    120

    180

    240

    300

    Page 115

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    ttcggcggag ggaccgaggt ggtggtcaaa cgt 333 <210> 282 <211> 654 <212> DNA <213> Synthetic <400> 282 gcctatgata tgacccagac tccagcctcc gtgtctgcag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtga gaacattggt agctacttag cctggtatca gcagaaacca 120 gggcagcctc ccgaactcct gatctacagg gcgtccactc tggcatctgg ggtcccatcg 180 cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcgg cgtggagtgt 240 gccgatgctg ccacttacta ctgtcaacag ggttataata gtgagaatct tgataatgct 300 ttcggcggag ggaccgaggt ggtggtcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654

    <210> 283 <211> 345 <212> DNA <213> Oryctolagus cuniculus <400> 283 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggaatcga cctcagtatg tattcaatgg gctgggtccg ccaggctcca 120 gggaaggggc tggaatacat cggatggatt agttatggtg gtactgcata ttacgcgagc 180 tgggcgaagg gccgattcac catctccaaa acctcgacca cggtggagct gaagatcacc 240 agtccgacaa tcgaggacac ggccacctat ttctgtgcca gagagactcc tgttaattat 300 tatttggaca tttggggcca ggggaccctc gtcaccgtct cgagc 345 <210> 284 <211> 1338 <212> DNA <213> Synthetic <400> 284 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggaatcga cctcagtatg tattcaatgg gctgggtccg ccaggctcca 120 gggaaggggc tggaatacat cggatggatt agttatggtg gtactgcata ttacgcgagc 180 tgggcgaagg gccgattcac catctccaaa acctcgacca cggtggagct gaagatcacc 240 agtccgacaa tcgaggacac ggccacctat ttctgtgcca gagagactcc tgttaattat 300 tatttggaca tttggggcca ggggaccctc gtcaccgtct cgagcgcctc caccaagggc 360

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    2016273912 14 Dec 2016

    ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480 ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540 agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600 aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 660 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acgccagcac gtaccgtgtg 900 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020 ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1080 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320 ctgtctccgg gtaaatga 1338

    <210> 285 <211> 33 <212> DNA <213> Oryctolagus cunicuius

    <400> 285 caggccagtg agaacattgg tagctactta gcc 33 <210> 286 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 286 agggcgtcca ctctggcatc t 21 <210> 287 <211> 36 <212> DNA <213> Oryctolagus cunicuius <400> 287 caacagggtt ataatagtga gaatcttgat aatgct 36 <210> 288 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 288 atgtattcaa tgggc 15

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    2016273912 14 Dec 2016 <210> 289 <211> 48 <212> DNA <213> Oryctolagus cunicuius <400> 289

    tggattagtt atggtggtac tgcatattac gcgagctggg cgaagggc 48 <210> 290 <211> 30 <212> DNA <213> Oryctolagus cunicuius <400> 290 gagactcctg ttaattatta tttggacatt 30

    <210> 291 <211> 333 <212> DNA <213> Synthetic <400> 291 gcctatgata tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtga gaacattggt agctacttag cctggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatagg gcttccactc tggcatctgg ggtcccatct 180 cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcaacag ggttacaata gtgagaatct tgataatgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgt 333 <210> 292 <211> 654 <212> DNA <213> Synthetic <400> 292 gcctatgata tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtga gaacattggt agctacttag cctggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatagg gcttccactc tggcatctgg ggtcccatct 180 cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcaacag ggttacaata gtgagaatct tgataatgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654 <210> 293

    Page 118

    2016273912 14 Dec 2016 <211> 354 <212> DNA <213> Synthetic <400> 293

    caggtacagc tggtggagtc tggtggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cttctggatt caccttcagt atgtattcaa tgggctgggt ccgccaggct 120 ccagggaagg ggctggaata catcggatgg attagttatg gtggtactgc atactacgct 180 agcagcgcta agggccgatt caccatctcc agagacaatt ccaagaacac gctgtacctg 240 caaatgtcta gcctgagagc cgaggacacg gctgtgtatt actgtgctag agagactcct 300 gttaattact acttggacat ttggggccaa ggtaccctcg tcaccgtctc gage 354

    <210> 294 <211> 1347 <212> DNA <213> Synthetic <400> 294 caggtacagc tggtggagtc tggtggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cttctggatt caccttcagt atgtattcaa tgggctgggt ccgccaggct 120 ccagggaagg ggctggaata catcggatgg attagttatg gtggtactgc atactacgct 180 agcagcgcta agggccgatt caccatctcc agagacaatt ccaagaacac gctgtacctg 240 caaatgtcta gcctgagagc cgaggacacg gctgtgtatt actgtgctag agagactcct 300 gttaattact acttggacat ttggggccaa ggtaccctcg tcaccgtctc gagcgcctcc 360 accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420 gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540 tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600 tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660 tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720 gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780 acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840 gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta cgccagcacg 900 taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960 aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020 aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080 aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140 gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200 tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260 gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320 agcctctccc tgtctccggg taaatga 1347

    Page 119

    2016273912 14 Dec 2016 <210> 295 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 295 caggccagtg agaacattgg tagctactta gcc 33 <210> 296 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 296 agggcttcca ctctggcatc t 21 <210> 297 <211> 36 <212> DNA <213> Oryctolagus cunicuius <400> 297 caacagggtt acaatagtga gaatcttgat aatgct 36 <210> 298 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 298 atgtattcaa tgggc 15 <210> 299 <211> 48 <212> DNA <213> Synthetic <400> 299 tggattagtt atggtggtac tgcatactac gctagcagcg ctaagggc 48 <210> 300 <211> 30 <212> DNA <213> Oryctolagus cunicuius <400> 300 gagactcctg ttaattacta cttggacatt 30 <210> 301 <211> 327 <212> DNA <213> Oryctolagus cunicuius <400> 301 gcattcgaat tgacccagac tccatcctcc gtggaggcag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtca gaacattgtt accaatttag cctggtatca acagaaacca 120 gggcagcctc ccaagctcct gatctatggt gcatccactc tggcatctgg ggtctcatcg 180 cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240

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    2016273912 14 Dec 2016

    gccgatgctg ccacttattt ctgtcagagc ggagggaccg aggtggtggt caaacgt tatgatggtt ttaatagtgc tgggttcggc 300 327 <210> 302 <211> 648 <212> DNA <213> Synthetic <400> 302 gcattcgaat tgacccagac tccatcctcc gtggaggcag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtca gaacattgtt accaatttag cctggtatca acagaaacca 120 gggcagcctc ccaagctcct gatctatggt gcatccactc tggcatctgg ggtctcatcg 180 cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240 gccgatgctg ccacttattt ctgtcagagc tatgatggtt ttaatagtgc tgggttcggc 300 ggagggaccg aggtggtggt caaacgtacg gtagcggccc catctgtctt catcttcccg 360 ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420 tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480 caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540 acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600 ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgttag 648

    <210> 303 <211> 360 <212> DNA <213> Oryctolagus cuniculus <400> 303 cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagcct ctggattctc cctcagtggc tacgacatga gctgggtccg ccaggctcca 120 ggaaaggggc tggaatacat cggactcatt agttatgatg gtaacacata ctacgcgacc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatcacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gaagtcttta tgctggtcct 300 aatgctggta tcggaccgtt taacatctgg ggccagggga ccctcgtcac cgtctcgagc 360 <210> 304 <211> 1353 <212> DNA <213> Synthetic <400> 304 cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagcct ctggattctc cctcagtggc tacgacatga gctgggtccg ccaggctcca 120 ggaaaggggc tggaatacat cggactcatt agttatgatg gtaacacata ctacgcgacc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtggatct gaaaatcacc 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gaagtcttta tgctggtcct 300

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    2016273912 14 Dec 2016

    aatgctggta tcggaccgtt taacatctgg ggccagggga ccctcgtcac cgtctcgagc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa tga 1353

    <210> 305 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 305 caggccagtc agaacattgt taccaattta gcc 33 <210> 306 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 306 ggtgcatcca ctctggcatc t 21 <210> 307 <211> 30 <212> DNA <213> Oryctolagus cunicuius <400> 307 cagagctatg atggttttaa tagtgctggg 30 <210> 308 <211> 15 <212> DNA <213> Oryctolagus cunicuius

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    2016273912 14 Dec 2016 <400> 308 ggctacgaca tgagc 15 <210> 309 <211> 48 <212> DNA <213> Oryctolagus cunicuius <400> 309

    ctcattagtt atgatggtaa cacatactac gcgacctggg cgaaaggc 48 <210> 310 <211> 45 <212> DNA <213> Oryctolagus cunicuius <400> 310 agtctttatg ctggtcctaa tgctggtatc ggaccgttta acatc 45

    <210> 311 <211> 327 <212> DNA <213> Synthetic <400> 311 gcattccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gaacattgtt accaacttag cctggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatggt gcatccactc tggcatctgg ggtcccatct 180 cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcagagc tatgatggtt tcaatagtgc tggtttcggc 300 ggaggaacca aggtggaaat caaacgt 327 <210> 312 <211> 648 <212> DNA <213> Synthetic <400> 312 gcattccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gaacattgtt accaacttag cctggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatggt gcatccactc tggcatctgg ggtcccatct 180 cgtttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagatgttg caacttatta ctgtcagagc tatgatggtt tcaatagtgc tggtttcggc 300 ggaggaacca aggtggaaat caaacgtacg gtagcggccc catctgtctt catcttcccg 360 ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420 tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480 caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540 acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600 ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgttag 648

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    2016273912 14 Dec 2016 <210> 313 <211> 369 <212> DNA <213> Synthetic <400> 313

    caggtacagc tggtggagtc tggtggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cttctggatt ctccctcagt ggctacgaca tgagctgggt ccgtcaggct 120 ccaggcaagg gactggagtg ggtgggactc attagttatg atggtaacac atactacgcg 180 acctccgcga aaggccgatt caccatctcc agagacaatt ccaagaacac gctgtacctg 240 caaatgtcta gcctgagagc cgaggacacg gctgtgtatt actgtgctag aagtctttat 300 gctggtccta atgctggtat cggaccgttt aacatctggg gccaaggtac cctcgtcacc 360

    gtctcgagc 369 <210> 314 <211> 1362

    <212> DNA <213> Synthetic <400> 314 caggtacagc tggtggagtc tggtggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cttctggatt ctccctcagt ggctacgaca tgagctgggt ccgtcaggct 120 ccaggcaagg gactggagtg ggtgggactc attagttatg atggtaacac atactacgcg 180 acctccgcga aaggccgatt caccatctcc agagacaatt ccaagaacac gctgtacctg 240 caaatgtcta gcctgagagc cgaggacacg gctgtgtatt actgtgctag aagtctttat 300 gctggtccta atgctggtat cggaccgttt aacatctggg gccaaggtac cctcgtcacc 360 gtctcgagcg cctccaccaa gggcccatcg gtcttccccc tggcaccctc ctccaagagc 420 acctctgggg gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480 acggtgtcgt ggaactcagg cgccctgacc agcggcgtgc acaccttccc ggctgtccta 540 cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag cagcttgggc 600 acccagacct acatctgcaa cgtgaatcac aagcccagca acaccaaggt ggacaagaga 660 gttgagccca aatcttgtga caaaactcac acatgcccac cgtgcccagc acctgaactc 720 ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 780 cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 840 ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900 cagtacgcca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960 aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1020 accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1080 cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1140 agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200 Page 124

    2016273912 14 Dec 2016 cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320 cactacacgc agaagagcct ctccctgtct ccgggtaaat ga 1362

    1260 <210> 315 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 315 caggccagtc agaacattgt taccaactta gcc 33 <210> 316 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 316 ggtgcatcca ctctggcatc t 21 <210> 317 <211> 29 <212> DNA <213> Oryctolagus cunicuius <400> 317 cagagctatg atggtttcaa tagtgctgg 29 <210> 318 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 318 ggctacgaca tgagc 15 <210> 319 <211> 48 <212> DNA <213> Synthetic <400> 319 ctcattagtt atgatggtaa cacatactac gcgacctccg cgaaaggc 48 <210> 320 <211> 45 <212> DNA <213> Oryctolagus cunicuius <400> 320 agtctttatg ctggtcctaa tgctggtatc ggaccgttta acatc 45 <210> 321 <211> 336 <212> DNA <213> Oryctolagus cunicuius <400> 321 gccgccgtgc tgacccagac tccatctccc gtgtctgcag ctgtgggagg cacagtcagc 60

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    2016273912 14 Dec 2016 atcagttgcc agtccagtca gaatgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccagggc agcctcccaa gctcctgatc tacaaggcat ccactctggc atctggggtc 180 ccatcgcggt tcaaaggcgg tggatctggg acagatttca ctctcaccat cagcgacgtg 240 cagtgtgacg ctgctgccac ttactactgt gcaggcggtt ataccagtag tagtgataat 300 gctttcggcg gagggaccga ggtggtggtc aaacgt 336 <210> 322 <211> 656 <212> DNA <213> Synthetic <400> 322 gccgccgtgc tgacccagac tccatctccc gtgtctgcag ctgtgggagg cacagtcagc 60 atcagttgcc agtccagtca gaatgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccagggc agcctcccaa gctcctgatc tacaaggcat ccactctggc atctggggtc 180 ccatcgcggt tcaaaggcgg tggatctggg acagatttca ctctcaccat cagcgacgtg 240 cagtgtgacg ctgctgccac ttactactgt gcaggcggtt ataccagtag tagtgataat 300 gctttcggcg gagggaccga ggtggtggtc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgtta 656 <210> 323 <211> 351 <212> DNA <213> Oryctolagus cunicuius <400> 323 cagtcggtgg aggcgtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagcct ctggattctc cctcagtacc tactggatga gctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggagacatt tattttagta atgaagaaac aaactacgcg 180 agctgggcga aaggccgatt taccatctcc aaaacctcga ccacggtgga tctgaatgtc 240 atcagtccga caaccgagga cacggccacc tatttctgtg ccagaggttc tcctgatgtt 300 gatattggta tagatatgtg gggcccgggc accctcgtca ccgtctcgag c 351 <210> 324 <211> 1344

    <212> DNA <213> Synthetic <400> 324 cagtcggtgg aggcgtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagcct ctggattctc cctcagtacc tactggatga gctgggtccg ccaggctcca 120

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    gggaaggggc tggaatggat cggagacatt tattttagta atgaagaaac aaactacgcg 180 agctgggcga aaggccgatt taccatctcc aaaacctcga ccacggtgga tctgaatgtc 240 atcagtccga caaccgagga cacggccacc tatttctgtg ccagaggttc tcctgatgtt 300 gatattggta tagatatgtg gggcccgggc accctcgtca ccgtctcgag cgcctccacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga gagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgc cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atga 1344

    <210> 325 <211> 39 <212> DNA <213> Oryctolagus cuniculus <400> 325 cagtccagtc agaatgttta taagaacaac tacttatcc 39 <210> 326 <211> 21 <212> DNA <213> Oryctolagus cuniculus <400> 326 aaggcatcca ctctggcatc t 21 <210> 327 <211> 33 <212> DNA <213> Oryctolagus cuniculus <400> 327 gcaggcggtt ataccagtag tagtgataat get 33

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    2016273912 14 Dec 2016 <210> 328 <211> 15 <212> DNA <213> Oryctolagus cuniculus <400> 328 acctactgga tgagc 15 <210> 329 <211> 51 <212> DNA <213> Oryctolagus cuniculus <400> 329

    gacatttatt ttagtaatga agaaacaaac tacgcgagct gggcgaaagg c 51 <210> 330 <211> 33 <212> DNA <213> Oryctolagus cuniculus <400> 330 ggttctcctg atgttgatat tggtatagat atg 33

    <210> 331 <211> 336 <212> DNA <213> Synthetic <400> 331 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc agtccagtca gaatgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccaggga aagtccctaa gctcctgatc tataaggcat ccactctggc atctggggtc 180 ccatctcgtt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240 cagcctgaag atgttgcaac ttattactgt gcaggcggtt ataccagtag tagtgataat 300 gctttcggcg gaggaaccaa ggtggaaatc aaacgt 336 <210> 332 <211> 657 <212> DNA <213> Synthetic <400> 332 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc agtccagtca gaatgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccaggga aagtccctaa gctcctgatc tataaggcat ccactctggc atctggggtc 180 ccatctcgtt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240 cagcctgaag atgttgcaac ttattactgt gcaggcggtt ataccagtag tagtgataat 300 gctttcggcg gaggaaccaa ggtggaaatc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480

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    2016273912 14 Dec 2016 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 333 <211> 360 <212> DNA <213> Synthetic <400> 333 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt acctactgga tgagctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggagac atttacttta gtaatgaaga aacaaactac 180 gcgagcagcg cgaaaggccg attcaccatc tccagagaca attccaagaa caccctgtat 240 cttcaaatga acagcctgag agctgaggac actgctgtgt attactgtgc tagaggttct 300 cctgatgttg atattggtat agatatgtgg ggcccaggga ccctcgtcac cgtctcgagc 360 <210> 334 <211> 1353 <212> DNA <213> Synthetic <400> 334

    gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt acctactgga tgagctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggagac atttacttta gtaatgaaga aacaaactac 180 gcgagcagcg cgaaaggccg attcaccatc tccagagaca attccaagaa caccctgtat 240 cttcaaatga acagcctgag agctgaggac actgctgtgt attactgtgc tagaggttct 300 cctgatgttg atattggtat agatatgtgg ggcccaggga ccctcgtcac cgtctcgagc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140

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    gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa tga 1353 <210> 335 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 335 cagtccagtc agaatgttta taagaacaac tacttatcc 39 <210> 336 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 336 aaggcatcca ctctggcatc t 21 <210> 337 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 337 gcaggcggtt ataccagtag tagtgataat get 33 <210> 338 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 338 acctactgga tgagc 15 <210> 339 <211> 51 <212> DNA <213> Synthetic <400> 339 gacatttact ttagtaatga agaaacaaac taegegagea gegegaaagg c 51

    <210> 340 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 340 ggttctcctg atgttgatat tggtatagat atg 33 <210> 341 <211> 336 <212> DNA <213> Oryctolagus cunicuius

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    2016273912 14 Dec 2016 <400> 341 gcagccgtgc tgacccagac accatcgccc gtgtctgcag ctgtgggaga cacagtcacc 60 atcaagtgcc agtccagtca gagtgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccagggc agcctcccaa gctcctgatc tatgatgcat ccaatctgcc atctggggtc 180 ccatcacggt tcagcggcag tggatctggg acacagttca ctctcaccat cagcggcgtg 240 cagtgtgacg atgctgccac ttactactgt ctaggcgatt atgatgatga tactgataat 300 ggtttcggcg gagggaccga ggtggtggtc aaacgt 336 <210> 342 <211> 657 <212> DNA <213> Synthetic <400> 342 gcagccgtgc tgacccagac accatcgccc gtgtctgcag ctgtgggaga cacagtcacc 60 atcaagtgcc agtccagtca gagtgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccagggc agcctcccaa gctcctgatc tatgatgcat ccaatctgcc atctggggtc 180 ccatcacggt tcagcggcag tggatctggg acacagttca ctctcaccat cagcggcgtg 240 cagtgtgacg atgctgccac ttactactgt ctaggcgatt atgatgatga tactgataat 300 ggtttcggcg gagggaccga ggtggtggtc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 343 <211> 336 <212> DNA <213> Oryctolagus cunicuius <400> 343 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcacagtct ctggaatcga cctcagtagc tatgcaatga tctgggtccg ccaggctcca 120 gggaaggggc tggaatacat cggaatcatt tggagtggtg gcacctacta cgcgacctgg 180 gcgaaaggcc gattcaccat ctccaaaacc tcgaccacgg tggatctgca aatcaccagt 240 ccgacaaccg aggacgcggc cacctatttc tgtgccgcag gtggtggtag tatttatgat 300 gtttggggcc cgggcaccct ggtcaccgtc tcgagc 336 <210> 344 <211> 1329 <212> DNA <213> Synthetic <400> 344 cagtcggtgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60

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    tgcacagtct ctggaatcga cctcagtagc tatgcaatga tctgggtccg ccaggctcca 120 gggaaggggc tggaatacat cggaatcatt tggagtggtg gcacctacta cgcgacctgg 180 gcgaaaggcc gattcaccat ctccaaaacc tcgaccacgg tggatctgca aatcaccagt 240 ccgacaaccg aggacgcggc cacctatttc tgtgccgcag gtggtggtag tatttatgat 300 gtttggggcc cgggcaccct ggtcaccgtc tcgagcgcct ccaccaaggg cccatcggtc 360 ttccccctgg caccctcctc caagagcacc tctgggggca cagcggccct gggctgcctg 420 gtcaaggact acttccccga accggtgacg gtgtcgtgga actcaggcgc cctgaccagc 480 ggcgtgcaca ccttcccggc tgtcctacag tcctcaggac tctactccct cagcagcgtg 540 gtgaccgtgc cctccagcag cttgggcacc cagacctaca tctgcaacgt gaatcacaag 600 cccagcaaca ccaaggtgga caagagagtt gagcccaaat cttgtgacaa aactcacaca 660 tgcccaccgt gcccagcacc tgaactcctg gggggaccgt cagtcttcct cttcccccca 720 aaacccaagg acaccctcat gatctcccgg acccctgagg tcacatgcgt ggtggtggac 780 gtgagccacg aagaccctga ggtcaagttc aactggtacg tggacggcgt ggaggtgcat 840 aatgccaaga caaagccgcg ggaggagcag tacgccagca cgtaccgtgt ggtcagcgtc 900 ctcaccgtcc tgcaccagga ctggctgaat ggcaaggagt acaagtgcaa ggtctccaac 960 aaagccctcc cagcccccat cgagaaaacc atctccaaag ccaaagggca gccccgagaa 1020 ccacaggtgt acaccctgcc cccatcccgg gaggagatga ccaagaacca ggtcagcctg 1080 acctgcctgg tcaaaggctt ctatcccagc gacatcgccg tggagtggga gagcaatggg 1140 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 1200 ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1260 tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1320

    ggtaaatga 1329

    <210> 345 <211> 39 <212> DNA <213> Oryctolagus cuniculus <400> 345 cagtccagtc agagtgttta taagaacaac tacttatcc 39 <210> 346 <211> 21 <212> DNA <213> Oryctolagus cuniculus <400> 346 gatgcatcca atctgccatc t 21 <210> 347 <211> 33 <212> DNA <213> Oryctolagus cuniculus

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    2016273912 14 Dec 2016 <400> 347 ctaggcgatt atgatgatga tactgataat ggt 33 <210> 348 <211> 15 <212> DNA <213> Oryctolagus cuniculus <400> 348 agctatgcaa tgatc 15 <210> 349 <211> 45 <212> DNA <213> Oryctolagus cuniculus <400> 349

    atcatttgga gtggtggcac ctactacgcg acctgggcga aaggc 45 <210> 350 <211> 24 <212> DNA <213> Oryctolagus cuniculus <400> 350 ggtggtggta gtatttatga tgtt 24

    <210> 351 <211> 336 <212> DNA <213> Oryctolagus cuniculus <400> 351 gccctggtga tgacccagac tccatcctcc acgtctgaac cagtgggagg cacagtcacc 60 atcaattgcc aggctagtca gaatattggt aacgacctat cctggtatca gcagaaacca 120 gggcagcctc ccgagctcct aatctattct acatccaaac tggcaactgg ggtcccaaag 180 cggttcagtg gcagcagatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240 gacgatgctg ccacttacta ctgtctaggt gtttatagtt atattagtga tgatggtaat 300 gctttcggcg gagggaccga ggtggtggtc aaacgt 336 <210> 352 <211> 657 <212> DNA <213> Synthetic <400> 352 gccctggtga tgacccagac tccatcctcc acgtctgaac cagtgggagg cacagtcacc 60 atcaattgcc aggctagtca gaatattggt aacgacctat cctggtatca gcagaaacca 120 gggcagcctc ccgagctcct aatctattct acatccaaac tggcaactgg ggtcccaaag 180 cggttcagtg gcagcagatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240 gacgatgctg ccacttacta ctgtctaggt gtttatagtt atattagtga tgatggtaat 300 gctttcggcg gagggaccga ggtggtggtc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420

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    2016273912 14 Dec 2016 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 353 <211> 360 <212> DNA <213> Oryctolagus cunicuius <400> 353 cagtcggtgg aggagttcgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcaccgtct ctggattctc cctcaataac tatgcaatga cctgggtccg ccaggctcca 120 gggaaggggc tggagtggat cgggatcatt ggtagtattg gtaccacata ctacgcgagc 180 tgggcgaaag gccgattctt catctccaaa acctcgacca ctgtggatct gaaaatcatt 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gagatgctgg cgttactgtt 300 gatggttatg gctactactt taacatctgg ggcccaggca ccctcgtcac cgtctcgagc 360 <210> 354 <211> 1353 <212> DNA <213> Synthetic <400> 354 cagtcggtgg aggagttcgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60 tgcaccgtct ctggattctc cctcaataac tatgcaatga cctgggtccg ccaggctcca 120 gggaaggggc tggagtggat cgggatcatt ggtagtattg gtaccacata ctacgcgagc 180 tgggcgaaag gccgattctt catctccaaa acctcgacca ctgtggatct gaaaatcatt 240 agtccgacaa ccgaggacac ggccacctat ttctgtgcca gagatgctgg cgttactgtt 300 gatggttatg gctactactt taacatctgg ggcccaggca ccctcgtcac cgtctcgagc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020

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    aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa tga 1353 <210> 355 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 355 caggctagtc agaatattgg taacgaccta tcc 33 <210> 356 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 356 tctacatcca aactggcaac t 21 <210> 357 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 357 ctaggtgttt atagttatat tagtgatgat ggtaatgct 39 <210> 358 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 358 aactatgcaa tgacc 15 <210> 359 <211> 48 <212> DNA <213> Oryctolagus cunicuius <400> 359 atcattggta gtattggtac cacatactac gcgagctggg cgaaaggc 48 <210> 360 <211> 45 <212> DNA <213> Oryctolagus cunicuius <400> 360 gatgctggcg ttactgttga tggttatggc tactacttta acatc 45

    <210> 361 <211> 336

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    2016273912 14 Dec 2016 <212> DNA <213> Oryctolagus cunicuius <400> 361 gccatcgaaa tgacccagac tccattctcc gtgtctgcag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtca gaccattagc aactacttag cctggtatca gcagaaacca 120 gggcagcctc ccaagctcct gatctatggt gcatccaatc tggaatctgg ggtcccatcg 180 cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240 gacgatgctg ccacttacta ctgtcaacag ggttatacta tcagtaatgt tgataacaat 300 gttttcggcg gagggaccga ggtggtggtc aaacgt 336 <210> 362 <211> 657 <212> DNA <213> Synthetic <400> 362 gccatcgaaa tgacccagac tccattctcc gtgtctgcag ctgtgggagg cacagtcacc 60 atcaagtgcc aggccagtca gaccattagc aactacttag cctggtatca gcagaaacca 120 gggcagcctc ccaagctcct gatctatggt gcatccaatc tggaatctgg ggtcccatcg 180 cggttcaaag gcagtggatc tgggacacag ttcactctca ccatcagcga cctggagtgt 240 gacgatgctg ccacttacta ctgtcaacag ggttatacta tcagtaatgt tgataacaat 300 gttttcggcg gagggaccga ggtggtggtc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 363 <211> 345 <212> DNA <213> Oryctolagus cunicuius

    <400> 363 cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggggatccct gacactcacc 60 tgcgcagcct ctggattctc cctcactggc tacaacttgg tctgggtccg ccaggctcca 120 gggaaggggc tggagtggat cggattcatt agttatggtg ataccacata ctacgcgagc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtgactct gacgatcacc 240 gatctgcaac cttcagacac gggcacctat ttctgtgcca gagagactgc taatacttat 300 gattatggca tctggggccc aggcaccctc gtcaccgtct cgagc 345 <210> 364 <211> 1338 <212> DNA <213> Synthetic

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    2016273912 14 Dec 2016 <400> 364

    cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggggatccct gacactcacc 60 tgcgcagcct ctggattctc cctcactggc tacaacttgg tctgggtccg ccaggctcca 120 gggaaggggc tggagtggat cggattcatt agttatggtg ataccacata ctacgcgagc 180 tgggcgaaag gccgattcac catctccaaa acctcgacca cggtgactct gacgatcacc 240 gatctgcaac cttcagacac gggcacctat ttctgtgcca gagagactgc taatacttat 300 gattatggca tctggggccc aggcaccctc gtcaccgtct cgagcgcctc caccaagggc 360 ccatcggtct tccccctggc accctcctcc aagagcacct ctgggggcac agcggccctg 420 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480 ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540 agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600 aatcacaagc ccagcaacac caaggtggac aagagagttg agcccaaatc ttgtgacaaa 660 actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720 ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780 gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840 gaggtgcata atgccaagac aaagccgcgg gaggagcagt acgccagcac gtaccgtgtg 900 gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960 gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020 ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1080 gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140 agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1200 tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260 ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320 ctgtctccgg gtaaatga 1338

    <210> 365 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 365 caggccagtc agaccattag caactactta gcc 33 <210> 366 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 366

    ggtgcatcca atctggaatc t 21 <210> 367 <211> 39

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    2016273912 14 Dec 2016 <212> DNA <213> Oryctolagus cunicuius <400> 367 caacagggtt atactatcag taatgttgat aacaatgtt 39 <210> 368 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 368 ggctacaact tggtc 15 <210> 369 <211> 48 <212> DNA <213> Oryctolagus cunicuius <400> 369 ttcattagtt atggtgatac cacatactac gcgagctggg cgaaaggc 48 <210> 370 <211> 30 <212> DNA <213> Oryctolagus cunicuius <400> 370 gagactgcta atacttatga ttatggcatc 30 <210> 371 <211> 336 <212> DNA <213> Synthetic <400> 371 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc aggctagtca gaccattagc aactacttag cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatggt gcatccaatc tggaatctgg agtcccatca 180 aggttcagcg gcagtggatc tggaacagaa ttcactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgtcaacag ggttatacta tcagtaatgt tgataacaat 300 gttttcggcg gaggaaccaa ggtggaaatc aaacgt 336 <210> 372 <211> 657 <212> DNA <213> Synthetic <400> 372 gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc aggctagtca gaccattagc aactacttag cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatggt gcatccaatc tggaatctgg agtcccatca 180 aggttcagcg gcagtggatc tggaacagaa ttcactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgtcaacag ggttatacta tcagtaatgt tgataacaat 300

    Page 138

    2016273912 14 Dec 2016 gttttcggcg gaggaaccaa ggtggaaatc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 373 <211> 354 <212> DNA <213> Synthetic <400> 373 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt ggctacaact tggtctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggattc attagttatg gtgataccac atactacgct 180 agctctgcta aaggccgatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag agagactgct 300 aatacttatg attatggcat ctggggccaa gggaccctcg tcaccgtctc gage 354 <210> 374 <211> 1347 <212> DNA <213> Synthetic <400> 374 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt ggctacaact tggtctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggattc attagttatg gtgataccac atactacgct 180 agctctgcta aaggccgatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag agagactgct 300 aatacttatg attatggcat ctggggccaa gggaccctcg tcaccgtctc gagcgcctcc 360 accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420 gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480 tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540 tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600 tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agagagttga gcccaaatct 660 tgtgacaaaa ctcacacatg cccaccgtgc ccagcacctg aactcctggg gggaccgtca 720 gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780 acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840 gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta cgccagcacg 900 taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960

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    aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020 aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1080 aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140 gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200 tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260 gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320 agcctctccc tgtctccggg taaatga 1347 <210> 375 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 375 caggctagtc agaccattag caactactta gcc 33 <210> 376 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 376 ggtgcatcca atctggaatc t 21 <210> 377 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 377 caacagggtt atactatcag taatgttgat aacaatgtt 39 <210> 378 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 378 ggctacaact tggtc 15 <210> 379 <211> 48 <212> DNA <213> Synthetic <400> 379 ttcattagtt atggtgatac cacatactac gctagctctg ctaaaggc 48

    <210> 380 <211> 30 <212> DNA <213> Oryctolagus cunicuius <400> 380 gagactgcta atacttatga ttatggcatc 30

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    2016273912 14 Dec 2016 <210> 381 <211> 336 <212> DNA <213> Oryctolagus cunicuius <400> 381

    gccgccgtgc tgacccagac tccatctccc gtgtctgcag ctgtgggagg cacagtcagc 60 atcagttgcc agtccagtca gaatgtttat aagaacaact atttatcctg gtatcagcag 120 aaaccagggc agcctcccaa gctcctgatc tacaaggctt ccactctggc atctggggtc 180 ccatcgcggt tcaaaggcag tggatctggg acagatttca ctctcaccat cagcgacgtg 240 cagtgtgacg ctgctgccac ttactactgt gcaggcggtt atagtagtag tagtgataat 300 gctttcggcg gagggaccga ggtggtggtc aaacgt 336

    <210> 382 <211> 657 <212> DNA <213> Synthetic <400> 382 gccgccgtgc tgacccagac tccatctccc gtgtctgcag ctgtgggagg cacagtcagc 60 atcagttgcc agtccagtca gaatgtttat aagaacaact atttatcctg gtatcagcag 120 aaaccagggc agcctcccaa gctcctgatc tacaaggctt ccactctggc atctggggtc 180 ccatcgcggt tcaaaggcag tggatctggg acagatttca ctctcaccat cagcgacgtg 240 cagtgtgacg ctgctgccac ttactactgt gcaggcggtt atagtagtag tagtgataat 300 gctttcggcg gagggaccga ggtggtggtc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 383 <211> 351 <212> DNA <213> Oryctolagus cunicuius <400> 383 cagtcggtgg aggcgtccgg gggtcgtctg gtcatgcctg gaggatccct gacactcacc 60 tgcacagcct ctggattctc cctcagtacc tactggatgt cctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggagacatt tattttagta atgaggaaac aaactacgcg 180 acctgggcga aaggccgatt taccatctcc aaaacctcga ccacggtgga tctgaatgtc 240 atcagtccga caaccgagga cacggccacc tatttctgtg caagaggttc tcctgatgtt 300 gagattgcta tagatatgtg gggccagggc accctcgtca ccgtctcgag c 351 <210> 384

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    2016273912 14 Dec 2016 <211> 1344 <212> DNA <213> Synthetic <400> 384

    cagtcggtgg aggcgtccgg gggtcgtctg gtcatgcctg gaggatccct gacactcacc 60 tgcacagcct ctggattctc cctcagtacc tactggatgt cctgggtccg ccaggctcca 120 gggaaggggc tggaatggat cggagacatt tattttagta atgaggaaac aaactacgcg 180 acctgggcga aaggccgatt taccatctcc aaaacctcga ccacggtgga tctgaatgtc 240 atcagtccga caaccgagga cacggccacc tatttctgtg caagaggttc tcctgatgtt 300 gagattgcta tagatatgtg gggccagggc accctcgtca ccgtctcgag cgcctccacc 360 aagggcccat cggtcttccc cctggcaccc tcctccaaga gcacctctgg gggcacagcg 420 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc gtggaactca 480 ggcgccctga ccagcggcgt gcacaccttc ccggctgtcc tacagtcctc aggactctac 540 tccctcagca gcgtggtgac cgtgccctcc agcagcttgg gcacccagac ctacatctgc 600 aacgtgaatc acaagcccag caacaccaag gtggacaaga gagttgagcc caaatcttgt 660 gacaaaactc acacatgccc accgtgccca gcacctgaac tcctgggggg accgtcagtc 720 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 780 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 840 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacgc cagcacgtac 900 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 960 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 1020 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 1140 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 1200 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320 ctctccctgt ctccgggtaa atga 1344

    <210> 385 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 385 cagtccagtc agaatgttta taagaacaac tatttatcc 39 <210> 386 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 386 aaggcttcca ctctggcatc t 21

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    2016273912 14 Dec 2016 <210> 387 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 387 gcaggcggtt atagtagtag tagtgataat get 33 <210> 388 <211> 15 <212> DNA <213> Oryctolagus cunieulus <400> 388 acctactgga tgtcc 15 <210> 389 <211> 51 <212> DNA <213> Oryctolagus cunieulus <400> 389 gacatttatt ttagtaatga ggaaacaaac tacgcgacct gggegaaagg c 51 <210> 390 <211> 33 <212> DNA <213> Oryctolagus cunieulus <400> 390 ggttctcctg atgttgagat tgetatagat atg 33 <210> 391 <211> 336 <212> DNA <213> Synthetic <400> 391 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc agtccagtca gaatgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccaggga aagtccctaa gctcctgatc tataaggcat ccactctggc atctggggtc 180 ccatctcgtt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240 cagcctgaag atgttgcaac ttattactgt gcaggcggtt ataccagtag tagtgataat 300 gctttcggcg gaggaaccaa ggtggaaatc aaacgt 336 <210> 392 <211> 657 <212> DNA <213> Synthetic <400> 392 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc agtccagtca gaatgtttat aagaacaact acttatcctg gtatcagcag 120 aaaccaggga aagtccctaa gctcctgatc tataaggcat ccactctggc atctggggtc 180 ccatctcgtt tcagtggcag tggatctggg acagatttca ctctcaccat cagcagcctg 240

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    2016273912 14 Dec 2016 cagcctgaag atgttgcaac ttattactgt gcaggcggtt ataccagtag tagtgataat 300 gctttcggcg gaggaaccaa ggtggaaatc aaacgtacgg tagcggcccc atctgtcttc 360 atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420 aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480 ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540 agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600 acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657 <210> 393 <211> 360 <212> DNA <213> Synthetic <400> 393 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt acctactgga tgagctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggagac atttacttta gtaatgaaga aacaaactac 180 gcgaccagcg cgaaaggccg attcaccatc tccagagaca attccaagaa caccctgtat 240 cttcaaatga acagcctgag agctgaggac actgctgtgt attactgtgc tagaggttct 300 cctgatgttg agattgctat agatatgtgg ggccaaggga ccctcgtcac cgtctcgagc 360 <210> 394 <211> 1353 <212> DNA <213> Synthetic <400> 394 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt acctactgga tgagctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggagac atttacttta gtaatgaaga aacaaactac 180 gcgaccagcg cgaaaggccg attcaccatc tccagagaca attccaagaa caccctgtat 240 cttcaaatga acagcctgag agctgaggac actgctgtgt attactgtgc tagaggttct 300 cctgatgttg agattgctat agatatgtgg ggccaaggga ccctcgtcac cgtctcgagc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840

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    tacgtggacg gcgtggaggt gcataatgcc aagacaaagc egegggagga gcagtacgcc 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa tga 1353 <210> 395 <211> 39 <212> DNA <213> Oryctolagus cunicuius <400> 395 cagtccagtc agaatgttta taagaacaac tacttatcc 39 <210> 396 <211> 21 <212> DNA <213> Oryctolagus cunicuius <400> 396 aaggcatcca ctctggcatc t 21 <210> 397 <211> 33 <212> DNA <213> Oryctolagus cunicuius <400> 397 gcaggcggtt ataccagtag tagtgataat get 33 <210> 398 <211> 15 <212> DNA <213> Oryctolagus cunicuius <400> 398 acctactgga tgagc 15 <210> 399 <211> 51 <212> DNA <213> Synthetic <400> 399 gacatttact ttagtaatga agaaacaaac tacgcgacca gegegaaagg c 51

    <210> 400 <211> 33 <212> DNA <213> Synthetic

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    2016273912 14 Dec 2016 <400> 400 ggttctcctg atgttgagat tgctatagat atg <210> 401 <211> 217 <212> PRT <213> Synthetic <400> 401

    Asp 1 lie Gin Met Thr 5 Gin Ser Pro Ser Thr 10 Leu Ser Ala Ser Val 15 Gly Asp Arg Val Thr lie Thr cys Gin Al a Ser Gin Ser lie Tyr Ser Asn 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu Leu lie 35 40 45 Tyr Asp Al a Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr cys Gin Gin Gly Phe Thr Val Ser Asp 85 90 95 lie Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190 Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys

    210 215 <210> 402 <211> 451

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    2016273912 14 Dec 2016 <212> PRT <213> Synthetic <400> 402

    Glu Val 1 Gin Leu Val 5 Glu Ser Gly Gly Gly 10 Leu Val Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser cys Al a Al a Ser Gly Phe Thr Val Ser Asn Tyr 20 25 30 Al a Val Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly lie lie Gly Arg Asn Gly Asn Thr T rp Tyr Al a Ser Ser Al a Arg 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Gly Tyr Gly Arg Ser Val Al a Tyr Tyr Val Phe Asn lie T rp Gly 100 105 110 Pro Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a 130 135 140 Al a Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Al a Arg Val Glu Pro Lys Ser cys 210 215 220 Asp Lys Thr Hi s Thr cys Pro Pro cys Pro Al a Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met

    245 250 255

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    2016273912 14 Dec 2016

    lie Ser Arg Thr 260 Pro Glu Val Thr cys 265 Val Val Val Asp Val 270 Ser Hi s Glu Asp Pro Glu Val Lys Phe Asn T rp Tyr Val Asp Gly Val Glu Val 275 280 285 Hi s Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Al a Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu Hi s Gin Asp T rp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys cys Lys Val Ser Asn Lys Al a Leu Pro Al a Pro lie 325 330 335 Glu Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser 355 360 365 Leu Thr cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu 370 375 380 T rp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg T rp Gin Gin Gly Asn Val Phe Ser cys Ser Val Met 420 425 430 Hi s Glu Al a Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser

    435 440 445

    Pro Gly Lys 450 <210> 403 <211> 654 <212> DNA <213> Synthetic <400> 403

    gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gagcatttac agcaatcttg cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatgat gcatccactc tggaatctgg agtcccatca 180 aggttcagcg gcagtggatc tgggacagag tacactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgccaacag ggttttactg ttagtgatat tgataatgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgtacggtag cggccccatc tgtcttcatc 360

    Page 148

    2016273912 14 Dec 2016 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654 <210> 404 <211> 1356 <212> DNA <213> Synthetic <400> 404 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt aactatgcag tgggctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggaatc attggtcgta atggtaacac atggtacgcg 180 agctctgcaa gaggccgatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag aggatatggc 300 cgtagtgttg cttactacgt ctttaacatc tggggcccag ggaccctcgt caccgtctcg 360 agcgcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacgc gagagttgag 660 cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg 720 ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780 cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840 tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900 gccagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960 aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020 tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080 gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140 atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200 gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260 tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320 acgcagaaga gcctctccct gtctccgggt aaatga 1356 <210> 405 <211> 217 <212> PRT <213> Synthetic

    Page 149

    2016273912 14 Dec 2016 <400> 405

    Asp 1 lie Gin Met Thr 5 Gin Ser Pro Ser Thr 10 Leu Ser Ala Ser Val 15 Gly Asp Arg Val Thr lie Thr cys Gin Al a Ser Gin Ser lie Tyr Ser Asn 20 25 30 Leu Al a T rp Tyr Gin Gin Lys Pro Gly Lys Al a Pro Lys Leu Leu lie 35 40 45 Tyr Asp Al a Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr cys Gin Gin Gly Phe Thr Val Ser Asp 85 90 95 lie Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr 100 105 110 Val Al a Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 180 185 190 Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu cys

    210 215 <210> 406 <211> 228 <212> PRT <213> Synthetic <400> 406

    Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 15 10 15

    Page 150

    2016273912 14 Dec 2016

    Ser Leu Arg Leu 20 Ser Cys Ala Ala Ser 25 Gly Phe Thr Val Ser 30 Asn Tyr Al a Val Gly T rp Val Arg Gin Al a Pro Gly Lys Gly Leu Glu T rp Val 35 40 45 Gly lie lie Gly Arg Asn Gly Asn Thr T rp Tyr Al a Ser Ser Al a Arg 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Gly Tyr Gly Arg Ser Val Al a Tyr Tyr Val Phe Asn lie T rp Gly 100 105 110 Pro Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a 130 135 140 Al a Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Al a Arg Val Glu Pro Lys Ser cys 210 215 220 Asp Lys Thr Hi s 225 <210> ‘ 407 <2ii> ; 217 <212> 1 PRT <213> : Syntheti c <400> ‘ 407 Asp lie Gin Met Thr Gin Ser Pro Ser Thr Leu Ser Al a Ser Val Gly 1 5 10 15 Asp Arg Val Thr lie Thr cys Gin Al a Ser Gin Ser lie Tyr Ser Asn

    Page 151

    2016273912 14 Dec 2016

    20 25 30

    Leu Ala Trp Tyr Gin Gin Lys Pro Gly Lys Ala Pro Lys Leu Leu lie 35 40 45 Tyr Asp Al a Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Asp Asp Phe Al a Thr Tyr Tyr Cys Gln Gin Gly Phe Thr Val Ser Asp 85 90 95 lie Asp Asn Al a Phe Gly Gly Gly Thr Lys Val Glu lie Lys Arg Thr 100 105 110 Val Ala Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 115 120 125 Lys Ser Gly Thr Al a Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro 130 135 140 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Ala Leu Gin Ser Gly 145 150 155 160 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His 180 185 190 Lys Val Tyr Al a cys Glu Val Thr His Gin Gly Leu Ser Ser Pro Val 195 200 205 Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 408 <211> ; 228 <212> PRT <213> : Syntheti c <400> 408 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu Val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Al a Ala Ser Gly Phe Thr Val Ser Asn Tyr 20 25 30 Ala Val Gly T rp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val

    35 40 45

    Page 152

    2016273912 14 Dec 2016

    Gly lie lie Gly Arg Asn Gly Asn Thr Trp Tyr Ala Ser Ser Al a Arg 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Al a Val Tyr Tyr cys Al a 85 90 95 Arg Gly Tyr Gly Arg Ser Val Al a Tyr Tyr Val Phe Asn lie T rp Gly 100 105 110 Pro Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Al a 130 135 140 Al a Leu Gly cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser T rp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe Pro Al a 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Al a Arg Val Glu Pro Lys Ser cys

    210 215 220

    Asp Lys Thr His 225 <210> 409 <211> 654 <212> DNA <213> Synthetic <400> 409

    gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gagcatttac agcaatcttg cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatgat gcatccactc tggaatctgg agtcccatca 180 aggttcagcg gcagtggatc tgggacagag tacactctca ccatcagcag cctgcagcct 240 gatgattttg caacttacta ctgccaacag ggttttactg ttagtgatat tgataatgct 300 ttcggcggag gaaccaaggt ggaaatcaaa cgtacggtag cggccccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420

    Page 153

    2016273912 14 Dec 2016 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg ttag 654 <210> 410 <211> 687 <212> DNA <213> Synthetic <400> 410 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccgtcagt aactatgcag tgggctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggaatc attggtcgta atggtaacac atggtacgcg 180 agctctgcaa gaggccgatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag aggatatggc 300 cgtagtgttg cttactacgt ctttaacatc tggggcccag ggaccctcgt caccgtctcg 360 agcgcctcca ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420 gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480 tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540 tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600 acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacgc gagagttgag 660 cccaaatctt gtgacaaaac tcactag 687 <210> 411 <211> 120 <212> PRT <213> Homo sapiens <400> 411

    Ser Ser Ser His Pro lie Phe His Arg Gly Glu Phe Ser Val Cys Asp 15 10 15

    Ser Val Ser Val Trp Val Gly Asp Lys Thr Thr Ala Thr Asp lie Lys 20 25 30

    Gly Lys Glu Val Met Val Leu Gly Glu Val Asn lie Asn Asn Ser Val 35 40 45

    Phe Lys Gin Tyr Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val 50 55 60

    Asp Ser Gly Cys Arg Gly lie Asp Ser Lys His Trp Asn Ser Tyr Cys

    65 70 75 80

    Thr Thr Thr His Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gin

    85 90 95

    Page 154

    2016273912 14 Dec 2016

    Ala Ala Trp Arg 100 Phe lie Arg lie Asp Thr Ala Cys 105 Val cys 110 Val Leu Ser Arg Lys Al a Val Arg Arg Al a 115 120 <210> 412 <211> 105 <212> PRT <213> Homo sapi ens <400> 412 Val Ala Al a Pro Ser Val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu 1 5 10 15 Lys Ser Gly Thr Al a Ser Val Val cys Leu Leu Asn Asn Phe Tyr Pro 20 25 30 Arg Glu Al a Lys Val Gin T rp Lys Val Asp Asn Al a Leu Gin Ser Gly 35 40 45 Asn Ser Gin Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr 50 55 60 Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Al a Asp Tyr Glu Lys Hi s 65 70 75 80 Lys Val Tyr Al a cys Glu Val Thr Hi s Gin Gly Leu Ser Ser Pro Val 85 90 95 Thr Lys Ser Phe Asn Arg Gly Glu cys 100 105 <210> 413 <211> 330 <212> PRT <213> Homo sapi ens <400> 413 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Al a Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Al a Al a Leu Gly cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser T rp Asn Ser Gly Al a Leu Thr Ser 35 40 45 Gly Val Hi s Thr Phe Pro Al a Val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gin Thr

    Page 155

    2016273912 14 Dec 2016

    65 70 75 80

    Tyr lie cys Asn Val 85 Asn His Lys Pro Ser 90 Asn Thr Lys Val Asp 95 Lys Arg Val Glu Pro Lys Ser cys Asp Lys Thr Hi s Thr cys Pro Pro cys 100 105 110 Pro Al a Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr Pro Glu Val Thr cys 130 135 140 Val Val Val Asp Val Ser Hi s Glu Asp Pro Glu Val Lys Phe Asn T rp 145 150 155 160 Tyr Val Asp Gly Val Glu Val Hi s Asn Al a Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gin Tyr Al a Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 Hi s Gin Asp T rp Leu Asn Gly Lys Glu Tyr Lys cys Lys Val Ser Asn 195 200 205 Lys Al a Leu Pro Al a Pro lie Glu Lys Thr lie Ser Lys Al a Lys Gly 210 215 220 Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu 225 230 235 240 Met Thr Lys Asn Gin Val Ser Leu Thr cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp lie Al a Val Glu T rp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg T rp Gin Gin Gly Asn 290 295 300 Val Phe Ser cys Ser Val Met Hi s Glu Al a Leu Hi s Asn Hi s Tyr Thr 305 310 315 320 Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys

    325 330 <210> 414 <211> 18

    Page 156

    2016273912 14 Dec 2016 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 414

    Met Arg Ser Leu Leu lie Leu Val Leu Cys Phe Leu Pro Leu Ala Ala 15 10 15

    Leu Gly <210> 415 <211> 16 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 415

    Met Arg Leu Leu Leu Leu Leu Leu Leu Leu Pro Leu Ala Ala Leu Gly 15 10 15 <210> 416 <211> 19 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 416

    Met Leu Leu Gin Ala Phe Leu Phe Leu Leu Ala Gly Phe Ala Ala Lys 15 10 15 lie Ser Ala <210> 417 <211> 35 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 417

    Met Arg Phe Pro Ser lie Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15

    Ala Leu Ala Ala Pro Val Asn Thr Thr Thr Glu Glu Gly Val Ser Leu 20 25 30

    Glu Lys Arg 35

    Page 157

    2016273912 14 Dec 2016 <210> 418 <211> 22 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 418

    Met Arg Phe Pro Ser lie Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15

    Ala Leu Ala Ala Pro Val 20 <210> 419 <211> 27 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 419

    Met Arg Phe Pro Ser lie Phe Thr Ala Val Leu Phe Ala Ala Ser Ser 15 10 15

    Ala Leu Ala Ala Pro Val Ser Leu Glu Lys Arg 20 25 <210> 420 <211> 41 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 420

    Met 1 Arg Phe Pro Ser 5 lie Phe Thr Ala Val 10 Leu Phe Al a Al a Ser 15 Ser Al a Leu Al a Al a Pro Val Asn Thr Thr Thr Glu Glu Gly Val Ser Leu 20 25 30 Glu Lys Arg Glu Al a Glu Al a Glu Al a

    35 <210> <211> <212> <213> 421 85 PRT Arti fici al <220> <223> Secretion peptide <400> 421

    Page 158

    2016273912 14 Dec 2016

    Met 1 Arg Phe Pro Ser 5 lie Phe Thr Ala Val 10 Leu Phe Ala Ala Ser 15 Ser Al a Leu Al a Al a Pro Val Asn Thr Thr Thr Glu Asp Glu Thr Al a Gin 20 25 30 lie Pro Al a Glu Al a Val lie Gly Tyr Ser Asp Leu Glu Gly Asp Phe 35 40 45 Asp Val Al a Val Leu Pro Phe Ser Asn Ser Thr Asn Asn Gly Leu Leu 50 55 60 Phe lie Asn Thr Thr lie Al a Ser lie Al a Al a Lys Glu Glu Gly Val 65 70 75 80 Ser Leu Glu Lys Arg

    <210> 422 <211> 44 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 422 Met Thr Lys 1 Pro Thr 5 Gin Val Leu Val Arg 10 Ser Val Ser lie Leu 15 Phe Phe lie Thr Leu 20 Leu Hi s Leu Val Val 25 Al a Leu Asn Asp Val 30 Al a Gly Pro Ala Glu 35 Thr Al a Pro Val Ser 40 Leu Leu Pro Arg

    <210> 423 <211> 22 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 423

    Met Phe Ser Pro lie Leu Ser Leu Glu lie lie Leu Ala Leu Ala Thr 15 10 15

    Leu Gin Ser Val Phe Ala

    20 <210> 424 <211> 22 <212> PRT <213> Arti fici al

    Page 159

    2016273912 14 Dec 2016 <220>

    <223> Secretion peptide <400> 424

    Met Gin Thr Leu Leu Val Ser Ser Leu Val Val Ser Leu Ala Ala Ala 15 10 15

    Leu Pro His Tyr lie Arg 20 <210> 425 <211> 22 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 425

    Met lie Phe Leu Lys Leu lie Lys Ser lie Val lie Gly Leu Gly Leu 15 10 15

    Val Ser Ala lie Gin Ala 20 <210> 426 <211> 24 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 426

    Met Lys Trp Val Thr Phe lie Ser Leu Leu Phe Leu Phe Ser Ser Ala 15 10 15

    Tyr Ser Arg Gly Val Phe Arg Arg 20 <210> 427 <211> 18 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 427

    Met Lys Trp Val Thr Phe lie Ser Leu Leu Phe Leu Phe Ser Ser Ala 15 10 15

    Tyr Ser <210> 428 <211> 24

    Page 160

    2016273912 14 Dec 2016 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 428

    Met Ala Leu Trp Met Arg Leu Leu Pro Leu Leu Ala Leu Leu Ala Leu 15 10 15

    Trp Gly Pro Asp Pro Ala Ala Ala 20 <210> 429 <211> 24 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 429

    Met Lys Tyr Thr Ser Tyr lie Leu Ala Phe Gin Leu Cys lie Val Leu 15 10 15

    Gly Ser Leu Gly Cys Asp Leu Pro 20 <210> 430 <211> 26 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 430

    Met Ala Ala Asp Ser Gin Thr Pro Trp Leu Leu Thr Phe Ser Leu Leu 15 10 15

    Cys Leu Leu Trp Pro Gin Glu Pro Gly Ala 20 25 <210> 431 <211> 27 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 431

    Met Lys Lys Asn Arg Met Met Met Met lie Trp Ser Val Gly Val Val 15 10 15

    Trp Met Leu Leu Leu Val Gly Gly Ser Tyr Gly 20 25

    Page 161

    2016273912 14 Dec 2016 <210> 432 <211> 18 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 432

    Met Gin Lys Leu lie lie Phe Ala Leu Val Val Leu Cys Val Gly Ser 15 10 15

    Gl u Al a <210> 433 <211> 18 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 433

    Met Lys Ala Leu lie Val Leu Gly Leu Val Leu Leu Ser Val Thr Val 15 10 15

    Gin Gly <210> 434 <211> 20 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 434

    Met Val Asp Gly Val Met lie Leu Pro Val Leu lie Met lie Ala Leu 15 10 15

    Pro Ser Pro Ser 20 <210> 435 <211> 19 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 435

    Met Gly Ala Ala Ala Lys Leu Ala Phe Ala Val Phe Leu lie Ser Cys 15 10 15

    Page 162

    2016273912 14 Dec 2016

    Ser Ser Gly <210> 436 <211> 31 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 436

    Met Leu Ser Leu Lys Pro Ser Trp Leu Thr Leu Ala Ala Leu Met Tyr 15 10 15

    Ala Met Leu Leu Val Val Val Pro Phe Ala Lys Pro Val Arg Ala 20 25 30 <210> 437 <211> 22 <212> PRT <213> Artificial <220>

    <223> Secretion peptide <400> 437

    Met Asp Met Arg Val Pro Ala Gin Leu Leu Gly Leu Leu Leu Leu Trp 15 10 15

    Leu Pro Gly Ala Lys Cys 20 <210> 438 <211> 651 <212> DNA <213> Artificial <220>

    <223> Humanized antibody <400> 438

    gctatccaga tgacccagtc tccttcctcc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgcc aggccagtca gagcattaac aatgagttat cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatagg gcatccactc tggcatctgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagac ttcactctca ccatcagcag cctgcagcct 240 gatgattttg caacttatta ctgccaacag ggttatagtc tgaggaacat tgataatgct 300 ttcggcggag ggaccaaggt ggaaatcaaa cgtacggtgg ctgcaccatc tgtcttcatc 360 ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 420 aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 480 aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 540 accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 600

    Page 163

    2016273912 14 Dec 2016 catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 651 <210> 439 <211> 1350 <212> DNA <213> Oryctolagus cunicuius <220>

    <223> Humanized antibody <400> 439

    gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt ctccctcagt aactactacg tgacctgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggcatc atctatggta gtgatgaaac cgcctacgct 180 acctccgcta taggccgatt caccatctcc agagacaatt ccaagaacac cctgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt actgtgctag agatgatagt 300 agtgactggg atgcaaagtt caacttgtgg ggccaaggga ccctcgtcac cgtctcgagc 360 gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 420 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 540 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 600 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 660 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 720 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 780 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 840 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacgcc 900 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 960 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1020 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1080 atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1260 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320 cagaagagcc tctccctgtc tccgggtaaa 1350

    <210> 440 <211> 660 <212> DNA <213> Artificial Sequence <220>

    <223> Humanized antibody <400> 440 caagtgctga cccagtctcc atcctccctg tctgcatctg taggagacag agtcaccatc 60

    Page 164

    2016273912 14 Dec 2016

    aattgccagg ccagtcagag tgtttatcat aacacctacc tggcctggta tcagcagaaa 120 ccagggaaag ttcctaagca actgatctat gatgcatcca ctctggcatc tggggtccca 180 tctcgtttca gtggcagtgg atctgggaca gatttcactc tcaccatcag cagcctgcag 240 cctgaagatg ttgcaactta ttactgtctg ggcagttatg attgtactaa tggtgattgt 300 tttgttttcg gcggaggaac caaggtggaa atcaaacgta cggtggctgc accatctgtc 360 ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420 ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480 tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540 agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600 gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660

    <210> 441 <211> 1326 <212> DNA <213> Artificial Sequence

    <220> <223> Humanized antibody <400> 441 gaggtgcagc ttgtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag tctctggaat cgacctcagt ggctactaca tgaactgggt ccgtcaggct 120 ccagggaagg ggctggagtg ggtcggagtc attggtatta atggtgccac atactacgcg 180 agctgggcga aaggccgatt caccatctcc agagacaatt ccaagaccac ggtgtatctt 240 caaatgaaca gcctgagagc tgaggacact gctgtgtatt tctgtgctag aggggacatc 300 tggggccaag ggaccctcgt caccgtctcg agcgcctcca ccaagggccc atcggtcttc 360 cccctggcac cctcctccaa gagcacctct gggggcacag cggccctggg ctgcctggtc 420 aaggactact tccccgaacc ggtgacggtg tcgtggaact caggcgccct gaccagcggc 480 gtgcacacct tcccggctgt cctacagtcc tcaggactct actccctcag cagcgtggtg 540 accgtgccct ccagcagctt gggcacccag acctacatct gcaacgtgaa tcacaagccc 600 agcaacacca aggtggacgc gagagttgag cccaaatctt gtgacaaaac tcacacatgc 660 ccaccgtgcc cagcacctga actcctgggg ggaccgtcag tcttcctctt ccccccaaaa 720 cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 780 agccacgaag accctgaggt caagttcaac tggtacgtgg acggcgtgga ggtgcataat 840 gccaagacaa agccgcggga ggagcagtac gccagcacgt accgtgtggt cagcgtcctc 900 accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 960 gccctcccag cccccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 1020 caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc 1080 tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 1140

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    2016273912 14 Dec 2016 ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1200 tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1260 gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt 1320 aaatga 1326

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