AU2003259704A1

AU2003259704A1 - Therapeutic polypeptides, nucleic acids encoding same, and methods of use

Info

Publication number: AU2003259704A1
Application number: AU2003259704A
Authority: AU
Inventors: David W. Anderson; Elina Catterton; Shlomit R. Edinger; Linda Gorman; Xiaojia Guo; Weizhen Ji; John R. Macdougall; Rachel Malcolm; Muralidhara Padigaru; Daniel K. Rieger; Kimberly A. Spytek; David J. Stone; Mei Zhong
Original assignee: CuraGen Corp
Current assignee: CuraGen Corp
Priority date: 2002-08-07
Filing date: 2003-08-07
Publication date: 2004-02-25
Also published as: WO2004015079A3; EP1539807A4; WO2004015079A2; CA2495563A1; JP2006515753A; EP1539807A2

Description

WO 2004/015079 PCT/US2003/024931 THERAPEUTIC POLYPEPTIDES, NUCLEIC ACIDS ENCODING SAME, AND METHODS OF USE TECHNICAL FIELD 5 The present invention relates to novel polypeptides, and the nucleic acids encoding them, having properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass diagnostic and prognostic assay procedures as well as 10 methods of treating diverse pathological conditions.

WO 2004/015079 PCT/US2003/024931 THIS PAGE INTENTIONALLY LEFT BLANK 2 WO 2004/015079 PCT/US2003/024931 THIS PAGE INTENTIONALLY LEFT BLANK 3 WO 2004/015079 PCT/US2003/024931 BACKGROUND OF THE INVENTION Eukaryotic cells are characterized by biochemical and physiological processes which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such 5 as vertebrates, or more particularly organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways involve extracellular signaling proteins, cellular receptors that bind the signaling proteins, and signal transducing components located within the cells. Signaling proteins may be classified as endocrine effectors, paracrine effectors or 10 autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example two different classes of 15 cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine 20 effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect. Signaling processes may elicit a variety of effects on cells and tissues including by 25 way of nonlimiting example induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation ofta cell or tissue, and suppression of differentiation or maturation of a cell or tissue. Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as 30 diminished or suppressed level of synthesis and secretion of protein effectors. In other classes of pathologies the dysregulation is manifested as increased or up-regulated level of synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected WO 2004/015079 PCT/US2003/024931 of suffering from a condition brought on by altered or mis-regulated levels of a. protein effector of interest. Therefore there is a need to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. There also is a need to provide the protein 5 effector as a product of manufacture. Administration of the effector to a subject in need thereof is useful in treatment of the pathological condition. Accordingly, there is a need for a method of treatment of a pathological condition brought on by a diminished or suppressed levels of the protein effector of interest. In addition, there is a need for a method of treatment of a pathological condition brought on by a increased or up-regulated levels of 10 the protein effector of interest. Antibodies are multichain proteins that bind specifically to a-given antigen, and bind poorly, or not at all, to substances deemed not to be cognate antigens. Antibodies are comprised of two short chains termed light chains and two long chains termed heavy chains. These chains are constituted of immunoglobulin domains, of which generally there 15 are two classes: one variable domain per chain, one constant domain in light chains, and three or more constant domains in heavy chains. The antigen-specific portion of the immunoglobulin molecules resides in the variable domains; the variable domains of one light chain and one heavy chain associate with each other to generate the antigen-binding moiety. Antibodies that bind immunospecifically to a cognate or target antigen bind with 20 high affinities. Accordingly, they are useful in assaying specifically for the presence of the antigen in a sample. In addition, they have the potential of inactivating the activity of the antigen. Therefore there is a need to assay for the level of a protein effector of interest in a biological sample from such a subject, and to compare this level with that characteristic of 25 a nonpathological condition. In particular, there is a need for such an assay based on the use of an antibody that binds immunospecifically to the antigen. There further is a need to inhibit the activity of the protein effector in cases where a pathological condition arises from elevated or excessive levels of the effector based on the use of an antibody that binds immunospecifically to the effector. Thus, there is a need for the antibody as a product of 30 manufacture. There further is a need for a method of treatment of a pathological condition brought on by an elevated or excessive level of the protein effector of interest based on administering the antibody to the subject.

WO 2004/015079 PCT/US2003/024931 SUMMARY OF THE INVENTION The invention is based in part upon the discovery of isolated polypeptides including amino acid sequences selected from mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38. The 5 novel nucleic acids and polypeptides are referred to herein as NOVia, NOV1b, NOV1b, NOVIc, NOV2a, NOV2b, NOV2c, NOV2d, NOV3a, NOV3b, etc. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as "NOVX" nucleic acid or polypeptide sequences. The invention also is based in part upon variants of a mature-form of the amino acid 10 sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed. In another embodiment, the invention includes the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an 15 integer between 1 and 38. In another embodiment, the invention also comprises variants of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also involves fragments of any of .20 the mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38, or any other amino acid sequence selected from this group. The inVention also comprises fragments from these groups in which up to 15% of the residues are changed. In another embodiment, the invention encompasses polypeptides that are naturally 25 occurring allelic variants of the sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38. These allelic variants include amino acid sequences that are the translations of nucleic acid sequences differing by a single nucleotide from nucleic acid sequences selected from the group consisting of SEQ ID NOS: 2n-1, wherein n is an integer between 1 and 38. The variant polypeptide where any 30 amino acid changed in the chosen sequence is changed to provide a conservative substitution. In another embodiment, the invention comprises a pharmaceutical composition involving a polypeptide with an amino acid sequence selected from the group consisting of WO 2004/015079 PCT/US2003/024931 SEQ ID NO:2n, wherein n is an integer between 1 and 38 and a pharmaceutically acceptable carrier. In another embodiment, the invention involves a kit, including, in one or more containers, this pharmaceutical composition. In another embodiment, the invention includes the use of a therapeutic in the 5 manufacture of a medicament for treating a syndrome associated with a human disease, the disease being selected from a pathology associated with a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 wherein said therapeutic is the polypeptide selected from this group. In another embodiment, the invention comprises a method for determining the 10 presence or amount of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between I and 38 in a sample, the method involving providing the sample; introducing the sample to an antibody that binds immunospecifically to the poljpeptide; and determining the presence or amount of antibody bound to the polypeptide, thereby determining the presence or amount of 15 polypeptide in the sample. In another embodiment, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 in a first mammalian subject, the method 20 involving measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and comparing the amount of the polypeptide in this sample to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample 25 indicates the presence of or predisposition to the disease. In another embodiment, the invention involves a method of identifying an agent that binds to a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38, the method including introducing the polypeptide to the agent; and determining whether the agent binds to the 30 polypeptide. The agent could be a cellular receptor or a downstream effector. In another embodiment, the invention involves a method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer WO 2004/015079 PCT/US2003/024931 between 1 and 38, the method including providing a cell expressing the polypeptide of the invention and having a property or function ascribable to the polypeptide; contacting the cell with a composition comprising a candidate substance; and determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an 5 alteration observed in the presence of the substance is not observed when the cell is contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent. In another embodiment, the invention involves a method for screening for a modulator of activity or of latency or predisposition to a pathology associated with a 10 polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between I and 38, the method including administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of the invention, wherein the test animal recombinantly expresses the polypeptide of the invention; measuring the activity of the polypeptide in the test animal after administering 15 the test compound; and comparing the activity of the protein in the test animal with the activity of the polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of, or predisposition to, a pathology associated with the polypeptide of the invention. The recombinant test animal could 20 express a test protein transgene or express the transgene under the control of a promoter at an increased level relative to a wild-type test animal The promoter may or may not b the native gene promoter of the transgene. In another embodiment, the invention involves a method for modulating the activity of a polypeptide with an amino acid sequence selected from the group consisting of SEQ 25 ID NO:2n, wherein n is an integer between 1 and 38, the method including introducing a cell sample expressing the polypeptide with a compound that binds to the.polypeptide in an amount sufficient to modulate the activity of the polypeptide. In another embodiment, the invention involves a method of treating or preventing a pathology associated with a polypeptide with an amino acid sequence selected from the 30 group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38, the method including administering the polypeptide to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject. The subject could be human.

WO 2004/015079 PCT/US2003/024931 In another embodiment, the invention involves a method of treating a pathological state in a mammal, the method including administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide having 5 the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 or a biologically active fragment thereof. In another embodiment, the invention involves an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide having an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ 10 ID NO:2n, wherein n is an integer between 1 and 38; a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; the amino acid 15 sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38; a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; a nucleic acid 20 fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 or any variant of the polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and the complement of any df the nucleic acid 25 molecules. In another embodiment, the invention comprises an isolated nucleic acid molecule having a.nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38, wherein the nucleic acid molecule 30 comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant. In another embodiment, the invention involves an isolated nucleic acid molecule including a nucleic acid sequence encoding a polypeptide having an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38 that encodes a variant polypeptide, WO 2004/015079 PCT/US2003/024931 wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant. In another embodiment, the invention comprises an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence 5 selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 2n-1, wherein n is an integer between 1 and 38. In another embodiment, the invention includes an isolated nucleic acid molecule 10 having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer 15 between 1 and 38; a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; a nucleic acid fragment of the sequence selected from the group consisting of 20 SEQ ID NO:2n-1, wherein n is an integer between 1 and 38; and a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ lID NO:2n-1, wherein n is an integer between 1 and 38 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed. 25 In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38, wherein the nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group 30 consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or a complement of the nucleotide sequence. In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ 1 ^~ WO 2004/015079 PCT/US2003/024931 ID NO:2n, wherein n is an integer between 1 and 38, wherein the nucleic acid molecule has a nucleotide sequence in which any nucleotide specified in the coding sequence of the chosen nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the 5 nucleotides in the chosen coding sequence are so changed, an isolated second polynucleotide that is a complement of the first polynucleotide, or a fragment of any of them. In another embodiment, the invention includes a vector involving the nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid 10 sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38. This vector can have a promoter operably linked to the nucleic acid molecule. This vector can be located within a cell. In another embodiment, the invention involves a method for determining the 15 presence or amount of a nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38 in a sample, the method including providing the sample; introducing the sample to a probe that binds to the nucleic acid molecule; and determining the presence or 20 amount of the probe bound to the nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in the sample. The presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type. The cell type can be cancerous. In another embodiment, the invention involves a method for determining the 25 presence of or predisposition for a disease associated with altered levels of a nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 38 in a first mammalian subject, the method including measuring the amount of the nucleic acid in a sample from 30 the first mammalian subject; and comparing the amount of the nucleic acid in the sample of step (a) to the amount of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

WO 2004/015079 PCT/US2003/024931 The invention further provides an antibody that binds immunospecifically to a NOVX polypeptide. The NOVX antibody may be monoclonal, humanized, or a fully human antibody. Preferably, the antibody has a dissociation constant for the binding of the NOVX polypeptide to the antibody less than 1 x 10'' M. More preferably, the NOVX 5 antibody neutralizes the activity of the NOVX polypeptide. In a further aspect, the invention provides for the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, associated with a NOVX polypeptide. Preferably the therapeutic is a NOVX antibody. In yet a further aspect, the invention provides a method of treating or preventing a 10 NOVX-associated disorder, a method of treating a pathological state in a mammal, and a method of treating or preventing a pathology associated with a polypeptide by administering a NOVX antibody to a subject in an amount sufficient to treat or prevent the disorder. Unless otherwise defined, all technical and scientific terms used herein have the 15 same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In 20 the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description and claims. 25 BRIEF DESCRIPTION OF THE DRAWINGS DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel nucleotides and polypeptides encoded 30 thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as "NOVX nucleic acids" or "NOVX polynucleotides" and the corresponding encoded polypeptides are referred to as "NOVX polypeptides" or "NOVX WO 2004/015079 PCT/US2003/024931 proteins." Unless indicated otherwise, "NOVX" is meant to refer to any of the novel sequences disclosed herein. Table A provides a summary of the NOVX nucleic acids and their encoded polypeptides. 5 TABLE A. Sequences and Corresponding SEQ ID Numbers SEQ ID SEQ ID NOVX Internal NO NO Assignment Identification (nucleic (amino Homolog acid) acid)_ NOVia CG121992-03 1 2 Chordin precursor Homo sapiens NOVlb CG121992-02 3 4 Chordin precursor Homo sapiens NOV1c CG121992-04 5 6 Chordin precursor Homo sapiens NOV2a CG186275-03 7 8 ADAM 22 precursor (A disintegrin and metalloproteinase domain 22) (Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 2) (Metalloproteinase disintegrin ADAM22 3) - Homo sapiens NOV3a 260368272 9 10 Beta-secretase - Homo sapiens NOV3b 260368280 11 12 Beta-secretase - Homo sapiens NOV3c 267441066 13 14 Beta-secretase - Homo sapiens NOV3d CG50586-03 15 16 Beta-secretase - Homo sapiens NOV4a CG50637-01 17 18 Transmembrane protein AMIGO - Homo sapiens NOV4b 277577082 19 20 Transmembrane protein AMIGO - Homo I _sapiens NOV4c 277577094 21 22 Transmembrane protein AMIGO - Homo -sapiens NOV4d 277577141 123 Transmembrane protein AMIGO - Homo WO 2004/015079 PCT/US2003/024931 -_ _sapiens NOV5a 306433917 25 26 Nephronectin - Homo sapiens NOV5b 306447063 27 28 Nephronectin - Homo sapiens NOV5c 306447071 29 30 Nephronectin - Homo sapiens NOV5d 306447075 31 32 Nephronectin - Homo sapiens NOV5e CG51117-09 33 34 Nephronectin - Homo sapiens NOV5f CG51117-14 35 36 Nephronectin - Homo sapiens NOV5g SNP13382208 37 38 Nephronectin - Homo sapiens NOV6a CG51923-01 39 40 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6b 305869563 41 42 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6c 305869567 43 44 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6d 306076041 45 46 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6e 317868343 47 48 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6f 317868367 49 50 Protocadherin Fat 2 precursor (hFat2) WO 2004/015079 PCT/US2003/024931 (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6g 317871203 51 52 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6h 317871219 53 54 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6i 317871243 55 56 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo ___________ ___ ____ ___ ___ ___ ___ _ ________sapiens NOV6j 317871246 57 58 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo ______________ ________sapiens NOV6k 317999764 59 60 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV61 318176301 61 62 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo sapiens NOV6m CG51923-02 63 64 Protocadherin Fat 2 precursor (hFat2) (Multiple epidermal growth factor-like domains 1) - Homo A I_ _sapiens NOV6n CG51923-03 65 66 Protocadherin Fat 2 _precursor (hFat2) WO 2004/015079 PCT/US2003/024931 (Multiple epidermal growth factor-like domains 1) - Homo sapiens SCG52919-06SZ-6 Homo sapiens 1 298521010 ~ 69 j70 SEZ-6 - Homo sapiens NOWc G52919-09 - 71 72 SEZ-6 - Homo sapiens NOV8a CG94946-01 73 74 AGRIN precursor Homo sapiens (Human), 2026 aa NOV8b 308909220 75 76 AGRIN precursor Homo sapiens (Human), 2026 aa Table A indicates the homology of NOVX polypeptides to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table A will be useful 5 in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table A. Pathologies, diseases, disorders and condition and the like that are associated with NOVX sequences include, but are not limited to: e.g., cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), vascular 10 calcification, fibrosis, atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, metabolic disturbances associated with obesity, transplantation, osteoarthritis, rheumatoid arthritis, osteochondrodysplasia, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, diabetes, metabolic 15 disorders, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, glomerulonephritis, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, psoriasis, skin disorders, graft versus host disease, AIDS, bronchial asthma, lupus, Crohn's disease; inflammatory bowel disease, ulcerative colitis, multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, infectious disease, anorexia, 20 cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, schizophrenia, depression, asthma, emphysema, allergies, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers, as WO 2004/015079 PCT/US2003/024931 well as conditions such as transplantation, neuroprotection, fertility, or regeneration (in vitro and in vivo). NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to 5 the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong. Consistent with other known members of the family of proteins, identified in 10 column 5 of Table A, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A. The NOVX nucleic acids and polypeptides can also be used to screen for molecules, 15 which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table A. The NOVX nucleic acids and polypeptides are also useful for detecting specific cell 20 types. Details of the expression analysis for each NOVX are presented in Example C. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g. detection of a variety of cancers. 25 Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein. NOVX clones NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to 30 the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

WO 2004/015079 PCT/US2003/024931 The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are 5 described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders. The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a 10 specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene 15 ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) a biological defense weapon. In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, 20 wherein n is an integer between 1 and 38; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 38, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) an amino acid sequence selected from the group 25 consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 38; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d). 30 In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence given SEQ ID NO: 2n, wherein n is an integer between 1 and 38; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID WO 2004/015079 PCT/US2003/024931 NO: 2n, wherein n is an integer between 1 and 38 wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n 5 is an integer between 1 and 38; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 38, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the 10 amino acid sequence selected from the group consisting of SEQ ID NO: 2n, wherein n is an integer between 1 and 38 or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules. 15 In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 38; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected 20 from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 38 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 38; and (d) a nucleic acid fragment 25 wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 38 is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed. NOVX Nucleic Acids and Polypeptides 30 One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX-encoding nucleic acids (e.g., NOVX mRNAs) and fragments for use as PCR WO 2004/015079 PCT/US2003/024931 primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The 5 nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA. A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a "mature" form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide or precursor form or proprotein. The naturally 10 occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product "mature" form arises, by way of nonlimiting example, as a result of one or more naturally occurring processing steps that may take place within the cell (e.g., host 15 cell) in which the gene product arises. Examples of such processing steps leading to a "mature" form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF, or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal 20 methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+1 to residue N remaining. Further as used herein, a "mature" form of a polypeptide or protein may arise from a step of 25 post-translational modification other than a proteolytic cleavage event. Such additional -processes include, by way of non-limiting example, glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them. The term "probe", as utilized herein, refers to nucleic acid sequences of variable 30 length, preferably between at least about 10 nucleotides (nt), about 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- WO 2004/015079 PCT/US2003/024931 stranded or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies. The term "isolated" nucleic acid molecule, as used herein, is a nucleic acid that is separated from other nucleic acid molecules which are present in the natural source of the 5 nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5'- and 3'-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally 10 flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an ."isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium, or of chemical precursors or other chemicals. A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the 15 nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or a complement of this nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and 20 cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2 Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, NY, 1993.) A nucleic acid of the invention can be amplified using cDNA, mRNA or 25 alternatively, genomic DNA, as a template with appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer. 30 As used herein, the term "oligonucleotide" refers to a series of linked nucleotide residues. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably WO 2004/015079 PCT/US2003/024931 about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or a complement thereof. Oligonucleotides may be chemically synthesized and may 5 also be used as probes. In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence shown in SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment 10 encoding a biologically-active portion of a NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, that it can hydrogen bond with few or no mismatches to the nucleotide sequence shown in SEQ ID 15 NO:2n-1, wherein n is an integer between 1 and 38, thereby forming a stable duplex. As used herein, the term "complementary" refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term "binding" means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, 20 non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates. 25 A "fragment" provided herein is defined as a sequence of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, and is at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid 30 sequence of choice. A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5' WO 2004/015079 PCT/US2003/024931 direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 3' direction of the disclosed sequence. 5 A "derivative" is a nucleic acid sequence or amino acid sequence formed from the native compounds either directly, by modification or partial substitution. An "analog" is a nucleic acid sequence or amino acid sequence that has a structure similar to, but not identical to, the native compound, e.g. they differs from it in respect to certain components or side chains. Analogs may be synthetic or derived from a different evolutionary origin 10 and may have a similar or opposite metabolic activity compared to wild type. A "homolog" is a nucleic acid sequence or amino acid sequence of a particular gene that is derived from different species. Derivatives and analogs may be full length or other than full length. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, 15 molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable 20 of hybridizing to the complement of a sequence encoding the proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MoLECULAR BiOLOGY, John Wiley & Sons, New York, NY, 1993, and below. A "homologous nucleic acid sequence" or "homologous amino acid sequence," or 25 variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences include those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, 30 homologous nucleotide sequences include nucleotide sequences encoding for a NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous WO 2004/015079 PCT/US2003/024931 nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, as well as a polypeptide possessing 5 NOVX biological activity. Various biological activities of the NOVX proteins are described below. A NOVX polypeptide is encoded by the open reading frame ("ORF') of a NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is 10 uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG "start" codon and terminates with one of the three "stop" codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bonafide cellular protein, a 15 minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more. The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/pr cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX 20 homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38; or an anti-sense strand nucleotide 25 sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38; or of a naturally occurring mutant of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38. Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe has a detectable label attached, e.g. the label can be a radioisotope, 30 a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express a NOVX protein, such as by measuring a level of a NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.

WO 2004/015079 PCT/US2003/024931 "A polypeptide having a biologically-active portion of a NOVX polypeptide" refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a 5. "biologically-active portion of NOVX" can be prepared by isolating a portion of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, that encodes a polypeptide having a NOVX biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g.,:by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX. 10 NOVX Single Nucleotide Polymorphisms Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a "cSNP" to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to 15 a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the 20 amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in 25 temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message. SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part of the initial or extended sequence were identified by BLASTN searches using 30 the relevant sequence to query human genomic databases. The genonic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and WO 2004/015079 PCT/US2003/024931 protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HIMMER, FASTA, Hybrid and other relevant programs. Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have 5 overlapped with regions defined by homology or exon prediction. They may also be. included because the location of the fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human 10 SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraToolsTm program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions of the genomic clones analyzed. The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, 15 from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate 20 DNA Sequencing. Genome Research. 10 (8) 1249-1265, 2000). Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments of the invention. NOVX Nucleic Acid and Polypeptide Variants 25 The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide 30 sequence encoding a protein having an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 38. In addition to the human NOVX nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, it will be appreciated by those skilled in the art that DNA WO 2004/015079 PCT/US2003/024931 sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to 5 nucleic acid molecules comprising an open reading frame (ORF) encoding a NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity 10 of the NOVX polypeptides, are intended to be within the scope of the invention. Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from a human SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the 15 NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions. Accordingly, in another embodiment, an isolated nucleic acid molecule of the 20 invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding 25 region. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least about 65% homologous to each other typically remain hybridized to each other. Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or 30 high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning. As used herein, the phrase "stringent hybridization conditions" refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different-in WO 2004/015079 PCT/US2003/024931 different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5 'C lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid 5 concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the 10 temperature is at least about 30 'C for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60 'C for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide. Stringent conditions are known to those skilled in the art and can be found in 15 Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM 20 EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65'C, followed by one or more washes in 0.2X SSC, 0.01% BSA at 50"C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to a sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic 25 acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein). In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or fragments, analogs or derivatives thereof, under conditions of 30 moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6X SSC, 5X Reinhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55 'C, followed by one or more washes in 1X SSC, 0.1% SDS at 37 'C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS WO 2004/015079 PCT/US2003/024931 IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Krieger, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY. In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID. NO:2n-1, wherein n is an integer 5 between 1 and 38, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5X SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40*C, followed by one or more washes in 2X SSC, 25 mM 10 Tris-HCI (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50'C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. 15 Proc Natl Acad Sci USA 78: 6789-6792. Conservative Mutations In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an 20 integer between 1 and 38, thereby leading to changes in the amino acid sequences of the encoded NOVX protein, without altering the functional ability of that NOVX protein. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in the sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 38. A "non-essential" amino acid residue is a residue that can be altered 25 from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an "essential" amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art. 30 Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, yet retain biological activity. In one embodiment, the isolated WO 2004/015079 PCT/US2003/024931 nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 40% homologous to the amino acid sequences of SEQ ID NO:2n, wherein n is an integer between 1 and 38. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ 5 ID NO:2n, wherein n is an integer between 1 and 38; more preferably at least about 70% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 38; still more preferably at least about 80% homologous to SEQ ID NO:2n, wherein n is an integer between I and 38; even more preferably at least about 90% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 38; and most preferably at least about 95% 10 homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 38. An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 38, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between I and 38, such that one or 15 more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced any one of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at 20 one or more predicted, non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), 25 uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with 30 another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of a nucleic acid of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, the WO 2004/015079 PCT/US2003/024931 encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined. The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved "strong" residues or fully 5 conserved "weak" residues. The "strong" group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the "weak" group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, 10 NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code. In one embodiment, a mutant NOVX protein can be assayed for (i) the ability to form protein:protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX 15 protein and a NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins). In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release). Interfering RNA 20 In one aspect of the invention, NOVX gene expression can be attenuated by RNA interference. One approach well-known in the art is short interfering RNA (siRNA) mediated gene silencing where expression products of a NOVX gene are targeted by specific double stranded NOVX derived siRNA nucleotide sequences that are complementary to at least a 19-25 nt long segment of the NOVX gene transcript, including 25 the 5' untranslated (UT) region, the ORF, or the 3' UT region. See, e.g., PCT applications W00/144895, W099/32619, WO01/75164, WO01/92513, WO 01/29058, WO01/89304, WO02/16620, and WO02/29858, each incorporated by reference herein in their entirety. Targeted genes can be a NOVX gene, or an upstream or downstream modulator of the NOVX gene. Nonlimiting examples of upstream or downstream modulators of a NOVX 30 gene include, e.g., a transcription factor that binds the NOVX gene promoter, a kinase or phosphatase that interacts with a NOVX polypeptide, and polypeptides involved in a NOVX regulatory pathway.

WO 2004/015079 PCT/US2003/024931 According to the methods of the present invention, NOVX gene expression is silenced using short interfering RNA. A NOVX polynucleotide according to the invention includes a siRNA polynucleotide. Such a NOVX siRNA can be obtained using a NOVX polynucleotide sequence, for example, by processing the NOVX ribopolynucleotide 5 sequence in a cell-free system, such as but not limited to a Drosophila extract, or by transcription of recombinant double stranded NOVX RNA or by chemical synthesis of nucleotide sequences homologous to a NOVX sequence. See, e.g., Tuschl, Zamore, Lehmann, Bartel and Sharp (1999), Genes -& Dev. 13: 3191-3197, incorporated herein by reference in its entirety. When synthesized, a typical 0.2 micromolar-scale RNA synthesis 10 provides about 1 milligram of siRNA, which is sufficient for 1000 transfection experiments using a 24-well tissue culture plate format. The most efficient silencing is generally observed with siRNA duplexes composed of a 21-nt sense strand and a 21-nt antisense strand, paired in a manner to have a 2-nt 3' overhang. The sequence of the 2-nt 3' overhang makes an additional small contribution 15 to the specificity of siRNA target recognition. The contribution to specificity is localized to the unpaired nucleotide adjacent to the first paired bases. In one embodiment, the nucleotides in the 3' overhang are ribonucleotides. In an alternative embodiment, the nucleotides in the 3' overhang are deoxyribonucleotides. Using 2'-deoxyribonucleotides in the 3' overhangs is as efficient as using ribonucleotides, but deoxyribonucleotides are often 20 cheaper to synthesize and are most likely more nuclease resistant. A contemplated recombinant expression vector of the invention comprises a NOVX DNA molecule cloned into an expression vector comprising operatively-linked regulatory sequences flanking the NOVX sequence in a manner that allows for expression (by transcription of the DNA molecule) of both strands. An RNA molecule that is antisense to 25 NOVX mRNA is transcribed by a first promoter (e.g., a promoter sequence 3' of the cloned DNA) and an RNA molecule that is the sense strand for the NOVX mRNA is transcribed by a second promoter (e.g., a promoter sequence 5' of the cloned DNA). The sense and antisense strands may hybridize in vivo to generate siRNA constructs for silencing of the NOVX gene. Alternatively, two constructs can be utilized to create the sense and 30 anti-sense strands of a siRNA construct. Finally, cloned DNA can encode a construct having secondary structure, wherein a single transcript has both the sense and complementary antisense sequences from the target gene or genes. In an example of this embodiment, a hairpin RNAi product is homologous to all or a portion of the target gene. In another example, a hairpin RNAi product is a siRNA. The regulatory sequences WO 2004/015079 PCT/US2003/024931 flanking the NOVX sequence may be identical or may be different, such that their expression may be modulated independently, or in a temporal or spatial manner. In a specific embodiment, siRNAs are transcribed intracellularly by cloning the NOVX gene templates into a vector containing, e.g., a RNA pol II transcription unit from 5 the smaller nuclear RNA (snRNA) U6 or the human RNase P RNA Hi. One example of a vector system is the GeneSuppressorM RNA Interference kit (commercially available from Imgenex). The U6 and HI promoters are members of the type III class of Pol III promoters. The +1 nucleotide of the U6-like promoters is always guanosine, whereas the +1 for Hi promoters is adenosine. The termination signal for these promoters is defined by five 10 consecutive thymidines. The transcript is typically cleaved after the second uridine. Cleavage at this position generates a 3' UU overhang in the expressed siRNA, which is similar to the 3' overhangs of synthetic siRNAs. Any sequence less than 400 nucleotides in length can be transcribed by these promoter, therefore they are ideally suited for the expression of around 21-nucleotide siRNAs in, e.g., an approximately 50-nucleotide RNA 15 stem-loop transcript. A siRNA vector appears to have an advantage over synthetic siRNAs where long term knock-down of expression is desired. Cells transfected with a siRNA expression vector would experience steady, long-term mRNA inhibition. In contrast, cells transfected with exogenous synthetic siRNAs typically recover from mRNA suppression within seven 20 days or ten rounds of cell division. The long-term gene silencing ability of siRNA expression vectors may provide for applications in gene therapy. In general, siRNAs are chopped from longer dsRNA by an ATP-dependent ribonuclease called DICER. DICER is a member of the RNase III family of double-stranded RNA-specific endonucleases. The siRNAs assemble with cellular proteins 25 into an endonuclease complex. In vitro studies in Drosophila suggest that the siRNAs/protein complex (siRNP) is then transferred to a second enzyme complex, called an RNA-induced silencing complex (RISC), which contains an endoribonuclease that is distinct from DICER. RISC uses the sequence encoded by the antisense siRNA strand to find and destroy mRNAs of complementary sequence. The siRNA thus acts as a guide, 30 restricting the ribonuclease to cleave only mRNAs complementary to one of the two siRNA strands. A NOVX mRNA region to be targeted by siRNA is generally selected from a desired NOVX sequence beginning 50 to100 nt downstream of the start codon. Alternatively, 5' or 3' UTRs and regions nearby the start codon can be used but are WO 2004/015079 PCT/US2003/024931 generally avoided, as these may be richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. An initial BLAST homology search for the selected siRNA sequence is done against an available nucleotide sequence library to ensure that.only one 5 gene is targeted. Specificity of target recognition by siRNA duplexes indicate that a single point.mutation located in the paired region of an siRNA duplex is sufficient to abolish target mRNA degradation. See, Elbashir et al. 2001 EMBO J. 20(23):6877-88. Hence, consideration should be taken to accommodate SNPs, polymorphisms, allelic variants or species-specific variations when targeting a desired gene. 10 In one embodiment, a complete NOVX siRNA experiment includes the proper negative control. A negative control siRNA generally has the same nucleotide composition as the NOVX siRNA but lack significant sequence homology to the genome. Typically, one would scramble the nucleotide sequence of the NOVX siRNA and do a homology search to make sure it lacks homology to any other gene. 15 Two independent NOVX siRNA duplexes can be used to knock-down a target NOVX gene. This helps to control for specificity of the silencing effect. In addition, expression of two independent genes can be simultaneously knocked down by using equal concentrations of different NOVX siRNA duplexes, e.g., a NOVX siRNA and an siRNA for a regulator of a NOVX gene or polypeptide. Availability of siRNA-associating proteins 20 is believed to be more limiting than target mRNA accessibility. A targeted NOVX region is typically a sequence of two adenines (AA) and two thymidines (TT) divided by a spacer region of nineteen (N19) residues (e.g., AA(N19)TT). A desirable spacer region has a G/C-content of approximately 30% to 70%, and more preferably of about 50%. If the sequence AA(N19)TT is not present in the target sequence, 25 an alternative target region would be AA(N21). The sequence of the NOVX sense siRNA corresponds to (N19)TT or N21, respectively. In the latter case, conversion of the 3' end of the sense siRNA to TT can be performed if such a sequence does not naturally occur in the NOVX polynucleotide. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3' 30 overhangs. Symmetric 3' overhangs may help to ensure that the siRNPs are formed with approximately equal ratios of sense and antisense target RNA-cleaving siRNPs. See, e.g., Elbashir, Lendeckel and Tuschl (2001). Genes & Dev. 15: 188-200, incorporated by reference herein in its entirely. The modification of the overhang of the sense sequence of WO 2004/015079 PCT/US2003/024931 the siRNA duplex is not expected to affect targeted mRNA recognition, as the antisense siRNA strand guides target recognition. Alternatively, if the NOVX target mRNA does not contain a suitable AA(N21) sequence, one may search for the sequence NA(N21). Further, the sequence of the sense 5 strand and antisense strand may still be synthesized as 5' (N19)TT, as it is believed that the sequence of the 3'-most nucleotide of the antisense siRNA does not contribute to specificity. Unlike antisense or ribozyme technology, the secondary structure of the target mRNA does not appear to have a strong effect on silencing. See, Harborth, et al. (2001) J. Cell Science 114: 4557-4565, incorporated by reference in its entirety. 10 Transfection of NOVX siRNA duplexes can be achieved using standard nucleic acid transfection methods, for example, OLIGOFECTAMINE Reagent'(commercially available from Invitrogen). An assay for NOVX gene silencing is generally performed approximately 2 days after transfection. No NOVX gene silencing has been observed in - the absence of transfection reagent, allowing for a comparative analysis of the wild-type 15 and silenced NOVX phenotypes. In a specific embodiment, for one well of a 24-well plate, :approximately 0.84 pg of the siRNA duplex is generally sufficient. Cells are typically seeded the previous day, and are transfected at about 50% confluence. The choice of cell culture media and conditions are routine to those of skill in the art, and will vary with the choice of cell type. The efficiency of transfection may depend on the cell type, but also on 20 the passage number and the confluency of the cells. The time and the manner of formation of siRNA-liposome complexes (e.g. inversion versus vortexing) are also critical. Low transfection efficiencies are the most frequent cause of unsuccessful NOVX silencing. The efficiency of transfection needs to be carefully examined for each new cell line to be used. Preferred cell are derived from a mammal, more preferably from a rodent such as a rat or 25 mouse, and most preferably from a human. Where used for therapeutic treatment, the cells are preferentially autologous, although non-autologous cell sources are also contemplated as within the scope of the present invention. For a control experiment, transfection of 0.84 p~g single-stranded sense NOVX siRNA will have no effect on NOVX silencing, and 0.84 tg antisense siRNA has a weak 30 :silencing effect when compared to 0.84 pug of duplex siRNAs. Control experiments again allow for a comparative analysis of the wild-type and silenced NOVX phenotypes. To control for transfection efficiency, targeting of common proteins is typically performed, for example targeting of lamin A/C or transfection of a CMV-driven EGFP-expression plasmid (e.g. commercially available from Clontech). In the above example, a determination of the WO 2004/015079 PCT/US2003/024931 fraction of lamin A/C knockdown in cells is determined the next day by such techniques as immunofluorescence, Western blot, Northern blot or other similar assays for protein expression or gene expression. Lamin A/C monoclonal antibodies may be obtained from Santa Cruz Biotechnology. 5 Depending on the abundance and the half life (or turnover) of the targeted NOVX polynucleotide in a cell, a knock-down phenotype may become apparent after 1 to 3 days, or even later. In cases where no NOVX knock-down phenotype is observed, depletion of the NOVX polynucleotide may be observed by immunofluorescence or Western blotting. If the NOVX polynucleotide is still abundant after 3 days, cells need to be split and 10 transferred to a fresh 24-well plate for re-transfection. If no knock-down of the targeted protein is observed, it may be desirable to analyze whether the target mRNA (NOVX or a NOVX upstream or downstream gene) was effectively destroyed by the transfected siRNA duplex. Two days after transfection, total RNA is prepared, reverse transcribed using a target-specific primer, and PCR-amplified with a primer pair covering at least one 15 exon-exon junction in order to control for amplification of pre-mRNAs. RT/PCR of a non-targeted mRNA is also needed as control. Effective depletion of the mRNA yet undetectable reduction of target protein may indicate that a large reservoir of stable NOVX protein may exist in the cell. Multiple transfection in sufficiently long intervals may be necessary until the target protein is finally depleted to a point where a phenotype may 20 become apparent. If multiple transfection steps are required, cells are split 2 to 3 days after transfection. The cells may be transfected immediately after splitting. An inventive therapeutic method of the invention contemplates administering a NOVX siRNA construct as therapy to compensate for increased or aberrant NOVX expression or activity. The NOVX ribopolynucleotide is obtained and processed into 25 siRNA fragments, or a NOVX siRNA is synthesized, as described above. The NOVX siRNA is administered to cells or tissues using known nucleic acid transfection techniques, as described above. A NOVX siRNA specific for a NOVX gene will decrease or knockdown NOVX transcription products, which will lead to reduced NOVX polypeptide production, resulting in reduced NOVX polypeptide activity in the cells or tissues. 30 The present invention also encompasses a method of treating a disease or condition associated with the presence of a NOVX protein in an individual comprising administering to the individual an RNAi construct that targets the mRNA of the protein (the nRNA that encodes the protein) for degradation. A specific RNAi construct includes a siRNA or a double stranded gene transcript that is processed into siRNAs. Upon treatment, the target WO 2004/015079 PCT/US2003/024931 protein is not produced or is not produced to the extent it would be in the absence of the treatment. Where the NOVX gene function is not correlated with a known phenotype, a control sample of cells or tissues from healthy individuals provides a reference standard for 5 determining NOVX expression levels. Expression levels are detected using the assays described, e.g., RT-PCR, Northern blotting, Western blotting, ELISA, and the like. A subject sample of cells or tissues is taken from a mammal, preferably a human subject, suffering from a disease state. The NOVX ribopolynucleotide is used to produce siRNA constructs, that are specific for the NOVX gene product. These cells or tissues are treated 10 by administering NOVX siRNA's to the cells or tissues by methods described for the transfection of nucleic acids into a cell or tissue, and a change in NOVX polypeptide or polynucleotide expression is observed in the subject sample relative to the control sample, using the assays described. This NOVX gene knockdown approach provides a rapid method for determination of a NOVX minus (NOVX~) phenotype in the treated subject 15 sample. The NOVX- phenotype observed in the treated subject sample thus serves as a marker for monitoring the course of a disease state during treatment. In specific embodiments, a NOVX siRNA is used in therapy. Methods for the generation and use of a NOVX siRNA are knowrf to those skilled in the art. Example techniques are provided below. 20 Production of RNAs Sense RNA (ssRNA) and antisense RNA (asRNA) of NOVX are produced using known methods such as transcription in RNA expression vectors. In the initial experiments, the sense and antisense RNA are about 500 bases in length each. The produced ssRNA and asRNA (0.5 VM) in 10 mM Tris-HCI (pH 7.5) with 20 mM NaCl 25 were heated to 95* C for 1 min then cooled and annealed at room temperature for 12 to 16 h. The RNAs are precipitated and resuspended in lysis buffer (below). To monitor annealing, RNAs are electrophoresed in a 2% agarose gel in TBE buffer and stained with ethidium bromide. See, e.g., Sambrook et al., Molecular Cloning. Cold Spring Harbor Laboratory Press, Plainview, N.Y. (1989). 30 Lysate Preparation Untreated rabbit reticulocyte lysate (Ambion) are assembled according to the manufacturer's directions. dsRNA is incubated in the lysate at 30" C for 10 min prior to the WO 2004/015079 PCT/US2003/024931 addition of mRNAs. Then NOVX mRNAs are added and the incubation continued for an additional 60 min. The molar ratio of double stranded RNA and mRNA is about 200:1. The NOVX mRNA is radiolabeled (using known techniques) and its stability is monitored by gel electrophoresis. 5 In a parallel experiment made with the same conditions, the double stranded RNA is internally radiolabeled with a 32 P-ATP. Reactions are stopped by the addition of 2 X proteinase K buffer and deproteinized as described previously (Tuschl et al., Genes Dev., 13:3191-3197 (1999)). Products are analyzed by electrophoresis in 15% or 18% polyacrylamide sequencing gels using appropriate RNA standards. By monitoring the gels 10 for radioactivity, the natural production of 10 to 25 nt RNAs from the double stranded RNA can be determined. The band of double stranded RNA, about 21-23 bps, is eluded. The efficacy of these 21-23 mers for suppressing NOVX transcription is assayed in vitro using the same rabbit reticulocyte assay described above using 50 nanomolar of double stranded 21-23 mer 15 for each assay. The sequence of these 21-23 mers is then determined using standard nucleic acid sequencing techniques. RNA Preparation 21 nt RNAs, based on the sequence determined above, are chemically synthesized using Expedite RNA phosphoramidites and thymidine phosphoramidite (Proligo, 20 Germany). Synthetic oligonucleotides are deprotected and gel-purified (Elbashir, Lendeckel, & Tuschl, Genes & Dev. 15, 188-200 (2001)), followed by Sep-Pak C18 cartridge (Waters, Milford, Mass., USA) purification (Tuschl, et al., Biochemistry, 32:11658-11668 (1993)). These RNAs (20 FM) single strands are incubated in annealing buffer (100 mM 25 potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesium acetate) for I min at 90 C followed by 1 h at 37* C. Cell Culture A cell culture known in the art to regularly express NOVX is propagated using standard conditions. 24 hours before transfection, at approx. 80% confluency, the cells are 30 trypsinized and diluted 1:5 with fresh medium without antibiotics (1-3 X 105 cells/ml) and transferred to 24-well plates (500 ml/well). Transfection is performed using a commercially available lipofection kit and NOVX expression is monitored using standard WO 2004/015079 PCT/US2003/024931 techniques with positive and negative control. A positive control is cells that naturally express NOVX while a negative control is cells that do not express NOVX. Base-paired 21 and 22 nt siRNAs with overhanging 3' ends mediate efficient sequence-specific mRNA degradation in lysates and in cell culture. Different concentrations of siRNAs are used. An 5 efficient concentration for suppression in vitro in mammalian culture is between 25 nM to 100 nM final concentration. This indicates that siRNAs are effective at concentrations that are several orders of magnitude below the concentrations applied in conventional antisense or ribozyme gene targeting experiments. The above method provides a way both for the deduction of NOVX siRNA 10 sequence and the use of such siRNA for in vitro suppression. In vivo suppression may be performed using the same siRNA using well known in vivo transfection or gene therapy transfection techniques. Antisense Nucleic Acids Another aspect of the invention pertains to isolated antisense nucleic acid molecules 15 that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or fragments, analogs or derivatives thereof. An "antisense" nucleic acid comprises a nucleotide sequence that is complementary to a "sense" nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or 20 complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 38, or antisense 25 nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, are additionally provided. In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence encoding a NOVX protein. The term "coding region" refers to the region of the nucleotide sequence comprising codons which 30 are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding the NOVX protein. The term "noncoding region" refers to 5' and 3' sequences WO 2004/015079 PCT/US2003/024931 which flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions). Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson 5 and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense 10 oligonucleotide can be, for example, about 5; 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides 15 designed to increase the biological stability of the molecules. or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used). Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, 20 xanthine, 4-acetylcytosine, 5-carboxymethylaminomethyl-2-thiouridine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 5-methoxyuracil, 3-methylcytosine, 5-methyleytosine, N6-adenine, 7-methylguanine, 25 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, 2-thiouracil, 4-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 30 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

WO 2004/015079 PCT/US2003/024931 The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional 5 nucleotide complementarity to form a -stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and 10 then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve 15 sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred. In yet another embodiment, the antisense nucleic acid molecule of the invention is an c-anomeric nucleic acid molecule. An a-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual p-units, 20 the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al., 1987. FEBS Lett. 215: 327-330. Ribozymes and PNA Moieties 25 Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject. 30 In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in WO 2004/015079 PCT/US2003/024931 Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of a NOVX cDNA disclosed herein (i.e., SEQ ID NO:2n-1, wherein n 5 is an integer between 1 and 38). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S. Patent 4,987,071 to Cech, et al. and U.S. Patent 5,116,742 to Cech, et al. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease 10 activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418. Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent 15 transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des.- 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15. In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, 20 or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al., 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural 25 nucleotide bases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomer can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675. 30 PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a'gene (e.g., PNA directed PCR clamping; as artificial WO 2004/015079 PCT/US2003/024931 restriction enzymes when used in combination with other enzymes, e.g., S 1 nucleases (See, Hyrup, et al., 1996.supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al., 1996, supra; Perry-O'Keefe, et al., 1996. supra). In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their 5 stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA 10 portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleotide bases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al., 1996. supra and Finn, et al., 1996. Nucl Acids Res 24: 3357-3363. For 15 example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5' end of DNA. See, e.g., Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule 20 with a 5' PNA segment and a 3' DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment. See, e.g., Petersen, et al., 1975. Bioorg. Med. Chem. Lett. 5: 1119-11124. In dther embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport 25 across the cell membrane (see, e.g., Letsinger, et al., 1989. Proc. Nati. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., 30 Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like.

WO 2004/015079 PCT/US2003/024931 NOVX Polypeptides A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 38. The invention also includes a 5 mutant or variant protein any of whose residues may be changed from the corresponding residues shown in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 38, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof. In general, a NOVX variant that preserves NOVX-like function includes any variant 10 in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a 15 conservative substitution as defined above. One aspect of the invention pertains to isolated NOVX proteins, and biologically-active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from 20 cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, a NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques. An "isolated" or "purified" polypeptide or protein or biologically-active portion 25 thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of NOVX proteins in which the.protein is separated from cellular components of the cells from which it is isolated or 30 recombinantly-produced. In one embodiment, the language "substantially free of cellular material" includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a "contaminating protein"), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about WO 2004/015079 PCT/US2003/024931 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and 5 most preferably less than about 5% of the volume of the NOVX protein preparation. The language "substantially free of chemical precursors or other chemicals" includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" 10 includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals. 15 Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between' 1 and 38) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of a NOVX protein. Typically, biologically-active portions 20 comprise a domain or motif with at least one activity of the NOVX protein. A biologically-active portion of a NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length. Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of 25 the functional activities of a native NOVX protein. In an embodiment, the NOVX protein has an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 38. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 38, and retains the functional activity of the protein of SEQ ID NO:2n, wherein n is an 30 integer between 1 and 38, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between WO 2004/015079 PCT/US2003/024931 1 and 38, and retains the functional activity of the NOVX proteins of SEQ ID NO:2n, wherein n is an integer between 1 and 38. Determining Homology Between Two or More Sequences To determine the percent homology of two amino acid sequences or of two nucleic 5 acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid 10 residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity"). The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs 15 known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 20 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38. The term "sequence identity" refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term "percentage of sequence identity" is calculated by comparing two 25 optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the 30 percentage of sequence identity. The term "substantial identity" as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent WO 2004/015079 PCT/US2003/024931 identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region. Chimeric and Fusion Proteins The invention also provides NOVX chimeric or fusion proteins. As used herein, a 5 NOVX "chimeric protein" or "fusion protein" comprises a NOVX polypeptide operatively-linked to a non-NOVX polypeptide. An "NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 38, whereas a "non-NOVX polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein that is not 10 substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within a NOVX fusion protein the NOVX polypeptide can correspond to all or a portion of a NOVX protein. In one embodiment, a NOVX fusion protein comprises at least one biologically-active portion of a NOVX protein. In another embodiment, a NOVX fusion 15 protein comprises at least two biologically-active portions of a NOVX protein. In yet another embodiment, a NOVX fusion protein comprises at least three biologically-active portions of a NOVX protein. Within the fusion protein, the term "operatively-linked" is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or 20 C-terminus of the NOVX polypeptide. In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides. 25 In another embodiment, the fusion protein is a NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence. In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion 30 protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a NOVX ligand and a NOVX protein on the WO 2004/015079 PCT/US2003/024931 surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of a NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well 5 as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with a NOVX ligand. A NOVX chimeric or fusion protein of the invention can be produced by standard 10 recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic 15 ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds:) CURRENT 20 PROTOCOLS iN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein. NOVX Agonists and Antagonists 25 The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An 30 antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of WO 2004/015079 PCT/US2003/024931 limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins. 5 Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a 10 variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of NOVX sequences therein. There are a variety of methods 15 which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. 20 Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. Acids Res. 11: 477. Polypeptide Libraries In addition, libraries of fragments of the NOVX protein coding sequences can be 25 used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of a NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form 30 double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with Si nuclease, and ligating the resulting fragment library into an expression vector. By this method, WO 2004/015079 PCT/US2003/024931 expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX proteins. Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA 5 libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of 10 vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. 15 Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al., 1993. Protein Engineering 6:327-331. Anti-NOVX Antibodies Included in the invention are antibodies to NOVX proteins, or fragments of NOVX proteins. The term "antibody" as used herein refers to immunoglobulin molecules and 20 immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab, and F(ab')2 fragments, and an Fab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, 25 which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgGi, IgG 2 , and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species. 30 An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the WO 2004/015079 PCT/US2003/024931 invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 38, and encompasses an epitope thereof such that an 5 antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly 10 these are hydrophilic regions. In certain embodiments of the invention, at least one epitope encompassed.by the antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, 15 are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 20 3824-3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein. The term "epitope" includes any protein determinant capable of specific binding to 25 an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. A NOVX polypeptide or a fragment thereof comprises at least one antigenic epitope. An anti-NOVX antibody of the present invention is said to specifically bind to 30 antigen NOVX when the equilibrium binding constant (KD) is 1 pM, preferably 100 nM, more preferably 10 nM, and most preferably 100 pM to about 1 pM, as measured by assays including radioligand binding assays or similar assays known to skilled artisans.

WO 2004/015079 PCT/US2003/024931 A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components. Various procedures known within the art may be used for the production of 5 polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, incorporated herein by reference). Some of these antibodies are discussed below. 10 Polyclonal Antibodies For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring 15 immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin 20 inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, 25 or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known 30 techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity WO 2004/015079 PCT/US2003/024931 chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia PA, Vol. 14, No. 8 (April 17, 2000), pp. 25-28). Monoclonal Antibodies 5 The term "monoclonal antibody" (MAb) or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus 10 contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it. Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an 15 immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro. The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells 20 of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly 25 myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium 30 for the hybridomas typically will include hypoxanthine, aminopterin, and thynmidine ("HAT medium"), which substances prevent the growth of HGPRT-deficient cells. Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a WO 2004/015079 PCT/US2003/024931 medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, California and the American Type Culture Collection, Manassas, Virginia. Human myeloma and mouse-human heteromyeloma cell lines also 5 have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63). The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the 10 binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, 15 Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen. After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding,1986). Suitable 20 culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal. The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification 25 procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., 30 by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce WO 2004/015079 PCT/US2003/024931 iinmunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Patent No. 4,816,567; Morrison, Nature 368, 812-13 5 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody. 10 Humanized Antibodies The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric 15 immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 20 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Patent No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor 25 in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will 30 comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)).

WO 2004/015079 PCT/US2003/024931 Human Antibodies Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are-termed "human antibodies", or "fully human antibodies" 5 herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be 10 produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). In addition, human antibodies can also be produced using additional techniques, 15 including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in 20 humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al,( Nature Biotechnology 14, 845-5 1 (1996)); Neuberger 25 (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)). Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT 30 publication W094/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial WO 2004/015079 PCT/US2003/024931 chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the 5 Xenomousem as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. 10 Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules. An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. 15 Patent No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem 20 cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker. A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Patent No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in 25 culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to fornm a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain. In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that 30 binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.

WO 2004/015079 PCT/US2003/024931 Fab Fragments and Single Chain Antibodies According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Patent No. 4,946,778). In addition, methods can be adapted for the construction of Fab 5 expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab')2 fragment produced by pepsin digestion of an 10 antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab')2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) F, fragments. Bispecific Antibodies Bispecific antibodies are monoclonal, preferably human or humanized, antibodies 15 that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit. Methods for making bispecific antibodies are known in the art. Traditionally, the 20 recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the 25 correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991). Antibody variable domains with the desired binding specificities (antibody-antigen 30 combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at WO 2004/015079 PCT/US2003/024931 least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986). 5 According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced 10 with larger side chains (e.g. tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers. 15 Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab') 2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to 20 generate F(ab') 2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other 25 Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes. Additionally, Fab' fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab')2 molecule. Each 30 Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

WO 2004/015079 PCT/US2003/024931 Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos. and Jun proteins were linked to the Fab' 5 portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The "diabody" technology described by Hollinger et al., Proc. Nati. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific 10 antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making 15 bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994). Antibodies with more than two valencies are contemplated. For example, tri'pecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991). Exemplary bispecific antibodies can bind to two different epitopes, at least one of 20 which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcyR), such as FcyRI (CD64), FcyRII (CD32) and FcyRII (CD16) so as to focus cellular defense mechanisms to the cell expressing the 25 particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF). 30 Heteroconjugate Antibodies Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted WO 2004/015079 PCT/US2003/024931 cells (U.S. Patent No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction 5 or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Patent No. 4,676,980. Effector Function Engineering It can be desirable to modify the antibody of the invention with respect to effector 10 function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). 15 See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. 20 See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989). Immunoconjugates The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments 25 thereof), or a radioactive isotope (i.e., a radioconjugate). Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, 30 alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAP]I, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the WO 2004/015079 PCT/US2003/024931 tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212 Bi, 1311, 131 n, 90 Y, and 86 Re. Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) 5 propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters .(such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-,diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 10 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. -See 15 W094/11026. In another embodiment, the antibody can be conjugated to a "receptor" (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) that is 20 in turn conjugated to a cytotoxic agent. Immunoliposomes The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., 25 Proc. NatI Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through 30 filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al .,J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A WO 2004/015079 PCT/US2003/024931 chemotherapeutic agent (such as Doxorubicin) is optionally contained within the-liposome. See Gabizon et al., J. National Cancer Inst., 81(19): 1484 (1989). Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention 5 In one embodiment, methods for the screening of antibodies that possess the desired specificity include, but are not limited to, enzyme linked immunosorbent assay (ELISA) and other immunologically mediated techniques known within the art. In a specific embodiment, selection of antibodies that are specific to a particular domain of an NOVX protein is facilitated by generation of hybridomas that bind to the fragment of an NOVX 10 protein possessing such a domain. Thus, antibodies that are specific for a desired domain within an NOVX protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein. Antibodies directed against a NOVX protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of a NOVX 15 protein (e.g., for use in measuring levels of the NOVX protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given' embodiment, antibodies specific to a NOVX protein, or derivative, fragment, analog or homolog thereof, that contain the antibody derived antigen binding domain, are utilized as pharmacologically active compounds (referred to hereinafter as 20 "Therapeutics"). An antibody specific for a NOVX protein of the invention (e.g., a monoclonal antibody or a polyclonal antibody) can be used to isolate a NOVX polypeptide by standard techniques, such as immunoaffinity, chromatography or immunoprecipitation. An antibody to a NOVX polypeptide can facilitate the purification of a natural NOVX antigen from 25 cells, or of a recombinantly produced NOVX antigen expressed in host cells. Moreover, such an anti-NOVX antibody can be used to detect the antigenic NOVX protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic NOVX protein. Antibodies directed against a NOVX protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing 30 procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, WO 2004/015079 PCT/US2003/024931 and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, $--galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein 5 isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 1251, 1311, 1 5 S or 3 H. Antibody Therapeutics 10 Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect 15 may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an 20 effector molecule. Thus the receptor mediates a signal transduction pathway for which ligand is responsible. Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the 25 disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor-based signal transduction event by the receptor. A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, 30 interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is WO 2004/015079 PCT/US2003/024931 administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week. 5 Pharmaceutical Compositions of Antibodies Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice 10 of components are provided, for example, in Remington : The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa. : 1995; Drug Absorption Enhancement : Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York. 15 If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an 20 antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary 25 activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. 30 The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, WO 2004/015079 PCT/US2003/024931 albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes. 5 Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), 10 polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT Tm (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and 15 lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. ELISA Assay An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be 20 polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab)2) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of 25 indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term "biological 30 sample", therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include WO 2004/015079 PCT/US2003/024931 Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting 5 immunoassays are described, for example in "ELISA: Theory and Practice: Methods in Molecular Biology", Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, NJ, 1995; "Immunoassay", E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, CA, 1996; and "Practice and Theory of Enzyme Immunoassays", P.,Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an 10 analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. NOYX Recombinant Expression Vectors and Host Cells Another aspect of the invention pertains to vectors, preferably expression vectors, 15 containing a nucleic acid encoding a NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional 20 DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. 25 Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is 30 intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

WO 2004/015079 PCT/US2003/024931 The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the 5 nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably-linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). 10 The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in 15 many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby 20 produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.). The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be 25 expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences 30 and T7 polymerase. Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such WO 2004/015079 PCT/US2003/024931 fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the 5 fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and 10 pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 1ld (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENzYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 15 60-89). One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is 20 to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques. In another embodiment, the NOVX expression vector is a yeast expression vector. 25 Examples of vectors for expression in yeast Saccharonyces cerivisae include pYepSec1 (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kurjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.). Alternatively, NOVX can be expressed in insect cells using baculovirus expression 30 vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39). In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian WO 2004/015079 PCT/US2003/024931 expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2; cytomegalovirus, and simian virus 5 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989. In another embodiment, the recombinantlmammalian expression vector is capable 10 of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 15 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banerji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary 20 gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the ca-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546). 25 The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid 30 cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in WO 2004/015079 PCT/US2003/024931 the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, 5 et al., "Antisense RNA as a molecular tool for genetic analysis," Reviews-Trends in Genetics, Vol. 1(1) 1986. Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms."host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms 10 refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein 15 can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and 20 "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold 25 Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals. For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these 30 integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector.

WO 2004/015079 PCT/US2003/024931 Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die). A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, 5 can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further 10 comprises isolating NOVX protein from the medium or the host cell. Transgenic NOVX Animals The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been 15 introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used 20 herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that 25 remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA 30 molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal. A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by WO 2004/015079 PCT/US2003/024931 microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences, i.e., any one of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human 5 NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular 10 cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYo, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other 15 transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying 20 other transgenes. To create a homologous recombinant animal, a vector is prepared which contains at least a portion of a NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of any one of SEQ ID NO:2n-1, wherein n is an 25 integer between 1 and 38), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous 30 recombination, the endogenous NOVX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby WO 2004/015079 PCT/US2003/024931 alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5'- and 3'-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene 5 in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5'- and 3'-termini) are included in the vector. See, e.g., Thomas, et al., 1987. Cell 51: 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., 10 by electroporation) and cells in which the introduced NOVX gene has homologously-recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al., 1992. Cell 69: 915. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND 15 EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline 20 transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169. In another embodiment, transgenic non-humans animals can be produced that 25 contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc. Nati. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al., 1991. Science 251:1351-1355. 30 If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

WO 2004/015079 PCT/US2003/024931 Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al., 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter Go phase. The quiescent cell can then be fused, e.g., through the 5 use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated. 10 Pharmaceutical Compositions The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as "active compounds") of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid 15 molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard 20 reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any 25 conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include 30 parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, WO 2004/015079 PCT/US2003/024931 glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or 5 dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or-plastic. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous 10 preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL M (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the 15 contaminating action of microorganisms such as bacteria and fungi. The carrier can-be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of 20 dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable 25 compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed 30 by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and WO 2004/015079 PCT/US2003/024931 freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral 5 therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also.be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The 10 tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or:gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring 15 agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Systemic administration can also be by transmucosal or transdermal means. For 20 transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are 25 formulated into ointments, salves, gels, or creams as generally known in the art. The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will 30 protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be WO 2004/015079 PCT/US2003/024931 obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to-those skilled in the art, for example, as described 5 in U.S. Patent No. 4,522,811. it is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to 10 produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. 15 The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Patent No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al., 1994. Proc. Nati. Acad. Sci. USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the 20 gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system. 25 The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. Screening and Detection Methods The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy 30 applications), to detect NOVX mRNA (e.g., in a biological sample) or a genetic lesion in a NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or WO 2004/015079 PCT/US2003/024931 excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting 5 disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in 10 both a positive and negative fashion. The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra. Screening Assays The invention provides a method (also referred to herein as a "screening assay") for 15 identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein. 20 In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of a NOVX protein or polypeptide or biologically-active portion thereof. The test compounds: of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable 25 parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the "one-bead one-compound" library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. 30 Anticancer Drug Design 12: 145. A "small molecule" as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, WO 2004/015079 PCT/US2003/024931 carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention. Examples of methods for the synthesis of molecular libraries can be found in the 5 art, for example in: DeWitt, et al., 1993. Proc. Nati. Acad. Sci. U.S.A. 90: 6909; Erb, et.al., 1994. Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem..37: 2678; Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int. Ed. EngL. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem. 37: 1233. 10 Libraries of compounds may be presented in solution (e.g., Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Patent No. 5,223,409), spores (Ladner, U.S. Patent 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. 15 Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382;1 Felici, 1991. J. Mol. Biol. 222: 301-3 10; Ladner, U.S. Patent No. 5,233,409.). In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind 20 to a NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in 25 a complex. For example, test compounds can be labeled with 1251, 35, 1 4 C, or 3 H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In 30 one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with WO 2004/015079 PCT/US2003/024931 a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound. In another embodiment, an assay is a cell-based assay comprising contacting a cell 5 expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test. compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be 10 accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule. As used herein, a "target molecule" is a molecule with which a NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses a NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu', a molecule associated with the internal 15 surface of a cell membrane or a cytoplasmic molecule. A NOVX target molecule can be a non-NOVX molecule or a NOVX protein or polypeptide of the invention. In one embodiment, a NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into 20 the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX. Determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by one of the methods described above for 25 determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca 2 ', diacylglycerol, IP 3 , etc.), detecting catalytic/enzymatic 30 activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising a NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

WO 2004/015079 PCT/US2003/024931 In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting a NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically-active portion thereof. Binding of the test compound to the NOVX protein can 5 be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to 10 interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound. In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining 15 the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to a NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, 20 determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate a NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra. In yet another embodiment, the cell-free assay comprises contacting the NOVX 25 protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the 30 activity of a NOVX target molecule. The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples WO 2004/015079 PCT/US2003/024931 of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamiide, Triton* X-100, Triton* X-1 14, Thesit*, Isotridecypoly(ethylene glycol ether),, N-dodecyl--N,N-dimethyl-3-ammonio-1-propane 5 sulfonate, 3-(3-cholamidopropyl) dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO). In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as 10 to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a 15 domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NOVX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under 20 conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity 25 determined using standard techniques. Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS 30 (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein WO 2004/015079 PCT/US2003/024931 trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using.antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity 5 associated with the NOVX protein or target molecule. In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of 10 expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compoundcan then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of 15 NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein. 20 In yet another aspect of the invention, the NOVX proteins can be used as "bait proteins" in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos, et al., 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993. Oncogene 8: 1693-1696; and Brent WO 94110300), to identify other proteins that bind to or 25 interact with NOVX ("NOVX-binding proteins" or "NOVX-bp") and modulate NOVX activity. Such NOVX-binding proteins are also involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway. The two-hybrid system is based on the modular nature of most transcription factors, 30 which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation WO 2004/015079 PCT/US2003/024931 domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional 5 regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX. The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein. 10 Detection Assays Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with 15 genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below. Chromosome Mapping Once the sequence (or a portion of the sequence) of a gene has been isolated, this 20 sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of the NOVX sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping of the NOVX sequences to chromosomes is an important first 25 step in correlating these sequences with genes associated with disease. Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can 30 then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment.

WO 2004/015079 PCT/US2003/024931 Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, 5 but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, 10 et al., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions. PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day 15 using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes. Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one 20 step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 25 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988). 30 Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding WO 2004/015079 PCT/US2003/024931 sequences are more likely to-be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping. Once a sequence has been-mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such 5 data are found, e.g., in McIusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through -linkage analysis (co-inheritance of physically adjacent.genes), described in, e.g., Egeland, et al., 1987. Nature, 325: 783-787. 10 Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for 15 structural alterations in the chromosomes, such as deletions.or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms. Tissue Typing 20 The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP ("restriction fragment length polymorphisms," described in U.S. Patent No. 25 5,272,057). Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5'- and 3'-termini of the sequences. These primers can then be 30 used to amplify an individual's DNA and subsequently sequence it. Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used WO 2004/015079 PCT/US2003/024931 to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual 5 humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs). Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. .10 Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If coding sequences, such as those of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, are used, a 15 more appropriate number of primers for positive individual identification would be 500-2,000. Predictive Medicine The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for 20 prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, 25 associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders 30 associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in a NOVX gene can be assayed in a biological sample. Such WO 2004/015079 PCT/US2003/024931 assays can be used for prognostic or predictive purpose to thereby prophylactically treat -an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity. Another aspect of the invention provides methods for determining NOVX protein, 5 nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as "pharmacogenomics"). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to 10 a particular agent.) Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials. These and other agents are described in further detail in the following sections. Diagnostic Assays 15 An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX 20 mRNA or genornic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions 25 to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein. An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or 30 F(ab') 2 ) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect 01- WO 2004/015079 PCT/US2003/024931 labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids 5 present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genonmic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, 10 immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. 15 In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. In another embodiment, the methods further involve obtaining a control biological 20 sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the- test sample. 25 The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a 30 suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.

WO 2004/015079 PCT/US2003/024931 Prognostic Assays The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the 5 preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression 10 or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest. For example, a test sample 15 can be a biological fluid (e.g., serum), cell sample, or tissue. Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For 20 example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic 25 acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity). The methods of the invention can also be used to detect genetic lesions in a NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, 30 the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding a NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least WO 2004/015079 PCT/US2003/024931 one of: (i) a deletion of one or more nucleotides from a NOVX gene; (ii) an addition of one or more nucleotides to a NOVX gene; (iii) a substitution of one or more nucleotides of a NOVX gene, (iv) a chromosomal rearrangement of a NOVX gene; (v) an alteration in the level of a messenger RNA transcript of a NOVX gene, (vi) aberrant modification of a 5 NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (viii) a non-wild-type level of a NOVX protein, (ix) allelic loss of a NOVX gene, and (x) inappropriate post-translational modification of a NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for 10 detecting lesions in a NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells. In certain embodiments, detection of the lesion involves the use of a probe/primer in 15 a polymerase chain reaction (PCR) (see, e.g., U.S. Patent Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc. Nati. Acad. Sci. USA 91: 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al., 1995. Nucl. Acids Res. 20 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to a NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or 25 detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein. Alternative amplification methods include: self sustained sequence replication (see, 30 Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); QP Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using WO 2004/015079 PCT/US2003/024931 techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In an alternative embodiment, mutations in a NOVX gene from a sample cell can be 5 identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes 10 (see, e.g., U.S. Patent No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site. In other embodiments, genetic mutations in NOVX can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high-density arrays containing hundreds or thousands of oligonucleotides probes. See, e.g., Cronin, et al., 1996. Human 15 Mutation 7: 244-255; Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, et al., supra.. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential 20 overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene. 25 In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. 30 Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al., 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen, et al., 1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Apple. Biochem. Biotechnol. 38: 147-159).

WO 2004/015079 PCT/US2003/024931 Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al., 1985. Science 230: 1242. In general, the art technique of "mismatch cleavage" starts by providing heteroduplexes of formed by 5 hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids 10 treated with Si nuclease to. enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., 15 Cotton, et al., 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection. In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA 20 mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on a NOVX sequence, e.g., a 25 wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Patent No. 5,459,039. In other embodiments, alterations in electrophoretic mobility Will be used to 30 identify mutations in NOVX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Apple. 9: 73-79. Single-stranded DNA fragments of sample and control NOVX WO 2004/015079 PCT/US2003/024931 nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may 5 be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet. 7: 5. In yet another embodiment, the movement of mutant or wild-type fragments in 10 polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al., 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is 15 used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753. Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the 20 known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane 25 and hybridized with labeled target DNA. Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, 30 et al., 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al., 1992. Mol. Cell Probes 6: 1. It is anticipated that in WO 2004/015079 PCT/US2003/024931 certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 199.1. Proc. Nati. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3'-terminus of the 5' sequence, making it possible to detect the presence of a-known mutation at a specific site by looking 5 for the presence or absence of amplification. The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a NOVX 10 gene. Furthermore, any cell type or tissue, preferably peripheral blood leukocytes,-in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells. 15 Pharmacogenomics Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity (e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders. The disorders include but are not limited to, e.g., those diseases, disorders and conditions listed 20 above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A. In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of 25 therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages 30 and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

WO 2004/015079 PCT/US2003/024931 Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be 5 differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or-genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited 10 enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans. As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic 15 polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome pregnancy zone protein precursor enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the 20 extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations.. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive 25 standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification. 30 Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness WO 2004/015079 PCT/US2003/024931 phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein. 5 Monitoring of Effects During Clinical Trials Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described 10 herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an' agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting 15 increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a "read out" or markers of the immune responsiveness of a particular cell. By way of example, and not of limitation, genes, including NOVX, that are 20 modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of 25 gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this 30 response state may be determined before, and at various points during, treatment of the individual with the agent. In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, WO 2004/015079 PCT/US2003/024931 peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the 5 preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or 10 samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the 15 effectiveness of the agent. Methods of Treatment The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include but are not limited to, e.g., those 20 diseases, disorders and conditions listed above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A. These methods of treatment will be discussed more fully, below. Diseases and Disorders 25 Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, 30 derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are "dysfunctional" (i.e., due to a heterologous insertion WO 2004/015079 PCT/US2003/024931 within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to "knockout" endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators ( i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention 5 or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner. Diseases and disorders that are characterized by decreased (relative to a subject:not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate 10 activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability. Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro 15 for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs 20 (e.g., Northern assays, dot blots, in situ hybridization, and the like). Prophylactic Methods In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. 25 Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending 30 upon the type of NOVX aberrancy, for example, a NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.

WO 2004/015079 PCT/US2003/024931 Therapeutic Methods Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of 5 NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a NOVX protein, a peptide, a NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX 10 protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As 15 such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another 20 embodiment, the method involves administering a NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity. Stimulation of NOVX activity is desirable in situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder 25 characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia). Determination of the Biological Effect of the Therapeutic In various embodiments of the invention, suitable in vitro or in vivo assays are 30 performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue. In various specific embodiments, in vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given WO 2004/015079 PCT/US2003/024931 Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, . chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to 5 administration to human subjects. Prophylactic and Therapeutic Uses of the Compositions of the Invention The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders. The disorders include but are not limited to, e.g., those diseases, disorders and conditions listed 10 above, and more particularly include those diseases, disorders, or conditions associated with homologs of a NOVX protein, such as those summarized in Table A. As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have 15 efficacy for treatment of patients suffering from diseases, disorders, conditions and the like, including but not limited to those listed herein. Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use 20 could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods. The invention will be further described in the following examples, which do not 25 limit the scope of the invention described in the claims. EXAMPLES Example A: Polynucleotide and Polypeptide Sequences, and Homology Data 30 WO 2004/015079 PCT/US2003/024931 Example 1. NOV1, CG121992, CHORDIN The NOVI clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1A. Table 1A. NOV1 Sequence Analysis NOVia, CG121992-03 SEQ ID NO: 1 3628 bp DNA Sequence ORF Start: ATG at 247 ORF Stop: TAG at 3193 CCCGGGTCAGCGCCCGCCCGCCCGCGCTCCTCCCGGCCGCTCCTCCCGCCCCcGGCCCGGCGCCG ACTCTGCGGCCGCCCGACGAGCCCCTCGCGGCACTGCCCCGGCCCC CCCCGGCCCCGCCCCCCTCC CGCCGCACCGCCCCCGGCCCGGCCCTCCGCCCTCCGCACTCCCGCCTCCCTCCCTCCGCCCGCTCCCG CGCCCTCCTCCCTCCCTCCTCCCCAGCTGTCCCGTTCGCGTCATGCCGAGCCTCCCGGCCCCGCCGGC CCCGCTGCTGCTCCTCGGGCTGCTGCTCCTCGGCTCCCGGCCGGCCCGCGGCGCCGGCCCCGAGCCCC CCGTGCTGCCCATCCGTTCTGAGAAGGAGCCGCTGCCCGTTCGGGGAGCGGCAGGCTGCACCTTCGGC GGGAAGGTCTATGCCTTGGACGAGACGTGGCACCCGGACCTAGGGGAGCCATTCGGGGTGATGCGCTG CGTGCTGTGCGCCTGCGAGGCGCCTCAGTGGGGTCGCCGTACCAGCGGCCCTGGCAGGGTCAGCTGCA AGAACATCAAACCAGAGTGCCCAACCCCGGCCTGTGGGCAGCCGCGCCAGCTGCCGGGACACTGCTGC CAGACCTGCCCCCAGGAGCGCAGCAGTTCGGAGCGGCAGCCGAGCGGCCTGTCCTTCGAGTATCCGCG GGACCCCGAGCATCGCAGTTATAGCGACCGCGGGGAGCCAGGCGCTGAGGAGCGGGCCCGTGGTGACG GCCACACGGACTTCGTGGCGCTGCTGACAGGGCCGAGGTCGCAGGCGGTGGCACGAGCCCGAGTCTCG CTGCTGCGCTCTAGCCTCCGCTTCTCTATCTCCTACAGGCGGCTGGACCGCCCTACCAGGATCCGCTT CTCAGACTCCAATGGCAGTGTCCTGTTTGACCACCCTGCAGCCCCCACCCAAGATGGCCTGGTCTGTG GGGTGTGGCGGGCAGTGCCTCGGTTGTCTCTGCGGCTCCTTAGGGCAGAACAGCTGCATGTGGCACTT GTGACACTCACTCACCCTTCAGGGGAGGTCTGGGGGCCTCTCATCCGGCACCGGGCCCTGGCTGCAGA GACCTTCAGTGCCATCCTGACTCTAGAAGGCCCCCCACAGCAGGGCGTAGGGGGCATCACCCTGCTCA CTCTCAGTGACACAGAGGACTCCTTGCATTTTTTGCTGCTCTTCCGAGGGCTGCTGGAACCCAGGAGT GGGGGTAAGTGGGATGGGGGCAAAACACGTGAGAAGGTTAGGGAGAGCACCTGTCTCAGAAAGGCCCA CATGTGCGGCCTTGCAGGACTAACCCAGGTTCCCTTGAGGCTCCAGATTCTACACCAGGGGCAGCTAC TGCGAGAACTTCAGGCCAATGTCTCAGCCCAGGAACCAGGCTTTGCTGAGGTGCTGCCCAACCTGACA GTCCAGGAGATGGACTGGCTGGTGCTGGGGGAGCTGCAGATGGCCCTGGAGTGGGCAGGCAGGCCAGG GCTGCGCATCAGTGGACACATTGCTGCCAGGAAGAGCTGCGACGTCCTGCAAAGTGTCCTTTGTGGGG CTGATGCCCTGATCCCAGTCCAGACGGGTGCTGCCGGCTCAGCCAGCCTCACGCTGCTAGGAAATGGC TCCCTGATCTATCACGTGCAAGTGGTAGGGACAAGCAGTGAGGTGGTGGCCATGACACTGGAGACCAA GCCTCAGCGGAGGGATCAGCGCACTGTCCTGTGCCACATGGCTGGACTCCAGCCAGGAGGACACACGG CCGTGGGTATCTGCCCTGGGCTGGGTGCCCGAGGGGCTCATATGCTOCTGCAGAATGAGCTCTTCCTG AACGTGGGCACCAAGGACTTCCCAGACGGAGAGCTTCGGGGGCACGTGGCTGCCCTGCCCTACTGTGG GCATAGCGCCCGCCATGACACGCTGCCCGTGCCCCTAGCAGGAGCCCTGGTGCTACCCCCTGTGAAGA GCCAAGCAGCAGGGCACGCCTGGCTTTCCTTGGATACCCACTGTCACCTGCACTATGAAGTGCTGCTG GCTGGGCTTGGTGGCTCAGAACAAGGCACTGTCACTGCCCACCTCCTTGCGCCTCCTGGAACGCCAGG GCCTCGGCGGCTGCTGAAGGGATTCTATGGCTCAGAGGCCCAGGGTGTGGTGAAGGACCTGGAGCCGG AACTGCTGCGGCACCTGGCAAAAGGCATGGCCTCCCTGATGATCACCACCAAGGGTAGCCCCAGAGGG GAGCTCCGAGGGCAGGTGCACATAGCCAACCAATGTGAGGTTGGCGGACTGCGCCTGGAGGCGGCCGG GGCCGAGGGGGTGCGGGCGCTGGGGGCTCCGGATACAGCCTCTGCTGCGCCGCCTGTGGTGCCTGGTC TCCCGGCCCTAGCGCCCGCCAAACCTGGTGGTCCTGGGCGGCCCCGAGACCCCAACACATGCTTCTTC GAGGGGCAGCAGCGCCCCCACGGGGCTCGCTGGGCGCCCAACTACGACCCGCTCTGCTCACTCTGCAC CTGCCAGAGACGAACGGTGATCTGTGACCCGGTGGTGTGCCCACCGCCCAGCTGCCCACACCCGGTGC AGGCTCCCGACCAGTGCTGCCCTGTTTGCCCTGAGAAACAAGATGTCAGAGACTTGCCAGGGCTGCCA AGGAGCCGGGACCCAGGAGAGGGCTGCTATTTTGATGGTGACCGGAGCTGGCGGGCAGCGGGTACGCG GTGGCACCCCGTTGTGCCCCCCTTTGGCTTAATTAAGTGTGCTGTCTGCACCTGCAAGGGGGGCACTG GAGAGGTGCACTGTGAGAAGGTGCAGTGTCCCCGCCTGGCCTGTGCCCAGCCTGTGCGTGTCAACCCC ACCGACTGCTGCAAACAGTGTCCAGTGGGGTCGGGGGCCCACCCCCAGCTGGGGGACCCCATGCAGGC TGATGGGCCCCGGGGCTGCCGTTTTGCTGGGCAGTGGTTCCCAGAGAGTCAGAGCTGGCACCCCTCAG TGCCCCCTTTTGGAGAGATGAGCTGTATCACCTGCAGATGTGGGGCAGGGGTGCCTCACTGTGAGCGG GATGACTGTTCACTGCCACTGTCCTGTGGCTCGGGGAAGGAGAGTCGATGCTGTTCCCGCTGCACGGC CCACCGGCGGCCAGCCCCAGAGACCAGAACTGATCCAGAGCTGGAGAAAGAAGCCGAAGGCTCTTAGG GAGCA GCCAGAGGGCCAAGTGACCAAGAGGATGGGGCCTGACGGAGGTCTGGAC TTCTTGCAT'iCTCCTGTGGGAAGCCCAGTGCCTTTGCTCCTCTGTCCTGCCTCTACTCCCACCCCCAC TACCTCTGGGAACCACAGCTCCACAAGGGGAGAGGCAGCTGGGCCAGACCGAGGTCACAGCCACTCC AAGTCCTGCCCTGCCACCCTCGGCCTCTGTCCTGGAAGCCCCACCCCTTTCCTCCTGTACATATGTC ATGCTGTTGGGATTTTTAATTTATCTTCACTCAGCACCAGGGCCCCCGACACTCCACTCCTGCT GCCCCTGAGCTGAGCAGAGTCATTATTGGAGAGTTTTGTATTTATTACATTTCTTTTTCAGTCA NOVla, CG11-999E03 JSEQ IDN:2L8 aM t 105031.2kD WO 2004/015079 PCT/US2003/024931 Poen Sequence_ MPSLPAPPAPLLLLGLLLLGSRPARGAGPEPPVLPIRSEKEPLPVRGAAGCTFGGKVYALDETWHPDL GEPFGVMRCVLCACEAPQWGRRTRGPGRVSCKNIKPECPTPACGQPRQLPGHCCQTCPQERSSSERQP SGLSFEYPRDPEHRSYSDRGEPGAEERARGDGHTDFVALLTGPRSQAVARARVSLLRSSLRFSISYRR LDRPTRIRFSDSNGSVLFEHPAAPTQDGLVCGVWRAVPRLSLRLLRAEQLHVALVTLTHPSGEVWGPL IRHRALAAETFSAILTLEGPPQQGVGCITLLTLSDTEDSLHFLLLFRGLLEPRSGGKWDGGKTREKVR ESTCLRKAHMCGLAGLTQVPLRLQILHQGQLLRELQANVSAQEPGFAEVLPNLTVQEMDWLVLGELQM ALEWAGRPGLRISGHIAARKSCDVLQSVLCGADALIPVQTGAAGSASLTLLGNGSLIYQVQVVGTSSE VVAMTLETKPQRRDQRTVLCHMAGLQPGGHTAVGICPGLGARGAHMLLQNELFLNVGTKDFPDGELRG HVAALPYCGHSARHDTLPVPLAGALVLPPVKSQAAGHAWLSLDTHCHLHYEVLLAGLGGSEQGTVTAH LLGPPGTPGPRRLLKGFYGSEAQGVVKDLEPELLRHLAKGMASLMITTKGSPRGELRGQVHIANQCEV GGLRLEAAGAEGVRALGAPDTASAAPPVVPGLPALAPAKPGGPGRPRDPNTCFFEGQQRPHGARWAPN YDPLCSLCTCQRRTVICDPVVCPPPSCPHPVQAPDQCCPVCPEKQDVRDLPGLPRSRDPGEGCYFDGD RSWRAAGTRWHPVVPPFGLIKCAVCTCKGGTGEVHCEKVQCPRLACAQPVRVNPTDCCKQCPVGSGAH PQLGDPMQADGPRGCRFAGQWFPESQSWHPSVPPFGEMSCITCRCGAGVPHCERDDCSLPLSCGSGKE SRCCSRCTAHRRPAPETRTDPELEKEAEGS NOVIb, CG121992-02 SEQ ID NO: 3 J2829 bp DNA Sequence ORF Start: ATG at 40 ORF Stop: TGA at 2410 CCTCCTCCCTCCCTCCTCCCCAGCTGTCCCGTTCGCGTCATGCCGAGCCTCCCGGCCCCGCCGGCCCC GCTGCTGCTCCTCGGGCTGCTGCTGCTCGGCTCCCGGCCGGCCCGCGGCGCCGGCCCCGAGCCCCCCG TGCTGCCCATCCGTTCTGAGAAGGAGCCGCTGCCCGTTCGGGGACCGCAGGCTGCACCTTCGGCGGG AAGGTCTATGCCTTGGACGAGACGTGGCACCCGGACCTAGGGGAGCCATTCGGGGTGATGCGCTGCGT GCTGTGCGCCTGCGAGGCGCCTCAGTCGGGTCGCCGTACCAGGGGCCCTGGCAGGGTCAGCTGCAAGA ACATCAAACCAGAGTGCCCAACCCCGGCCTGTGGGCAGCCGCGCCAGCTGCCGGGACACTGCTGCCAG ACCTGCCCCCAGGAGCGCAGCAGTTCGGAGCGGCAGCCGAGCGGCCTGTCCTTCGAGTATCCGCGGGA CCCGGAGCATCGCAGTTATAGCGACCGCGGGGAGCCAGGCGCTGAGGAGCGGGCCCGTGGTGACGGCC ACACGGACTTCGTGGCGCTGCTGACAGGGCCGAGGTCGCAGGCGGTGGCACGAGCCCGAGTCTCGCTG CTGCGCTCTAGCCTCCGCTTCTCTATCTCCTACAGGCGGCTGGACCGCCCTACCAGGATCCGCTTCTC AGACTCCAATGGCAGTGTCCTGTTTGAGCACCCTGCAGCCCCCACCCAAGATGGCCTGGTCTGTGGGG TGTGGCGGGCAGTGCCTCGGTTGTCTCTGCGCTCCTTAGGGCAGAACAGCTGCATGTGGCACTTGTG ACACTCACTCACCCTTCAGGGGAGGTCTGGGGGCCTCTCATCCGGCACCGGGCCCTGGCTGCAGAGAC CTTCAGTGCCATCCTGACTCTAGAAGGCCCCCCACAGCAGGGCGTAGGGGGCATCACCCTGCTCACTC TCAGTGACACAGAGGACTCCTTGCATTTTTTGCTGCTCTTCCGAGGGCTGCTGGAACCCAGGAGTGGG GGACTAACCCAGGTTCCCTTGAGGCTCCAGATTCTACACCAGGGGCAGCTACTGCGAGAACTTCAGGC CAATGTCTCAGCCCAGGAACCAGGCTTTGCTGAGGTGCTGCCCAACCTGACAGTCCAGGAGATGGACT GGCTGGTGCTGGGGGAGCTGCAGATGGCCCTGGAGTGGGCAGGCAGGCCAGGGCTGCGCATCAGTGGA CACATTGCTGCCAGGAAGAGCTGCGACGTCCTGCAAAGTGTCCTTTGTGGGGCTGATGCCCTGATCCC AGTCCAGACGGGTGCTGCCGGCTCAGCCAGCCTCACGCTGCTAGGAAATGGCTCCCTGATCTATCAGG TGCAAGTGGTAGGGACAAGCAGTGAGGTGGTGGCCATGACACTGGAGACCAAGCCTCAGCGGAGGGAT CAGCGCACTGTCCTGTGCCACATGGCTGGACTCCAGCCAGGAGGACACACGGCCGTGGGTATCTGCCC TGGGCTGGGTGCCCGAGGGGCTCATATGCTGCTGCAGAATGAGCTCTTCCTGAATGTGGGCACCAAGG ACTTCCCAGACGGAGAGCTTCGGGGGCACGTGGCTGCCCTGCCCTACTGTGGGCATAGCGCCCCGCCAT GACACGCTGCCCGTGCCCCTAGCAGGAGCCCTGGTGCTACCCCCTGTGAAGAGCCAAGCAGCAGGGCA CGCCTGGCTTTCCTTGGATACCCACTGTCACCTGCACTATGAAGTGCTGCTGGCTGGGCTTGGTGGCT CAGAACAAGGCACTGTCACTGCCCACCTCCTTGGGCCTCCTGGAACGCCAGGGCCTCGGCGGCTGCTG AAGGGATTCTATGGCTCAGAGCCCCAGGGTGTGGTGAAGGACCTGGAGCCGGAACTGCTGCGGCACCT GGCAAAAGGCATGGCCTCCCTGCTGATCACCACCAAGGGTAGCCCCAGAGGGGAGCTCCGAGGGCAGG TCCACATAGCCAACCAATGTGAGGTTGGCGGACTGCGCCTGGAGGCGGCCGGGGCCGAGGGGGTGCGG GCGCTGGGGGCTCCGGATACAGCCTCTGCTGCGCCGCCTGTGGTGCCTGGTCTCCCGGCCCTAGCGCC CGCCAAACCTGGTGGTCCTGGGCGGCCCCGAGACCCCAACACATGCTTCTTCGAGGGGCAGCAGCGCC CCCACGGGGCTCGCTGGGCGCCCAACTACGACCCGCTCTGCTCACTCTGCACCTGCCAGAGACGAACG GTGATCTGTGACCCGGTGGTGTGCCCACCGCCCAGCTGCCCACACCCGGTGCAGGCTCCCGACCAGTG CTGCCCTGTTTGCCCTGAGAAACAAGATGTCAGAGACTTGCCAGGGCTGCCAAGGAGCCGGGACCCAG GAGAGGGGGGGCACTGGAGAGGTGCACTGTGAGAAGGTGCAGTGTCCCCGGCTGGCCTGTGCCCAGCC TGTGCGTGTCAACCCCACCGACTCCTGCAAACAGTGTCCAGTGGGGTCGGGGGCCCACCCCCAGCTGG GGGACCCCATGCAGGCTGATGGGCCCCGGGGCTGCCGTTTTGCTGGGCAGTGGTTCCCAGAGAGTCAG AGCTGCCACCCCTCAGTGCCCCCGTTTGGAGAGATGAGCTGTATCACCTGCAGATGTGGGGCAGGGGT GCCTCACTGTGAGCGGGATGACTGTTCACTGCCACTGTCCTGTGGCTCGGGGAACGAGAGTCGATGCT GTTCCCGCTGCACGGCCCACCGGCGGCCAGCCCCAGAGACCAGAACTGATCCAGAGCTGGAGAAAGAA GCCGAAGGCTCTTAGGGAGCAGCCAGAGGGCCAAGTGACCA NOVlb, CG121992-02 SEQ ID NO: 4 790 aa MWat 84215.7kD Protein Sequence a I MPSLPAPPAPLLLLGLLLLGSRPARGAGPEPPVLPIRSEKEPLPVRGAAGCTFGGKVYALDETWHPDL GEPFGVMRCVLCACEAPQWGRRTRGPGRVSCKNIKPECPTPACGQPRQLPGHCCQTCPQERSSSERQP SGLSFEYPRDPEHRSYSDRGEPGAEERARGDGHTDFVALLTGPRSOAVARARVSLLRSSLRFSISYRR I InA WO 2004/015079 PCT/US2003/024931 LDRPTRIRFSDSNGSVLFEHPAAPTQDGLVCGVWRAVPRLSLRLLRAEQLHVAVTLTHPSGEWGPL IRHRALAAETFSAILTLEGPPQQGVGGITLLTLSDTEDSLHFLLLFRGLLEPRSGGLTQVPLRLQILH QGQLLRELQANVSAQEPGFAEVLPNLTVQEMDWLVLGELQMALEWAGRPGLRISGHIAARKSCDVLQS VLCGADALIPVQTGAAGSASLTLLGNGSLIYQVQVVGTSSEVVAMTLETKPQRRDQRTVLCHMAGLQP GGHTAVGICPGLGARGAHMLLQNELFLNVGTKDFPDGELRGHVAALPYCGHSARHDTLPVPLAGALVL PPVKSQAAGHAWLSLDTHCHLHYEVLLAGLGGSEQGTVTAHLLGPPGTPGPRRLLKGFYGSEAQGVVK DLEPELLRHLAKGMASLLITTKGSPRGELRGQVHIANQCEVGGLRLEAAGAEGVRALGAPDTASAAPP VVPGLPALAPAKPGGPGRPRDPNTCFFEGQQRPHGARWAPNYDPLCSLCTCQRRTVICDPVVCPPPSC PHPVQAPDQCCPVCPEKQDVRDLPGLPRSRDPGEGGHWRGAL NOVIc, CG121992-04 SEQ ID NO: 5 12319 bp DNA Sequence IORF Start: at 1 ORF Stop: at end of sequence GTTCGGGGAGCGGCAGGCTGCACCTTCGGCGGGAAGGTCTATGCCTTGGACGAGACGT GGCACCCGGACCTAG'GGAGCCATTCGGGGTGATGCGCTGCGTGCTGTGCGCCTGCGAGGCGCCTCAG TGGGGTCGCCGTACCAGGGGCCCTGGCAGGGTCAGCTGCAAGAACATCAAACCAGAGTGCCCAACCCC GGCCTGTGGGCAGCCGCGCCAGCTGCCGGGACACTGCTGCCAGACCTGCCCCCAGGAGCGCAGCAGTT CGGAGCGGCAGCCGAGCGGCCTGTCCTTCGAGTATCCGCGGGACCCCGAGCATCGCAGTTATAGCGAC CGCGGGGAGCCAGGCGCTGAGGAGCGGGCCCGTGGTGACGGCCACACGGACTTCGTGGCGCTGCTGAC AGGGCCGAGGTCGCAGGCGGTGGCACGAGCCCGAGTCTCGCTGCTGCGCTCTAGCCTCCGCTTCTCTA TCTCCTACAGGCGGCTGGACCGCCCTACCAGGATCCGCTTCTCAGACTCCAATGGCAGTGTCCTGTTT GAGCACCCTGCAGCCCCCACCCAAGATGGCCTGGTCTGTGGGGTGTGGCGGGCAGTGCCTCGGTTGTC TCTGCGGCTCCTTAGGGCAGAACAGCTGCATGTGGCACTTGTGACACTCACTCACCCTTCAGGGGAGG TCTGGGGGCCTCTCATCCGGCACCGGGCCCTGGCTGCAGAGACCTTCAGTGCCATCCTGACTCTAGAA GGCCCCCCACAGCAGGGCGTAGGGGGCATCACCCTGCTCACTCTCAGTGACACAGAGGACTCCTTGCA TTTTTTGCTGCTCTTCCGAGGGCTGCTGGAACCCAGGAGTGGGGGTAAGTGGGATGGGGGCAAAACAC GTGAGAAGGTTAGGGAGAGCACCTGTCTCAGAAAGGCCCACATGTGCGGCCTTGCAGGACTAACCCAG GTTCCCTTGAGGCTCCAGATTCTACACCAGGGGCAGCTACTGCGAGAACTTCAGGCCAATGTCTCAGC CCAGGAACCAGGCTTTGCTGAGGTGCTGCCCAACCTGACAGTCCAGGAGATGGACTGGCTGGTGCTGG GGGAGCTGCAGATGGCCCTGGAGTGGGCAGGCAGGCCAGGGCTGCGCATCAGTGGACACATTGCTGCC AGGAAGACCTGCGACGTCCTGCAAAGTGTCCTTTGTGGGGCTGATGCCCTGATCCCAGTCCAGACGGG TGCTGCCGGCTCAGCCAGCCTCACGCTGCTAGGAAATGGCTCCCTGATCTATCAGGTGCAAGTGGTAG GGACAAGCAGTGAGGTGGTGGCCATCACACTGGAGACCAAGCCTCAGCGGAGGGATCAGCGCACTGTC CTGTGCCACATGGCTGGACTCCAGCCAGGAGGACACACGGCCGTGGGTATCTGCCCTGGGCTGGGTGC CCGAGGGGCTCATATGCTGCTGCAGAATGAGCTCTTCCTGAACGTGGGCACCAAGGACTTCCCAGACG GAGAGCTTCGGGGGCACGTGGCTGCCCTGCCCTACTGTGGGCATAGCGCCCGCCATGACACGCTGCCC GTGCCCCTAGCAGGAGCCCTGGTGCTACCCCCTGTGAAGAGCCAAGCAGCAGGGCACGCCTGGCTTTC CTTGGATACCCACTGTCACCTGCACTATGAAGTGCTGCTGGCTGGGCTTGGTGGCTCAGAACAAGGCA CTGTCACTGCCCACCTCCTTGGGCCTCCTGGAACGCCAGGGCCTCGGCGGCTGCTGAAGGGATTCTAT GGCTCAGAGGCCCAGGGTGTGGTGAAGGACCTGGAGCCGGAACTGCTGCGGCACCTGGCAAAAGGCAT GGCCTCCCTGATGATCACCACCAAGGGTAGCCCCAGAGGGGAGCTCCGAGGGCAGGTGCACATAGCCA ACCAATGTGAGGTTGGCGGACTGCGCCTGGAGGCGGCCGGGCCCGAGGGGGTGCGGGCGCTGGGGGCT CCGGATACAGCCTCTGCTGCGCCGCCTGTGGTGCCTGGTCTCCCGGCCCTAGCGCCCGCCAAACCTGG TGGTCCTGGGCGGCCCCGAGACCCCAACACATGCTTCTTCGAGGGGCACCAGCGCCCCCACGGGGCTC GCTGGGCGCCCAACTACGACCCGCTCTGCTCACTCTGCACCTGCCAGAGACGAACGGTGATCTGTGAC CCGGTGGTGTGCCCACCGCCCAGCTGCCCACACCCGGTGCAGGCTCCCGACCAGTGCTGCCCTGTTTG CCCTGAGAAACAAGATGTCAGAGACTTGCCAGCGCTGCCAAGGAGCCGGGACCCAGGAGAGGGGGGGC ACTGGAGAGGTGCACTG NOVIc, CG121992-04 SEQ ID NO: 6 773 aa MW at 82722.9kD Protein Sequence VRGAAGCTFGGKVYALDETWHPDLGEPFGVMRCVLCACEAPQWGRRTRGPGRVSCKNIOKPECPTPAC QPRQLPGHCCQTCPQERSSSERQPSGLSFEYPRDPEHRSYSDRGEPGAEERARGDGHTDFVALLTGPR SQAVARARVSLLRSSLRFSISYRRLDRPTRIRFSDSNGSVLFEHPAAPTQDGLVCGVWRAVPRLSLRL LRAEQLHVALVTLTHPSGEVWGPLIRHRALAAETFSAILTLEGPPQQGVGGITLLTLSDTEDSLHFLL LFRGLLEPRSGGKWDGGKTREKVRESTCLRKAHMCGLAGLTQVPLRLQILHQGQLLRELQANVSAQEP GFAEVLPNLTVQEMDWLVLGELQMALEWAGRPGLRISGHIAARKSCDVLQSVLCGADALIPVQTGAAG SASLTLLGNGSLIYQVQVVGTSSEVVAMTLETKPQRRDQRTVLCHMAGLQPGGHTAVGICPGLGARGA HMLLQNELFLNVGTKDFPDGELRGHVAALPYCGHSARHDTLPVPLAGALVLPPVKSQAAGHAWLSLDT HCHLHYEVLLAGLGGSEQGTVTAHLLGPPGTPGPRRLLKGFYGSEAQGVVKDLEPELLRHLAKGMASL MITTKGSPRGELRGQVHIANQCEVGGLRLEAAGAEGVRALGAPDTASAAPPVVPGLPALAPAKPGPG RPRDPNTCFFEGQQRPHGARWAPNYDPLCSLCTCQRRTVICDPVVCPPPSCPHPVQAPDQCCPVCPEK QDVRDLPGLPRSRDPGEGGHWRGAL A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 1B. Table 1B. Comparison of the NOVI protein sequences. 1 (11r WO 2004/015079 PCT/US2003/024931 NOVi1a MPSLPAPPAPLLLLGLLLLGSRPARCAGPEPPVLPIRSEKEPLPVRGAAGCTFGGKVYAL Novib MPSLPAPPAPLLLLGLLLLGSRPARAGPEPPV.PIRSEKEPLPVRGAACCTFGGKXYAL NOVIC--------------------------------------------------- VRGAAGCTFGGKXIYALT NOVia DETWflPDLGEPFGVMRCVLCACEAkPQWGRRTRGPGRVSCKNIKPECPTPACGQPRQLpGH NOVIb DETWHPDLGEPFGVMRCVLCACEAPQWGRRTRGPGRVSCKNIKPECPTPACCQPRQLPGH NOVic DETWHPDLGEPFGVMRCVLCACEAPQWGRRTRGPGRVSCKNIKPECPTPACGQPRQLPGH NOVia CCQTCPQERSSSERQPSGLSFEYPRDPEHRSYSDRGEPGAEERARGDGHTDFVALLTGPR NOVIb CCQTCPQERSSSERQPSGLSFEYPRDPEHRSYSDRGEPGAEERARGDGHTDFVALLTGPR NOVic CCQTCPQERSSSERQPSGLSFEY P1DPEHRSYSDRGEPGAEERARGDGHTDFVALLTGPR NOVia SQAVARARVSLLRSSLRFSI SYRRLDRPTRIRFSDSWGSVLFEHPAAPTQDGLVCGVWRA NOVIb SQAVARARVSLLRSSLRFSISYRRLDRPTRIRFSDSNGSVLFEHPA.APTQDGLVCGVWRA NOVic SQAVAARVSLLRSSLRFSISYRRLDRPTRIRFSDSNSVLFEHPAPTQDGLVCGVWRA NOVia VPRLSLRLLRAEQLHVALVTLTHPSGEVWGPLIRH-RALAAETFSAILTLEGPPQQGVGGI NOVib VPRLSLRLLRAEQLHVALVTLT1iPSGEVWGPLIFRiRALAAETFSAILTLEGPPQQGvooI NOVic VPRLSLRLLRAEQLHVALVTLTHPSGEVWGPLIRHRALAAETFSAILTLEGPPQQGVGGI NOVIa TLLTLSDTEDSLHFLLLFRGLLEPRSGGKDGGKTREKVRESTCLRKAHCGLAGLTQVP Novib 'LLTLSDTEDSLHFLLLFRGLLEPRSGG---------------------------- LTQVP NOVic TLLTLSDTED8LHFLLLFRGLLEPRSGGKWDGGKTREKVRESTCLRKAHM'CGLAGLTQVP NOVia LRLQILHQGQLLRELQANVSAQEPGFAEVLPNLTVQEMDWLVLGELQMALEWAGRPGLRI NOVlb LRLQILHQGQLLRELQAVSAQEPGFAVLPNLTVQEMDWLVLGELQMALEWAGRPGLRI NOVic LRLQILHQGQLLRELQAVSAQEPGFAELPNLTVQEMDWLVLGELQMALEWAGRPGLRI NOVia SGHIAARKSCDVLQSVLCGADALIPVQTGAAGSASITLLGNGSLIYQVQVVGTSSEVVAM NOVIb SGHIAARKSCDVLQSVLCGAfALIPVQTGAAGSASLTLLGNGSLIYQVQVVGTSSEVVAM NOVic SGHIARKSCDVLQSV.CGADALIPVQTGAAGSASLTLLGNGSLIYQVQVVGTSSEwVAM N4OVia TLETKPQRRDQRTVLCHMAGLQPGGHTAVGICPGLGARGAHMLLQNELFLNVGTKDFPDG NOVlb TLETKPQRRDQRTVLCHMAGLQPGGHTAVGICPGLGARGAH-MLLQNELFLNVGTKDFPDG NOVic TLETKPQRRDQRTVLCHMAGLQPGGHTAVGICPGLGARGAIMLLQNELFLNVGTKDFPDG NOVi a ELRGHVAALPYCGHSARHDTLPVPLAGALVLPPV{SQAAGHAWLSLDTHCHLHYEVLLAG NOVib ELRGHVAAIJPYCGHSARNDTLPVPLAGALVLPPVKSQAAG{AWLSLDTHCHLHYEVLLAG NOVIc ELRGHVAALPYCGHSARHDTLPVPLAGALVLPPVKSQAAGHAWLSLDTHCHLHYEVLLAG NOVia LCCSEQGTVTAHLLGPPGTPGPRRLLKGFYGSEAQGVVKDLEPELLHLAKGMAjSLMITT NoVlb LCGSEQGTVTAHLLGPPGTPGPRIRLLKGFYGSEAQGVVKD LEPELLRHLAKGMASLLuTT NOVic LCGSEQGTVTAHLLGPPGTPGRRIJIKGFYGSEAQGVVKDLEPELLRHLAKGMASLMITT NOVia KGSPRGELRGQVHIANQCEVGGLRLEAAGAEGVRALGAPDTASAAPPVVPGLPALAPAK NOVIb KGSPRGELRGQVHIANQCEVGGLRLEAAGAEGVRALGAPDTASAAPPVVPGLPALAPAK NOVlc KGSPRGELRGQVHIANQCEVGGLRLE.AAGAEGVRALGAPDTASAAPPVVPGLPAJAAK NOVia PGGPGRPRDPUTCFFEGQQRPHGARWAPNYDPLCSLCTCQRRTVICDPWV NOVIb PGGPGRPRDPNTCFFEGQQRPHGARWAPNYDPLCSLCTCQRRTVICDPVV NOVic PGGPGRPRDPNTCFFEGQQRPHGARWAPNYDPLCSLCTCQRRTVICDPVV NOVIa CPPPSCPHPVQAPDQCCPVCPEKQDVRDLPGLPRSRDPGEGCYFDGDRSWRAAGTRW NOVIb CPPPSCPHPVQAPDQCCPVCPEKQDVRDLPGLPRSRDPGEG ------ GHWRGAL-- NOVIc CPPPSCPHPVQAPDQCCPVCPEkQDVRDLPGLPRSRDPGEG ------ GHWRGAL-- I n/'~ WO 2004/015079 PCT/US2003/024931 NOVla HPVVPPFGLIKCAVCTCKGGTGEVHCEKVQCPRLACAQPVRVNPTDCCKQCPVGSGAHPQ - NOV1b --------------- ---- --- ----------------- NOVlc ---------------- ------------ ------------------ NOVla LGDPMQADGPRGCRFAG.QWFPESQSWHPSVPPFGEMSCITCRCGAGVPHCERDDCSLPLS NOV1b ---------------- ---- ------ ----------- NOV1c ----------------------- NOVla CGSGKESRCCSRCTAHRRPAPETRTDPELEKEAEGS NOVIb --------------------------- NOV1c ------ -------- ----------- NOVIa (SEQ ID NO: 2) NOV1b (SEQ ID NO: 4) NOV1c (SEQ ID NO: 6) NOV la, lb have a cleavable signal peptide corresponding to amino acid residues 1 to 23 of SEQ ID NO:2 and 4 respectively. NOVIa mature protein corresponds to amino acid residues 24-982 of SEQ ID NO:2. NOV~b mature protein corresponds to amino acid 5 residues 24-790 of SEQ ID NO:4. NOV1 sequences contain von Willebrand factor type C domains corresponding to amino acid residues 51-125 and 705-762 of NOV1b, SEQ ID NO:4; amino acid residues 51-125, 732-789, 811-877 and 899-959 of NOVia SEQ ID NO:2; and amino acid residues 7-81 and 688-745 of NOVic SEQ ID NO:6. NOVIa and NOV1c have a novel insertion at amino acid residues 329-355 of SEQ ID NO:2 and 10 residues 285-311 of SEQ ID NO:6 respectively. A search of the NOVLa protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1D. Table ID. Geneseq Results for NOVia NOVia Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region ABG31265 Human chordin (CHRD) protein - 1..982 954/982 (97%) 0.0 Homo sapiens, 955 aa. 1..955 955/982 (97%) [W0200254940-A2, 18-JJL 2002] AAE12889 Human chordin protein - Homo 1..982 954/982 (97%) 0.0 sapiens, 955 aa. [W0200164885- 1..955 955/982 (97%) Al, 07-SEP-2001] WO 2004/015079 PCT/US2003/024931 AAW48978 Mature human chordin protein - 1..982 954/982 (97%) 0.0 Homo sapiens, 954 aa. 1..954 954/982 (97%) [WO9821335-Al, 22-MAY-1998] In a BLAST search of public sequence databases, the NOVla protein was found to have homology to the proteins shown in the BLASTP data in Table 1E. Table 1E. Public BLASTP Results for NOVia P NOVia Identities/ Protein Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion Q9H2XO Chordin precursor - Homo 1..982 954/982 (97%) 0.0 sapiens (Human), 955 aa. 1..955 955/982 (97%) Q9ZOE2 Chordin precursor - Mus 1..982 824/985 (83%) 0.0 musculus (Mouse), 948 aa. 1..948 863/985 (86%) 057465 Chordin - Gallus gallus 11..966 523/985 (53%) 0.0 (Chicken), 940 aa. 5..927 651/985 (65%) Q8N2W7 Hypothetical protein - Homo 570..982 413/413 (100%) 0.0 sapiens (Human), 413 aa 1.413 413/413 (100%) (fragment). Q8TEH7 FLJ00220 protein - Homo 382..815 430/434 (99%) 0.0 sapiens (Human), 503 aa 68..501 432/434 (99%) (fragment). Chordin is a bone morphogenetic protein (BMP) antagonist. BMPs were originally identified by an ability of demineralized bone extract to induce endochondral osteogenesis 5 in vivo in an extraskeletal site. To date, 15 BMPs have been identified and all are members of the transforming growth factor-beta superfamily of secreted signaling molecules and regulate tissue differentiation and maintenance. They play roles in embryogenesis by binding to specific serine/threonine kinase receptors, which transduce the signal to the nucleus. In contrast, there are proteins that antagonize the BMP functions by specifically 10 binding to BMPs and preventing their binding to specific receptors or their signaling. Chordin can interfere with normal embryogenesis by binding to TGF-beta likeBMPs and sequestering them in latent complexes. It has been shown that BMP1 and TLL1 counteracted the effects of chordin upon overexpression in Xe'nopus embryos (Scott et al. "Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family 15 member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis." Dev. Biol. 213: 283-300, 1999). They suggested that BMP1 is the major chordin antagonist in early mammalian *1 fn WO 2004/015079 PCT/US2003/024931 embryogenesis and in pre- and postnatal skeletogenesis. It also directly binds BMP-4 and BMP-2, and interferes with the binding of these proteins to their receptors. Bone metastases are a frequent clinical problem in patients with breast, prostate, and other cancers. Formation of these lesions is a site-specific process determined by 5 multiple cellular and molecular interactions between the cancer cells and the bone microenvironment. BMP has been shown to be one of the significant factors in the prognosis of bone tumors. The overexpression of BMP2, BMP4, and BMP6 were found in most osteosarcomas or prostate cancers with metastases (Hamdy, F., Autzen, P., Robinson, MC., Wilson Home, CH., Neal, DE. and Robson CN. "Immunolocalization and messenger 10 RNA expression of bone morphogenetic protein-6 in human bening and malignant prostatic tissue." Cancer Research 57: 4427-4431, 1997; Guo, W., Gorlick, R., Ladanyi, M., Meyers, PA., Huvos, AG., Bertino, JR., and Healey, JH. "Expression of bone morphogenetic proteins and receptors in sarcomas." Clinical Orthopaedics and Related Research 365: 175-183, 1999.) suggesting a close association 15 between BMPs and skeletal metastases. BMP-2, -4, -6 may be responsible, in part, for osteoblastic changes in metastatic lesions secondary to prostate cancer. NOVI has a role in the regulation of morphogenesis and cancer development. It is an important antibody or protein therapeutic target for the related diseases. NOVIa has a nucleic acid of 3628 nucleotides (designated CuraGen Acc. No. 20 CG121992-03) encoding a novel CHORDIN-like splice variant with deletion of exon 19 causing a frameshift staring from 784 aa. An open reading frame was identified beginning at nucleotides 247-249 and ending at nucleotides 3193-3195. This sequence represents a splice form of CHORDIN as indicated with 1 amino acid change L630M and insertion in frame of 27 amino acids KWDGGKTREKVRESTCLRKAHMCGLAG (SEQ ID NO:77). 25 The encoded protein having 982 amino acid residues contains 2 of 4 repeated von Willebrand factor type C domains compared to full length chordin. The von Willebrand factor (VWF) type C domain is found in multidomain protein/multifunctional proteins involved in maintaining homeostasis. The duplicated VWFC domain participates in oligomerization, but not in the initial dimerization step. The presence of this region in a 30 number of other complex-forming proteins points to involvment of the VWFC domain in complex formation. The CHORDIN-like genes disclosed in this invention map to chromosome 3. The PSORT, SignalP results for the CHORDIN-like protein NOVIa predict that this sequence 1 [A WO 2004/015079 PCT/US2003/024931 has a signal peptide and is likely to be localized extracellularly with a certainty of 0.5469. The signal peptide is predicted by SignalP to be cleaved at amino acid between position 26 and 27: ARG-AG. Example 2. NOV2, CG186275, ADAM 22 5 The NOV2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 2A. Table 2A. NOV2 Sequence Analysis NOV2a, CG186275-03 SEQ ID NO: 7 2847 bp DNA Sequence ORF Start: ATG at 47 ORF Stop: TAA at 2795 CATGAGGAGCTGAGCGTCTCGGGCGAGGCGGCTGACGGCAGCACCATGCAGGCGGCAGTGGCTGTGT CCGTGCCCTTCTTGCTGCTCTGTGTCCTGGGGACCTGCCCTCCGGCGCGCTGCGGCCAGGCAGGAGAC GCCTCATTGATGGAGCTAGAGAAGAGGAAGGAAAACCGCTTCGTGGAGCGCCAGAGCATCGTGCCACT GCGCCTCATCTACCGCTCGGGCGGCGAAGACGAAAGTCGGCACGACGCGCTCGACACGCGGGTGCGGG GCGACCTCGGTGGCCGGCAGATTCAGATGTTTTTGAAGTCAGAATCCCAGAAGACCATATACCAGATA CAGTTGACTCATGTTGACCAAGCAAGCTTCCAGGTTGATGCCTTTGGAACGTCATTCATTCTCGATGT CGTGCTAAATCATGATTTGCTGTCCTCTGAATACATAGAGAGACACATTGAACATGGAGGCAAGACTG TGGAAGTTAAAGGAGGAGAGCACTGTTACTACCAGGGCCATATCCGAGGAAACCCTGACTCATTTGTT GCATTGTCAACATGCCACGGACTTCATGGGATGTTCTATGACGGGAACCACACATATCTCATTGAGCC AGAAGAAAATGACACTACTCAAGAGGATTTCCATTTTCATTCAGTTTACAAATCCAGACTGTTTGAAT TTTCCTTGGATGATCTTCCATCTGAATTTCAGCAAATAAACATTACTCCATCAAAATTTATTTTGAAG CCAAGACCAAAAAGGAGTAAACGGCAGCTTCGTCGATATCCTCGTAATGTAGAAGAAGAAACCAAATA CATTGAACTGATGATTGTGAATGATCACCTTATGTTTAAAAAACATCGGCTTTCCGTTGTACATACCA ATACCTATGCGAAATCTGTGGTGAACATGGCAGATTTAATATATAAAGACCAACTTAAGACCAGGATA GTATTGGTTGCTATGGAAACCTGGGCGACTGACAACAAGTTTGCCATATCTGAAAATCCATTGATCAC CCTACGTGAGTTTATGAAATACAGGAGGGATTTTATCAAAGAGAAAAGTGATGCAGTTCACCTTTTTT CGGGAAGTCAATTTGAGAGTAGCCGGAGCGGGGCAGCTTATATTGGTGGGATTTGCTCGTTGCTGAAA GGAGGAGGCGTGAATGAATTTGGGAAAACTGATTTAATGGCTGTTACACTTGCCCAGTCATTAGCCCA TAATATTGGTATTATCTCAGACAAAAGAAAGTTAGCAAGTGGTGAATGTAAATGCGAGGACACGTGGT CCGGGTGCATAATGGGAGACACTGGCTATTATCTTCCTAAAAAGTTCACCCAGTGTAATATTGAAGAG TATCATGACTTCCTGAATAGTGGAGGTGGTGCCTGCCTTTTCAACAAACCTTCTAAGCTTCTTGATCC TCCTGAGTGTGGCAATGGCTTCATTGAAACTGAGAGGAGTGTGATTGTGGAACCCCGGCCGAATGTG TCCTTGAAGGAGCAGAGTGTTGTAAGAAATGCACCTTGACTCAAGACTCTCAATGCAGTGACGGTCTT TGCTGTAAAAAGTGCAAGTTTCAGCCTATGGGCACTGTGTGCCGAGAAGCAGTAAATGATTGTGATAT TCGTGAAACGTGCTCAGGAAATTCAAGCCAGTGTGCCCCTAATATTCATAAAATGGATGGATATTCAT GTGATGGTGTTCAGCGAATTTGCTTTGGAGGAAGATGCAAAACCAGAGATAGACAATGCAAATACATT TGGGGGCAAAAGGTGACAGCATCAGACAAATATTGCTATGAGAAACTGAATATTGAAGGGACGGAGAA GGGTAACTGTGGGAAAGACAAAGACACATGGATACAGTGCAACAAACGGGATGTGCTTTGTGGTTACC TTTTGTGTACCAATATTGGCAATATCCCAAGGCTTCGAGAACTCGATGGTGAAATCACATCTACTTTA GTTGTGCAGCAAGGAAGAACATTAAACTGCAGTGGTGGGCATGTTAAGCTTGAAGAAGATGTAGATCT TGGCTATGTGGAAGATCGGACACCTTGTGGTCCCCAAATGATGTGCTTAGAACACAGGTGTCTTCCTG TGGCTTCTTTCAACTTTAGTACTTGCTTGAGCAGTAAAGAAGGCACTATTTGCTCAGGAAATGGAGTT TGCAGTAATGAGCTGAAGTGTGTGTGTAACAGACACTGGATAGGTTCTGATTGCAACACTTACTTCCC TCACAATGATGATGCAAAGACTGGTATCACTCTGTCTGGCAATGGTGTTGCTGGCACCAATATCATAA TAGGCATAATTGCTGGCACCATTTTAGTGCTGGCCCTCATATTAGGAATAACTGCGTGGGGTTATAAA AACTATCGAGAACAGAGGTCAAATGGGCTCTCTCATTCTTGGAGTGAAAGGATTCCAGACACAAAACA TATTTCAGACATCTGTGAAAATGGGCGACCTCGAAGTAACTCTTGGCAAGGTAACCTGGGAGGCAACA AAAAGAAAATCAGAGGCAAAAGATTTAGACCTCGGTCTAATTCAACTGAGTATTTAAACCCATGGTTC AAAAGAGACTATAATGTAGCTAAGTGGGTAGAAGATGTGAATAAA.AACACTGAAGAACCATACTTTAG GACTTTATCTCCTGCCAAGTCTCCTTCTTCATCAACTGGGTCTATTGCCTCCAGCAGAAAATACCCTT ACCCAATGCCTCCACTTCCTGATGAGGACAAGAAAGTGAACCGACAAAGTGCCAGGCTATGGGAGACA TCCATTTAAGATCAACTGTTTACATGTGATACATCGAAAACTGTTTACTTCAACTTTTA NOV2a, CG186275-03 SEQ ID NO: 8 916 aa IMW at 102480.1kD Protein Sequence MQAAVAVSVPFLLLCVLGTCPPARCGQAGDASLMELEKRKENRFVERQSIVPLRLIYRSGGEDESRHD ALDTRVRGDLGGRQIQMFLKSESQKTIYQIQLTHVDQASFQVDAFGTSFILDVVLNHDLLSSEYIERH IEHGGKTVEVKGGEHCYYQGHIRGNPDSFVALSTCHGLHGMFYDGNHTYLIEPEENDTTQEDFHFHSV YKSRLFEFSLDDLPSEFOOINITPSKFILKPRPKRSKROLRRYPRNVEEETKYI ELMIVNDHLMFKKH 1 1"I WO 2004/015079 PCT/US2003/024931 RLSVV1TNTAKSVVNMADLIYKDQLKTRIVLVAMETWATDNKFAISENPLITLREFMKYRRDFIKEK SDAVHLFSGSQFESSRSGAAYlGGICSLLKGGGVFGKTDLMAVTLAQSLAHNIGIISDKRKLASGE CKCEDTWSGCIMGDTGYYLPKKFTQCNIEEYHDFLNSGGGACLFNKPSKLLDPPECGNGFIETGEECD CGTPAECVLEGAECCKKCTLTQDSQCSDGLCCKKCKFQPMGTVCREAVNDCDIRETCSGNSS.QCAPNI HKMDGYSCDGVQGICFGGRCKTRDRQCKYIWGQKVTASDKYCYEKLNIEGTEKGNCGKDKDTWIQCNK RDVLCGYLLCTNIGNIPRLGELDGEITSTLVVQQGRTLNCSGGHVKLEEDVDLGYVEDGTPCGPQMMC LEHRCLPVASFNFSTCLSSKEGTICSGNGVCSNELKCVCNRHWIGSDCNTYFPHNDDAKTGITLSGNG VAGTNIIIGIIAGTILVLALILGITAWGYKNYREQRSNGLSHSWSERIPDTKHISDICENGPRSNSW QGNLGGNKKKIRGKRFRPRSNSTEYLNPWFKRDYNVAKWVEDVNKNTEEPYFRTLSPAKSPSSSTGSI ASSRKYPYPMPPLPDEDKKVNRQSARLWETSI Further analysis of the NOV2a protein yielded the following properties. NOV2a has a cleavable signal peptide corresponding to amino acid residues 1-25 of -SEQ ID NO:8. NOV2a has a novel insertions at amino acid residues 81-98 and 841-871 as well as a deletion of 36 amino acids between residues 784-784 of SEQ ID NO: 8. 5 A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2B. Table 2B. Geneseq Results for NOV2a NOV2a Identities/ Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region AAY25119 Human MDC2-beta protein - Homo 1..840 821/840 (97%) 0.0 sapiens, 823 aa. [JP11155574-A, 1..823 822/840 (97%) 15-JUN-1999] AAY30208 Amino acid sequence of the human 40..916 830/913 (90%) 0.0 SVPH3-13 protein - Homo sapiens, 1..867 831/913 (90%) 867 aa. [W09941388-A2, 19-AUG 1999] AAY25118 Human MDC2-alpha protein - 1..840 821/876 (93%) 0.0 Homo sapiens, 859 aa. 1..859 822/876 (93%) [JP11155574-A, 15-JUN-1999] AAR75352 Human fetal brain MDC protein - 52..787 407/742 (54%) 0.0 Homo sapiens, 769 aa. [EP633268- 50..768 518/742 (68%) A2, 11-JAN-1995] AAR67759 Human fetal brain MDC protein - 123..787 382/670 (57%) 0.0 Homo sapiens, 670 aa. [EP633268- 4..669 485/670 (72%) A2, 11-JAN-1995] In a BLAST search of public sequence databases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2C. Table 2C. Public BLASTP Results for NOV2a Protein Protein/Organism/Length NOV2a Tdentities/ Fxneet WO 2004/015079 PCT/US2003/024931 Accession Residues/ Similarities for Value Number Match the Matched Residues Portion Q9POK1 ADAM 22 precursor (A disintegrin 1..916 868/952 (91%) 0.0 and metalloproteinase domain 22) 1..906 869/952 (91%) (Metalloproteinase-like, disintegrin like, and cysteine-rich protein 2) (Metalloproteinase-disintegrin ADAM22-3) Homo sapiens (Human), 906 aa. Q9R1V6 ADAM 22 precursor (A disintegrin 1..840 751/876 (85%) 0.0 and metalloproteinase domain 22) - 1..857 783/876 (88%) Mus musculus (Mouse), 857 aa. 042596 ADAM 22 precursor (A disintegrin 13..916 613/970 (63%) 0.0 and metalloproteinase domain 22) 12..935 709/970 (72%) (Metalloprotease-disintegrin MDC11b) (MDC11.2) - Xenopus laevis (African clawed frog), 935 aa. 075078 ADAM 11 precursor (A disintegrin 52..787 408/742 (54%) 0.0 and metalloproteinase domain 11) 50..768 518/742 (68%) (Metalloproteinase-like, disintegrin like, and cysteine-rich protein) (MDC) Homo sapiens (Human), 769 aa. Q9R1V4 ADAM 11 precursor (A disintegrin 52..787 409/743 (55%) 0.0 and metalloproteinase domain 11) 54..772 517/743 (69%) (Metalloproteinase-like, disintegrin like, and cysteine-rich protein) (MDC) - Mus musculus (Mouse), 773 aa. PFam analysis predicts that the NOV2a protein contains the domains shown in the Table 3F. Table 2D. Domain Analysis of NOV2a Identities/ Pfam Domain NOV2a Match Region Amino Similarities Expect Acid residues of SEQ ID NO: 8 for the Matched Value Region PepM12Bpropep 120..228 31/119 (26%) 6.3e-17 76/119 (64%) Reprolysin 256..455 69/206 (33%) 1.4e-89 172/206 (83%) disintegrin 470..546 35/79 (44%) 4.2e-17 52/79 (66%) EGF 696..728 10/48 (21%) 0.4 WO 2004/015079 PCT/US2003/024931 21/48 (44%) The cellular disintegrins, also known as ADAM (a disintegrin and metalloproteinase) and MDC (metalloproteinase-like, disintegrin-like, and cysteine-rich) proteins, are regulators of cell-cell and cell-matrix interactions. They contain multiple regions, including pro-, metalloproteinase-like, disintegrin-like, cysteine-rich, epidermal 5 growth factor-like, transmembrane, and cytoplasmic domains. NOV 2a has a nucleic acid of 2847 nucleotides (designated CuraGen Acc. No. CG186275-03) encoding a novel ADAM 22-like protein. An open reading frame was identified beginning at nucleotides 47-49 and ending at nucleotides 2795-2797. The encoded protein has 916 amino acid residues and is a splice form of ADAM 22 as indicated 10 in position 81 with one exon insertion of 18 amino acids RQIQMFLKSESQKTIYQI (SEQ ID NO:79). NOV3 genes disclosed in this invention map to chromosome 7q21 The presence of identifiable domains in the protein was determined by searches of domain databases such as Pfam, PROSITE, ProDom, Blocks or Prints and then identified by the Interpro domain accession number. Significant domains include reprolysin, 15 disintegrin and metalloendopeptidase domains. Reprolysin, found in CD156 (also called ADAMS (EC 3.4.24.-) or MS2 human) has been implicated in extravasation of leukocytes. The members of this family are enzymes that cleave peptides. These proteases require zinc for catalysis. Members of this family are also known as adamalysins. Most members of this family are snake venom endopeptidases, 20 but there are also some mammalian proteins such as P78325, and fertilin Q28472. Fertilin and closely related proteins appear to not have some active site residues and may not be active enzymes. Metalloendopeptidase M12B contains a sequence motif similar to the 'cysteine switch' of the matrixins. Many of the proteins with this domain are zinc proteases that may 25 mediate cell-cell or cell-matrix interactions. The adhesion of platelets to the extracellular matrix, and platelet-platelet interactions, are essential in thrombosis and haemostasis. Platelets adhere to damaged blood vessels, release biologically active chemicals, and aggregate, a function that is inhibited in normal blood. The binding of fibrinogen to the glycoprotein IlIbIfia complex of activated platelets is essential to platelet aggregation and 30 is induced by many agonists, including ADP, collagen, thrombin, epinephrine and prostaglandin endoperoxide analogue. Snake venoms affect blood coagulation and platelet function in a complex manner: some induce aggregation and release reactions, and some WO 2004/015079 PCT/US2003/024931 inhibit them. Disintegrin, a component of some snake venoms, rather than inhibiting the release reactions, operates by inhibiting platelet aggregation, blocking the binding of fibrinogen to the receptor-glyco-protein complex of activated platelets. They act by binding to the integrin glycoprotein Ilb-IIIareceptor on the platelet surface and inhibit aggregation 5 induced by ADP, thrombin, platelet-activating factor and collagen. The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant. Disintegrins are peptides of about 70 amino acid residues that contain many cysteines all involved in disulfide bonds. Disintegrins contain an Arg-Gly-Asp (RGD) 10 sequence, a recognition site of many adhesion proteins. The RGD sequence of disintegrins interacts with the glycoprotein Ib-IIEa complex. Example 3. NOV3 CG50586, Beta-secretase 15 The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 3A. Table 3A. NOV3 Sequence Analysis NOV3a, 260368272 SEQ ID NO: 9 1140 bp DNA Sequence lORF Start: at 1 lORF Stop: end of sequence AAGAATAAAGTTAAAGGCAGCCAAGGGCAGTTTCCACTAACACAGAATGTAACCGTTG TTGAAGGTGGAACTGCAATTTTGACCTGCAGGGTTGATCAAAATGATAACACCTCCCTCCAGTGGTCA AATCCAGCTCAACAGACTCTGTACTTTGACGACAAGAAAGCTTTAAGGGACAATAGGATCGAGCTGGT TCGCGCTTCCTGGCATGAATTGAGTATTAGTGTCAGTAATGTGTCTCTCTCTGATGAAGGACAGTACA CCTGTTCTTTATTTACAATGCCTGTCAAAACTTCCAAGGCATATCTCACCGTTCTGGGTGTTCCTGAA AAGCCTCAGATTAGTGGATTCTCATCACCAGTTATGCAGGGTGACTTGATGCAGCTGACTTGCAAAAC ATCTGGTAGTAAACCTGCAGCTGATATAAGATGGTTCAAAAATGACAAAGAGATTAAAGATGTAAAAT ATTTAAAAGAAGAGGATGCAAATCGCAAGACATTCACTGTCAGCAGCACACTGGACTTCCGAGTGGAC CGGAGTGATGATGGAGTGGCGGTCATCTGCAGAGTAGATCACGAATCCCTCAATGCCACCCCTCAGGT AGCCATGCAGGTGCTAGAAATACACTATACACCATCAGTTAAGATTATACCATCGACTCCTTTTCCAC AAGAAGGACAGCCTTTAATTTTGACTTGTGAATCCAAAGGAAAACCACTGCCAGAACCTGTTTTGTGG ACAAAGGATGGCGGAGAATTACCAGATCCTGACCGAATGGTTGTGAGTGGTAGGGAGCTAAACATTCT TTTCCTGAACAAAACGGATAATGGTACATATCGATGTGAAGCCACAAACACCATTGGCCAAAGCAGTG CGGAATATGTTCTCATTGTGCATGATCCTAATGCTTTGGCTGGCCAGAATGGCCCTGACCATGCTCTC ATAGGAGGAATAGTGGCTGTAGTTGTATTTGTCACGCTGTGTTCTATCTTTCTGCTTGGTCGATATCT GGCAAGGCATAAAGGAACGTATTTAACAAATGAAGCTAAAGGAGCTGAAGATGCACCAGATGCTGATA CACCCATTATCAATGCTGAAGGCAGCCAAGTCAATGCTGAAGAGAAAAAAGAGTATTTCATT NOV3a, 260368272 SEQ ID NO: 10 381 aa MW at 42300.3kD Protein Sequence SKNKVKGSQGQFPLTQNVTVVEGGTAILTCRVDQNDNTSLQWSNPAQQTLYFDDKKALRDNRIELV RASWHELSISVSNVSLSDEGQYTCSLFTMPVKTSKAYLTVLGVPEKPQISGFSSPVMEGDLMQLTCKT SGSKPAADIRWFKNDKEIKDVKYLKEEDANRKTFTVSSTLDFRVDRSDDGVAVICRVDHESLNATPQV AMQVLEIHYTPSVKIIPSTPFPQEGQPLILTCESKGKPLPEPVLWTKDGGELPDPDRMVVSGRELNIL FLNKTDNGTYRCEATNTIGQSSAEYVLIVHDPNALAGQNGPDHALIGGIVAVVVFVTLCSIFLLGRYL ARHKGTYLTNEAKGAEDAPDADTAIINAEGSQVNAEEKKEYFI SEQ ID NO: 11 786 bp WO 2004/015079 PCT/US2003/024931 NOV3b, 260368280 SEQ ID NO: 11 786 bp DNA Sequence NOV3b, 260368280 ORF Start: at 1 ORF Stop: end of sequence DNA Sequence GGAACTGCAATTTTGACCTGCAGGGTTGATCAAAATGATAACACCTCCCTCCAGT GGTCAAATCCAGCTCAACAGACTCTGTACTTTGACGACAAGAAAGCTTTAAGGGACAATAGGATCGAG CTGGTTCGCGCTTCCTGGCATGAATTGAGTATTAGTGTCAGTGATGTGTCTCTCTCTGATGAAGGACA GTACACCTGTTCTTTATTTACAATGCCTGTCAAAACTTCCAAGGCATATCTCACCGTTCTGGGTGTTC CTGAAAAGCCTCAGATTAGTGGATTCTCATCACCAGTTATGGAGGGTGACTTGATGCAGCTGACT.TGC AAAACATCTGGTAGTAAACCTGCAGCTGATATAAGATGGTTCAAAAATGACAAAGAGATTAAAGATGT AAAATATTTAAAAGAAGAGGATGCAAATCGCAAGACATTCACTGTCAGCAGCACACTGGACTTCCGAG TGGACCGGAGTGATGATGGAGTGGCGGTCATCTGCAGAGTAGATCACGAATCCCTCAATGCCACCCCT CAGGTAGCCATGCAGGTGCTAGAAATACACTATACACCATCAGTTAAGATTATACCATCGACTCCTTT TCCACAAGAAGGACAGCCTTTAATTTTGACTTGTGAATCCAAAGGAAAACCACTGCCAGAACCTGTTT TGTGGACAAAGGATGGCGGAGAATTACCAGATCCTGACCGAATGGTTGTGAGTGGTAGGGAGCTAAAC ATTCTTTTCCTGAACAAAACGGATAATGGTACATATCGATGTGAAGCC NOV3b, 260368280 SEQ ID NO: 12 262 aa MW at 29748.3kD Protein Sequence GGTAILTCRVDQNDNTSLQWSNPAQQTLYFDDKKALRDNRIELVRASWHELSISVSDVSLSDEGQ YTCSLFTMPVKTSKAYLTVLGVPEKPQISGFSSPVMEGDLMQLTCKTSGSKPAADIRWFKNDKEIKDV KYLKEEDANRKTFTVSSTLDFRVDRSDDGVAVICRVDHESLNATPQVAMQVLEIHYTPSVKIIPSTPF PQEGQPLILTCESKGKPLPEPVLWTKDGGELPDPDRMVVSGRELNILFLNKTDNGTYRCE NOV3c, 267441066 ISEQ ID NO: 13 1074 bp DNA Sequence IORF Start: at 1 JORF Stop: end of sequence ATGATTTGGAAACGCAGCGCCGTTCTCCGCTTCTACAGTGTCTGCGGGCTCCTGG TACAAGCGGCTGCTTCAAAGAATAAAGTTAAAGGCAGCCAAGGGCAGTTTCCACTAACACAGAATGTA ACCGTTGTTGAAGGTGGAACTGCAATTTTGACCTGCAGGGTTGATCAAAATGATAACACCTCCCTCCA GTGGTCAAATCCAGCTCAACAGACTCTGTACTTTGACGACAAGAAAGCTTTAAGGGACAATAGGATCG AGCTGGTTCGCGCTTCCTGGCATGAATTGAGTATTAGTGTCAGTGATGTGTCTCTCTCTGATGAAGGA CAGTACACCTGTTCTTTATTTACAATGCCTGTCAAAACTTCCAAGGCATATCTCACCGTTCTGGATGT AAAATATTTAAAAGAAGAGGATGCAAATCGCAAGACATTCACTGTCAGCAGCACACTGGACTTCCGAG TGGACCGGAGTGATGATGGAGTGGCGGTCATCTGCAGAGTAGATCACGAATCCCTCAATGCCACCCCT CAGGTAGCCATGCAGGTGCTAGAAATACACTATACACCATCAGTTAAGATTATACCATCGACTCCTTT TCCACAAGAAGGACAGCCTTTAATTTTGACTTGTGAATCCAAAGGAAAACCACTGCCAGAACCTGTTT TGTGGACAAAGGATGGCGGAGAATTACCAGATCCTGACCGAATGGTTGTGAGTGGTAGGGAGCTAAAC ATTCTTTTCCTGAACAAAACGGATAATGGTACATATCGATGTGAAGCCACAAACACCATTGGCCAAAG CAGTGCGGAATATGTTCTCATTGTGCATGATCCTAATGCTTTGGCTGGCCAGAATGGCCCTGACCATG CTCTCATAGGAGGAATAGTGGCTGTAGTTGTATTTGTCACGCTGTGTTCTATCTTTCTGCTTGGTCGA TATCTGGCAAGGCATAAAGGAACGTATTTAACAAATGAAGCTAAAGGAGCTGAAGATGCACCAGATGC TGATACAGCCATTATCAATGCTGAAGGCAGCCAAGTCAATGCTGAAGAGAAAAAAGAGTATTTCATT NOV3c, 267441066 SEQ ID NO: 14 358 aa MW at 40019.9kD Protein Sequence MIWKRSAVLRFYSVCGLLVQAAASKNKVKGSQGQFPLTQNVTVVEGGTAILTCRVDQNDNTSLQ WSNPAQQTLYFDDKKALRDNRIELVRASWHELSISVSDVSLSDEGQYTCSLFTMPVKTSKAYLTVLDV KYLKEEDANRKTFTVSSTLDFRVDRSDDGVAVICRVDHESLNATPQVAMQVLEIHYTPSVKIIPSTPF PQEGQPLILTCESKGKPLPEPVLWTKDGGELPDPDRMVVSGRELNILFLNKTDNGTYRCEATNTIGQS SAEYVLIVHDPNALAGQNGPDHALIGGIVAVVVFVTLCSIFLLGRYLARHKGTYLTNEAKGAEDAPDA DTAIINAEGSQVNAEEKKEYFI SEQ ID NO: 15 918 bp ORF Start: a 1 lORF Stop: end of sequence AAGAATAAAGTTAAAGGCAGCCAAGGGCAGTTTCCACTAACACAGAATGTAACCGTTGTTGAAGGTGG AACTGCAATTTTGACCTGCAGGGTTGATCAAAATGATAACACCTCCTCCAGTGGTCAAATCCAGCTC AACAGACTCTGTACTTTGACGACAAGAAAGCTTTAAGGGACAATAGGATCGAGCTGGTTCGCGCTTCC TGGCATGAATTGAGTATTAGTGTCAGTGATGTGTCTCTCTCTGATGAAGGACAGTACACCTGTTCTTT ATTTACAATGCCTGTCAAAACTTCCAAGGCATATCTCACCGTTCTGGGTGTTCCTGAAAAGCCTCAGA TTAGTGGATTCTCATCACCAGTTATGGAGGGTGACTTGATGCAGCTGACTTGCAAAACATCTGGTAGT AAACCTGCAGCTGATATAAGATGGTTCAAAAATGACAAAGAGATTAAAGATGTAAAATATTTAAAAGA AGAGGATCAAATCGCAAGACATTCACTGTCACCAGCACACTGGACTTCCGAGTGGACCGGAGTGATG ATGGAGTGGCGGTCATCTGCAGAGTAGATCACGAATCCCTCAATGCCACCCCTCAGGTAGCCATGCAG

GTGCTAGAAATACACTATACACCATCAGTTAAGATTATACCATCGACTCCTTTTCCACAAGAAGGACA

WO 2004/015079 PCT/US2003/024931 GCCTTTAATTTTGACTTGTGAATCCAAAGGAAAACCACTGCCAGAACCTGTTTTGTGGACAAAGGATG GCGGAGAATTACCAGATCCTGACCGAATGGTTGTGAGTGGTAGGGAGCTAAACATTCTTTTCCTGAAC

AAAACGGATAATGGTACATATCGATGTGAAGCCACAAACACCATTGGCCAAAGCAGTGCGGAATATGT

TCTCATTGTGCATGATCCTAATGCTTTGGCTGGC NOV3d, CG50586-03 SEQ ID NO: 16 306 aa MW at 33839.9kD Protein Sequence I SKGSQGQFPLTQNVTVVEGGTAILTCRVDQNDNTSLQWSNPAQQTLYFDDKKALRDNRIELVRAS WHELSISVSDVSLSDEGQYTCSLFTMPVKTSKAYLTVLGVPEKPQISGFSSPVMEGDLMQLTCKTSGS KPAADIRWFKNDKEIKDVKYLKEEDANRKTFTVSSTLDFRVDRSDDGVAVICRVDHESLNATPQVAMQ VLEIHYTPSVKIIPSTPFPQEGQPLILTCESKGKPLPEPVLWTKDGGELPDPDRMVVSGRELNILFLN KTDNGTYRCEATNTIGQSSAEYVLIVHDPNALAG A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in TAble 3B. Table 3B. Comparison of the NOV3 protein sequences. NOV3d 1 ---------------------- - K G F Q V T T 32 NOV3b 1 ------------------------------------------------- G LTCRVD---- - 11. NOV3a 1 --------------------- SKIIINVGQQPTNTVEGALCV 33 NOV3c 1 TGSTMIWKRSAVLRFYSVCGLLVQAAASKNKVKGSQGQFLNVEGA CR 60 NOV3d 33 QNDNTSLQWPAQQTL LRNILVRASWHL VD E T 92 NOV3b 12 71. NOV3a 34 93 NOV3c 61 120 NOV3d 93 T K A V P GF MEK PN 152 NOV3b 72 TMPKTSAYP M MPA lk 131 NOV3a 94 TPK KYTLVKMGF VEDMLNDK1lk153 NOV~c 121 T P K KA L V -- ---- ---- --- --- --- - --- --- ------ -D- ------- 135 NOV3d 153 212 NOV3b 132 191 NOV3a 154 DR C 213 NOV3c 136 -VYKEDNKFVSTDRDRDGAVCVHLAPVMQVLEIHYTP 194 NOV3d 213 SVKe 272 NOV3b 192 251 NOV3a 214 273 NOV3c 195 254 NOV3d 273 --- --- - - -- ---- - ------------- NOV3b 252 -- -- - - -------------------------- 2 NOV3a 274 LaKaEPDADT llNAEGSQVNA K L 333 NOV3a 255 314 NOV3b ( ID-NO:-12) NOV3a 334 __________________________________________OM_ 384 NOV3c 3SE ID3N5 NOV3a (SEQ ID NO: 10) NOV3b (SEQ ID NO: 12) NOV3c (SEQ ID NO: 14) NOV3d (SEQ ID NO: 16) Further analysis of th& NOV3c protein yielded the following properties shown in Table 3C. 5 Table 3C. Protein Sequence Properties NOV3a WO 2004/015079 PCT/US2003/024931 SignalP analysis: Cleavage site between pos. 28 and 29 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 9; pos.chg 2; neg.chg 0 H-r'egion: length 4; peak value -0.57 PSG score: -4.98 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -4.54 possible cleavage site: between 27 and 28 >> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 2 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood =-11.94 Transmembrane 299 - 315 PERIPHERAL Likelihood = 6.26 (at 183) ALOM score: -11.94 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 306 Charge difference: 3.5 C( 2.5) - N(-1.0) C > N: C-terminal side will be inside >>> Single TMS is located near the C-terminus >>> membrane topology: type Nt (cytoplasmic tail 1 to 298) MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 7.03 Hyd Moment (95): 5.62 G content: 4 D/E content: 1 S/T content: 9 Score: -2.29 Gavel: prediction of cleavage sites for mitochondrial preseq R-3 motif at 17 LRFYIS NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 9.6% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none SKL2: 2nd peroxisomal targeting signal: none WO 2004/015079 PCT/US2003/024931 VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 21 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues A search of the NOV3c protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3D. Table 3D. Geneseq Results for NOV3a NOV3a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region AAB61142 Human NOV12 protein - Homo 105 ... 362 236/262 (90%) 0.0 sapiens, 404 aa. [W0200075321- 143.. .404 240/262 (91%) A2, 14-DEC-2000] ABG66677 Human novel polypeptide #12 - 14.. .444 236/262 (90%) 0.0 Homo sapiens, 404 aa. 6...437 240/262 (91%) AAY33741 Beta-secretase - Homo sapiens, 105.. .286 159/187 (85%) 0.0 444 aa. 143...329 163/187 (87%) WO 2004/015079 PCT/US2003/024931 In a BLAST sea-ch of public sequence databases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3E. Table 3E. Public BLASTP Results for NOV3a Protein fNOV3a Identities/ Accession Protein/Organism/Length Residues/ Similarities for Expect Number Match the Matched Value Residues Portion CAC22523 Sequence 23 from Patent 105.. 362 236/262 (90%) 0.0 W00075321 - Homo sapiens 143.. 404 240/262 (91%) (Human), 404 aa. Q8BLQ9 Weakly similar to BK134P22.1 - 105.. .362 232/262 (88%) 0.0 Mus musculus (Mouse), 404 aa. 143...404 237/262 (90%) Q8BYP1 Weakly similar to BK134P22.1 - 105...362 232/262 (88%) 0.0 Mus musculus (Mouse), 404 aa. 143.. .404 237/262 (90%) 5 PFam analysis predicts that the NOV3c protein contains the domains shown in the Table 3F. Table 3F. Domain Analysis of NOV3a Pfam Domain NOV3a Match Region Score E-Value Amino acid residues of SEQ ID NO:10 ig 50 ... 119 26.1 0.00081 ig 208 ... 265 38.3 1.7e-07 A de n1o_--E3_CR1_ 211 ... 280 -120 -. 2_ 3. 13 111 Example 4. NOV4, CG50637, T-CELL SURFACE GLYCOPROTEIN CD1B PRECURSOR The NOV4 clone was analyzed, and the nucleotide and encoded polypeptide 10 sequences are shown in Table 4A. Table 4A. NOV4 Sequence Analysis NOV4a, CG50637-01 ISEQ ID NO: 17 11680 bp DNA Sequence ORF Start: ATG at 177 ORF Stop: TGA at 1656 TGACAGGCCGGCCGGTGAGGCGCCGCCGGGAGAGGCCGCGACGGAGCTCCCAGACCGGCCATGGGCTG AGACACGTCCTCGCCGAGCAGTGACCCTTCCGTACCCCACCAGAACATGCCCGGGTGACCTCCTCCCA GATCTTCCTTGTGGCCTTCCTCGCCCACTCCAGTGACACTATGCACCCCCACCGTGACCCGAGAGGCC TCTGGCTCCTGCTGCCGTCCTTGTCCCTGCTGCTTTTTGAGGTGGCCAGAGCTGGCCGAGCCGTGGTT AGCTGTCCTGCCGCCTGCTTGTGCGCCAGCAACATCCTCAGCTGCTCCAAGCAGCAGCTGCCCAATGT GCCCCATTCCTTGCCCAGTTACACAGCACTACTGGACCTCAGTCACAACAACCTGAGCCGCCTGCGGG CCGAGTGGACCCCCACGCGCCTGACCCAACTGCACTCCCTGCTGCTGAGCCACAACCACCTGAACTTC

ATCTCCTCTGAGGCCTTTTCCCCGGTACCCAACCTGCGCTACCTGGACCTCTCCTCCAACCAGCTGCG

WO 2004/015079 PCT/US2003/024931 TACACTGGATGAGTTCCTGTTCAGTGACCTGCAAGTACTGGAGGTGCTGCTGCTCTACAATAACCACA TCATGGCGGTGGACCGGTGCGCCTTCGATGACATGGCCCAGCTGCAGAAACTCTACTTGAGCCAGAAC CAGATCTCTCGCTTCCOTCTGGAACTGGTCAAGGAAGGAGCCAAGCTACCCAAACTAACGCTCCTGGA TCTCTCTTCTAACAAGCTGAAGAACTTGCCATTGCCTGACCTGCAGAAGCTGCCGGCCTGGATCAAGA ATGGGCTGTACCTACATAACAACCCCCTGAACTGCGACTGTGAGCTCTACCAGCTGTTTTCACACTGG CAGTATCGGCAGCTGAGCTCCGTGATGGACTTTCAAGAGGATCTGTACTGCATGAACTCCAAGAAGCT GCACAATGTCTTCAACCTGAGTTTCCTCAACTGTGGCGAGTACAAGGAGCGTGCCTGGGAGGCCCACC TGGGTGACACCTTGATCATCAAGTGTGACACCAAGCAGCAAGGGATGACCAAGGTGTGGGTGACACCA AGTAATGAACGGGTGCTAGATGAGGTGACCAATGGCACAGTGAGTGTGTCTAAGGATGGCAGTCTTCT TTTCCAGCAGGTGCAGGTCGAGGACGGTGGTGTGTATACCTGCTATGCCATGGGAGAGACTTTCAATG AGACACTGTCTGTGGAATTGAAAGTGCACAATTTCACCTTGCACGGACACCATGACACCCTCAACACA GCCTATACCACCCTAGTGGGCTGTATCCTTAGTGTGGTCCTGGTCCTCATATACCTATACCTCACCCC TTGCCGCTGCTGGTGCCGGGGTGTAGAGAAGCCTTCCAGCCATCAAGGAGACAGCCTCAGCTCTTCCA TGCTTAGTACCACACCCAACCATGATCCTATGGCTGGTGGGGACAAAGATGATGGTTTTGACCGGCGG GTGGCTTTCCTGGAACCTGCTGGACCTGGGCAGGGTCAAAACGGCAAGCTCAAGCCAGGCAACACCCT GCCAGTGCCTGAGGCCACAGGCAAGGGCCAACGGAGGATGTCGGATCCAGAATCAGTCAGCTCGGTCT TCTCTGATACGCCCATTGTGGTGTGAGCAGGATGGGTTGGTGGGAGA NOV4a, CG50637-01 SEQ ID NO: 18 493 aa MW at 55238.6kD Protein Sequence MHPHRDPRGLWLLPSLSLLLFEARAGRAVVSCPAACLCASNILSCSKQQLPNVPHSLPSYTALLDL SHLSRLRAEWTPTRLTQLHSLLLSHNHLNFISSEAFSPVPNLRYLDLSSNQLRTLDEFLFSDLQVL EVLLLYNNHIMAVDRCAFDDMAQLQKLYLSQNQISRFPLELVKEGAKLPKLTLLDLSSNKLKNLPLPD LQKLPAWIKNGLYLHNNPLNCDCELYQLFSHWQYRQLSSVMDFQEDLYCMNSKKLHNVFNLSFLNCGE YKERAWEAHLGDTLIIKCDTKQQGMTKVWVTPSNERVLDEVTNGTVSVSKDGSLLFQQVQVEDGGVYT CYAMGETFNETLSVELKVHNFTLHGHHDTLNTAYTTLVGCILSVVLVLIYLYLTPCRCWCRGVEKPSS HQGDSLSSSMLSTTPNHDPMAGGDKDDGFDRRVAFLEPAGPGQGQNGKLKPGNTLPVPEATGKGQRRM SDPESVSSVFSDTPIVV NOV4b, 277577082 SEQ ID NO: 19 1476 bp DNA Sequence iORi Start: at 1 ORF Stop: end of sequence ATGCACCCCCACCGTGACCCGAGAGGCCTCTGGCTCCTGCTG CCGTCCTTGTCCCTGCTGCTTTTTGAGGTGGCCAGAGCTGGCCGAGCCGTGGTTAGCTGTCCTGCCGC CTGCTTGTGCGCCAACATCCTCAGCTGCTCCAAGCAGCAGCTGCCCAATGTGCCCCATTCCTTGCCCA GTTACACAGCACTACTGGACCTCAGTCACAACAACCTGAGCCGCCTGCGGGCCGAGTGGACCCCCACG CGCCTGACCCAACTGCACTCCCTGCTGCTGAGCCACAACCACCTGAACTTCATCTCCTCTGAGGCCTT TTCCCCGGTACCCAACCTGCGCTACCTGGACCTCTCCTCCAACCAGCTGCGTACACTGGATGAGTTCC TGTTCAGTGACCTGCAAGTACTGGAGGTGCTGCTGCTCTACAATAACCACATCATGGCGGTGGACCGG TGCGCCTTCGATGACATGGCCCAGCTGCAGAAACTCTACTTGAGCCAGAACCAGATCTCTCGCTTCCC TCTGGAACTGGTCAAGGAAGGAGCCAAGCTACCCAAACTAACGCTCCTGGATCTCTCTTCTAACAAGC TGAAGAACTTGCCATTGCCTGACCTGCAGAAGCTGCCGGCCTGGATCAAGAATGGGCTGTACCTACAT AACAACCCCCTGAACTGCGACTGTGAGCTCTACCAGCTGTTTTCACACTGGCAGTATCGGCAGCTGAG CTCCGTGATGGACTTTCAAGAGGATCTGTACTGCATGAACTCCAAGAAGCTGCACAATGTCTTCAACC TGAGTTTCCTCAACTGTGGCGAGTACAAGGAGCGTGCCTGGGAGGCCCACCTGGGTGACACCTTGATC ATCAAGTGTGACACCAAGCAGCAAGGGATGACCAAGGTGTGGGTGACACCAAGTAATGAACGGGTGCT AGATGAGGTGACCAATGGCACAGTGAGTGTGTCTAAGGATGGCAGTCTTCTTTTCCAGCAGGTGCAGG TCGAGGACGGTGGTGTGTATACCTGCTATGCCATGGGAGAGACTTTCAATGAGACACTGTCTGTGGAA TTGAAAGTGCACAATTTCACCTTGCACGGACACCATCACACCCTCAACACAGCCTATACCACCCTAGT GGGCTGTATCCTTAGTGTGGTCCTGGTCCTCATATACCTATACCTCACCCCTTGCCGCTGCTGGTGCC GGGGTGTAGAGAAGCCTTCCAGCCATCAAGGAGACAGCCTCAGCTCTTCCATGCTTAGTACCACACCC AACCATGATCCTATGGCTGGTGGGGACAAAGATGATGGTTTTGACCGGCGGGTGGCTTTCCTGGAACC TGCTGGACCTGGGCAGGGTCAAAACGGCAAGCTCAAGCCAGGCAACACCCTGCCAGTGCCTGAGGCCA CAGGCAAGGGCCAACGGAGGATGTCGGATCCAGAATCAGTCAGCTCGGTCTTCTCTGATACGCCCATT GTGGTG NOV4b,7/7577082 SEQ ID NO: 20 492 aa MW at 56294.8kD Protein Sequence 1 PHRDPRGLWLLLPSLSLLLFEVARAGRAVVSCPAACLCANILSCSKQQLPNVPHSLPS YTALLDLSHNNLSRLRAEWTPTRLTQLHSLLLSHNHNFISSEAFSPVPNLRYLDLSSNQLRTLDEFL FSDLQVLEVLLLYNNHIMAVDRCAFDDMAQLQKLYLSQNQISRFPLELVKEGAKLPKLTLLDLSSNKL KNLPLPDLQKLPAWIKNGLYLHNNPLNCDCELYQLFSHWQYRQLSSVMDFQEDLYCMNSKKLHNVFNL SFLNCGEYKERAWEAHLGDTLIIKCDTKQQGMTKVWVTPSNERVLDEVTNGTVSVSKDGSLLFQQVQV EDGGVYTCYAMGETFNETLSVELKVHNFTLHGHHDTLNTAYTTLVGCILSVVLVLIYLYLTPCRCWCR GVEKPSSHQGDSLSSSMLSTTPNHDPMAGGDKDDGFDRRVAFLEPAGPGQGQNGKLKPGNTLPVPEAT GKGQRRMSDPESVSSVFSDTPIVV SEQID NO: 21 1398 bp WO 2004/015079 PCT/US2003/024931 NOV4c, 277577094 SEQ ID NO: 21 1398 bp DNA Sequence NOV4c, 277577094 ORF Start: at 1 ORF Stop: end of sequence DNA Se quence GGCCGAGCCGTGGTTAGCTGTCCTGCCGCCTGCTTGTGCGCCAGCAACATCCTCAGCT GCTCCAAGCAGCAGCTGCCCAATGTGCCCCATTCCTTGCCCAGTTACACAGCACTACTGGACCTCAGT CACAACAACCTGAGCCGCCTGCGGGCCGAGTGGACCCCCACGCGCCTGACCCAACTGCACTCCCTGCT GCTGAGCCACAACCACCTGAACTTCATCTCCTCTGAGGCCTTTTCCCCGGTACCCAACCTGCGCTACC TGGACCTCTCCTCCAACCAGCTGCGTACACTGGATGAGTTCCTGTTCAGTGACCTGCAAGTACTGGAG GTGCTGCTGCTCTACAATAACCACATCATGGCGGTGGACCGGTGCGCCTTCGATGACATGGCCCAGCT GCAGAAACTCTACTTGAGCCAGAACCAGATCTCTCGCTTCCCTCTGGAACTGGTCAAGGAAGGAGCCA AGCTACCCAAACTAACGCTCCTGGATCTCTCTTCTAACAAGCTGAAGAACTTGCCATTGCCTGACCTG CAGAAGCTGCCGGCCTGGATCAAGAATGGGCTGTACCTACATAACAACCCCCTGAACTGCGACTGTGA GCTCTACCAGCTGTTTTCACACTGGCAGTATCGGCAGCTGAGCTCCGTGATGGACTTTCAAGAGGATC TGTACTGCATGAACTCCAAGAAGCTGCACAATGTCTTCAACCTGAGTTTCCTCAACTGTGGCGAGTAC AAGGAGCGTGCCTGGGAGGCCCACCTGGGTGACACCTTGATCATCAAGTGTGACACCAAGCAGCAAGG GATGACCAAGGTGTGGGTGACACCAAGTAATGAACGGGTGCTAGATGAGGTGACCAATGGCACAGTGA GTGTGTCTAAGGATGGCAGTCTTCTTTTCCAGCAGGTGCAGGTCGAGGACGGTGGTGTGTATACCTGC TATGCCATCGCAGAGACTTTCAATGAGACACTGTCTGTGGAATTGAAAGTGCACAATTTCACCTTGCA CGGACACCATGACACCCTCAACACAGCCTATACCACCCTAGTGGGCTGTATCCTTAGTGTGGTCCTGG TCCTCATATACCTATACCTCACCCCTTGCCGCTGCTGGTGCCGGGGTGTAGAGAAGCCTTCCAGCCAT CAAGGAGACAGCCTCAGCTCTTCCATGCTTAGTACCACACCCAACCATGATCCTATGGCTGGTGGGGA CAAAGATGATGGTTTTGACCGGCGGGTGGCTTTCCTGGAACCTGCTGGACCTGGGCAGGGTCAAAACG GCAAGCTCAAGCCAGGCAACACCCTGCCAGTGCCTGAGGCCACAGGCAAGGGCCAACGGAGGATGTCG GATCCAGAATCAGTCAGCTCGGTCTTCTCTGATACGCCCATTGTGGTG NOV4c, 277577094 SEQ ID NO: 22 466 aa AMW at 52731.6kD Protein Sequence GRAVVSCPAACLCASNILSCSKQQLPNVPHSLPSYTALLDLSHNNLSRLRAEWTPTRLTQLHSLL LSHNHLNFISSEAFSPVPNLRYLDLSSNQLRTLDEFLFSDLQVLEVLLLYNNHIAVDRCAFDDMAQL QKLYLSQNQISRFPLELVKEGAKLPKLTLLDLSSNKLKNLPLPDLQKLPAWIKNGLYLHNNPLNCDCE LYQLFSHWQYRQLSSVMDFQEDLYCMNSKKLHNVFNLSFLNCGEYK.ERAWEAHLGDTLIIKCDTKQQG MTKVWVTPSNERVLDEVTNGTVSVSKDGSLLFQQVQVEDGGVYTCYAMGETFNETLSVELKVHNFTLH GHHDTLNTAYTTLVGCILSVVLVLIYLYLTPCRCWCRGVEKPSSHQGDSLSSSMLSTTPNHDPMAGGD KDDGFDRRVAFLEPAGPGQGQNGKLKPGNTLPVPEATGKGQRRMSDPESVSSVFSDTPIVV SEQ ID NO: 23 717 bp ORF Start: at 1 ORF Stop: end of sequence AGCTGTCCTGCCGCCTGCTTGTGCGCCAGCAACATCCTCAGCTGCTCCAAGCAGCAGC TGCCCAATGTGCCCCATTCCTTGCCCAGTTACACAGCACTACTGGACCTCAGTCACAACAACCTGACC CGCCTGCGGGCCGAGTGGACCCCCACGCGCCTGACCCAACTGCACTCCCTGCTGCTGAGCCACAACCA CCTGAACTTCATCTCCTCTGAGCCCTTTTCCCCGGTACCCAACCTGCGCTACCTGGACCTCTCCTCCA ACCAGCTGCGTACACTGGATGAGTTCCTGTTCAGTGACCTGCAAGTACTGGAGGTGCTGCTGCTCTAC AATAACCACATCATGGCGGTGGACCGGTGCGCCTTCGATGACATGGCCCAGCTGCAGAAACTCTACTT GAGCCAGAACCAGATCTCTCGCTTCCCTCTGGAACTGGTCAAGGAAGGAGCCAAGCTACCCAAACTAA CGCTCCTGGATCTCTCTTCTAACAAGCTGAAGAACTTGCCATTGCCTGACCTGCAGAAGCTGCCGGCC TGGATCAAGAATGGGCTGTACCTACATAACAACCCCCTGAACTGCGACTGTGAGCTCTACCAGCTGTT TTCACACTGGCAGTATCGGCAGCTGAGCTCCGTGATGGACTTTCAAGAGGATCTGTACTGCATGAACT CCAAGAAGCTGCACAATGTCTTCAACCTGAGTTTCCTCAACTGTGGC NOV4d, 277577141 SEQ ID NO: 24 239 aa MW at 28046.9kD Protein Sequence SCPAACLCASNILSCSKQQLPNVPHSLPSYTALLDLSHNNLSRLRAEWTPTRLTQLHSLLLSHNH LNFISSEAFSPVPNLRYLDLSSNQLRTLDEFLFSDLQVLEVLLLYNNHIMAVDRCAFDDMAQLQKLYL SQNQISRFPLELVKEGAKLPKLTLLDLSSNKLKNLPLPDLQKLPAWIKNGLYLHNNPLNCDCELYQLF SHWQYRQLSSVMDFQEDLYCMNSKKLHNVFNLSFLNCG A ClustalW comparison of the above protein sequences yields the following 5 sequence alignment shown in Table 4B. Table 4B. Comparison of the NOV4 protein sequences.

WO 2004/015079 PCT/US2003/024931 NOV4a MHPHRDPRGLWLLLPSLSLLLFEVARAGRAVVSCPAACLCASNILSCSKQQL NOV4b MHPHRDPRGLWLLLPSLSLLLFEVARAGRAVVSCPAACLCA-NILSCSKQQL NOV4c --------------------------- GRAVVSCPAACLCASNILSCSKQQL NOV4d -------------------------------- SCPAACLCASNILSCSKQQL NOV4a PNVPHSLPSYTALLDLSHNNLSRLRAEWTPTRLTQLHSLLLSHNHLNFISSEAFSPVPNL NOV4b PNVPHSLPSYTALLDLSHNNLSRLRAEWTPTRLTQLHSLLLSHNHLNFISSEAFSPVPNL NOV4c PNVPHSLPSYTALLDLSHNNLSRLRAEWTPTRLTLHSLLLSHNHLNFISSEAFSPVPNL NOV4d PNVPHSLPSYTALLDLSHNNLSRLRAEWTPTRLTQLHSLLLSHNHLNFISSEAFSPVPNL NOV4a RYLDLSSNQLRTLDEFLFSDLQVLEVLLLYNNHIMAVDRCAFDDMAQLQKLYLSQNQISR NOV4b RYLDLSSNQLRTLDEFLFSDLQVLEVLLLYNNHIMAVDRCAFDDMAQLQKLYLSQNQISR NOV4c RYLDLSSNQLRTLDEFLFSDLQVLEVLLLYNNHIMAVDRCAFDDMAQLQKLYLSQNQISR NOV4d RYLDLSSNQLRTLDEFLFSDLQVLEVLLLYNNHIMAVDRCAFDDMAQLQKLYLSQNQISR NOV4a FPLELVKEGAKLPKLTLLDLSSNKLKNLPLPDLQKLPAWIKNGLYLHNNPLNCDCELYQL NOV4b FPLELVKEGAKLPKLTLLDLSSNKLKNLPLPDLQKLPAWIKNGLYLHNNPLNCDCELYQL NOV4c FPLELVKEGAKLPKLTLLDLSSNKLKNLPLPDLQKLPAWIKNGLYLHNNPLNCDCELYQL NOV4d FPLELVKEGAKLPKLTLLDLSSNKLKNLPLPDLQKLPAWIKNGLYLHNNPLNCDCELYQL NOV4a FSHWQYRQLSSVMDFQEDLYCMNSKKLHNVFNLSFLNCGEYKERAWEAHLGDTLIIKCDT NOV4b FSHWQYRQLSSVMDFQEDLYCMNSKKLHNVFNLSFLNCGEYKERAWEAHLGDTLIIKCDT NOV4c FSHWQYRQLSSVDFQEDLYCMNSKKLHNVFNLSFLNCGEYKERAWEAHLGDTLIIKCDT NOV4d FSHWQYRQLSSVMDFQEDLYCMNSKKLHNVFNLSFLNCG-------------------- NOV4a KQQGMTKVWVTPSNERVLDEVTNGTVSVSKDGSLLFQQVQVEDGGVYTCYAMGETFNETL NdV4b KQQGMTKVWVTPSNERVLDEVTNGTVSVSKDGSLLFQQVQVEDGGVYTCYAMGETFNETL NOV4c KQQGMTKVWVTPSNERVLDEVTNGTVSVSKDGSLLFQQVQVEDGGVYTCYAMGETFNETL NOV4d

---

~-- - ~~-~ NOV4a SVELKVHNFTLHGHHDTLNTAYTTLVGCILSVVLVLIYLYLTPCRCWCRGVEKPSSHQGD NOV4b SVELKVHNFTLHGHHDTLNTAYTTLVGCILSVVLVLIYLYLTPCRCWCRGVEKPSSHQGD NOV4c SVELKVHNFTLHGHHDTLNTAYTTLVGCILSVVLVLIYLYLTPCRCWCRGVEKPSSHQGD NOV4d ---------------------- ~-~ NOV4a SLSSSMLSTTPNHDPMAGGDKDDGFDRRVAFLEPAGPGQGQNGKLKPGNTLPVPEATGKG NOV4b SLSSSMLSTTPNHDPMAGGDKDDGFDRRVAFLEPAGPGQGQNGKLKPGNTLPVPEATGKG NOV4c SLSSSMLSTTPNHDPMAGGDKDDGFDRRVAFLEPAGPGQGQNGKLKPGNTLPVPEATGKG NOV4d

------------

~~~~~~-~ NOV4a QRRMSDPESVSSVFSDTPIVV NOV4b QRRMSDPESVSSVFSDTPIVV NOV4c QRRMSDPESVSSVFSDTPIVV NOV4d ------------------- ~~ NOV4a (SEQ ID NO: 18) NOV4b (SEQ ID NO: 20) NOV4c (SEQ ID NO: 22) NOV4d (SEQ ID NO: 24) Further analysis of the NOV4a protein yielded the following properties shown in Table 4C. Table 4C. Protein Sequence Properties NOV4a SignalP analysis: Cleavage site between residues 35 and 36.

WO 2004/015079 PCT/US2003/024931 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 5; pos.chg 1; neg.chg 0 H-region: length 7; peak value -5.92 PSG score: -10.32 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -0.90 possible cleavage site: between 35 and 36 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 3 INTEGRAL Likelihood = -2.28 Transmembrane 17 - 33 INTEGRAL Likelihood = -2.18 Transmembrane 38 - 54 INTEGRAL Likelihood =-10.83 Transmembrane 384 - 400 PERIPHERAL Likelihood = 2.44 (at 132) ALOM score: -10.83 (number of TMSs: 3) MTOP: Prediction of membrane topology (Hartmann etaal.) Center position for calculation: 24' Charge difference: -2.0 C( 1.0) - N( 3.0) N >= C: N-terminal side will be inside >>> membrane topology: type 3a MITDISC: discrimination of mitochondrial targeting seq R content: 2 Hyd Moment(75): 5.88 Hyd Moment(95): 6.17 q content: 1 D/E content: 2 S/T content: 5 Score: -4.21 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 47 GRA|W NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 8.5% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none SKL2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: found KLPK at 190 WO 2004/015079 PCT/US2003/024931 RNA-binding mot if : none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: Leucine zipper pattern (PS00029): *** found *** LSCSKQQLPNVPHSLPSYTALL at 52 LDLSSNQLRTLDEFLFSDLQVL at 122 LKVHNFTLHGHHDTLNTAYTTL at 363 none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytplasmic/Nuclear discrimination Prediction: nuclear Reliability: 55.5 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4D. Table 4D. Geneseq Results for NOV4a NOV4a Identities/ Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region AAB49650 Human SEC2 protein sequence SEQ 9..500 492/493 (99%) 0.0 ID 4 - Homo sapiens, 493 aa. 1..493 492/493 (99%) [W0200070046-A2, 23-NOV-2000] ABJ10921 Human secreted protein (SECP) #17 9..500 492/493 (99%) 0.0 - Homo sapiens, 493 aa. 1..493 492/493 (99%) WO 2004/015079 PCT/US2003/024931 ABB17119 Human nervous system related 158.335 177/178 (99%) 0.0 polypeptide SEQ ID NO 5776 - 27.204 177/178 (99%) Homo sapiens, 212 aa. [W0200159063-A2, 16-AUG-2001] In a BLAST search of public sequence databases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4E. Table 4E. Public BLASTP Results for NOV4a NOV4a Identities/ Protein Residues/ Similarities for Expect Accessio otein/Organism/Length Match the Matched Value Residues Portion Q86WK6 Transmembrane protein AMIGO 9.. .500 492/493 (99%) 0.0 - Homo sapiens (Human), 493 aa. 1...493 492/493 (99%) Q81W71 Hypothetical protein - Homo 9..500 491/493 (99%) 0.0 sapiens (Human), 493 aa. 1..493 493/493 (99%) Q8ZD8 Transmembrane protein AMIGO 9..500 440/492 (89%) 0.0 Mus musculus (Mouse), 492 aa. L.492 463/492 (94%) PFam analysis predicts that the NOV4a protein contains the domains shown in the 5 Table 4F. Table 4F. Domain Analysis of NOV4a NOV4a Match Region Pfam Domainf Amino acid residues of SEQ ID NO:18 Score E-Value LRRNT 41..67 11.6 1.2 LRR 69..91 4.2 3e+02 LRR 94..117 15.4 1.3 LRR 118..141 23.4 0.0053 LRR 142..165 8.3 78 LRR 166..185 11.2 24 LRR 193..216 19.3 0.093 LRRCT 228..278 30.0 5.6e-05 Ig 290. .350 20.7 0.036 WO 2004/015079 PCT/US2003/024931 Example 5. NOV5, CG51117-09, Nephronectin The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 5A. Table 5A. NOV5 Sequence Analysis NOVa, 306433917 SEQ ID NO: 5 1413bp DNA Sequence __ _0F Start: at 1p: end of sequence TGCCAACCACGATGCAAACATGGTGAATGTATCGGGCCAAACAAGTGCAAGTGTCATC CTGGTTATGCTGGAAAAACCTGTAATCAAGATCTAAATGAGTGTGGCCTGAAGCCCCGGCCCTGTAAG CACAGGTGCATGAACACTTACGGCAGCTACAAGTGCTACTGTCTCAACGGATATATGCTCATGCCGGA TGGTTCCTGCTCAAGTGCCCTGACCTGCTCCATGGCAAACTGTCAGTATGGCTGTGATGTTGTTAAAG GACAAATACGGTGCCAGTGCCCATCCCCTGGCCTGCAGCTGGCTCCTGATGGGAGGACCTGTGTAGAT GTTGATGAATGTGCTACAGGAAGAGCCTCCTGCCCTAGATTTAGGCAATGTGTCAACACTTTTGGGAG CTACATCTGCAAGTGTCATAAAGGCTTCGATCTCATGTATATTGGAGACATAGACGAATGCTCACTTG GTCAGTATCAGTGCAGCAGCTTTGCTCGATGTTATAACGTACGTGGGTCCTACAAGTGCAAATGTAAA GAAGGATACCAGGGTGATGGACTGACTTGTGTGTATATCCCAAAAGTTATGATTGAACCTTCAGGTCC AATTCATGTACCAAAGGGAAATGGTACCATTTTAAAGGGTGACACAGGAAATAATAATTGGATTCCTG ATGTTGGAAGTACTTGGTCGCCTCCGAAGACACCATATATTCCTCCTATCATTACCAACAGGCCTACT TCTAAGCCAACAACAAGACCTACACCAAAGCCAACACCAATTCCTACTCCACCACCACCACCACCCCT GCCAACAGAGCTCAGAACACCTCTACCACCTACAACCCCAGAAAGGCCAACCACCGGACTGACAACTA TAGCACCAGCTGCCAGTACACCTCCAGGAGGGATTACAGTTGACAACAGGGTACAGACAGACCCTCAG AAACCCAGAGGAGATGTGTTCAGTGTTCTGGTACACAGTTGTAATTTTGACCATGGACTTTGTGGATG GATCAGGGAGAAAGACAATGACTTGCACTGGGAACCAATCAGGGACCCAGCAGGTGGACAATATCTGA CAGTGTCGGCAGCCAAAGCCCCAGGGGGAAAAGCTGCACGCTTGGTGCTACCTCTCGGCCGCCTCATG CATTCAGGGGACCTGTGCCTGTCATTCAGGCACAAGGTGACGGGGCTGCACTCTGGCACACTCCAGGT GTTTGTGAGAAAACACGGTGCCCACGGAGCAGCCCTGTGGGGAAGAAATGGTGGCCATGGCTGGAGGC AAACACAGATCACCTTGCGAGGGGCTGACATCAAGAGCGTCGTCTTCAAAGGTGAAAAAAGGCGTGGT CACACTGGGGAGATTGGATTAGATGATGTGAGCTTGAAAAAAGCCCACTGCTCTGAAGAACGC NOV5a, 306433917 SEQ ID NO: 26 ,471 aa |MW at 51775.8kD Protein Sequence CQPRCKHGECIGPNKCKCHPGYAGKTCNQDLNECGLKPRPCKHRCMNTYGSYKCYCLNGYMLMPD GSCSSALTCSMANCQYGCDVVKGQIRCQCPSPGLQLAPDGRTCVDVDECATGRASCPRFRQCVNTFGS YICKCHKGFDLMYIGDIDECSLGQYQCSSFARCYNVRGSYKCKCKEGYQGDGLTCVYIPKVMIEPSGP IHVPKGNGTILKGDTGNNNWIPDVGSTWWPPKTPYIPPIITNRPTSKPTTRPTPKPTPIPTPPPPPPL PTELRTPLPPTTPERPTTGLTTIAPAASTPPGGITVDNRVQTDPQKPRGDVFSVLVHSCNFDHGLCGW IREKDNDLHWEPIRDPAGGQYLTVSAAKAPGGKAARLVLPLGRLMHSDLCLSFRHKVTGLHSGTLQV FVRKHGAHGAALWGRNGGHGWRQTQITLRGADIKSVVFKGEKRRGHTGEIGLDDVSLKKGHCSEER NOV5b, 306447063 SEQ ID NO: 27 1743 bp DNA Sequence IORF Start: at 1 JORF Stop: end of sequence ATGGATTTTCTCCTGGCGCTGGTGCTGGTATCCTCGCTC TACCTGCAGGCCGCCGCCGAGTTCGACGGGAGTAGGTGGCCCAGGCAAATAGTGTCATCGATTGGCCT ATGTCGTTATGGTGGGAGGATTGACTGCTGCTGGGGCTGGGCTCGCCAGTCTTGGGGACAGTGTCAGC CTTTCTACGTCTTAAGGCAGAGAATAGCCAGGATAAGGTGCCAGCTCAAAGCTGTGTGCCAACCACGA TGCAAACATGGTGAATGTATCGGGCCAAACAAGTGCAAGTCTCATCCTGGTTATGCTGGAAAAACCTG TAATCAAGATCTAAATGAGTGTGGCCTGAAGCCCCGGCCCTGTAAGCACAGGTGCATGAACACTTACG GCAGCTACAAGTGCTACTGTCTCAACGGATATATGCTCATGCCGGATGGTTCCTGCTCAAGTGCCCTG ACCTGCTCCATGGCAAACTGTCAGTATGGCTGTGATGTTGTTAAAGGACAAATACGGTGCCAGTGCCC ATCCCCTGGCCTGCAGCTGGCTCCTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAGGAA GAGCCTCCTGCCCTAGATTTAGGCAATGTGTCAACACTTTTGGGAGCTACATCTGCAAGTGTCATAAA GGCTTCGATCTCATGTATATTGGAGGCAAATATCAATGTCATGACATAGACGAATGCTCACTTGGTCA GTATCAGTGCAGCAGCTTTGCTCGATGTTATAACGTACGTGGGTCCTACAAGTGCAAATGTAAAGAAG GATACCAGGGTGATGGACTGACTTGTGTGTATATCCCAAAAGTTATGATTGAACCTTCAGGTCCAATT CATGTACCAAAGGGAAATGGTACCATTTTAAAGGGTGACACAGAAATAATAATTGGATTCCTGATGT TGGAAGTACTTGGTGGCCTCCGAAGACACCATATATTCCTCCTATCATTACCAACAGGCCTACTTCTA AGCCAACAACAAGACCTACACCAAAGCCAACACCAATTCCTACTCCACCACCACCACCACCCCTGCCA ACAGAGCTCAGAACACCTCTACCACCTACAACCCCAGAAAGGCCAACCACCGGACTGACAACTATAGC ACCAGCTGCCAGTACACCTCCAGGAGGGATTACAGTTGACAACAGGGTACAGACAGACCCTCAGAAAC CCAGAGGAGATGTGTTCATTCCACGGCAACCTTCAAATGACTTGTTTGAAATATTTGAAATAGAAAGA GGAGTCAGTGCAGACGATGAAGCAAAGGATGATCCAGGTGTTCTGGTACACAGTTGTAATTTTGACCA

TGGACTTTGTGGATGGATCAGGGAGAAAGACAATGACTTGCACTGGGAACCAATCAGGGACCCAGCAG

WO 2004/015079 PCT/US2003/024931 GTGGACAATATCTGACAGTGTCGGCAGCCAANGCCCCAGGGGGAAAAGCTGCACGCTTGGTGCTACCT CTCGGCCGCCTCATGCATTCAGGGGACCTGTGCCTGTCATTCAGGCACAAGGTGACGGGGCTGCACTC TGGCACACTCCAGGTGTTTGTGAGAAAACACGGTGCCCACGGAGCAGCCCTGTGGGGAAGAAATGGTG GCCATGGCTGGAGGCAAACACAGATCACCTTGCGAGGGGCTGACATCAAGAGCGTCGTCTTCAAAGGT GAAAAAAGGCGTGGTCACACTGGGGAGATTGGATTAGATGATGTGAGCTTGAAAAAAGGCCACTGCTC TGAA iDFLLALVLVSSLYLQAAAEFDGSRRIVSSIGLCRYGGRIDCCWGWARQSWGQCQP FYVLRQRIARIRCQLKAVCQPRCKHGECIGPNKCKCHPGYAGKTCNQDLNECGLKPRPCKHRCMNTYG SYKCYCLNGYMLMPDGSCSSALTCSMANCQYGCDVVKGQIRCQCPSPGLQLAPDGRTCVDVDECATGR ASCPRFRQCVNTFGSYICKCHKGFDLYIGGKYQCHDIDECSLGQYQCSSFARCYNVRGSYKCKCKEG YQGDGLTCVYIPKVMIEPSGPIHVPKGNGTILKGDTGNNNWIPDVGSTWWPPKTPYIPPIITNRPTSK PTTRPTPKPTPIPTPPPPPPLPTELRTPLPPTTPERPTTGLTTIAPAASTPPGGITVDNRVQTDPQKP RGDVFIPRQPSNDLFEIFEIERGVSADDEAKDDPGVLVHSCNFDHGLCGWIREKDNDLHWEPIRDPAG GQYLTVSAAKAPGGKAARLVL PLGRLMHSGDLCLSFRHKVTGLHSGTLQVFVRKHGAHGAALWGRNGG HGWRQTQITLRGADIKSVVFKGEKRRGHTGEIGLDDVSLKKGHCSE NOV5c, 306447071 SEQ ID NO: 29 1689 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence ATGGATTTTCTCCTGGCGCTGGTGCTGGTATCCTCGCTCTACCTGCAGGCGGCCGCCG AGTTCGACGGGAGGTGGCCCAGGCAAATAGTGTCATCGATTGGCCTATGTCGTTATGGTGGGAGGATT GACTGCTGCTGGGGCTGGGCTCGCCAGTCTTGGGGACAGTGTCAGCCTGTGTGCCAACCACGATGCAA ACATGGTGAATGTATCGGGCCAAACAAGTGCAAGTGTCATCCTGGTTATGCTGGAAAAACCTGTAATC AAGATCTAAATGAGTGTGGCCTGAAGCCCCGGCCCTGTAAGCACAGGTGCATGAACACTTACGGCAGC TACAAGTGCTACTGTCTCAACGGATATATGCTCATGCCGGATGGTTCCTGCTCAAGTGCCCTGACCTG CTCCATGGCAAACTGTCAGTATGGCTGTGATGTTGTTAAAGGACAAATACGGTGCCAGTGCCCATCCC CTGGCCTGCACCTGGCTCCTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAGGAAGAGCC TCCTGCCCTAGATTTAGGCAATGTGTCAACACTTTTGGGAGCTACATCTGCAAGTGTCATAAAGGCTT CGATCTCATGTATATTGGAGGCAAATATCAATGTCATGACATAGACGAATGCTCACTTGGTCAGTATC AGTGCAGCAGCTTTGCTCGATGTTATAACGTACGTGGGTCCTACAAGTGCAAATGTAAAGAAGGATAC CAGGGTGATGGACTGACTTGTGTGTATATCCCAAAAGTTATGATTGAACCTTCAGGTCCAATTCATGT ACCAAAGGGAAATGGTACCATTTTAAAGGGTGACACAGGAAATAATAATTGGATTCCTGATGTTGGAA GTACTTGGTGGCCTCCGAAGACACCATATATTCCTCCTATCATTACCAACAGGCCTACTTCTAAGCCA ACAACAAGACCTACACCAAAGCCAACACCAATTCCTACTCCACCACCACCACCACCCCTGCCAACAGA GCTCAGAACACCTCTACCACCTACAACCCCAGAAAGGCCAACCACCGGACTGACAACTATAGCACCAG CTGCCAGTACACCTCCAGGAGGGATTACAGTTGACAACAGGGTACAGACAGACCCTCAGAAACCCAGA GGAGATGTGTTCATTCCACGGCAACCTTCAAATGACTTGTTTGAAATATTTGA G CAGTGCAGACGATGAAGCAAAGGATGATCCAGGTGTTCTGGTACACAGTTGTAATTTTGACCATGGAC TTTGTGGATGGATCAGGGAGAAAGACAATGACTTGCACTGGGAACCAATCAGGGACCCAGCAGGTGGA CAATATCTGACAGTGTCGGCAGCCAAAGCCCCAGGGGGAAAAGCTGCACGCTTGGTGCTACCTCTCGG CCGCCTCATGCATTCAGGGGACCTGTGCCTGTCATTCAGGCACAAGGTGACGGGGCTGCACTCTGGCA CACTCCAGGTGTTTGTGAGAAAACACGGTGCCCACGGAGCAGCCCTGTGGGGAAGAAATGGTGGCCAT GGCTGGAGGCAAACACAGATCACCTTGCGAGGGGCTGACATCAAGAGCGTCGTCTTCAAAGGTGAAAA AAGGCGTGGTCACACTGGGGAGATTGGATTAGAGATGTAGCTTGAAAAAAGGCCACTGCTCTGAA NOV5c, 306447071 SEQ ID NO: 30 563 aa MW at 62132.5kD Protein Sequence MDFLLALVLVSSLYLQAAAEFDGRWPRQIVSSIGLCRYGGRIDCCWGWARQSWGQCQPVCQPRCK HGECIGPNKCKCHPGYAGKTCNQDLNECGLKPRPCKHRCMNTYGSYKCYCLNGYMLMPDGSCSSALTC SMANCQYGCDVVKGQIRCQCPSPGLHLAPDGRTCVDVDECATGRASCPRFRQCVNTFGSYICKCHKGF DLMYIGGKYQCHDIDECSLGQYQCSSFARCYNVRGSYKCKCKEGYQGDGLTCVYIPKVMIEPSGPIHV PKGNGTILKGDTGNNNWIPDVGSTWWPPKTPYIPPIITNRPTSKPTTRPTPKPTPIPTPPPPPPLPTE LRTPLPPTTPERPTTGLTTIAPAASTPPGGITVDNRVQTDPQKPRGDVFIPRQPSNDLFEIFEIERGV SADDEAKDDPGVLVHSCNFDHGLCGWIREKDNDLHWEPIRDPAGGQYLTVSAAKAPGGKAARLVLPLG RLMHSGDLCLSFRHKVTGLHSGTLQVFVRKHGAHGAALWGRNGGHGWRQTQITLRGADIKSVVFKGEK RRGHTGEIGLDDVSLKKGHCSE NOV5d, 306447075 SEQ ID NO: 31 1740 bp DNA Sequence ORF Start: at 1 ORE Stop: end of sequence ATGGATTTTCTCCTGGCGCTGGTGCTGGTATCCTCGCTCTACCTGCAGGCGGCCGCCG AGTTCGACGGGAGGTGGCCCAGGCAAATAGTGTCATCGATTCGCCTATGTCGTTATGGTGGGAGGATT GACTGCTGCTGGGGCTGGGCTCGCCAGTCTTGGGGACAGTGTCAGCCTTTCTACGTCTTAAGGCAGAG AATAGCCAGGATAAGGTGCCAGCTCAAAGCTGTCTGCCAACCACGATGCAAACATGGTGAATGTATCG GGCCAAACAAGTGCAAGTGTCATCCTGGTTATGCTGGAAAAACCTGTATC ATCT TGAGTG WO 2004/015079 PCT/US2003/024931 GGCCTGAAGCCCCGGCCCTGTAAGCACAGGTGCATGAACACTTACGGCAGCTACAAGTGCTACTGTCT CAACGGATATATGCTCATGCCGGATGGTTCCTGCTCAAGTGCCCTGACCTGCTCCATGGCAAACTGTC AGTATGGCTGTGATGTTGTTAAAGGACAAATACGGTGCCAGTGCCCATCCCCTGGCCTGCAGCTGGCT CCTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAGGAAGAGCCTCCTGCCCTAGATTTAG CCAATGTGTCAACACTTTTGGGAGCTACATCTGCAAGTGTCATAAAGGCTTCGATCTCATGTATATTG GAGGCAAATATCAATGTCATGACATAGACGAATGCTCACTTGGTCAGTATCAGTGCAGCACCTTTGCT CGATGTTATAACGTACGTGGGTCCTACAAGTGCAAATGTAAAGAAGGATACCAGGGTGATGGACTGAC TTGTGTGTATATCCCAAAAGTTATGATTGAACCTTCAGGTCCAATTCATGTACCAAAGGGAAATGGTA CCATTTTAAAGGGTGACACAGGAAATAATAATTGGATTCCTGATGTTGGAAGTACTTGGTGGCCTCCG AAGACACCATATATTCCTCCTATCATTACCAACAGGCCTACTTCTAAGCCAACAACAAGACCTACACC AAAGCCAACACCAATTCCTACTCCACCACCACCACCACCCCTGCCAACAGAGCTCAGAACACCTCTAC CACCTACAACCCCAGAAAGGCCAACCACCGGACTGACAACTATAGCACCAGCTGCCAGTACACCTCCA GGAGGGATTACAGTTGACAACAGGGTACAGACAGACCCTCAGAAACCCAGAGGAGATGTGTTCATTCC ACGGCAACCTTCAAATGACTTGTTTGAAATATTTGAAATAGAAAGAGGAGTCAGTGCAGACGATGAAG CAAAGGATGATCCAGGTGTTCTGGTACACAGTTGTAATTTTGACCATGGACTTTGTGGATGGATCAGG GAGAAAGACAATGACTTGCACTGGGAACCAATCAGGGACCCAGCAGGTGGACAATATCTGACAGTGTC GGCAGCCAAAGCCCCAGGGGGAAAAGCTGCACGCTTGGTGCTACCTCTCGGCCGCCTCATGCATTCAG GGGACCTGTGCCTGTCATTCAGGCACAAGGTGACGGGGCTGCACTCTGGCACACTCCAGGTGTTTGTG AGAAAACACGGTGCCCACGGAGCAGCCCTGTGGGGAAGAAATGGTGGCCATGGCTGGAGGCAAACACA GATCACCTTGCGAGGGGCTGACATCAAGAGCGTCGTCTTCAAAGGTGAAAAAAGGCGTGGTCACACTG GGGAGATTGGATTAGATGATGTGAGCTTGAAAAAAGGCCACTGCTCTGAA NOV5d, 306447075 SEQ ID NO: 32 1586 aa 1MW at 64240.OkD Protein Sequence MDFLLALVLVSSLYLQAAAEFDGRWPRQIVSSIGLCRYGGRIDCCWGWARQSWGQCQPFYVLRQR IARIRCQLKAVCQPRCKHGECIGPNKCKCHPGYAGKTCNQDLNECGLKPRPCKHRCMNTYGSYKCYCL NGYMLMPDGSCSSALTCSMANCQYGCDVVKGQIRCQCPSPGLQLAPDGRTCVDVDECATGRASCPRFR QCVNTFGSYICKCHKGFDLMYIGGKYQCHDIDECSLGQYQCSSFARCYNVRGSYKCKCKEGYQGDGLT CVYIPKVMIEPSGPIHVPKGNGTILKGDTGNNNWIPDVGSTWWPPKTPYIPPIITNRPTSKPTTRPTP KPTPIPTPPPPPPLPTELRTPLPPTTPERPTTGLTTIAPAASTPPGGITVDNRVQTDPQKPRGDVFIP RQPSNDLFEIFEIERGVSADDEAKDDPGVLVHSCNFDHGLCGWIREKDNDLHWEPIRDPAGGQYLTVS AAKAPGGKAARLVLPLGRLMHSGDLCLSFRHKVTGLHSGTLQVFVRKHGAHGAALWGRNGGHGWRQTQ ITLRGADIKSVVFKGEKRRGHTGEIGLDDVSLKKGHCSEVDG NOV5e, CG51117-09 SEQ ID NO: 33 1839 bp DNA Sequence ORF Start: ATG at 1 ORF Stop: at 1850 ATGGATTTTCTCCTGGCGCTGGTGCTGGTATCCTCGCTCTACCTGCAGGCGGCCGCCG AGTTCGACGGGAGTAGGTGGCCCAGGCAAATAGTGTCATCGATTGGCCTATGTCGTTATGGTGGGAGG ATTGACTGCTGCTGGGGCTGGGCTCGCCAGTCTTGGGGACAGTGTCAGCCTTTCTACGTCTTAAGGCA GAGAATAGCCAGGATAAGGTGCCAGCTCAAAGCTGTGTGCCAACCACGATGCAAACATGGTGAATGTA TCCGGCCAAACAAGTGCAAGTGTCATCCTGGTTATGCTGGAAAAACCTGTAATCAAGACGAGCACATC CCAGCTCCTCTTGACCAAGGCAGTGAACAGCCTCTTTTCCAACCCCTGGATCACCAAGCCACAAGTTT GCCTTCAAGGGATCTAAATGAGTGTGGCCTGAAGCCCCGGCCCTGTAAGCACAGGTGCATGAACACTT ACGGCAGCTACAAGTGCTACTGTCTCAACGGATATATGCTCATGCCGGATGGTTCCTGCTCAAGTGCC CTGACCTGCTCCATGGCAAACTGTCAGTATGGCTGTGATGTTGTTAAAGGACAAATACGGTGCCAGTG CCCATCCCCTGGCCTGCAOCTGGCTCCTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAG GAAGAGCCTCCTGCCCTAGATTTAGGCAATGTGTCAACACTTTTGGGAGCTACATCTGCAAGTGTCAT AAAGGCTTCGATCTCATGTATATTGGAGGCAAATATCAATGTCATGACATAGACGAATGCTCACTTGG TCAGTATCAGTGCAGCAGCTTTGCTCGATGTTATAACGTACGTGGGTCCTACAAGTGCAAATGTAAAG AAGGATACCAGGGTGATGGACTGACTTGTGTGTATATCCCAAAAGTTATGATTGAACCTTCAGGTCCA ATTCATGTACCAAAGGGAAATGGTACCATTTTAAAGGGTGACACAGGAAATAATAATTGGATTCCTGA TGTTGGAAGTACTTGGTGGCCTCCGAAGACACCATATATTCCTCCTATCATTACCAACAGGCCTACTT CTAAGCCAACAACAAGACCTACACCAAAGCCAACACCAATTCCTACTCCACCACCACCACCACCCCTG CCAACAGAGCTCAGAACACCTCTACCACCTACAACCCCAGAAAGGCCAACCACCGGACTGACAACTAT AGCACCAGCTGCCAGTACACCTCCAGGAGGGATTACAGTTGACAACAGGGTACAGACAGACCCTCAGA AACCCAGAGGAGATGTGTTCATTCCACGGCAACCTTCAAATGACTTGTTTGAAATATTTGAAATAGAA AGAGGAGTCAGTGCAGACGATGAAGCAAAGGATGATCCAGGTGTTCTGGTACACAGTTGTAATTTTGA CCATGGACTTTGTGGATGGATCAGGGAGAAAGACAATGACTTGCACTGGGAACCAATCAGGGACCCAG CAGGTGGACAATATCTGACAGTGTCGGCAGCCAAAGCCCCAGGGGGAAAAGCTGCACGCTTGGTGCTA CCTCTCGGCCGCCTCATGCATTCAGGGGACCTGTGCCTGTCATTCAGGCACAAGGTGACGCGGCTGCA CTCTGGCACACTCCAGGTGTTTGTGAGAAAACACGGTGCCCACGGAGCAGCCCTGTGGGGAAGAAATG GTGGCCATGGCTGGAGGCAAACACAGATCACCTTGCGAGGGGCTGACATCAAGAGCGTCGTCTTCAAA GGTGAAAAAAGGCGTGGTCACACTGGGGAGATTGGATTAGATGATGTGAGCTTGAAAAAAGGCCACTG CTCTGAAGAACGC NOV5e, CG51117-09 SEQ ID NO: 34 _613 aa MW at 67402.4kD Protein Sequence I I 1 1O WO 2004/015079 PCT/US2003/024931 FLLVLVSSLYLQAAAEDGSRWPRQIVSSIGLCRYGGRIDCCWGWARQSWGQCQPFYVLRQRIA RIRCQLKAVCQPRCKHGECIGPNKCKCHPGYAGKTCNQDEHIPAPLDQGSEQPLFQPLDHQATSLPSR DLNECGLKPRPCKHRCMNTYGSYKCYCLNGYMLMPDGSCSSALTCSMANCQYGCDVVKGQIRCQCPSP GLQLAPDGRTCVDVDECATGRASCPRFRQCVNTFGSYICKCHKGFDLMYIGGKYQCHDIDECSLGQYQ CSSFARCYNVRGSYKCKCKEGYQGDGLTCVYIPKVMIEPSGPIHVPKGNGTILKGDTGNNNWIPDVGS TWWPPKTPYIPPIITNRPTSKPTTRPTPKPTPIPTPPPPPPLPTELRTPLPPTTPERPTTGLTTIAPA ASTPPGGITVDNRVQTDPQKPRGDVFIPRQPSNDLFEIFEIERGVSADDEAKDDPGVLVHSCNFDHGL CGWIREKDNDLHWEPIRDPAGGQYLTVSAAKAPGGKAARLVLPLGRLMHSGDLCLSFRHKVTGLHSGT LQVFVRKHGAHGAALWGRNGGHGWRQTQITLRGADIKSVVFKGEKRRGHTGEIGLDDVSLKKGHCSEER NOV5f, CG51117-14 SEQ ID NO: 35 |933 bp DNA Sequence ORF Start: at 1 tORF Stop: at 944 CTGACTTGTGTGTATATCCCAAAAGTTATGATTGAACCTTCAGGTCCAATTCATGTAC CAAAGGGAAATGGTACCATTTTAAAGGGTGACACAGGAAATAATAATTGGATTCCTGATGTTGGAAGT ACTTGGTGGCCTCCGAAGACACCATATATTCCTCCTATCATTACCAACAGGCCTACTTCTAAGCCAAC AACAAGACCTACACCAAAGCCAACACCAATTCCTACTCCACCACCACCACCACCCCTGCCAACAGAGC TCAGAACACCTCTACCACCTACAACCCCAGAAAGGCCAACCACCGGACTGACAACTATAGCACCAGCT GCCAGTACACCTCCAGGAGGGATTACAGTTGACAACAGGGTACAGACAGACCCTCAGAAACCCAGAGG AGATGTGTTCATTCCACGGCAACCTTCAAATGACTTGTTTGAAATATTTGAAATAGAAAGAGGAGTCA GTGCAGACGATGAAGCAAAGGATGATCCAGGTGTTCTGGTACACAGTTGTAATTTTGACCATGGACTT TGTGGATGGATCAGGGAGAAAGACAATGACTTGCACTGGGAACCAATCAGGGACCCAGCAGGTGGACA ATATCTGACAGTGTCGGCAGCCAAAGCCCCAGGGGGAAAAGCTGCACGCTTGGTGCTACCTCTCGGCC GCCTCATGCATTCAGGGGACCTGTGCCTGTCATTCAGGCACAAGGTGACGGGGCTGCACTCTGGCACA CTCCAGGTGTTTGTGAGAAAACACGGTGCCCACGGAGCAGCCCTGTGGGGAAGAAATGGTGGCCATGG CTGGAGGCAAACACAGATCACCTTGCGAGGGGCTGACATCAAGAGCGTCGTCTTCAAAGGTGAAAAAA GGCGTGGTCACACTGGGGAGATTGGATTAGATGATGTGAGCTTGAAAAAAGGCCACTGC NOV5f, CG51 117-14 SEQ ID NO: 36 311 aa IM at 33658.lkD Protein Sequence LTCVYIPKVMIEPSGPIHVPKGNGTILKGDTGNNNWIPDVGSTWWPPKTPYIPPIITNRPTSKPTTRP TPKPTPIPTPPPPPPLPTELRTPLPPTTPERPTTGLTTIAPAASTPPGGITVDNRVQTDPQKPRGDVF IPRQPSNDLFEIFEIERGVSADDEAKDDPGVLVHSCNFDHGLCGWIREKDNDLHWEPIRDPAGGQYLT VSAAKAPGGKAARLVL PLGRLMHSGDLCLSFRHKVTGLHSGTLQVFVRKHGAHGAALWGRNGGHGWRQ TQITLRGADIKSVVFKGEKRRGHTGEIGLDDVSLKKGHC NOV5g, SNP13382208 of SEQ ID NO: 37 2112 bp CG51117-03, DNA Sequence ORF Start: ATG at 203 ORF Stop: TAA at 1949 SNP Pos: 1794 SNP Change: G to A eoGGAGGGGCTCCGGGCGCCGCCAGCAGACCTGCTCCCCCCGCGCGCCTCGCCGCTGTCCTCCGGGA GCGGCAGCAGTAGCCCGGGCGGCGAGGGCTGGGGGTTCCTCGAGACTCTCAGAGGGGCGCCTCCCATC GGCGCCCACCACCCCAACCTGTTCCTCGCGCGCCACTGCGCTGCGCCCCAGGACCCGCTGCCC CAT GGATTTTCTCCTGGCGCTGGTGCTGGTATCCTCGCTCTACCTGCAGGCGGCCGCCGAGTTCGACGGGA GGTGGCCCAGGCAAATAGTGTCATCGATTGGCCTATGTCGTTATGGTGGGAGGATTGACTGCTGCTGG GGCTGGGCTCGCCAGTCTTGGGGACAGTGTCAGCCTTTCTACGTCTTAAGGCAGAGAATAGCCAGGAT AAGGTGCCAGCTCAAAGCTGTGTGCCAACCACGATGCAAACATGGTGAATGTATCGGGCCAAACAAGT GCAAGTGTCATCCTGGTTATGCTGGAAAAACCTGTATTCAAGTTTTAAATCAGTGTGGCCTGAAGCCC CGGCCCTGTAAGCACAGGTGCATGAACACTTACGGCAGCTACAAGTGCTACTGTCTCAACGGATATAT GCTCATGCCGGATGGTTCCTGCTCAAGTGCCCTGACCTGCTCCATGGCAAACTGTCAGTATGGCTGTG ATGTTGTTAAAGGACAAATACGGTGCCAGTGCCCATCCCCTGGCCTGCAGCTGGCTCCTGATGGGAGG ACCTGTGTAGATGTTGATGAATGTGCTACAGGAAGAGCCTCCTGCCCTAGATTTAGGCAATGTGTCAA CACTTTTGGGAGCTACATCTGCAAGTGTCATAAAGGCTTCGATCTCATGTATATTGGAGGCAAATATC AATGTCATGACATAGACGAATGCTCACTTGGTCAGTATCAGTGCAGCAGCTTTGCTCGATGTTATAAC GTACGTGGGTCCTACAAGTGCAAATGTAAAGAAGGATACCAGGGTGATGGACTCACTTGTGTGTATAT CCCAAAAGTTATGATTGAACCTTCAGGTCCAATTCATGTACCAAAGGGAAATGGTACCATTTTAAAGG GTGACACAGGAAATAATAATTGGATTCCTGATGTTGGAAGTACTTGGTGGCCTCCGAAGACACCATAT ATTCCTCCTATCATTACCAACAGGCCTACTTCTAAGCCAACAACAAGACCTACACCAAAGCCAACACC AATTCCTACTCCACCACCACCACCACCCCTGCCAACAGAGCTCAGAACACCTCTACCACCTACAACCC CAGAAAGGCCAACCACCGGACTGACAACTATAGCACCAGCTGCCAGTACACCTCCAGGAGGGATTACA GTTGACAACAGGGTACAGACAGACCCTCAGAAACCCAGAGGAGATGTGTTCATTCCACGGCAACCTTC AAATGACTTGTTTGAAATATTTGAAATAGAAAGAGGAGTCAGTGCAGACGATGAAGCAAAGGATGATC CAGGTGTTCTGGTACACAGTTGTAATTTTGACCATGGACTTTGTGGATGGATCAGGGAGAAAGACAAT GACTTGCACTGGGAACCAATCAGGGACCCAGCAGGTGGACAATATCTGACAGTGTCGCAGCCAAAGC CCCAGGGGGAAAAGCTGCACGCTTGGTGCTACCTCTCGGCCGCCTTATGCATTCAGGGGACCTGTGCC TGTCATTCAGGCACAAGGTGACGGGGCTGCACTCTGGCACACTCCAGGTGTTTGTGAGAAAACACGGT GCCCACGGAGCAGCCCTGTGGGGAAATGGTGGCCATGGCTGGAGGCAAACACAGATCACCTTGCG

AGGGGCTGACATCAAGAGCGTCGTCTTCAAAGGTGAAAAAAGCGTGGTCACACTGGGGAGATTGGAT

WO 2004/015079 PCT/US2003/024931

TAGAGATGTGAGCTTGPAAAAAGGCCACTGCTCTGAAGAACGCTAACAACTCCAGAACTAACAATGA

ACTCCTATGTTGCTCTATCCTCTTTTTCCAATTCTCATCTTCTCTCCTCTTCTCCCTTTTATCAGGCC TAGGAGAAGAGTGGGTCAGTGGGTCAGAAGGAAGTCTATTTGGTGACCCAGGTTCTTCTGGCCTGCTT TT NOV5g, SNP13382208 of SEQ ID NO: 8 582 aa MW at 63963.9kD CG51117-03, Protein Sequence ISNP Pos: 531 SNPChange: Arg to Lys MFLLALVLVSSLYLQAAAEFDGRPRQIVSSIGLCRYGGRIDCCWGWARQSWGQCQPFYVLRQRIAR IRCQLKAVCQPRCKHGECIGPNKCKCHPGYAGKTCIQVLNECGLKPRPCKHRCMNTYGSYKCYCLNGY MLMPDGSCSSALTCSMANCQYGCDVVKGQIRCQCPSPGLQLAPDGRTCVDVDECATGRASCPRFRQCV NTFGSYICKCHKGFDLMYIGGKYQCHDIDECSLGQYQCSSFARCYNVRGSYKCKCKEGYQGDGLTCVY IPKVMIEPSGPIHVPKGNGTILKGDTGNNNWIPDVGSTWWPPKTPYIPPIITNRPTSKPTTRPTPKPT PIPTPPPPPPLPTELRTPLPPTTPERPTTGLTTIAPAASTPPGGITVDNRVQTDPQKPRGDVPIPRQP SNDLFEIFEIERGVSADDEKDPGVLVHSCNFDHGLCGWIREKDNDLHWEPIRDPAGGQYLTVSAAK APGGKAARLVLPLGRLMHSGDLCLSFRHKVTGLHSGTLQVFVRKHGAHGAALWGKNGGHGWRQTQITL ,RGADIKSVVFKGEKRRGHTGEIGLDDVSLKKGHCSEER Further analysis of the NOV5a protein yielded the following properties shown in Table 5B. Table 5C. Protein Sequence Properties NOV5e SignalP analysis:- Cleavage site between residues 19 and 20 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 2; pos.chg 0; neg.chg 1 H-region: length 17; peak value 0.00 PSG score: -4.40 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -0.34 possible cleavage site: between 17 and 18 >> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -4.19 Transmembrane 3 - 19 PERIPHERAL Likelihood = 5.67 (at 516) ALOM score: -4.19 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 10 Charge difference: 0.0 C( 0.0) - N( 0.0) N >= C: N-terminal side will be inside >>> membrane topology: type 2 (cytoplasmic tail 1 to 3) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 4.41 Hyd Moment(95): 7.23 G content: 0 D/E content: 2 S/T content: 2 Score: -6.55 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found WO 2004/015079 PCT/US2003/024931 NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues.: 11.9% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none SKL2: 2nd peroxisomal targeting signal: found RIARIRCQL at 66 VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytplasmic/Nuclear discrimination Prediction: nuclear Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues A search of the NOV5e protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5D.

WO 2004/015079 PCT/US2003/024931 Table 5C. Geneseq Results for NOV5e NOV5e Identities/ Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region ABR47621 Breast cancer associated protein 138..613 476/476 (100%) 0.0 sequence SEQ ID NO:484 - Homo 107..582 476/476 (100%) sapiens, 582 aa. [W02003004989 A2, 16-JAN-2003] AAB70547 Human PRO17 protein sequence 138..613 476/476 (100%) 0.0 SEQ ID NO:34 - Homo sapiens, 107..582 476/476 (100%) 582 aa. [W0200110902-A2, 15 FEB-2001] ABG69659 Human secreted protein SCEP-39 - 135..613 477/479 (99%) 0.0 Homo sapiens, 566 aa. 88..566 479/479 (100%) [W0200248337-A2, 20-JUN-2002] ABJ37055 Human breast cancer / ovarian 103..613 506/511 (99%) 0.0 cancer related protein #31 - Homo 51..560 509/511(99%) sapiens, 560 aa. [W02003000012 A2, 03-JAN-2003} In a BLAST search of public sequence databases, the NOV5e protein was found to have homology to the proteins shown in the BLASTP data in Table SD. Table 5D. Public BLASTP Results for NOV5e NOV5e Identities/ Residues/ Similarities for Expect Accession Protein/Organism/Length Match the Matched Value Number Residues Portion CAC33425 Sequence 33 from Patent 138..613 476/476 (100%) 0.0 W00110902 - Homo sapiens 107..582 476/476 (100%) (Human), 582 aa. Q923T5 Nephronectin - Mus musculus 1.578 536/609 (88%) 0.0 (NMouse), 609 aa. 1..609 566/609 (93%) Q91XL5 Nephronectin - Mus musculus 25..609 503/585 (85%) 0.0 (Mouse), 592 aa. 24..592 534/585 (91%) 1 1 PFam analysis predicts that the NOV5e protein contains the domains shown in the Table SE. Table 5E. Domain Analysis of NOV5e Pfam Domain NOV e Match Region Score E-Value Amino acid residues of SEQ ID NO: 34Srl WO 2004/015079 PCT/US2003/024931 EGF 78..104 18.9 0.12 EGF 141..175 15.6 0.26 EGF 181..215 20.7 0.035 EGF 221..260 2.7 6.1 MAM 470..611 102.4 8.6e-27 The epithelial-mesenchymal interactions required for kidney organogenesis are disrupted in mice lacking the integrin alpha8betal. None of this integrin's known ligands, however, appears to account for this phenotype. To identify a more relevant ligand, 5 Brandenberger et al. (2001) used a soluble integrin alpha8betal heterodimer fused to alkaline phosphatase (AP) to probe blots and cDNA libraries. In newborn mouse kidney extracts, alpha8betal-AP detects a novel ligand of 70-90 kD. This protein, named nephronectin, is an extracellular matrix protein with five EGF-like repeats, a mucin region containing a RGD sequence, and a COOH-terminal MAM domain. Integrin alpha8betal 10 and several additional RGD-binding integrins bind nephronectin. Nephronectin mRNA is expressed in the ureteric bud epithelium, whereas alpha8betal is expressed in the metanephric mesenchyme. Nephronectin is localized in the extracellular matrix in the same distribution as the ligand detected by alpha8betal-AP and forms a complex with alpha8betal in vivo. Thus, these results strongly suggest that nephronectin is a relevant 15 ligand mediating alpha8betal function in the kidney. Nephronectin is expressed at numerous sites outside the kidney, so it may also have wider roles in development. (Brandenberger et al. J Cell Biol 2001 Jul 23;154(2):447-58) NOV5e is a novel nucleic acid of 613 nucleotides (designated CuraGen Acc. No. CG51117-09) encoding a novel Nephronectin-like protein. This sequence represents a 20 splice form of Nephronectin as indicated in positions with one exon insertion 30 amino acids and one amino acid S insertion at position 24 and maps to chromosome 6 The presence of identifiable domains in the protein disclosed herein was determined by searches versus domain databases such as Pfam, PROSITE, ProDom, Blocks or Prints and then identified by the Interpro domain accession number. A 170 amino acid domain, 25 the so-called MAM domain, has been recognised in the extracellular region of functionally diverse proteins. These proteins have a modular, receptor-like architecture comprising a signal peptide, an N-terminal extracellular domain, a single transmembrane domain and an intracellular domain. Such proteins include meprin (a cell surface glycoprotein); A5 antigen WO 2004/015079 PCT/US2003/024931 (a developmentally-regulated cell surface protein); and receptor-like tyrosine protein phosphatase. The MAM domain is thought to have an adhesive function. It contains 4 conserved cysteine residues, which probably form disulphide bridges. A sequence of about thirty to forty amino-acid residues long found in the sequence 5 of epidermal growth factor (EGF) has been shown to be present, in a more or less conserved form, in a large number of other, mostly animal proteins. The list of proteins currently known to contain one or more copies of an EGF-like pattern is large and varied. The functional significance of EGF domains in what appear to be unrelated proteins is not yet clear. However, a common feature is that these repeats are found in the extracellular 10 domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandin G/H synthase). The EGF domain includes six cysteine residues which have been shown (in EGF) to be involved-in disulfide bonds. The main structure is a two stranded beta-sheet followed by a loop to a C-terminal short two-stranded sheet. Subdomains between the conserved cysteines vary in length. 15 NOV5a, clone 306433917 is a splice variant with deletion of amino acid sequences GKYQCH , EHIPAPLDQGSEQPLFQPLDHQATSLPSR (SEQ ID NO:79) and PRQPSNDLFEIFEIERGVSADDEAKDDPG (SEQ ID NO:80) one deleted exon 29 amino acids, plus 1 amino acid changes 1322S compared to NOV5e. NOV5b, 5c, 5d, assemblies 306447063, 306447071, 306447075 respectively were found to encode an open reading 20 frame between residues 1 to 611 of NOV5e, CG51117-09. The cloned insert NOV5c 306447071 is a splice variant of parent with one exon deletion 17 amino acids FYVLRQRIARIRCQLKA (SEQ ID NO:81), deletion of amino acid sequence EIIIPAPLDQGSEQPLFQPLDHQATSLPSR (SEQ ID NO:82) plus I amino acid S deletion at position 24, amino acid changes Q159H compare to NOV5e. The cloned insert 25 NOV5d 306447075 has a deletion of amino acid sequence EIIIPAPLDQGSEQPLFQPLDHQATSLPSR (SEQ ID NO:83) plus 1 amino acid S deletion at position 24 compared to NOV5e NOV5b, 306447063 has has a deletion of amino acid sequence EHIPAPIDQGSEQPLFQPLDHQATSLPSR (SEQ ID NO:84) compared to NOV5e 30 Example 6. NOV6, CG51923, Protocadherin Fat 2 precursor The NOV6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 6A. Table 6A. NOV6 Sequence Analysis WO 2004/015079 PCT/US2003/024931 NOV6a, CG51923-01 SEQ ID NO: 39 14536 bp DNA Sequence ORF Start: ATG at 14 ORF Stop: TAG at 13061 GGAGTTTTCCACCATGACTATTGCCCTGCTGGGTTTTGCCATATTCTTGCTCCATTGTGCGACCTGTG AGAAGCCTCTAGAAGGGATTCTCTCCTCCTCTGCTTGGCACTTCACACACTCCCATTACAATGCCACC ATCTATGAAAATTCTTCTCCCAAGACCTATGTGGAGAGCTTCGAGAAAATGGGCATCTACCTCGCGGA GCCACAGTGGGCAGTGAGGTACCGGATCATCTCTGGGGATGTGGCCAATGTATTTAAAACTGAGGAGT ATGTGGTGGGCAACTTCTGCTTCCTAAGAATAAGGACAAAGAGCAGCAACACAGCTCTTCTGAACAGA GAGGTGCGAGACAGCTACACCCTCATCATCCAAGCCACAGAGAAGACCTTGGAGTTGGAAGCTTTGAC CCGTGTGGTGGTCCACATCCTGGACCAGAATGACCTGAAGCCTCTCTTCTCTCCACCTTCGTACAGAG TCACCATCTCTGAGGACATGCCCCTGAAGAGCCCCATCTGCAAGGTGACTGCCACAGATGCTGATCTA GGCCAGAATGCTGAGTTCTATTATGCCTTTAACACAAGGTCAGAGATGTTTGCCATCCATCCCACCAG CGGTGTGGTCACTGTGGCTGGGAAGCTTAACGTCACCTGGCGAGGAAAGCATGAGCTCCAGGTGCTAG CTGTGGACCGCATGCGGAAAATCTCTGAGGGCAATGGGTTTGGCAGCCTGGCTGCACTTGTGGTTCAT GTGGAGCCTGCCCTCAGGAAGCCCCCAGCCATTGCTTCGGTGGTGGTGACTCCACCAGACAGCAATGA TGGTACCACCTATGCCACTGTACTGGTCGATGCAAATAGCTCAGGAGCTGAAGTGGAGTCAGTGCAAG TTGTTGGTGGTGACCCTGGAAAGCACTTCAAAGCCATCAAGTCTTATGCCCGGAGCAATGAGTTCAGT TTGGTGTCTGTCAAAGACATCAACTGGATGGAGTACCTTCATGGGTTCAACCTCAGCCTCCAGGCCAG GAGTGGGAGCGGCCCTTATTTTTATTCCCAGATCAGGGGCTTTCACCTACCACCTTCCAAACTGTCTT CCCTCAAATTCGAGAAGGCTGTTTACAGAGTGCAGCTTAGTGAGTTTTCCCCTCCTGGCAGCCGCGTG GTGATGGTGAGAGTCACCCCAGCCTTCCCCAACCTGCAGTATGTTCTAAAGCCATCTTCAGAGAATGT AGGATTTAAACTTAATGCTCGAACTGGGTTGATCACCACCACAAAGCTCATGGACTTCCACGACAGAG CCCACTATCAGCTACACATCAGAACCTCACCGGGCCAGGCCTCCACCGTGGTGGTCATTGACATTGTG GACTGCAACAACCATGCCCCCCTCTTCAACAGCTCTTCCTATGATGGTACCTTGGATGAGAACATCCC TCCAGGCACCAGTGTTTTGGCTGTGACTGCCACTGACCGGGATCATGGGGAAAATGGATATGTCACCT ATTCCATTGCTGGACCAAAAGCTTTGCCATTTTCTATTGACCCCTACCTGGGGATCATCTCCACCTCC AAACCCATGGACTATGAACTCATGAAAAGAATTTATACCTTCCGGGTAAGAGCATCAGACTGCGGATC CCCTTTTCGCCGGGAGAAGGAAGTGTCCATTTTTCTTCAGCTCAGGAACTTGAATGACAACCAGCCTA TGTTTGAAGAAGTCAACTGTACAGGGTCTATCCGCCAAGACTGGCCAGTAGGGAAATCGATAATGACT ATGTCAGCCATAGATGTGGATGAGCTTCAGAACCTAAAATACGAGATTGTATCAGGCAATGAACTAGA GTATTTTGATCTAAATCATTTCTCCGGAGTGATATCCCTCAAACGCCCTTTTATCAATCTTACTGCTG GTCAACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAAAACTATGCCTCACCCACAACT TTGAATATTACTGTGGTGAAGGACCCTCATTTTGAAGTTCCTGTAACATGTGATAAAACAGGGGTATT GACACAATTCACAAAGACTATCCTCCACTTTATTGGGCTTCAGAACCAGGAGTCCAGTGATGAGGAAT TCACTTCTTTAAGCACATATCAGATTAATCATTACACCCCACAGTTTGAGGACCACTTCCCCCAATCC ATTGATGTCCTTGAGAGTGTCCCTATCAACACCCCCTTGGCCCGCCTAGCAGCCACTGACCCTGATGC TGGTTTTAATGGCAAACTGGTCTATGTGATTGCAGATGGCAATGAGGAGGGCTGCTTTGACATAGAGC TGGAGACAGGGCTGCTCACTGTAGCTGCTCCCTTGGACTATGAAGCCACCAATTTCTACATCCTCAAT GTAACAGTATATGACCTGGGCACACCCCAGAAGTCCTCCTGGAAGCTGCTGACAGTGAATGTGAAAGA CTGGAATGACAACGCACCCAGATTTCCTCCCGGTGGGTACCAGTTAACCATCTCGGAGGACACAGAAG TTGGAACCACAATTGCAGAGCTGACAACCAAAGATGCTGACTCGGAAGACAATGGCAGGGTTCCCTAC ACCCTGCTAAGTCCCACAGAGAAGTTCTCCCTCCACCCTCTCACTGGGGAACTGGTTGTTACAGGACA CCTGGACCGCGAATCAGAGCCTCGGTACATACTCAAGGTGGAGGCCAGGGATCAGCCCAGCAAAGGCC ACCAGCTCTTCTCTGTCACTGACCTGATAATCACATTGGAGGATGTCAACGACAACTCTCCCCAGTGC ATCACAGAACACAACAGGCTGAAGGTTCCAGAGGACCTGCCCCCCGGGACTGTCTTGACATTTCTGGA TGCCTCTGATCCTGACCTGGGCCCCGCAGGTGAAGTGCGATATGTTCTGATGGATGGCGCCCATGGGA CCTTCCGGGTGGACCTGATGACAGGGGCGCTCATTCTGGAGAGAGAGCTGGACTTTGAGAGGCGAGCT GGGTACAATCTGAGCCTGTGGGCCAGTGATGGTGGGAGGCCCCTAGCCCGCAGGACTCTCTGCCATGT GGAGGTGATCGTCCTGGATGTGAATGAGAATCTCCACCCTCCCCACTTTGCCTCCTTCGTGCACCAGG GCCAGGTGCAGGAGAACAGCCCCTCGGGAACTCAGGTGATTGTAGTGGCTGCCCAGGACGATGACAGT GGCTTGGATGGGGAGCTCCAGTACTTCCTGCGTGCTGGCACTGGACTCGCAGCCTTCAGCATCAACCA AGATACAGGAATGATTCAGACTCTGGCACCCCTGGACCGAGAATTTGCATCTTACTACTGGTTGACGG TATTAGCAGTGGACAGGGGTTCTGTGCCCCTCTCTTCTGTAACTGAAGTCTACATCGAGGTTACGGAT GCCAATGACAACCCACCCCAGATGTCCCAAGCTGTGTTCTACCCCTCCATCCAGGAGGATGCTCCCGT GGGCACCTCTGTGCTTCAACTGGATGCCTGGGACCCAGACTCCAGCTCCAAAGGGAAGCTGACCTTCA ACATCACCAGTGGGAACTACATGGGATTCTTTATGATTCACCCTGTTACAGGTCTCCTATCTACAGCC CAGCAGCTGGACAGAGAGAACAAGGATGAACACATCCTGGAGGTGACTGTGCTGGACAATGGGGAACC CTCACTGAAGTCCACCTCCAGGGTGGTGGTAGGCATCTTGGACGTCAATGACAATCCACCTATATTCT CCCACAAGCTCTTCAATGTCCGCCTTCCAGAGAGGCTGAGCCCTGTGTCCCCTGGGCCTGTGTACAGG CTGGTGGCTTCAGACCTGGATGAGGGTCTTAATGGCAGAGTCACCTACAGTATCGAGGACAGCTATGA GGAGGCCTTCAGTATCGACCTGGTCACAGGTGTGGTTTCATCCAACAGCACTTTTACAGCTGGAGAGT ACAACATCCTAACGATCAAGGCAACAGACAGTGGGCAGCCACCACTCTCAGCCAGTGTCCGGCTACAC ATTGAGTGGATCCCTTGGCCCCGGCCGTCCTCCATCCCTCTGGCCTTTGATGAGACCTACTACAGCTT TACGGTCATGGAGACGGACCCTGTGAACCACATGGTGGGGGTCATCAGCGTAGAGGGCAGACCCGGAC TCTTCTGGTTCAACATCTCAGGTGGGGATAAGGACATGGACTTTGACATTGAGAAGACCACAGGCAGC ATCGTCATTGCCAGGCCTCTTGATACCAGGAGAAGGTCGAACTATAACTTGACTGTTGAGGTGACAGA TGGGTCCCGCACCATTGCCACACAGGTCCACATCTTCATGATTGCCAACATTAACCACCATCGGCCCC A('TTTCTGGAAACTCG'TTATCGAAGTCAGAG TTCCCCAGG('ACACCGTGCCAGGGG(ITAGAGC'CTGCGA 1 1 I WO 2004/015079 PCT/US2003/024931 GTCCAGGCCATAGATCAAGACAAGGGCAAAAGCCTCATCTATACCATACATGGCAGCCCAGACCCAGG AAGTGCCAGCCTCTTCCAGCTGACCCAAGCAGTGGTGTCCTGGTACGGTGGGAATTGGACCTCG GCTCGGGGCCCTCCCAsGCACACACTGACAGTCATGTCCGAGACCAGGATACCTATCAAGAGGAC TTCGTGTGGGTGACCATTCATGTGGAGGATGGACCTCCACCCACCCCGCTTCACTCAGCTCCATTA TGAGGCAAGTGTTCCTGACACCATAGCCCCCGGCACAGAGCTGCTGCAGGTCCGAGCCATGGATGCTG .ACCGGGGAGTCAATGCTGAGGTCCACTACTCCCTCCTGAAGGGACAGCGAAGGTTTCTTCACATC AATGCCCTGCTAGGCATCATTACTCTAGCTCAAAAGCTTGATCAGGCAAATCATGCCCCACATACTCT GACAGTGAGGCAGAGATCAAGGCTCCCCACATGGCATGACCTGGCTACATGATCATTCATGTCT ATCCCTCAGAT GGAGTGCCCCCATCTTTTCAATCTGAGTACTTTGTAGAGATCCCTAATCAATC CCTGTTGGTTCCCCAATCCTCCTTGTCTCTGCTATGAGCCCCTCTGAAGTTACCTATGAGTTAAGAGA .. GGGAAATAAGGATGGAGTCTTCTCTATGACTCATATTCTGGCCTTATTTCCACCCAGAGATTG ACCATGAGAAAATCTCGTCTTACCAGCTGAATCCGAGCACCATATGGCAGTCATTTACTGAT TTCATGCCTCTGACAGTGACAAAGAAGCTAATTCCTTGTTGGTCTATAAATTTTGGAGCCGGAGGCC TTGAAGTTTTTCAAAATTGATCCCAGCATGGGAACCCTAACCATTGTATCAGAGATGGATTATGAGAG * OATCCCCTCTTTCCAATTCTGTGTCTATGTCCATGACCAGGAGCCCTGTATTATTTGCACCCAGAC .CGCAGCTATAGCGGTTATGTCCCCCGTCCGAAAAA GAGGTAGCAATAGTCGGGCCTATCCATCCAGGCATGGAGCTTCTCATGGTGCGGGCCAGCGATGAAGA CTCAGAAGTCAATTATACATCAAACTGGCAATGCTGATGAACTGTTACCATCCATCCTGTCACTG GTAGCATATCTGTGCTGAATCCTGCTTTCCTGGGACTCTCTCGGAAGCTCACCATCAGGGCTTCTGAT GGCTTGTATCAAGACACTGCGCTGGTAAAATTTCTTTGACCCAGTGCTTGACAAGCTTGCAGTT . TGATCAGGATGTCTACTGGGCAGCTGTGAAGGAAACTTGCAGGACAGAGCACTGGTGATTCTTG GTGCCCAGGGCZATCATTTGAATGACACCCTTTCCTACTTTCTCTTGAATGGCACAGATATGTTTCATI ATGGTCCAGTCAGCAGGTGTGTTGCAGACAAGACGTGTGGCGTTTGACCGGGAGCAGCAGGACACTCA TGAGTTGGCAGTGGAGTGAGGGACAATCGGACACCTCAGCGGGTGGCT'CAGGGTTTGGTCAGAGTCT CTATTGAGGATGTCAATGACAATCCCCCCTTTAGCATCTGCCCTATTACACAATCATCCAAGAT GGCACAGAGCCAGGGGATGtCCTCTTTCAGGTATCTGCCACTGATGAGGACTTGGGGACAALTGGGGC TGTTACATATGAATTTGCAGAAGATTACACATATTTCCGAATTGACCCCTATCTTGGGGACATATCAC TCAAGAAACCCTTTGATTATCAGCTTTAATAAATATCACCTCAAGTCATTGCTCGGGATGGAGGA ACCACCCAATAGAAGATGTATTAAAAACACCCGTC GAGTCCTTATTACAAAGTCAGAGTACCTGAAAATATCACCCTCTATACCCCATTCTCCACACCCAGG CCCCGCAGTCCAGAGGGACTCCGGCTCATCTACACATTGTGGAGGAAGACCCTTGATGCTGTTCACC iACTGACTTCAAGACTGGTGTCCTAACAGTAACAGGGCCTTTGGACTATGAGTCCAAGACCAACATGT AGGATGTCAATGATACCCTCCCACTTTTTCCCATTGGTCTATACCACTTCCATCTCAGAGGCTTG CCTGCTCAGACCCCTGTGATCCAACTGTTGGCTTCTGACCAGGACTCAGGGCGGAACCGTGACGTCTC TTATCAGATTGTGGAGCATGCCTCAGATGTTTCCAGTTCTTCCAGATCATGGGAGCACAGGGGAGA TGTCCACAGTTCAAGAACTGGATTATGAAGCCCAACAACACTTTCATGTGAAAGTCAGGGCCATGGAT AAAGGAGATCCCCCACTCACTGGTAAACCCTTGTGGTTGTCAATGTGTCTGATATCATGACAACCC CCCAGAGTTCAGACAACCTCAATATGAGCCAATGTCAGTGAACTGGCACCTGTGACACCTGGTTC TTAAAGTCCAGGCTATTGACCCTGACAGCAGAGACACCTCCCGCCTGAGTACCTATTCTTTCTGGC AATCAGGACAGGCACTTCTTCATTAACAGCTCATCGGGAATAATTTCTATGTTCACCTTTGCAL GCACCTGGACTCTTCTTACAATTTGAG3GGTAGGTGCTTCTGATGGAGTCTTCCGACACTGTGCCTG TGTACATCAACACTACAAATGCCAACAAGTACAGCCCAGAGTTCCAGCAGCACCTTTATGAGGCAGAA *TTAGCAGAGAATGCAATGGTTGGAACCAAGGTGATTGATTTGCTAGCCATAGACAGATAGTGGTCC CTTCATTGTAATTACAAACTGAATAAGTTCTACCAT GCAATCATTCGACGACGAAATACGGGGCTGTTAGT ATGGCTCGGGATGGAGGAGGAAGAGTAGCCTTCTGCACGGTGAGA TCATCCTCACAGATG-)ATGA CAACCCCCCACAGTTCAAAGCATCTGAGTACACAGTATCCATTCATCCAATGTCAGTAGACTCTC CGGTTATCCAGGTGTTGGCCTATGATGCAGATGAGGTCAGAACGCAGATGTCACCTACTCAGTGAC CCAGAGGACCTAGTTAAATGTCATTTTACCCAGTCACTGGTGTGGTCAAGGTGAAGACAG CCTGGTGGGATTGGAAAATCAGACCCTTGACTTCTTCATCAGCCCAGATGGAGGCCCTCCTCACT GGAACTCTCTGGTGCCAGTACACTTCAGGTGGTTCCTALGTATCCTTACCGATTTTCTGAA CCTTTGTATACTTTCTCTGCACCTGAGACCTTCCAGAGGGTCTGATTGGGATTGTTAGCAGT GGACCAACATACAATTGGCGGATCCTAACAAGAGT TCTTCTCCCTAGACCCAGACACAGGGTCATAGGTGAGGAGCCCATGGACCACATCCACCA TTGTACCAGATTGATGTGATGGCACATTGCCTTCAGAACACTGATGTGGTGTCCTTGGTCTCTGTCAA CATCCAAGTGGGAGACGTCAATGACAATAG3GCCTGTATTTGAGGCTGATCCATATAAGGCTGTCCTCA CTGAGAATATGCCAGTGGGGACCTCAGTCATTCAAGTGACTGCCATTGACAAGGACACTGGGAGAGAT GGCCAGGTGAGCTACAGCCTGTCTGCAGACCCTGGTAGCATGTCCATGAGCTCTTTGCCATTGACAG TGAGAGTGGTTGGATCACCACACTCCAGGAACTTGACTGTGAGACCTGCCAGACTTATCATTTTCATG TGGTGGCCTATGACCACGGACAGACCATCCAGCTATCCTCTCAGGCCCTGGTTCAGGTCTCCATTACA I GATGAGAATGACAATGCTCCCCGATTTGCTTCTGAAGAGTACAGACGATCTGTGGTTGAGAACAGTGA GCCTrGCGACTGTGGCGACTCTAAGACCCTGGATGCTGACATTTCTGAGCAGACAGGCAGGTCA CCTGCTACATCACAGAGGGAGACCCCCTGCGCCAGTTTGGCATCAGCCAAGTTGGAGATGAGTGGAGG ATTTCCTCAAGGAAGACCCTGGACCGCGAGCATACAGCCAAGTACTTGCTCAGAGTCACAGCATCTGA TGCA TCGCTGtATTCA

TTTTCGAGCATAACCCCCG

WO 2004/015079 PCT/US2003/024931 GTTCACAGCTTCTCTATACTGGCAAGGTTCATGAAGATGTATTTCCAGGACACTTCATTTTGAAGGTT TCTGCCACAGACTTGGACACTGATACCAATGCTCAGATCACATATTCTCTGCATGGCCCTGGGGCGCA TGAATTCAAGCTGGATCCTCATACAGGGGAGCTGACCACACTCACTGCCCTAGACCGAGGGAG ATGTGTTCAACCTTGTTGCCAAGGCGACGGATGGAGGTGGCCGATCGTGCCAGGCAGACATCACCCTC CATGTGGAGGATGTGAATGACAAXTGCCCCGCGGTTCTTCCCCAGCCACTGTGCTGTGGCTGTCTTCGA CAACACCACAGTGAGACCCCTGTGGCTGTAGTATTTGCCCGGGATCCCGACCAAGGCGCCATGCCC AGGTGGTTTACTCTCTGCCGGATTCAGCCGAAGGCCACTTTTCCATCGACGCCACCACGGGGGTGATC CGCCTGGAAAAGCCGCTGCAOGTCAGGCCCCAGGCACCACTGGAGCTCACGGTCCGTGCCTCTGACCT GGGCACCCCAATACCGCTGTCCACGCTGGGCACCGTCACAGTCTCGGTGGTGGGCCTAGAAGACTACC TGCCCGTGTTCCTGAACACCGAGCACAGCGTGCACGTGCCCGAGGACGCCCCACCTGGCACGGAGGTG CTGCAGCTGGCCACCCTCACTCCCCCGGGCGCAGAGAAGACCGGCTACCGCGTGGTCAGCGGACGA GCAAGGCAGGTTCCGCCTGGATGCTCGCACAGGGATCCTGTATGTCAACGCAAGCCTGGACTTTGAGA CAAGCCCCAAGTACTTC-CTGTCCATTGAGTGCAGCCGGAAGAGCTCCTCTTCCCTCAGTGACGTGACC ACA GTCATGGTCAACATCACTGATGTCAATGAACACCGGCCCCAATTCCCCCAAGATCCATATAGCAC AAGGGTCTTAGAGAATGCCCTTGTGGGTGACGTCATCCTCACGGTATCAGCGACTGATGAAGATGGAC CCCTAAATAGTGACATTACCTATAGCCTCATAGGAGGGAACCAGCTTGGGCACTTCACCATTCACCCC AAAAAGGGGGAGCTACAGGTGGCCAAGGCCCTGGACCCGGGAACAGGCCTCTAGTTATTCCCTGAAGCT CCGAGCCACAGACAGTGGGCAGCCTCCACTGCATGAGGACACAGACATCGCTATCCAAGTGGCTGATG TCAATGATAACCCACCGAGATTCTTCCAGCTCAACTACAGCACCACTGTCCAGGAGAACTCCCCCATT GGCAGCAAAGTCCTGCAGCTGATCCTGAGTGACCCAGATTCTCCAGAGAATGGCCCCCCCTACTCGTT TCGAATCACCOAGGGGAACAACCGCTCTCCTITCCGAGTGACCCCGGATGGATGGCTGGTGACTGCTG AGGCCTAAGCAGGAGGGCTCAGGAATGGTATCAGCTTCAGATCCAGGCGTCAGACAGTGGCATCCCT CCCCTCTCGTCTTTGACGTCTGTCCGTGTCCATGTCACAGAGCAGAGCCACTATGCACCTTCTGCTCT CCCACTGGAGATCTTCATCACTGTTGGAGAGGATGAGTTCCAGGGTGGCATGGTCGGOTAGATCCATG CCACAGACCGAGACCCCCAGGACACGCTGACCTATAGCCTGGCAGAAGAGGAGACCCTGGGCAGGCAC TTCTCAGTGGGTGCGCCTGATGGCAAGATTATCGCCGCCCAGCGCCTGCCTCGTGGCCACTACTCGTT CAACGTCACGGTCAGCGATGGGACCTTCACCACGACTGCTGGGGTCCATGTGTACGTGTGGCATGTGG GGCAGGAGGCTCTGCAGCAGGCCATGTGGATCGGCCTTCTACCAGCTCACCCCCGAGCAGCTGGTGAGT GACCACTGGCGGAACCTGCAGAGGTTCCTCAGCCATAAGCTGGACATCAAACGGGCTAACATTCACTT GGCCAGCCTCCAGCCTGCAGAGGCCGTGGCTGGTGTGGATGTGCTCCTGGTCTrTGAGGGGCATTCTG GAACCTTCTACGAGTTTCAGGAGCTAGCATCCATCATCACTCACTCAGCCAAGGAGATCGAGCATTCA GTGGGGGTTCAGATGCGGTCAGCTATGCCCATGGTGCCCTGCCAGGGGCCAACCTGCCAGGGTCAAAT CTGCCATAACACAGTGCATCTGGACCCCAAGGTTCGGCCCACGTACAGCACCGCCAGGCTCAGCATCC TAACCCCGCGGCACCACCTGCAGAGGAGCTGCTCCTGCAATGGTACTGCTACAAGGTTCAGTGGTCAG AGCTATGTGCGGTACAGGGCCCCAGCGGCTCGCAACTGGCACATCCATTTCTATCTGAAAACACTCCA GCCACAGGCCATTCTTCTATTCACCAATGAAACAGCGTCCGTCTCCCTGAAGCTGGCCAGTGGAGTGC CCCAGCTGGAATACCACTGTCTGGGTGGTTTCTATGGAABACCTTTCCTCCCAGCGCCATGTGATGAC CACGAGTGGCACTCCATCCTGGTGGAGGAGATGGACGCTTCCATTCGCCTGATGGTTGACAGCATGGG CAACACCTCCCTTGTGGTCCCAGAGAACTGCCGTGGTCTGAGGCCCGAAALGGCACCTCTTGCTGGGCG GCCTCATTCTGTTGCATTCTTCCTCGAATGTCTCCCAGGGCTTTGAAGGCTGCCTGGATGCTGTCGTG GTCAACGAAGAOGCTCTAGATCTGCTGGCCCCTGGCAALGACGGTGGCAGGCTTGCTGGAGACACAAGC CCTCACCCAGTGCTGCCTCCACAGTGACTACTGCAGCCAGAACACATGCCTCAATGGTGGAGTGCT CATGGACCCATGGGGCAGGCTATGTCTGCAAATGTCCCCCACAGTTCTCTGGGAAGCACTGTGAACAA GGAAGGGAGAACTGTACTTTTGCACCCTGCCTGGAAGGTGGAACTTGCATCCTCTCCCCCAAGGAGC TTCCTGTAACTGCCCTCATCCTTACACAGGAGACAGGTGTGAAATGGACGCGAGGCGGTTGTTCAGAAG GACACTGCCTAGTCACTCCCGAGATCCAAAGGGGGGACTGGGGGCAGCAGGAGTTACTGATCATCAA G.TGGCCGTGGCGTTCATTATCATAAGCACTGTCGGGCTTCTCTTCTACTGCCCCCGTTGCAAGTCTCA CAAGCCTGTGGCCATGGAGGACCCAGACCTCCTGGCCAGGAGTGTTGGTGTTGACACCCAAGCCATGC CTCACACCACATATCACCTGACACCACACGACGAA GCCTCTGTTCCAAATGAACTCGTCACATTTGGACCCAATTCTAAGCAACGGCCAGTGGTCTGCAGTGT GCCCCCAGACTCCCCCAGCTGCGGTCCCTTCCCACTCTGACAATGAGCCTGTCATTAAGAGACCT GGTCCAGCGAGGAGATGGTGTACCCTGGCGGAGCCATGGTCTGGCCCCCTACTTACTCCA GGAACGAA CGCTGGAATACCCCCACTCCGAAGTGACTCAGGGCCCTCTGCCGCCCTCGGCTCACCGCCACTCAAC CCCAGTCGTGATGCCAGAGCCTAATGGCCTCTATGGGGGCTTCCCCTTCCCCCTGGAGATGGAAAACA AGCGGGCACCTCTCCCACCCCGTTACAGCAACCAGAACCTGGAAGATCTGATGCCCTCTCGGCCCCCT AGTCCCCGGGAGCGCCTGGTTGCCCCCTGTCTCAATGAGTACACGCCATCAGCTACTACCACTCGCA GTTCCGGCAGGGAGGGGGAGGGCCCTGCCTGGCAGACGGGGGCTACAAGGGGGTGGGTATGCGCCTCA GCCGAGCTGGGCCCTCTTATGCTGTCTGTGAGGTGGAGGGGGCACCTCTTGCAGGCCAGGGCCAGCCC CGGGTGCCCCCCAACTATGAGGGCTCTGACATGGTGGAGAGTGATTATGGCAGCTGTGAGGAGGTCAT GTTCTZGTCCTCCGOCAGAGCGGCAAGCGATGCTTTTCTTCC TGTCTCGTAGGGGGTGAGTTGAGTGTG( CTGGGAGAGTGGGAGGGAAGCCCTCAGCCCAGGCTGTTGT CCCTTGAAATGTGCTCTTCCAATCCCCCACCTAGTCCCTGAGGGTGGAGGGAAGCTGAGGATAGAGCT CCAGAAACAGCACTAGGGTCCCAGGAGAGGGGCATTTCTAGAGCAGTGACCCTGGAAALACCAGGAACA ATTGACTCCTGGGGTGGGCGACAGACAGGAGGGCTCCCTGATCTGCCGGCTCTCAGTCCCCGGGGCAA AGCCTGATTGACTGTGCTGGCTCAACTTCACCAAGATGCATTCTCATACCTGCCCACAGCTCCATTTT GGAGGCAGCCAGGTTGGTGCCTGACAGACAACCACTACGCGGGCCGTACAGAGGAGCTCTAGAGGGCT GCGTGGCATCCTCCTAGGGGCTGAGAGGTGAGCAGCAGGGGAGCGGCACAGTCCCCTCTGCCCCTGC 1 ')P7 WO 2004/015079 PCT/US2003/024931 GGAAAAATGTG ATGGAGGGCAACAAGGACTCCGAGGAGCACCACCAGCCTCGGG.CCCCAGACTC CCGCTCCTCAGCCTACACGCAGAGGAACQGCGCCCACCTCAGAGTCACACCACTGGCTGCCAGTCAGG CCTGCCAGGAGTCTACACACTCTGAACCTTCTTTGTTAGATTCAGACCTCAWCGGACTCTGGP TCTACCLGTCCGCCTTGCAAGAGGACATCTATTAA TTCTTIAGGCACTTTTTGACTTGCTGTCTGGATGAGTTTCCTCAATGGGATTTTTCTTCCCTAGACAC AAGATTACCTTTGGCGTGACAGACGACCGGCAGTG CACCTGCCATTGCCTCCTCTCCACTGCAGACGCCTGCCCATCAGTATTACCTGCAGCGACTCAACCC TATGCATGGAGGGTCAATGTGGGCACATGTCTACACATGTGGGTGCCCATGGATAGTACGTGTGTAC CATGTGTAGAGTGTATGTACCCAGGAGTGGTGGGGACCAGAAGCCTCTGTCGCCTTTGGTGACCTCAC (ACTCCCTCCCACCCAGTCCCTCCCTCTGGTCCACTGCCTTTTCATATGTGTTGTTTCT@CAGACAGA AG-TCAAAAGGAAGAGCAGTGGAGCCTTGCCCACAGGGCTGCTGCTTCATGCGAGAGGGAGATGTGTGG GCGAGAGCCAATTTGTGTGAGTGGTTTGTGGCTGTGTGTGTGACTGTGAGTGTGAGTGACAGATACAT AGTTTCATTGGTCATTTTTTTTTTAACTAAAG TTTTTTACTGTT NOV6a, CG51923-01 SEQ ]D NO: 40 439aa jMW at 479387.3kD Protein Sequencej MTALGFAIFLLHCATCEKPLEGILSSSAWHFTHSHYNATIYENSSPKTVESFEKMGIYLEPQWA VRYRII SGDVANVFKTEEYVGNFCFLRIRTKSSNTALLNREVDSYTLIIQATEKTLELELTRVVW HILDQNDLKPIFSPPSYRVTISEDMPLKSPICKVTATDALGQNAEF 'AFNTRSEMFAIHPTSGVVT VAKNTRKEQLVRRIENFSLAVHEARPAAVVPDNGT ATVLVDANSSGAEVESVEVVGDPGKHFKAIKSYARSNEFSLVS IWEYhHGFLSLQASGSG PYYQRFLPKSLFKVRQSFSPSVMRTAPLYLPSNGK NARTGLITTTKLMDFHDRHYQLHIRTSPGQASTVIDIVDNHPLFNRSSYGTLDENIPPGTS VLAVTATDRDHGENGYVTYSIAGPKALPFSIDPYLGII STSKPMDYELMKRIYTFRVRASDWGSPFRR EKEVSIFLQLRLNDNQPMFEE-VNCTGSIRQDWPVGKSIMTMSAIDDELQNLKYEVSGNELEYFDL NHFSGVISLKRPFINLTAGQPTSYSLKITASDGKNYAS PTTLNILTVVKDPHFEVPVTCDKTGVLTQFT KTTLHFIGLQNQESSDEEFTSLSTYQINHYTPQFEDHFPQSIDVL~ESVPINTPLRLATDPDAGFNG KLVYVIADNEEGCFDIELETGLLTVAAPLDYEAT YIL DLGTPQKSSWKLLDN APRFPPGGYQLTI SEDTEVGTTIAELTTKASEDNGRVRYTLLSPTEKFSLHPLTGELVTGHLDRE SEPRYLKVEARDQPSKGHQLFSVTDLIITLEDDNSPQCITE FVEDLPPGTVLFLDASDP DLPGVYLDAGFVLTAIEELFRAYLLADGPARLHEI LDVENLHPPHFASFVHQGQVQENSPSGTQVIQDDDSGLDGELQYFLAGTGLAASINQDTGM IQTIJAPLDREFASYYWLTVLAVDRGSVPLSSVTEVYIEVTDANDNPPQMSQAVFYPSIQEDAPVGTSV LQLDAWDPDSSSKGLTFNITSGNYGFFMIHPVTGLLSTAQQLDRENDEHILEVTVJDNGEPSLKS TSRVVVGILDVNDNPPIFSHKLFNVLPERLSPVSPGPVYRVASDLDEGLNGRVYSIEDSYEEAFS IDLVTGVVSSNSTFTAGENILTIATDSGQPPLSASVLHIEWIPWPRPSSIPLFDETYYSFTM TDPVNHIYVGVISVEGRPGLFWFNI SGGDKDMDFDIEKTTGSIVIARPLDTRRRSNYNLTVEVTDGSRT IATQVHIFMIANINHHRPQFLETRYEVRVPQDTVPGVLLRVQAIDQDKGKSLIYTIHGSQDPGSASL FQDSGLTGLLSPQTTMRQEPKNVVIVDNHPFQHES PDIPTLQRMARVAVYLKNSGFIALITAKDAHPTTK EDQGSPQWHDLATVIIHYPSDRSAPIFSKSEYVEIPESIPVGSPILLVSAMSPSEVTYELREGNKD GVSNYGITKLHKSYLIGNMGFDMVDIEDAMLSFGI EAAPLYSMIMDKNNPFVIHASDSDKANSLLVYKLEEAIKFFKIDPSMGTLTIVSEMDYESMPSF QFCVYHDQGSPVLFAPRPAQVIIHRDVNDSPPRFSEQIYAIVGPIHPGMELLSDEDSEVN YSIKTGNADEAVTIHPVTGSISVLNPAFLGLSRKLTIRASDGLYQDTALVKI SLTQVLDKSLQFDQDV YAVKENLQDRKALVILCAQGNLNDTLSYFLLNGTDMFHVQSAGLQTRGVAFDREQQDTHELAV EVRDNRTPQRVAQGLVRVSIEDVNDNPPKFKHLPYTIIQDGTEPGDVLFQVSATDEDLGTNGAVTYE FAEDYTYFRIDPYLGDISLKKPFDYQALNKYHLKVIARDGGTPSLQSEEE- V'NSNPLFQSPYY KVRVPENITLYTPILHTQARSPELRLIYNIVEEEPLFTTDFKTLTGPLDYESKTVTV ATDTALGSFSE-ATVEVLVEDVNDNPPTFSQLVYTTSISEGLPAQTPVIQLLASDQDSGRRDVSYQIV EDGSDVSKFFQINGSTGEMSTVQELDYEAQQHFHVKVKGDPPLTGETLNSDINNPPEFR QPYAVEACHVKQIPSDSLELLGQRFISSISFLKHD SYLVADVRTPYNTAKSEQHYEANMGKILADDGYT DYTIINKLASEKFSINPNGQIATLQKLDRENSTERVIAIADGGRVAFCTVKIILTDENNPPQ FKASEYTVSIQSNVSKDS PVIQVLAYDADEGNADVTYSVNPEDLVKDVINPVTVKSLVGL ENQTLDFFIKAQDGGPPHNSLVPVRLQVVPKKVSLPKFSEPLYTFSAPEDLPEGSEIGIVAVAQD PVYLRTPSKGFLPTVKRPMHSKYIVACQTVSVVIV DVDRVEDYALEMVTVQTIDDGDQSRSDGNHLADEG ITTLQELDCETCQTYFVVAYDHGQTIQLSSQLVQVSITDNNAPRFASEEYRGSVENSEPGEL VATLKTLDADISEQNRQVTCYITEGDPLGQFGISQVGDERISSRKTLDREHTAKYLLRVTASDGKFQ ASVTVEIFVLDVNDNSPQCSQLLYTGKVHEDVFPGHFILKVSATDLDTDTNAQITYSLHGPGHEFK DPTETLADEKVNVKTGGSCAILVDNNPFPHAAFNT KTPVAVVFARDPDQGANAQVVYSLPDSAECHFSIDATTGVILEKPLQVRPQAPLELTVRSDLGTPI PLSTLGTVTVSVGLEDYLPVFLNTEHSVQVPEDAPPGTEVLQLATLTRPGAEKTGYRVSGNEQGRF RLDARTGILYVNASLDFETSPKYFLSIECSRKSSSSLSDVTTVNITDVNEHRPQFPQDPYSTRVLE NALVGDVILTVSATDEDGPLNSDITYSLGGNQLGHFTIHPKKGELQVADREQASSYSLLPTD SGQPPLHEDTDIAIQVADDNPPRFFQLNYSTTVQENSPIGSKVQLILSDPDSPENGPPYSFRITK VNNSFRVTPDCTA'LSRRAOEWYOLOIOASDSGIPPLSqSLTSVRHVEOSHAPSALPLEI WO 2004/015079 PCT/US2003/024931 FITVGEDEFQGGMVGKIHATDRDPOQD'LTYSLAEEETLGRHFSVGAPDGKIIAAQGLPRGHYSFNVTV SDGTFTTTAGVHVYVWHVGQEALQQAMWMGFYQLTPEELVSDHWRNLQRFLSHKLDIKRANIHLASLQ PAEAVAGVDVLLVFEGHSGTFYEFQELASIITHSAKEMEHSVGVQMRSAMPMVPCQGPTCQGQICHNT VHLDPKVGPTYSTARLSILTPRHHLQRSCSCNGTATRFSGQSYVRYRAPAARNWHIHFYLKTLQPQAI LLFTNETASVSLKLASGVPQLEYHCLGGFYGNLSSQRHVNDHEWHSILVEEMDASIRLMVDSMGNTSL VVPENCRGLRPERHLLLGGLILLHSSSNVSQGFEGCLDAVVVNEEALDLLAPGKTVAGLLETQALTQC CLHSDYCSQNTCLNGGKCSWTHGAGYVCKCPPQFSGKHCEQGRENCTFAPCLEGGTCILSPKGASCNC PHPYTGDRCEMEARGCSEGHCLVTPEIQRGDWGQQELLIITVAVAFIIISTVGLLFYCRRCKSHKPVA MEDPDLLARSVGVDTQAMPAIELNPLSASSCNNLNQPEPSKASVPNELVTFGPNSKQRPVVCSVPPRL PPAAVPSHSDNEPVIKRTWSSEEMVYPGGAMVWPPTYSRNERWEYPHSEVTQGPLPPSAHRHSTPVVM PEPNGLYGGFPFPLEMENKRAPLPPRYSNQNLEDLMPSRPPSPRERLVAPCLNEYTAISYYHSQFRQG GGPCLADGGYKGVGMRIS~PYVEEALGG AGPYGDVEDGCEM NOV6b, 305869563 SEQ ID NO: 41 12019 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GATGGAGGAGGAAGAGTAGCCTTCTGCAEGGTGAAGATCATCCTCACAGATGAAAATGA CAACCCCCCACAGTTCAAAGCATCTGAGTACACAGTATCCATTCAATCCAATGTCAGTAAAGACTCTC CGGTTATCCAGGTGTTGGCCTATGATGCAGATGAAGGTCAGAACGCAGATGTCACCTACTCAGTGAAC CCAGAGGACCTAGTTAAAGATGTCATTGAAATTAACC~CAGTCACTGGTGTGGTCAAGGTGAAAGACAG CCTGGTGGGATTGGAAAATCAGACCCTTGACTTCTTCATCAAAGCCCAAGATGGAGGCCCTCCTCACT GGAACTCTCTGGTGCCAGTACGACTTCAGGTGGTTCCTAAAAAAGTATCCTTACCGAAATTTTCTGAA CCTTTGTATACTTTCTCTGCACCTGAAGACCTTCCAGAGGGGTCTGAAATTGGGATTGTTAAAGCAGT GGCAGCTCAAGATCCAGTCATCTACAGTCTAGTGCGGGGCACTACACCTGAGAGCAACAAGGATGGTG TCTTCTCCCTAGACCCAGACACAGGGGTCATAAAGGTGAGGAAGCCCATGGACCACGAATCCACCAAA TTGTACCAGATTGATGTGATGGCACATTGCCTTCAGAALCACTGATGTGGTGTCCTTGGTCTCTGTCAA CATCCAAGTGGGAGACGTCAATGACAATAGGCCTGTATTTGAGGCTGATCCATATAAGGCTGTCCTCA CTGAGAATATGCCAGTGGGGACCTCAGTCATTCAAGTGACTGCCATTGACAAGGACACTGGGAGAGAT GGCCAGGTGAGCTACAGGCTGTCTGCAGACCCTGGTAGCAATGTCCATG AGCTCTTTGCCATTGA CAG TGAGAGTGGTTGGATCACCACACTCCAGGAACTTGACTGTGAGACCTGC.,CAGACTTATCATTTTCATG TGGTGGCCTATGACCACGGACAGACCATCCAGCTATCCTCTCAGGCCCTGGTTCAGGTCTCCATTACA GATGAGAATGACAATGCTCCCCGATTTGCTTCTGAAGAGTACAGAGGATCTGTGGTTGAGAACAGTGA GCCTGGCGAACTGGTGGCGACTCTAAAGACCCTGGATG3CTGACATTTCTGAGCAGAACAGGCAGGTCA CCTGCTACATCACAGAGGGAGACCCCCTGGGCCAGTTTGGCATCAGCCAAGTTGGAGATGAGTGGAGG ATTTCCTCAAGGAAGACCCTGGACCGCGAGCATACAGCCAAGTACTTGCTCAGAGTCACAGCATCTGA TGGCAAGTTCCATGCTTCGGTCACTGTGGAGATCTTTGTCCTGGACGTCAATGATAACAGCCCACAGT GTTCACAGCTTCTCTATACTGGCAAGGTTCATGAAGATGTATTTCCAGGACACTTCATTTTGAAGGTT TCTGCCACAGACTTGGACACTGATACCAATGCTCAGATCACATATTCTCTGCATGGCCCTGGGGCGCA TGAATTCAAGCTGGATCCTCATACAGGGGAGCTGACCACACTCACAGCCCTAGACCGAGAAAGGAAGG ATGTGTTCAACCTTGTTGCCAAGGCGACGGATGGAGGTGGCCGATCGTGCCAGGCAGACATCACCCTC CATGTGGAGGATGTGAATGACAATGCCCCGCGGTTCTTCCCCAGCCACTGTGCTGTGGCTGTCTTCGA CAACACCACAGTGAAGACCCCTGTGGCTGTAGTATTTGCCCGGGATCCCGACCAAGGCGCCAATGCCC AGGTGGTTTACTCTCTGCCGGATTCAGCCGAAGGCCACTTTTCCATCGACGCCACCACGGGGGTGATC CGCCTGGAAAAGCCGCTGCAGGTCAGGCCCCAGGCACCACTGGAGCTCACGGTCCGTGCCTCTGACCT

GGGCACCCCAATACCGCTGTCCACGCTGGGCACCGTCACAGTCTCGGTGGTGGGCCTAGAAGACTACC

TGCCCGTGTTCCTGAACACCGAGCACAGCGTGCAGGTGCCCGAGGACGCCCCACCT NOV6b, 305869563 SEQ IID NO: 42 679 aa MWat ~73948kD Protein Sequence )GGCGRVAFO IILTDENDNPOSEASEYTVSIQSNVSKDSPVIQVLAYDADEGQNADVTYSVN PEDLVKDVIEINPVTGVVKVKDSLVGLENQTLDFFIKAQDGGPPHWNSLVPVRLQVVPKKVSLPKFSE PLYTFSAPEDLPEGSEIGIVKAVAAQDPVIYSLVRGTTPESNKDGVFSLDPDTGVIKVRKPMDHESTK. LYQIDVMAHCLQNTDVVSLVSVNIQVGDVNDNRPVFEADPYKAVLTENMPVGTSVIQVTAIDKDTGRD GQVSYRLSADPGSNVHELFAIDSESGWITTLQELDCETCQTYHFHVVAYDHGQTIQLSSQALVQVSIT DENDNAPRFASEEYRGSVVENSEPGELVATLKTLDADISEQNRQVTCYITEGDPLGQFGISQVGDEWR ISSRKTLDREHTAKYLLRVTASDGKFHASVTVEIFVLDVNDNSPQCSQLLYTGKVHEDVFPGHFILKV SATDLDTDTNAQITYSLHGPGAHEFKLDPHTGELTTLTALDRERKDVFNLVAKATDGGGRSCQADITL HVEDVNDNAPRFFPSHCAVAVFDNTTVKTPVAVVFARDPDQGANAQVV-YSLPDSAEGHFSIDATTGVI RLEKPLQVRPQAPLELTVRASDLGTPIPLSTLGTVTVSVVGLEDYLPVFLNTEHSVQVPEDAPP NOVc, 3058656 SEQ ID NO: 43 2037 bp DNA Sequence JORF Start: at 1 1ORF Stop- end of sequence GATGGAGGAGGAAGAGTAGCCTTCTGCAddsidAAGATCATCCTCACAGATGAAAATGA CAACCCCCCACAGTTCAAAGCATCTGAGTACACAGTATCCATTCAATCCAATGTCAGTAAAGACTCTC CGGTTATCCAGGTGTTGGCCTATGATGCAGATGAAGGTCAGAACGCAGATGTCACCTACTCAGTGAAC CCAGAGGACCTAGTTAAAGATGTCATTGAAATTAACCCAGTCACTGGTGTGGTCAAGGTGAAAGACAG CCTGGTGGGATTGGAAAATCAGACCCTTGACTTCTTCATCAAAGCCCAAGATGGAGGCCCTCCTCACT

IGGAACTCTCTGGTGCCAGTACGACTTCAGGTGGTTCCTAAAAAAGTATCCTTACCGAAATTTTCTGAA,

WO 2004/015079 PCT/US2003/024931 CCTTTGTATACTTTCTTGCACCTGAAGACCTTCCAGAGGGGTCTGAAATTGGGATTGTTAAAGCAGT GGCAGCTCAAGATCCAGTCATCTACAGTCTAGTGCGGGGCACTACACCTGAGAGCAACAAGGATGGTG TCTTCTCCCTAGACCCAGACACAGGGGTCATAAAGGTGAGGAAGCCCATGGACCACGAATCCACCAAA TTGTACCAGATTGATGTGATGGCACATTGCCTTCAGAACACTGATGTGGTGTCCTTGGTCTCTGTCAA CATCCAAGTGGGAGACGTCAATGACAATAGGCCTGTATTTGAGGCTGATCCATATAAGGCTGTCCTCA CTGAGAATATGCCAGTGGGGACCTCAGTCATTCAAGTGACTGCCATTGACAAGGACACTGGGAGAGAT GGCCAGGTGAGCTACAGGCTGTCTGCAGACCCTGGTAGCAATGTCCATGAGCTCTTTGCCATTGACAG TGAGAGTGGTTGGATCACCACACTCCAGGAACTTGACTGTGAGACCTGCCAGACTTATCATTTTCATG TGGTGGCCTATGACCACGGACAGACCATCCAGCTATCCTCTCAGGCCCTGGTTCAGGTCTCCATTACA GATGAGAATGACAATGCTCCCCGATTTGCTTCTGAAGAGTACAGAGGATCTGTGGTTGAGAACAG.TGA GCCTGGCGAACTGGTGGCGACTCTAAACACCCTGGATGCTGACATTTCTGAGCAGAACAGGCAGGTCA CCTGCTACATCACAGAGGGAGACCCCCTGGGCCAGTTTGGCATCAGCCAAGTTGGAGATGAGTGGAGG ATTTCCTCAAGGAAGACCCTGGACCGCGAGCATACAGCCAAGTACTTGCTCAGAGTCACAGCATCTGA TGGCAAGTTCCAGGCTTCGGTCACTGTGGAGATCTTTGTCCTGGACGTCAATGATAACAGCCCACAGT GTTCACAGCTTCTCTATACTGGCAAGGTTCATGAAGATGTATTTCCAGGACACTTCATTTTGAAGGTT TCTGCCACAGACTTGGACACTGATACCAATGCTCAGATCACATATTCTCTGCATGGCCCTGGGGCGCA TGAATTCAAGCTGGATCCTCATACAGGGGAGCTGACCACACTCACTGCCCTAGACCGAGAAACGAAGG ATGTGTTCAACCTTGTTGCCAAGGCGACGGATGGAGGTGGCCGATCGTGCCAGGCAGACATCACCCTC CATGTGGAGGATGTGAATGACAATGCCCCGCGGTTCTTCCCCAGCCACTGTGCTGTGGCTGTCTTCGA CAACACCACAGTGAAGACCCCTGTGGCTGTAGTATTTGCCCGGGATCCCGACCAAGGCGCCAATGCCC AGGTGGTTTACTCTCTGCCGGATTCAGCCGAAGGCCACTTTTCCATCGACGCCACCACGGGGTGATC CGCCTGGAAAAGCCGCTGCAGGTCAGGCCCCAGGCACCACTGGAGCTCACGGTCCGTGCCTCTGACCT GCGCACCCCAATACCGCTGTCCACGCTGGGCACCGTCACAGTCTCGGTGGTGGGCCTAGAAGACTACC TGCCCGTGTTCCTGAACACCGAGCACAGCGTGCAGGTGCCCGAGGACGCCCCACCT NOV6c, 305869567 SEQ ID NO: 44 679 aa MW at -73939 kD Protein Sequence DGGGVAFTV ILTI)FDNPPQFKASEYTVSIQSNVSKDSPVIQVLAYDADEGQNADVTYSVN PEDLVKDVIE INPVTGVVKVKDSLVGLENQTLDFFIKAQDGGPPHWNSLVPVRLQVVPKKVSL PKFSE PLYTFSAPEDLPEGSEIGIVKAVAAQDPVIYSLVRGTTPESNKDGVFSLDPDTGVIKVRKPMDHESTK LYQIDVMAHCLQNTDVVSLVSVNIQVGDVNDNRPVFEADPYKA-VLTENMPVGTSVIQVTAIDKDTGRD GQVSYRLSADPGSNVHELFAIDSESGWITTLQELDCETCQTYHFHVVAYDHGQTIQL SSQALVQVSIT DENDNAPRFASEEYRGSVVENSEPGELVATLKTLDADISEQNRQVTCYITEGDPLGQFGISQVGDEWR ISSRKTLDREHTAKYLLRVTASDGKFQASVTVEIFVLDVNDNSPQCSQLLYTGKVHEDVFPGHFILKV SATDLDTDTNAQITYSLHGPGAHEFKLDPHTGELT TLTALDRERKDVFNLVAKATDGGGRSCQADITL HVEDVNDNAPRFF PSHCAVAVFDNTTVKTPVAVVFARDPDQGANAQVVYSLPDSAEGHFSIDATTGVI RLEKPLQVRPQAPLELTVRASDLGTPIPLSTLGTVTVSVVGLEDYLPVFLNTEHSVQVPEDAPP-,, NOV6d, 306076041 SEQ ID NO: 45 1455 bp DNA Sequence |ORF Start: at 1 ORF Stop: end of sequence GACCCCCAGGACACGCTGACCTATAGCCTGGCAGAAGAGGAGACCCTGGGCAGGCACTT CTCAGTGGGTGCGCCTGATGGCAAGATTATCGCCGCCCAGGGCCTGCCTCGTGGCCACTACTC GTTCA ACGTCACGGTCAGCGATGGGACCTTCACCACGACTGCTGG3GGTCCATGTGTATGTGTGGCATGTGGGG CAGGAGGCTCTGCAGCAGGCCATATGGATGGGCTTCTACCAGCTCACCCCCGAGGAGCTGGTGAGTGA CCACTGGCGGAACCTGCAGAGGTTCCTCAGCCATAAGCTGGACATCAAACGGGCTAACATTCACTTGG CCAGCCTCCAGCCTGCAGAGGCCGTGGCTGGTGTGGATGTGCTCCTGGTCTTTGAGGGGCATTCTGGA ACCTTCTACGAGTTTCAGGAGCTAGCATCCATCATCACTCACTCAGCCAAGGAGATGGAGCATTCAGT GGGGGTTCAGATGCGGTCAGCTATGCCCATGGTGCCCTGCCAGGGGCCAACCTGCCAGGGTCAAATCT GCCATAACACAGTGCATCTGGACCCCAAGGTTGGGCCCACGTACAGCACCGCCAGGCTCAGCATCCTA ACCCCGCGGCACCACCTGCAGAGGAGCTGCTCCTGCAATGGTACTGCTACAAGGTTCAGTGGTCAGAG CTATGTGCGGTACAGGGCCCCAGCGGCTCGGAACTGGCACATCCAT TTCTATCTGAAAACACTCCAGC CACAGGCCATTCTTCTATTCACCAATGAAACAGCGTCCGTCTCCCTGAAGCTGGCCAGTGGAGTGCCC CAGCTGGAATACCACTGTCTGGGTGGTTTCTATGGAAACCTTTCCTCCCAGCGCCATGTGAATGACCA CGAGTGGCACTCCATCCTGGTGGAGGAGATGGACGCTTCCATTCGCCTGATGGTTGACAGCATGGGCA ACACCTCCCTTGTGGTCCCAGAGAACTGCCGTGGTCTGAGGCCCGAAAGGCACCTCTTGCTGGGCG.GC CTCATTCTGTTGCATTCT TCCTCGAATGTCTCCCAGGGCTTTGAAGGCTGCCTGGATGCTGTCGTGG'l CAACGAAGAGGCTCTAGATCTGCTGGCCCCTGGCAAGACGGTGGCAGGCTTGCTGGAGACACAAGCCC TCACCCAGTGCTGCCTCCACAGTGACTACTGCAGCCAGAACACATGCCTCAATGGTGGGAAGTGCTCA TGGACCCATGGGGCAGGCTATGTCTGCAAATGTCCCCCACAGTTCTCTGGGAAGCACTGTGAACAAGG AAGGGAGAACTGTACTTTTGCACCCTGCCTGGAAGGTGGAACTTGCATCCTCTCCCCCAAAGGAGCT'I CCTGTAACTGCCCTCATCCTTACACAGGAGACAGGTGTGAAATGGAGGCGAGGGGTTGTTCAGAAGGA CACTGCCTAGTCACTCCCGAGATCCAAAGGGGGGAC NOV6d, 306076041 SQINO46 485 aa MW at ~53871kD Protein Sequence ]E DN:4 DPQDTLTYSLAETLGlinFSVGAPDGKIIAAQGLPRGHYSFNVTVSDGTFTTTGHYWV

OEALOOAIWMGFYOLTPEELVSDHWRNLORFLSHKLDIKRANIHLASLOPAEAVAGVDVLLVFEGHSG

WO 2004/015079 PCT/US2003/024931 TFYEFQELASIITHSAKEMEHSVVQMRSAMPMVPCQGPTCQGQICHNTVHLDPKVGPTYSTARLSIL TPRHHLQRSCSCNGTATRFSGQSYVRYRAPAARNWHIHFYLKTLQPQAILLFTNETASVSLKLASGVP QLEYHCLGGFYGNLSSQRHVNDHEWHSILVEEMDASIRLMVDSMGNTSLVVPENCRGLRPERHLLLGG LILLHSSSNVSQGFEGCLDAVVVNEEALDLLAPGKTVAGLLETQALTQCCLHSDYCSQNTCLNGGKCS WTHGAGYVCKCPPQFSGKHCEQGRENCTFAPCLEGGTCILSPKGASCNCPHPYTGDRCEMEARGCSEG HCLVTPEIQRGD NOV6e, 317868343 SEQ ID NO: 47 1977 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence ATGACTATTGCCCTGCTGGGTTTTGCCNTATTCTTGCTCCATTGTGCGACCTGTGAGAA GCCTCTAGAAGGGATTCTCTCCTCCTCTGCTTGGCACTTCACACACTCCCATTACAATGCCACCATCT ATGAAAATTCTTCTCCCAAGACCTATGTGGAGAGCTTCGAGAAAATGGGCATCTACCTCGCGGAGCCA CAGTGGGCAGTGAGGTACCGGATCATCTCTGGGGATGTGGCCAATGTATTTAAAACTGAGGAGTATGT GGTGGGCAACTTCTGCTTCCTAAGAATAAGGACAAAGAGCAGCAACACAGCTCTTCTGAACAGAGAGG TGCGAGACAGCTACACCCTCATCATCCAAGCCACAGAGAAGACCTTGGAGTTGGAAGCTTTGACCCGT GTGGTGGTCCACATCCTGGACCAGAATGACCTGAAGCCTCTCTTCTCTCCACCTTCGTACAGAGTCAC CATCTCTGAGGACATGCCCCTGAAGAGCCCCATCTGCAAGGTGACTGCCACAGATGCTGATCTAGGCC AGAATGCTGAGTTCTATTATGCCTTTAACACAAGGTCAGAGATGTTTGCCATCCATCCCACCAGCGGT GTGGTCACTGTGGCTGGGAAGCTTAACGTCACCTGGCGAGGAAAGCATGAGCTCCAGGTGCTAGCTGT GGACCGCATGCGGAAAATCTCTGAGGGCAATGGGTTTGGCAGCCTGGCTGCACTTGTGGTTCATGTGG AGCCTGCCCTCAGGAAGCCCCCAGCCATTGCTTCAGTGGTGGTGACTCCACCAGACAGCAATGATGGT ACCACCTATGCCACTGTACTCGTCGATGCAAATAGCTCAGGAGCTGAAGTGGAGTCAGTGGAAGTTGT TGGTGGTGACCCTGGAAAGCACTTCAAAGCCATCAAGTCTTATGCCCGGAGCAATGAGTTCAGTTTGG TGTCTGTCAAAGACATCAACTGGATGGAGTACCTTCATGGGTTCAACCTCAGCCTCCAGGCCAGGAGT GGGAGCGGCCCTTATTTTTATTCCCAGATCAGGGGCTTTCACCTACCACCTTCCAAACTGTCTTCCCT CAAATTCGAGAAGGCTGTTTACAGAGTGCAGCTTAGTGAGTTTTCCCCTCCTGGCAGCCGCGTGGTGA TGGTGAGAGTCACCCCAGCCTTCCCCAACCTGCAGTATGTTCTAAAGCCATCTTCAGAGAATGTAGGA TTTAAACTTAATGCTCGAACTGGGTTGATCACCACCACAAAGCTCATGGACTTCCACGACAGAGCCCA CTATCAGCTACACATCAGAACCTCACCGGGCCAGGCCTCCACCGTGGTGGTCATTGACATTGTGGACT GCAACAACCATGCCCCCCTCTTCAACAGGTCTTCCTATGATGGTACCTTGGATGAGAACATCCCTCCA GGCACCAGTGTTTTGGCTGTGACTGCCACTGACCGGGATCATGGGGAAAATGGATATGTCACCTATTC CATTGCTGGACCAAAAGCTTTGCCATTTTCTATTGACCCTTACCTGGGGATCATCTCCACCTCCAAAC CCATGGACTATGAACTCATGAAAAGAATTTATACCTTCCGGGTAAGAGCATCAGACTGGGGATCCCCT TTTCGCCGGGAGAAGGAAGTGTCCATTTTTCTTCAGCTCAGGAACTTGAATGACAACCAGCCTATGTT TGAAGAAGTCAACTGTACAGGTTCTATCTGCCAAGACTGGCCAGTAGGGAATCGATAATGACTATGT CAGCCATAGATGTGGATGACTTCAGAACCTAAAATACGAGATTGTATCAGGCAATGAACTAGAGTAT TTTGATCTAAATCATTTCTCCGGAGTGATATCCCTCAAACGCCCTTTTATCAATCTTACTGCTGGTCA ACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAAAACTATGCCTCACCCACAACTTTGA ATATTACTGTGGTG NOV6e, 317868343 SEQ ID NO: 48 606 aa MW at -73978kD Protein Sequence TIATLGFAFLLHCATCEKPLEGILSSSAWFTHSHYNATIYENSSPKTYVESFEKMGIYLAEP QWAVRYRIISGDVANVFKTEEYVVGNFCFLRIRTKSSNTALLNREVRDSYTLIIQATEKTLELEALTR VVVHILDQNDLKPLFSPPSYRVTISEDMPLKSPICKVTATDADLGQNAEFYYAFNTRSEMFAIHPTSG VVTVAGKLNVTWRGKHELQVLAVDRMRKISEGNGFGSLAALVVHVEPALRKPPAIASVVVTPPDSND TTYATVLVDANSSGAEVESVEVVGGDPGKHFKAIKSYARSNEFSLVSVKDINWMEYLHGFNLSLQARS GSGPYFYSQIRGFHLPPSKLSSLKFEKAVYRVQLSEFSPPGSRVVMVRVTPAFPNLQYVLKPSSENVG FKLNARTGLITTTKLMDFHDRAHYQLHIRTSPGQASTVVVIDIVDCNNHAPLFNRSSYDGTLDENIPP GTSVLAVTATDRDHGENGYVTYSIAGPKALPFSIDPYLGIISTSKPMDYELMKRIYTFRVRASDWGSF FRREKEVSIFLQLRNLNDNQPMFEEVNCTGSICQDWPVGKSIMTMSAIDVDELQNLKYEIVSGNE FDLNHFSGVISLKRPFINLTAGQPTSYSLKITASDGKNYASPTTLNITVVLEA NOV6f, 317868367 ISEQ ID NO: 49 1977 bp DNA Sequence OR Start: at 1. ORF Stop: end of sequence ATGACTATTGCCCTGCTGGGTTTTGCCATATTCTTGCTCCATTGTGCGACCTGTGAGAA GCCTCTAGAAGGGATTCTCTCCTCCTCTGCTTGGCACTTCACACACTCCCATTACAATGCCACCATCT ATGAAAATTCTTCTCCCAAGACCTATGTGGAGAGCTTCGAGAAAATGGGCATCTACCTCGCGGAGCCA CAGTGGGCAGTGAGGTACCGGATCATCTCTGGGGATGTGGCCAATGTATTTAAACTGAGGAGTATGT GGTGGGCAACTTCTGCTTCCTAAGAATAAGGACAAAGAGCAGCAACACAGCTCTTCTGAACAGAGAGG TGCGAGACAGCTACACCCTCATCATCCAAGCCACAGAGAAGACCTTGGAGTTGGAAGCTTTGACCCGT GTGGTGGTCCACATCCTGGACCAGAATGACCTGAAGCCTCTCTTCTCTCCACCTTCGTACAGAGTCAC CATCTCTGAGGACATGCCCCTGAACACCCCCATCTGCAAGGTGACTGCCACAGATGCTGATCTAGGCC AGAATGCTGAGTTCTATTATGCCTTTAACACAAGGTCAGAGATGTTTGCCATCCATCCCACCAGCGGT GTGGTCACTGTGGCTGGGAAGCTTAACGTCACCTGGCGAGGAAAGCATGAGCTCCAGGTGCTAGCTGT GGACCGCATGCGGAAAATCTCTGAGGGCAATGGGTTTGGCAGCCTGGCTGCACTTGTGGTTCATGTGG

AGCCTGCCCTCAGGAAGCCCCCAGCCATTGCTTCGGTGGTGGTGACTCCACCAGACAATGATGGT

WO 2004/015079 PCT/US2003/024931 ACCACCTATGCCACTGTACTGGTCGITGCAAATAGCTCAGGAGCTGAAGTGGAGTCAGTGGAAGTTGT TGGTGGTGACCCTGGAAAGCACTTCAAAGCCATCAAGTCTTATGCCCGGAGCAATGAGTTCAGTTTGG TGTCTGTCAAAGACATCAACTGGATGGAGTACCTTCATGGGTTCAACCTCAGCCTCCAGGCCAGGAGT GGGAGCGGCCCTTATTTTTATTCCCAGATCAGGGGCTTTCACCTACCACCTTCCAAACTGTCTTCCCT CAAATTCGAGAAGGCTGTTTACAGAGTGCAGCTTAGTGAGTTTTCCCCTCCTGGCAGCCGCGTGGTGA TGGTGAGAGTCACCCCAGCCTTCCCCAACCTGCAGTATGTTCTAAAGCCATCTTCAGAGAATGTAGGA TTTAAACTTAATGCTCGAACTGGGTTGATCACCACCACAAAGCTCATGGACTTCCACGACAGAGCCCA CTATCAGCTACACATCAGAACCTCACCGGGCCAGGCCTCCACCCTGGTGGTCATTGACATTGTGGACT GCAACAACCATGCCCCCCTCTTCAACAGGTCTTCCTATGATGGTACCTTGGATGAGAACATCCCTCCA GGCACCAGTGTTTTGGCTGTGACTGCCACTGACCCGCATCATGGGGAAAATGGATATGTCACCTATTC CATTGCTGGACCAAAAGCTTTGCCATTTTCTATTGACCCTTACCTGGGGATCATCTCCACCTCCAAAC CCATGGACTATGAACTCATGAAAAGAATTTATACCTTCCGGGTAAGAGCATCAGACTGGGGATCCCCT TTTCGCCGGGAGAAGGAAGTGTCCATTTTTCTTCAGCTCAGGAACTTGAATGACAACCAGCCTATGTT TGAAGAAGTCAACTGTACAGGGTCTATCCGCCAAGACTGGCCAGTAGGGAAATCGATAATGACTATGT CAGCCATAGATGTGGATGAGCTTCAGAACCTAAAATACGAGATTGTATCAGGCAATGAACTAGAGTAT TTTGATCTAAATCATTTCTCCGGAGTGATATCCCTCAAACGCCCTTTTATCAATCTTACTGCTGGTCA ACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAAAACTATGCCTCACCCACAACTTTGA ATATTACTGTGGTG NOV6f, 317868367 SEQ ID NO: 50 659 aa MW at 74031.4kD Protein Sequence_ 99TIAGFIFLLHATCE FLILSSSAWHFTHSHYNATIYENSSPKTYVESFEKMGIYLAEP QWAVRYRI ISGDVANVFKTEEYVVGNFCFLRIRTKSSNTALLNREVRDSYTLIIQATEKTLELEALTR VVVHILDQNDLKPLFSPPSYRVTISEDMPLKSPICKVTATDADLGQNAEFYYAFNTRSEMFAIHPTSG VVTVAGKLNVTWRGKHELQVLAVDRMRKISEGNGFGSLAALVVHVEPALRKPPAIASVVVTPPDSNDG TTYATVLVDANSSGAEVESVEVVGGDPGKHFKAIKSYARSNEFSLVSVKDINWMEYLHGFNLSLQARS GSGPYFYSQIRGFHLPPSKLSSLKFEKAVYRVQLSEFSPPGSRVVMVRVTPAFPNLQYVLKPSSENVG FKLNARTGLITTTKLMDFHDRAHYQLHIRTSPGQASTVVVIDIVDCNNHAPLFNRSSYDGTLDENIPP GTSVLAVTATDRDHGENGYVTYSIAGPKALPFSIDPYLGIISTSKPMDYELMKRIYTFRVRASDWGSP FRREKEVSIFLQLRNLNDNQPMFEEVNCTGSIRQDWPVGKSIMTMSAIDVDELQNLKYEIVSGNELEY FDLNHFSGVISLKRPFINLTAGQPTSYSLKITASDGKNYASPTTLNITVV NOV6g, 317871203 EQ ID NO: 51 11923 bp DNA Sequence ORF Start: at 1 JORF Stop: end of sequence GAGAAGCCTCTAGAAGGGATTCTCTCCTCCTCTGCTTGGCACTTCACACACTCCCATTA CAATGCCACCATCTATGAAAATTCTTCTCCCAAGACCTATGTGGAGAGCTTCGAGAAAATGGGCATCT ACCTCGCGGAGCCACAGTGGGCAGTGAGGTACCGGATCATCTCTGGGGATGTGGCCAATGTATTTAAA ACTGAGGAGTATGTGGTGGGCAACTTCTGCTTCCTAAGAATAAGGACAAAGAGCAGCAACACAGCTCT TCTGAACAGAGAGGTGCGAGACAGCTACACCCTCATCATCCAAGCCACAGAGAAGACCTTGGAGTTGG AAGCTTTGACCCGTGTGGTGGTCCACATCCTGGACCAGAATGACCTGAAGCCTCTCTTCTCTCCACCT TCGTACAGAGTCACCATCTCTGAGGACATGCCCCTGAAGAGCCCCATCTGCAAGGTGACTGCCACAGA TGCTGATCTAGGCCAGAATGCTGAGTTCTATTATGCCTTTAACACAAGGTCAGAGATGTTTGCCATCC ATCCCACCAGCGGTGTGGTCACTGTGGCTGGGAAGCTTAACGTCACCTGGCGAGGAAAGCATGAGCTC CAGGTGCTAGCTGTGGACCGCATGCGGAAAATCTCTGAGGGCAATGGGTTTGGCAGCCTGGCTGCACT TGTGGTTCATGTGGAGCCTGCCCTCAGGAAGCCCCCAGCCATTGCTTCAGTGGTGGTGACTCCACCAG ACAGCAATGATGGTACCACCTATGCCACTGTACTGGTCGATGCAAATAGCTCAGGAGCTGAAGTGGAG TCAGTGGAAGTTGTTGGTGGTGACCCTGGAAAGCACTTCAAAGCCATCAAGTCTTATGCCCGGAGCAA TGAGTTCAGTTTGGTGTCTGTCAAAGACATCAACTGGATGGAGTACCTTCATGGGTTCAACCTCAGCC TCCAGGCCAGGAGTGGGAGCGGCCCTTATTTTTATTCCCAGATCAGGGGCTTTCACCTACCACCTTCC AAACTGTCTTCCCTCAAATTCGAGAAGGCTGTTTACAGAGTGCAGCTTAGTGAGTTTTCCCCTCCTGG CAGCCGCGTGGTGATGGTGAGAGTCACCCCAGCCTTCCCCAACCTGCAGTATGTTCTAAAGCCATCTT CAGAGAATGTAGGATTTAAACTTAATGCTCGAACTGGGTTGATCACCACCACAAAGCTCATGGACTTC CACGACAGAGCCCACTATCAGCTACACATCAGAACCTCACCGGGCCAGGCCTCCACCGTGGTGGTCAT TGACATTGTGGACTGCAACAACCATGCCCCCCTCTTCAACAGGTCTTCCTATGATGGTACCTTGGATG AGAACATCCCTCCAGGCACCAGTGTTTTGGCTGTGACTGCCACTGACCGGGATCATGGGGAAAATGGA TATGTCACCTATTCCATTGCTGGACCAAAAGCTTTGCCATTTTCTATTGACCCTTACCTGCGGATCAT CTCCACCTCCAAACCCATGGACTATGAACTCATGAAAAGAATTTATACCTTCCGGGTAAGAGCATCAG ACTGGGGATCCCCTTTTCGCCGGGAGAAGGAAGTGTCCATTTTTCTTCAGCTCAGGAACTTGAATGAC AACCAGCCTATGTTTGAAGAAGTCAACTGTACAGGGTCTATCTGCCAAGACTGGCCAGTAGGGAAATC GATAATGACTATGTCAGCCATAGATGTGGATGAGCTTCAGAACCTAAAATACGAGATTGTATCAGGCA ATGAACTAGAGTATTTTGATCTAAATCATTTCTCCGGAGTGATATCCCTCAAACGCCCTTTTATCAAT CTTACTGCTGGTCAACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAAAACTATGCCTC ACCCACAACTTTGAATATTACTGTGGTG NOVS6g, 317871203 SEQ ID NO: 52 641 aa MW at 72058.OkD P t rotein Sequence

IA^

WO 2004/015079 PCT/US2003/024931 TEYVVGNFCFLRIRTKSSNTALLNREVRDSYTLIIQAT EKTL ELEALTRVVVHILDQNDLKPLFSPP SYRVTISEDMPLKSPICKVTATDADLGQNAEFYYAFNTRSEMFAIHPTSGVVTVAGKLNVTWRGKHEL QVLAVDRMRKISEGNGFGSLAALVVHVEPALRKPPAIASVVVTPPDSNDGTTYATVLVDANSSGAEVE SVEVVGGDPGKHFKAIKSYARSNEFSLVSVKDINWMEYLHGPNLSLQARSGSGPYFYSQIRGFHLPPS KLSSLKFEKAVYRVQLSEFSPPGSRVVMVRVTPAF PNLQYVLKPSSENVGFKLNARTGLITTTKLMDF HDRAHYQLHIRTSPGQASTVVVIDIVDCNNHAPLFNRSSYDGTLDENIPPGTSVLAVTATDRDHGENG YVTYSIAGPKALPF SIDPYLGIISTSKPMDYELMKRIYTFRVRASDWGSPFRREKEVSIFLQLRNLND NQPMFEEVNCTGSICQDWPVGKSIMTMSAIDVDELQNLKYEIVSGNELEYFDLNHFSGVISLKRPFIN NOV6h, 317871219 SEQ ID NO: 53 1518 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence AGAGTCACCATCTCTGAGGACATGCCCCTGAAGAGCCCCATCTGCAAGGTGACTGCCAC AGATGCTGATCTAGCCCAGAATGCTGAGTTCTATTATGCCTTTAACACAAGGTCAGAGATGTTTGCCA TCCATCCCACCAGCGGTGTGGTCACTGTGGCTGGGAAGCTTAACGTCACCTGGCGAGGAAAGCATGAG CTCCAGGTGCTACTGTGGACCGCATGCGGAAAATCTCTGAGGGCAATGGGTTTGGCAGCCTGGCTGC ACTTGTGGTTCATGTGGAGCCTGCCCTCAGGAAGCCCCCAGCCATTGCTTCAGTGGTGGTGACTCCAC CAGACAGCAATGATGGTACCACCTATGCCACTGTACTGGTCGATGCAAATAGCTCAGGAGCTGAAGTG GAGTCAGTGGAAGTTGTTGGTGGTGACCCTGGAAAGCACTTCAAAGCCATCAAGTCTTATGCCCGGAG CAATGAGTTCAGTTTGGTGTCTGTCAAAGACATCAACTGGATGGAGTACCTTCATGGGTTCAACCTCA GCCTCCAGGCCAGGAGTGGGAGCGGCCCTTATTTTTATTCCCAGATCAGGGGCTTTCACCTACCACCT TCCAAACTGTCTTCCCTCAAATTCGAGAAGGCTGTTTACAGAGTGCAGCTTAGTGAGTTTTCCCCTCC TGGCAGCCGCGTGGTGATGGTGAGAGTCACCCCAGCCTTCCCCAACCTGCAGTATGTTCTAAAGCCAT CTTCAGAGAATGTAGGATTTAAACTTAATGCTCGAACTGGGTTGATCACCACCACAAAGCTCATGGAC TTCCACGACAGAGCCCACTATCAGCTACACATCAGAACCTCACCGGGCCAGGCCTCCACCGTGGTGGT CATTGACATTGTGGACTGCAACAACCATGCCCCCCTCTTCAACAGGTCTTCCTATGATGGTACCTTGG ATGAGAACATCCCTCCAGGCACCAGTGTTTTGGCTGTGACTGCCACTGACCGGGATCATGGGGAAAAT GGATATGTCACCTATTCCATTGCTGGACCAAAAGCTTTGCCATTTTCTATTGACCCTTACCTGGGGAT CATCTCCACCTCCAAACCCATGGACTATGAACTCATGAAAAGAATTTATACCTTCCGGGTAAGAGCAT CAGACTGGGGATCCCCTTTTCGCCGGGAGAAGGAAGTGTCCATTTTTCTTCAGCTCAGGAACTTGAAT GACAACCAGCCTATGTTTGAAGAAGTCAACTGTACAGGTTCTATCTGCCAAGACTGGCCAGTAGGGAA ATCGATAATGACTATGTCAGCCATAGATGTGGATGAGCTTCAGAACCTAAAATACGAGATTGTATCAG GCAATGAACTAGAGTATTTTGATCTAAATCATTTCTCCGGAGTGATATCCCTCAAACGCCCTTTTATC AATCTTACTGCTGGTCAACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAAAACTATGC CTCACCCACAACTTTGAATATTACTGTGGTG NOV6h, 317871219 SEQ ID NO: 54 506 aa MW at -56527kD Protein Sequence RVTISEDPLKSPICKTATDADLGQNAEFYYAFNTRSEMFAIHPTSGVVTVAGKLNVTWRGKHE LQVLAVDRMRKISEGNGFGSLAALVVHVEPALRKPPAIASVVVTPPDSNDGTTYATVLVDANSSGAEV ESVEVVGGDPGKHFKAIKSYARSNEFSLVSVKDINWMEYLHGFNLSLQARSGSGPYFYSQIRGFHLPP SKLSSLKFEKAVYRVQLSEFSPPGSRVVMVRVTPAFPNLQYVLKPSSENVGFKLNARTGLITTTKLMD FHDRAHYQLHIRTSPGQASTVVVIDIVDCNNHAPLFNRSSYDGTLDENIPPGTSVLAVTATDRDHGEN GYVTYSIAGPKALPFSIDPYLGIISTSKPMDYELMKRIYTFRVRASDWGSPFRREKEVSIFLQLRNLN DNQPMFEEVNCTGSICQDWPVGKSIMTMSAIDVDELQNLKYEIVSGNELEYFDLNHFSGVISLKRPFI NLTAGQPTSYSIKITASDGKNYASPTTLNITVV NOV6i, 317871243 SEQ ID NO: 55 1518 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence AGAGTCACCATCTCTGAGGACATGCCCCTGAAGAGCCCCATCTGCAAGGTGACTGCCAC AGATGCTGATCTAGGCCAGAATGCTGAGTTCTATTATGCCTTTAACACAAGGTCAGAGATGTTTGCCA TCCATCCCACCAGCGGTGTGGTCACTGTGGCTGGGAAGCTTAACGTCACCTGGCGAGGAAAGCATGAG CTCCAGGTGCTAGCTGTGGACCGCATGCGGAAAATCTCTGAGGGCAATGGGTTTGGCAGCCTGGCTGC ACTTGTGGTTCATGTGGAGCCTGCCCTCAGGAAGCCCCCAGCCATTGCTTCOGTGGTGGTGACTCCAC CAGACAGCAATGATGGTACCACCTATGCCACTGTACTGGTCGATGCAAATAGCTCAGGAGCTGAAGTG GAGTCAGTGGAAGTTGTTGGTGGTGACCCTGGAAAGCACTTCAAAGCCATCAAGTCTTATGCCCGGAG CAATGAGTTCAGTTTGGTGTCTGTCAAAGACATCAACTGGATGGAGTACCTTCATGGGTTCAACCTCA GCCTCCAGGCCAGGAGTGGGAGCGGCCCTTATTTTTATTCCCAGATCAGGGGCTTTCACCTACCACCT TCCAAACTGTCTTCCCTCAAATTCGAGAAGGCTGTTTACAGAGTGCAGCTTAGTGAGTTTTCCCCTCC TGGCAGCCGCGTGGTGATGGTGAGAGTCACCCCAGCCTTCCCCAACCTGCAGTATGTTCTAAAGCCAT CTTCAGAGAATGTAGGATTTAAACTTAATGCTCGAACTGGGTTGATCACCACCACAAAGCTCATGGAC TTCCACGACAGAGCCCACTATCAGCTACACATCAGAACCTCACCGGGCCAGGCCTCCACCGTGGTGGT CATTGACATTGTGGACTGCAACAACCATGCCCCCCTCTTCAACAGGTCTTCCTATGATGGTACCTTGG ATGAGAACATCCCTCCAGGCACCAGTGTTTTGGCTGTGACTGCCACTGACCGGGATCATGGGGAAAAT GGATATGTCACCTATTCCATTGCTGGACCAAAAGCTTTGCCATTTTCTATTGACCCTTACCTGGGGAT CATCTCCACCTCCAAACCCATGGACTATGAACTCATGAAAAGAATTTATACCTTCCGGGTAAGAGCAT CAGACTGGGGATCCCCTTTTCGCCGGGAGAAGGAAGTGTCCATTTTTCTTCAGCTCAGGACTTGAT I A)~ WO 2004/015079 PCT/US2003/024931 GACAACCAGCCTATGTTTGAAGAAGTCAACTGTACAGGGTCTATCCGCCAAGACTGGCCAGTAGGGAA ATCGATAATGACTATGTCAGCCATAGATGTGGATGAGCTTCAGAACCTAAAATACGAGATTGTATCAG GCAATGAACTAGAGTATTTTGATCTAAATCATTTCTCCGGAGTGATATCCCTCAAACGCCCTTTTATC AATCTTACTGCTGGTCAACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAAAACTATGC CTCACCCACAACTTTGAATATTACTGTGGTG NOV6i, 317871243 SEQ ID NO: 56 506 aa MW at -56580kD Protein Sequence RVTISEDMPLKSPICKVTATDADLGQNAEFYYAFNTRSEMFAIHPTSGVVTVAGKLNVTWRGKHE LQVLAVDRMRKISEGNGFGSLAALVVHVEPALRKPPAIASVVVTPPDSNDGTTYATVLVDANSSGAEV ESVEVVGGDPGKHFKAIKSYARSNEFSLVSVKDINWMEYLHGFNLSLQARSGSGPYFYSQIRGFHLPP SKLSSLKFEKAVYRVQLSEFSPPGSRVVMVRVTPAFPNLQYVLKPSSENVGFKLNARTGLITTTKLMD FHDRAHYQLHIRTSPGQASTVVVIDIVDO-NNHAPLFNRSSYDGTLDENIPPGTSVLAVTATDRDHGEN GYVTYSIAGPKALPFSIDPYLGIISTSKPjMDYELMKRIYTFRVRASDWGSPFRREKEVSIFLQLRNLN DNQPMFEEVNCTGSIRQDWPVGKSIMTMSAIDVDELQNLKYEIVSGNELEYFDLNHFSGVISLKRPFI NLTAGQPTSYSLKITASDGKNYASPTTLNITVV NOV6j,317871246 SEQ [D NO: 57 11992 bp DNA Sequence ORF Start:. at 1 ORF Stop: end of sequence ACAGGGCACCGCCAAGACTGGCCAGTAGGGA AATCGATAATGACTATGTCAGCCATAGATGTGGATGAGCTTCAGAACCTAAAATACGAGATTGTATCA GGCAATGAACTAGAGTATTTTGATCTAAATCATT TCTCCGGAGTGATATCCCTCAAACGCCCTTTTAT CAATCTTACTGCTGGTCAACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAAAACTATG CCTCACCCACAACTTTGAATATTACTGTGGTGAAGGACCCTCATTTTGAAGTTCCTGTAACATGTGAT AAAACAGGGGTATTGACACAATTCACAAAGACTATCCTCCACTTTATTGGGCTTCAGAACCAGGAGTC CAGTGATGAGGAATTCACTTCTTTAAGCACATATCAGATTAATCATTACACCCCACAGTTTGAGGACC ACTTCCCCCAATCCATTGATGTCCTTGAGAGTGTCCC.TATCAACACCCCCTTGGCCCGCCTAGCAGCC ACTGACCCTGATGCTGGTTTTAATGGCAAACTGGTCTATGTGATTGCAGATGGCAATGAGGAGGGCTG CTTTGACATAGAGCTGGAGACAGGGCTGCTCACTGTAGCTGCTCCCTTGGACTATGAAGCCACCAATT TCTACATCCTCAATGTAACAGTATATGACCTGGGCACACCCCAGAAGTCCTCCTGGAAGCTGCTGACA GTGAATGTGAAAGACTGGAATGACAACGCACCCAGATTTCCTCCCGGTGGGTACCAGTTAACCATCTC GGAGGACACAGAAGTTGGAACCACAATTGCAGAGCTGACAACCAAAGATGCTGACTCGGAAGACAATG GCAGGGTTCGCTACACCCTGCTAAGTCCCACAGAGAAGTTCTCCCTCCACCCTCTCACTGGGGAACTG GTTGTTACAGGACACCTGGACCGCGAATCAGAGCCTCGGTACATACTCAAGGTGGAGGCCAGGGATCA GCCCAGCAAAGGCCACCAGCTCTTCTCTGTCACTGACCTGATAATCACATTGGAGGATGTCAACGACA ACTCTCCCCAGTGCATCACAGAACACAACAGGCTGAAGGTTCCAGAGGACCTGCCCCCCGGGACTGTC TTGACATTTCTGGATGCCTCTGATCCTGACCTGGGCCCCGCAGGTGAAGTGCGATATGTTCTGATGGA TGGCCCCATGGGACCTTCCGGGTGGACCTGATGACAGGGGCGCTCATTCTGGAGAGAGAGCTGGACT TTGAGAGGCGAGCTGGGTACAATCTGAGCCTGTGGGCCAGTGATGGTGGGAGGCCCCTAGCCCGCAGG ACTCTCTGCCATGTGGAGGTGATCGTCCTGGATGTGAATGAGAATCTCCACCCTCCCCACTTTGCCTC CTTCGTGCACCAGGGCCAGGTGCAGGAGAACAGCCCCTCGGGAACTCAGGTGATTGTAGTGGCTGCCC AGGACGATGACAGTGGCTTGGATGGGGAGCTCCAGTACTTCCTGCGTGCTGGCACTGGACTCGCAGCC TTCAGCATCAACCAAGATACAGGAATGATTCAGACTCTGGCACCCCTGGACCGAGAATTTGTATCTTA CTACTGGTTGACGGTATTAGCAGTGGACAGGGGTTCTGTGCCCCTCTCTTCTGTAACTGAAGTCTACA TCGAGGTTACGGATGCCAATGACAACCCACCCCAGATGTCCCAAGCTGTGTTCTACCCCTCCATCCAG GAGGATGCTCCCGTGGGCACCTCTGTGCTTCAACTGGATGCCTGGGACCCAGACTCCAGCTCCAAAGG GAAGCTGACCTTCAACATCACCAGTGGGAACCACATGGGATTCTTTATGATTCACCCTGTTACAGGTC TCCTATCTACAGCCCAGCAGCTGGACAGAGAGAACAAGGATGAACACATCCTGGAGGTGACTGTGCTG GACAATGGGGAACCCTCACTGAAGTCCACCTCCAGGGTGGTGGTAGGCATCTTG NOV6j, 317871246 ESEQ ID NO: 58 664 aa MW at ~74703kD Protein SequenceII TGSIRQDWPVGKSIMTMSAIDVDELQNLKYEIVSGNELEYFDLNHFSGVISLKRPFI NLTAGQPTSYSLKITASDGKNYASPTTLNITVVKDPHFEVPVTCDKTGVLTQFTKTILHFIGLQNQES SDEEFTSLSTYQINHYTPQFEDHFPQSIDVLESVPINTPLARLAATDPDAGFNGKLVYVIADGNEEGC FDIELETGLLTVAAPLDYEATNFYILNVTVYDLGTPQKSSWKLLTVNVKDWNDNAPRFPPGGYQLTIS EDTEVGTTIAELTTKDADSEDNGRVRYTLLSPTEKFSLHPLTGELVVTGHLDRESEPRYILKVEARDQ PSKGHQLFSVTDLIITLEDVNDNSPQCITEHNRLKVPEDLPPGTVLTFLDASDPDLGPAGEVRYVLMD GAHGTFRVDLMTGALILERELDFERRAGYNqLSLWASDGGRPLARRTLCHVEVIVLDVNENLHPPHFAS FVHQGQVQENSPSGTQVIVVAAQDDDSGLDGELQYFLRAGTGLAAFSINQDTGMIQTLAPLDREFVSY YWLTVLAVDRGSVPLSSVTEVYIEVTDANDNPPQMSQAVFYPSIQEDAPVGTSVLQLDAWDPDSSSKG KLTFNITSGNHMGFFMIHPVTGLLSTAQQLDRENKDEHILEVTVLDNGEPSLKSTSRVVVGIL NOV6k, 317999764 SEQ ID NO: 59 11773 bp DNA Sequence ORF Start: at 1 OFStop: end of sequence TACCCCTCCATCCAGGAGGATGCTCCCGTGGGCACCTCTGTGCTTCAACTGGATGCCTG -I A A WO 2004/015079 PCT/US2003/024931 GGACCCAGACTCCAGCTCCAAAGGGAAGCITGACCTTCAACATCACCAGTGGGAACCACATGGGATTCT TTATG3ATTCACCCTGTTACAGGTCTCCTATCTACAGCCCAGCAGCTGGACAAGAGACAGGATGAA CACATCCTGGAGGTGACTGTCTGGACATGGGACCCTCACTGAGTCCACCTCCAGGGTGGTGGT AGGCATCTTGGACGTCAATGACAATCCACCTATATTCTCCCACAGCTCTTATGTCCGCCTTCCAG AGAGGCTGAGCCCTGTIGTCCCCTGGGCCTGTGTACAGGCTGGTGGCTTCAGACCTGGATGAGGGTCTT ATGGCAGAGTCACcTACAGTATCGACGGACAGCGATGAGGAGGCCTTCAGTATCGACCTGGTCACAGG TGTGGTTTCATCCAGCAGCACTTTTACAGCTGGAGAGTACACATCCTACGATCAOGCAACAOACA GTGGGCAGCCACCACTCTCAGCCAGTGTCCGGCTACACATTGAGTGGATCCCTTGGCCCCGGCCGTCC TCCATCCCTCTGGCCTTTGATGAGACCTACTACAGCTTTACGGTCATGGAGACGGACCCTGTGAACCA CATGGTGGGGGTCATCAGCGTAGAGGGCAGACCCGGACTCTTCTGGTTCAACATCTCAGGTGGGGATA AGGACATGGACTTTGACATTGAGAAGACCACAGGCAGCATCGTCATTGCCAGGCCTCT.TGATACCAGG AGAAGGTCGAACTATAACTTGACTGTTGAGGTGACAGATGGGTCCCGCACCATTGCCACACAGGTCCA CATCTTCATGATTGCCAACATTAACCACCATCGGCCCCAGTTTCTGGAAACTCGTTATGAAGTCA.GAG TTCCGAACTCAGGAACCTGGGCAGCTGTAGCAGCA *AGCCTCATCTATACCATACATGGCAGCCAAGACCCAGGAGTGCCAGCCTCTTCCAGCTGGACCCAAG CAGTGGTGTCCTGGTAACGGTGGGAAAATTGGACCTCGGCTCGGGGCCCTCCCAGCACACACTGACAG TCATGGTCCGAGACCAGGAAATACCTATCAAGAGGAACTTCGTGTGGGTGACCATTCATGTGGAGGAT GGAAACCTCCACCCACCCCGCTTCACTCAGCTCCATTATGAGGCAAGTGTTCCTGACACCATAGCCCC CGGCACAGAGCTGCTGCAGGTCCGAGCCATGGATGCTGACCGGGGAGTCAATGCTGAGGTCCACTACT *CCCTCCTGAAAGGGAACAGCGAAGGTTTCTTCAACATCAATGCCCTGCTAGGCATCATTACTCTAGCT CAAAGCTTGATCAGGCCAATCATCCCCACATACTCTGACAGTGAAGGCAGAAGATCAGGCTCCCC ACAATGGCATGACCTGGCTACAGTGATCATTCATGTCTATCCCTCAGATAGGAGTGCCCCCATCTTTT CAAATCTGAGTACTTTGTA GAGATCCCTGAATCAATCCCTGTTGGTTCCCCATCCTCCTTGTCTCT GCTATGAGCCCCTCTAGTTACCTATGAGTTAGAGAGGGAAATAGGATGGAGTCTTCTCTATGAA CTCATATTCTGGCCTTATtTCCACCCAGAAGAAATTGGACCATAGAATCTCGTCTTACCAGCTGA AAATCCGAGGCAGC *NOV6Tk, 317999764 jSEQ ID NO: 60 j51 aa MW at -65 888kD Protein Sequence I-. YPSIQEDAPVGTSVLQLDAWDPDSSSKGKLTFISGNHGFFMIHPVTGLLSTAQQLDR~END HILEVTVLDNGEPSLKSTSRVVVGILDVNDNPPIFSHKLFNRLPELSPVSPGPVYRVASDLDEGL NGVYIDDEFILTVSSTTGENLIADGPLAVLIWPPP SI PLAFDETYYSFTMETDPVNH1MGVISVEGRPGLFWFNISGGDKDMDFDIEKTTGSIVIRPLDT RRSNYNLTVEVTDSRTIATQVHIFMIANINHHRPQFLETRYEVRVPQDTPGVELLRVQAIDQDKGK SLIYTHGSQDPGSASLFQLDPSSGV NTVGKL DLGSGPSQHTLQEIPPTRNVWTIHED GNLHPPRFTQLHYEASVPDTIAPGTELLQVDARGNAEVYSLLKGNSEGFFNINALLGIITLA QKLDQAMAPHTLTVKAEDQGSPQWHDLATVIIHVYPSDRSAPIFSKSEYFVEIPESIPVGSPILLVS ASPSEVTYELREGNKDGVFSMNSYSGLISTQKKLDHEKISSYQLKIRGS NOV61, 318176301 SEQ ID NO: 61 12019 bp DNA Sequence ~ ORF StA: at 1 ORF Stop: end of sequence GAGGCAAGTGTTCCTGACACCATAGCCCCCGGCACAGAGCTGCTGCAGGTCCGAGCCAT GCATGCTGACCGGGGAGTCATGCTGAGGTCCACTACTCCCTCCTGAGGGAACAGCGAAGGTTTCT TCAACATCAATGCCCTGCTAGGCATCATTACTCTAGCTCAAAAGCTTGATCAGG.CAAATCATGCCCCA CATACTCTGACAGTGAAGGCAGAAGATCAAGGCTCCCCACATGGCATGACCTGGCTACAGTCATCAT TCATGTCTATCCCTCAGATAGGAGTGCCCCCATCTTTTCAATCTGAGTACTTTGTAGAGATCCCTG AATCATCCCTGTTGGTTCCCCAATCCTCCTTGTCTCTGCTATGACCCOCTCTGAAGTTACCTATGAG TTAAGAGACCGAAATAAGGATGGAGTCTTCTCTATGAACTCATATTCTGGCCTTATTTCCACCCAGAA GAATTGGACCATGAGAAAATCTCGTCTTACCAGCTGAAAATCCGAGGCAGCCATATGGCAGGTGCAT TTACTGATGTCATGTGGTGGTTGACATATTGATGAATGACATGCTCCTATGTTCTTAGTCA ACTTTTGTGGGCCAAATTAGTGAAGCAGCTCCACTGTATACCATGATCATGGATAACACACCC CTTTATAGCCGCGGCAAAGTATCTTGTTTAATTGG CGGAGGCCTTGAAGTTTTTCAAATTGATCCCAGCATGGCCCTACCATTGTATCAGAGATGGAT TATGAGAGCATGCCCTCTTTCCAATTCTGTGTCTATGTCCATGACCAAGAGCCCTGTATTATTTGC ACCCAGACCTGCCCAAGTCATCATTCATGTCAGAGATGTGATGATTCCCCTCCCAGATTCTCAGAAC AGATATATGAGGTAGCAATAGTCGGGCCTATCCATCCAGGCATGGAGCTTCTCATGGTGCGGGCCAGC GATGAAGACTCAGAAGTCAATTATAGCATCAACTGGCAATGCTGATGAAGCTGTT.A CCATCCATCC TGTCACTGGTAGCATAkTCTGTGCTGAATCCTGCTTTCCTGGGACTCTCTCGGAGCTCACCATCAG CTCCTGTGACAAATCCGTAAATCTGCCATCTAAAG TTGCAGTTTGATCAGGATGTCTACTGGGCAGCTGTGACGAGAACTTGCAGGACAGAAGGCACTGGT CATTCTTGGTGCCCAGGCCAATCATTTGAATGACACCCTTTCCTACTTTCTCTTGAATGGCACAGATA TGTTTCATATGGTCCAGTCAGCAGGTGTGTTGCAGACAAGAGGTGTGGCGTTTGACCGGGAGCAGCAG GACACTCATGAGTTGGCAGTGGAAGTGAGGGACAATCGGACACCTCAGCGGGTGGCTCAGGGTTTGGT CAGAGTCTCTATTGAGGATGTCAATGACAATCCCCCCAATTTAAGCATCTGCCCTATTACACAATCA TCCAAGATGGCACAGAGCCAGGGGATGTCCTCTTTCAGGTATCTGCCACTGATGAGGACTTGGGGACA AATGGGGCTGTTACATATGAATTTGCAGAAGATTACACATATTTCCGAATTGACCCCTATCTTGGGGA CATATCACTCAAGAACCCTTTGATTATAAGCTTTAATAATATCACCTCAAGTCATTGCTCGGG ATGGAGGAACGCCATCCCTCCAGAGTGAGGAAGAGGTACTGTCACTGTGAGTfAATCCACCCA I AC WO 2004/015079 PCT/US2003/024931 CTGTTTCAGAGTCCTTATTAcAAAGTCAGAGTACCTGAAAATATCACCCTCTATACCCCAATTCTCCA CACCCAGGCCCGGAGTCCAGAGGGACTCCGGCTCATCTACAACATTGTGGAGGAAGAACCCTTGATGC TGTTCACCACTGACT TCAAGACTGGTGTCCTAACAGTAACAGGGCCTTTGGACTAT NOV1,38160 SEQ ID NO: 62 673 aa {MW at ~75571kD Protein Sequence FASVPDTIAPTELL RAM DRGAEVHYSLLKGNSEGFFNINALLGIITLAQKLDQANA HTLTVKAEDQGSPQWHDLATVIIHVYPSDRSAPIFSKSEYFVEIPESIPVGSPILLVSAMSPSEVTYE LREGNKDGVFSMNSYSGLISTQKKLDHEKISSYQLKIRGSNMAGAFTDvmVVVDIIDENDNAPMFLKS TFVGQISEAAPLYSMIMDKNNNPFVIHASDSDKEANSLLVYKILEPEALKFFKIDPSMGTLTIVSEMD YESMPSFQFCVYVHDQGSPVLFAPRPAQVIIHVRDVNDSPPRFSEQIYEVAIVGPIHPGMELLMVRAS DEDSEVNYSIKTGNADEAVTIHPVTGSISVLNPAFLGLSRKLTIRASDGLYQDTALVKISLTQVLDKS LQFDQDVYWAAVKENLQDRKALVILGAQGNHLNDTLSYFLLNGTDMFHMVQSAGVLQTRGVAFDREQQ DTHELAVEVRDNRTPQ2RVAQGLVRVSIEDVNDNPPKFKHLPYYTIIQDGTEPGDVLFQVSATDEDLGT NGAVTYEFAEDYTYFRIDPYLGDISLKKPFDYQALNKYHLKVIARDGGTPSLQSEEEVLVTVRNKSNP LFQSPYYKVRVPENITLYTPILHTQARSPEGLRLIYNIVEEEPLMLFTTDFKTGVLTVTGPLDY NOV6m, CG51923-02 SEQ ID NO: 63 3666 bp DNA Sequence IOR Start: at 1 ORF Stop: end of sequence TATAAGGCTGTCCTCACTGAATGCATGGGGACCTCAGTATTCAGTGACTGCCATTAA GGACACTGGGAGAGATGGCCAGGTGAGCTACAGGCTGTCTGCAGACCCTGGTAGCAATGTCCATGAGC TTTTTGCCATTGACAGTGAGAGTGGTTGGATCACCACACTCCAGGAACTTGACTGTGAGACCTGCCAG ACTTATCATTTTCATGTGGTGGCCTATGACCACGGACAGACCATCCAGCTATCCTCTCAGGCCCTGGT TCAGGTCTCCATTACAGATGAGAATGACAATGCTCCCCGATTTGCTTCTGAAGAGTACAGAGGATCTG TGGTTGAGAACAGTGAGCCTGGCGAACTGGTGGCGACTCTAAAGACCCTGGATGCTGACATTTCTGAG CAGAACAGGCAGGTCACCTGCTACATCACAGAGGGAGACCCCCTGGGCCAGTTTGGCATCAGCCAAGT TGGAGATGAGTGGAGGATTTCCTCAAGGAAGACCCTGGACCGCGAGCATACAGCCAAGTACTTGCTCA GAGTCACAGCATCTGATGGCAAGTTCCAGGCTTCGGTCACTGTGGAGATCTTTGTCCTGGACGTCAAT CATAACAGCCCACAGTGTTCACAGCTTCTCTATACTGGCAAGGTTCATGAAGATGTATTTCCAGGACA CTTCATTTTGAAGGCTTCTGCCACAGACTTGGACACTGATACCAATGCTCAGATCACATATTCTCTGC ATGGCCCTGGGGCGCATGAATTCAAGCTGGATCCTCATACAGGGGAGCTGACCACACTCACAGCCCTA GACCGAGAAAGGAAGGATGTGTTCAACCTTGTTGCCAAGGCGACGGATGGAGGTGGCCGATCGTGCCA GGCAGACATCACCCTCCATGTGGAGGATGTGAATGACAATGCCCCGCGGTTCTTCCCCAGCCACTGTG CTGTGGCTGTCTTCGACAACACCACAGTGAAGACCCCTGTGGCTGTAGTATTTGCCCGGGATCCCGAC CAAGGCGCCAATGCCCAGGTGGTTTACTCTCTGCCGGATTCAGCCGAAGGCCACTTTTCCATCGACGC CACCACGGGGGTGATCCGCCTGGAAAAGCCGCTGCAGGTCAGGCCCCAGGCACCACTGGAGCTCACGG TCCGTGCCTCTGACCTGGGCACCCCAATACCGCTGTCCACGCTGGGCACCGTCACAGTCTCGGTGGTG GGCCTAGAAGACTACCTGCCCGTGTTCCTGAACACCGAGCACAGCGTGCAGGTGCCCGAGGACCCCC ACCTGGCACGGAGGTGCTGCAGCTGGCCACCCTCACTCGCCCCGGCGCAGAGAAGACCGGCTACCGCG TGGTCAGCGGGAACGAGCAACCCAGGTTCCGCCTGGATGCTCGCACAGGGATCCTGTATGTCAACGCA AGCCTGGACTTTGAGACAAGCCCCAAGTACTTCCTGTCCATTGAGTGCAGCCGGAAGAGCTCCTCTTC CCTCAGTGACGTGACCACAGTCATGGTCAACATCACTGATGTCAATGAACACCCCCCC AAGATCCATATAGCACAAGGGTCTTAGAGAATGCCCTTGTGGGTGACGTCATCCTCACGGTATCAGCG ACTGATGAAGATGGACCCCTAAATAGTGACATTACCTATAGCCTCATAGGAGGGAACCAGCTTGGGCA CTTCACCATTCACCCCAAAAAGGGGGAGCTACAGGTGGCCAAGGCCCTGGACCGGGAACAGGCCTCTA GTTATTCCCTGAAGCTCCGAGCCACAGACAGTGGGCAGCCTCCACTGCATGAGGACACAGACATCGCT ATCCAAGTGGCTGATGTCAATGATAACCCACCGAGATTCTTCCAGCTCAACTACAGCACCACTGTCCA GGAGAACTCCCCCATTGGCAGCAAAGTCCTGCAGCTGATCCTGAGTGACCCAGATTCTCCAGAGAATG GCCCCCCCTACTCGTTTCGAATCACCAAGGGGAACAACGGCTCTGCCTTCCGAGTGACCCCGGATGGA TGGCTGGTGACTGCTGAGGGCCTAAGTAGGAGCGCTCAGGAATGGTATCAGCTTCAGATCCAGGCGTC AGACAGTGGCATCCCTCCCCTCTCGTCTTCGACGTCTGTCCGTGTCCATGTCACAGAGCAGAGCCACT ATGCACCTTCTGCTCTCCCACTGGAGATCTTCATCACTGTTGGAGAGGATGAGTTCCAGGGTGGCATG GTGGGTAAGATCCATGCCACAGACCGAGACCCCCAGGACACGCTGACCTATAGCCTGGCAGAAGAGGA GACCCTGGGCAGGCACTTCTCAGTGGGTGCGCCTGATGGCAAGATTATCGCCGCCCAGGACCTGCCTC GTGGCCACTACTCGTTCAACGTCACGGTCAGCGATGGGACCTTCACCACGACTGCTGGGGTCCATGTG TATGTGTGGCATGTGGGGCAGGAGGCTCTGCAGCAGGCCATATGGATGGGCTTCTACCAGCTCACCCC CGAGGAGCTGGTGAGTGACCACTGGCGGAACCTGCAGAGGTTCCTCAGCCATAAGCTGGACATCAAAC GGGCTAACATTCACTTGGCCAGCCTCCAGCCTGCAGAGGCCGTGGCTGGTGTGGACGTGCTCCTGGTC TTTGAGGGGCATTCTGGAACCTTCTACGAGTTTCAGGAGCTAGCATCCATCATCACTCACTCAGCCAA GGAGATGGAGCATTCAGTGGGGGTTCAGATGCGGTCAGCTATGCCCATGGTGCCCTGCCAGGGGCCAA CCTGCCAGGGTCAAATCTGCCATAACACAGTGCATCTGGACCCCAAGGTTGGGCCCACGTACAGCACC GCCAGGCTCAGCATCCTAACCCCGCGGCACCACCTGCAGAGGAGCTGCTCCTGCAATGGTACTGCTAC AAGGTTCAGTGGTCAGAGCTATGTGCGGTACAGGGCCCCAGCGGCTCGGAACTGGCACATCCATTTCT ATCTGAAAACACTCCAGCCACAGGCCATTCTTCTATTCACCAATGAAACAGCGTCCGTCTCCCTGAAG CTGGCCAGTGGAGTGCCCCAGCTGGAATACCACTGTCTGGGTGGTTTCTATGGAAACCTTTCCTCCCA GCGCCATGTGAATGACCACGAGTGGCACTCCATCCTGGTGGAGGAGATGGACGCTTCCATTCGCCTGA TGGTTGACAGCATGGGCAACACCTCCCTTGTGGTCCCAGAGAACTGCCGTGGTCTCAGGCCCGAAAGG

CACCTCTTGCTGGGCGGCCTCATTCTGTTGCATTCTTCCTCGATGTCTCCCAGGGCTT

WO 2004/015079 PCT/US2003/024931 CCTGGATGCTGTCGTGGTCAACGAAGAGGCTCTAGATCTGCTGGCCCCTGGCAAGACGGTGGCAGGCT TGCTGGAGACACAAGCCCTCACCCAGTGCTGCCTCCACAGTGACTACTGCAGCCAGCMCACATGCCTC AATGGTGGGAAGTGCTCATGGACCCACGGGGCAGGCTATGTCTGCATGTCCCCCACAGTTCTCTGG GAAGCACTGTGACAAGAGGGAGACTGTACTTTTGCACCCTGCCTGGAAGGTGACTTGCATCC YKAVLTENMPVGTSVIQVAIDKDTGRDGQVSYRLSDPGSNVHELFAIDSESGWITTLQELDCETCQ TYHFHWVAYDHGQTIQLSSQALVQVSITDENPRFASEEYRGSVESEPGELVATLKTLDDISE QNQTYTGPGFIQGERSRTLRHAYLVADKQSTEFLV DNSPQCSQILYTGKHEDVFPGHFILKASATDLDTDTNAQITYSLHGPGAHEFKLDPHTGELTTLTAL D)RERKDVFLVAATDGGRSCQAITLVEDVNDAPRFFPSHCAVAVFDNTVKTPVAVFRPD QGANAQVWYSLPDSAEGHFSIDATTGVIRIEKPLQPQAPLELVRSDLGTPIPLSTLGVTVSVV GLEDYLPVFLNTEHSVQVPEDAPPGTEQLATLTRPGAEKTGYRSGNEQGRFLDTGILYVNA SLDFETSPKYFLSIECSRKSSSSLSDVTTVITDNEHRPQFPQDPYSTRLEAVGDVILTVSA TDEDGPLNSDITYSLIGGNQLGHFTIHPKKGELQVKADREQASSYSLKLRTDSGQPPLHEDTDIA IQVADVNDNPPRFFQLNYSTTVQENSPIGSKVLQLILSDPDSPENGPPYSFRITKGNGSAFRVTPDG WIVTAELSRAQEWQLQIQASDSGIPPLSSSTSVRVTQSHASLEITVDFGM VGKIHATDRDPQDTLTYSLAEEETLGHFSVGAPDGKI I2AQDLPRGHYSFNVTVSDGTFTTTAGVHiV YVWGQEALQQAIWMGFYQLTPEELVSDHWQRFLSHDIKIHLASLQPAEAVAV.VLV FEHGFEQLSIHAEESGQRSMMPQPCGIHTHDKGTS ARLSILTPRHHLQRSCSCNGTATRFSGQSYRPAANIHFYLKTLQPQAILLFTNETASVSLK LASGVPQIEYHCLGGFYGNJSSQRHDHEWIVEEASIVSMGNTSLVPENCRGLRPER HLLLGGLILLHSSSNVSQGFEGCLDAVVNEql LDLLAPGKVAGLLETQALTQCCLHSDYCSQNTCL NGKSTGGVKPQSKCQRNTFPLGTISKACCHYGRE NOV6n, CG51923-03 ~SEQ ID NO: 65 14279 b DNA Sequence ~ ORF Start: ATG at 14 1O Stop: TAG at 12806 GG.AGTTTTCCACCATGACTATTGCCCTGCTGGGTTTTGCCATATTCTTC.CTCCATTGTGCGACCTGT AGAAGCCTCTAGJGGGATTCTCTCCTCCTCTGCTTGGCACTTCACACACTCCCATTACATGCCACC ATCTATGAAAATTCTTCTCCCAAGACCTATGTGGAGAGCTCGAGAATGGGCATCTACCTCGCGGA GCCACAGTGGGCAGTGAGGTACCGGATCATCTCTGGGGATGTGCATGTATTTAAACTGAGGAGT CCGTGTGGTGGTCCACATCCTGGACCAGAATGACCTGAACCTCTCTTCTCTCCACCTTCGTACAGAG TCACCATCTCTGAGGACATGCCCCTGAAGAGCCCCATCTGCAAGGTGACTGCCACAGATGCTGATCTA GGCCAGAATGCTGAGTTCTATTATGCCTTTACACAAGGTCAGAGATGTTTGCCATCCATCCCACCAC CGGTGTGGTCACTGTGGCTGGGAAGCTTAACGTCACCTGCGAGAGCATGAGCTCCAGGTGCTAG CTGTGOACCGCATGCGGAAAATCTCTGAGGGCAATGGGTTTGGCAGCCTGGCTGCACTTGTGGTTCAT GTGGAGCCTGCCCTCAGGAAGCCCCCACCCATTGCTTCGGTGGTGGTGACTCCACCAGACAGCAATGA TGGTACCACCTATGCCACTGTACTGGTCGATGCAATAGCTCAGGAGCTGAAGTCGAGTCAGTGGAAG TTGTTGGTGGTGACCCTGGAAGCACTTCAAAGCCATCAGTCTTATGCCCGGACCATGAGTTCAGT TTGGTGTCTGTCAAAGACATCAACTGGATGGAGTACCTTCATGGGTTCAACCTCAGCCTCCAGGCCAG GAGTGGGAGCGGCCCTTATTTTTATTCCCAGATCAGGGGCTTTCACCTACCACCTTCCACTGTCTT CCCTCAAATTCGAGAAGG.CTGTTTACAGAGTGCAGCTTAGTGAGTTTTCCCCTCCTGGCAGCCGCGTG GTGATGGTGAGAGCACCCCAGCCTTCCCCAACCTGCAGTATGTTCTAGCCATCTTCAGAGAATGT AGGATTTAAACTTAATGCTCGACTGGGTTGATCACCACCACAAGCTCATGGACTTCCACGAC-AGAG CCCACTATCAGCTACACATCAGAACCTCACCGGGCCAGGCCTCCACCGTGGTGGTCATTGACATTGTG GACTGCAACAACCATGCCCCCCTCTTCAACAGGTCTTCCTATGATGGTACCTTGATGGCATCCC TCCAGGCACCAGTGTTTTGGCTGTGACTGCCACTGACCGGGATCATGGGAATGGATATGTCACCT ATTCCATTGCTGGACCAAAACCTTTGCCATTTTCTATTGACCCCTACCTGGGGATCATCTCCACCTCC AAACCCATGGACTATGAACTCATGAAAALGAA.WTTATACCTTCCGGGTAAGACATCAGACTGGGGATC CCCTTTTCGCCGGGAOAGGAAGTGTCCATTTTTCTTCAGCTCAGGACTTGAATGACACCAGCCTA TGTTTGAAGAAGTCAACTGTACAGGGTCTATCCGCCACTCGCCAGTAGGAATCGATATOACT ATGTCAGCCATAGATGTGGATGAGCTTCAGCCT-TACGAGATTGTATCAGGCAATGACTAGA GTATTTTGATCTAATCATTTCTCCGGAGTGATATCCCTCACGCCCTTTTATCATCTTACTGCTG GTCAACCCACCAGTTATTCCCTGAAGATTACAGCCTCAGATGGCAAALCTATGCCTCACCCACAACT TTGAATATTACTGTGGTGAAGGACCCTCATTTTGAGTTCCTGTACATGTGATAACAGGGGTATT GACACATTCACAAGACTATCCTCCACTTTATTGGGCTTCAGAACCAGGAGTCCAGTGATGAGGAAT TCACTTCTTTAAGCACATATCACATTATCA?TACACCCCACAGTTTGAGGACCACTTCCCCCAATCC ATTGATGTCCTTGAGAGTGTCCCTATCAACACCCCCTTGGCCCGCCTAGCAGCCACTGACCCTGALTGC TGGTTTTAATGGCAAACTGGTCTATGTGATTGCAGATGGCATGAGGAGGGCTGCTTTGACATAGAGC TGGAGACAGGGCTGCTCACTGTAGCTGCTCCCTTGGACTATGAGCCACCAATTTCTACATCCTCAAT GTAACAGTATATGACCTCGCACACCCCAGGTCCTCCTGGAGCTGCTGACAGTGATGTGALGA CTGGAATGACAACCCACCCAGATTTCCTCCCGTGGTACCAGTTAACCATCTCGGAGGACACAGG

TTGACCATCGGTAACALGTCGCCGAAATGACTCCA

WO 2004/015079 PCT/US2003/024931 ACCCTGCTAAGTCCCACAGAGAAGTTCTCCCTCCACCCTCTCACTGGGGAACTGGTTGTTACAGGAC CCTGGACCGCGAATCAGAGCCTCGGTACATACTCAAGGTGGAGGCCAGGGATCAGCCCAGAAGGCC ACCAGCTCTTCTCTGTCACTGACCTGATAATCACATTGGAGGATGTCAACGACACTCTCCCCAGTGC ATcAcAGAAcAcAACAGGCTGAAGGTTCCAGAGGACCTGCCCCCCGGGACTGTCTTGACATTTCTA TGCCTCTGATCCTGACCTGGGCCCCGCAGGTGAGTGCGATATGTTCTGATGGATGCCCCATGGGA CCTTCCGGGTGGACCTGATGACAGGGGCGCTCATTCTGGAGAGAGAGCTGGACTTTGAGAGGCGAC GGGTACAATCTGAGCCTGTGGGCCAGTGALTGGTGGGAGGCCCCTAGCCCGCAGGACTCTCTGCCATGT GGAGGTGATCGTCCTGGATGTGAATGAGATCTCCACCCTCCCCACTTTGCCTCCTCGTGCACCAG GCCAGGTGCAGGAGAACAGCCCCTCGGGAACTCACGTGATTGTAGTGGCTGCccAGGAcGATGACAGT GGTGAGGACCATCTQGGGCGCCGATGACTCGACAC AGATACAGGAATGATTCAGACTCTGGCACCCCTGACCGAGATTTGCATCTTACTACTGGTTGACGG TATTAGCAGTGGACAGGGGTTCTGTGCCCCTCTCTTCTGTAACTGAGTCTACATCGAGGTTACGGAT GGGCACCTCTGTGCTTCAACTGGATGCCTGGGACCCAACTCCAGCTCCAAGGGAGCTQACCTTCA ACATCACCAGTGGGAACTACATGGGATTCTTTATGATTCACCCTGTTACAGGTCTCCTATCTACAGCC CAGCAGCTGGACAGAGAGAACAAGGATGACACATCCTGGAGGTGACTGTGCTGGACATGGGGAACC CTCACTGAAGTCCACCTCCAGGGTGGTGGTAGGCATCTTGGACGTAATGACAMTCCACCTATATTCT CCCACAAGCTCTTCAATGTCCGCCTTCCAGAGAGGCTGAGCCCTGTGTCCCCTGGGCCTGTGTACAGG CTGGTGGCTTCAGACCTGGATGAGGGTCTTAA~TGGCAGAGTCACCTACAGTATCGAGGACAGCTATGA GGAGGCCTTCAGTATCGACCTGGTCACAGGTGTGGTTTCATCCAACAGCACTTTTACAGCTGGAGAGT ACAACATCCTAACGATCAAGGCAACAGACAGTGGGCAGCCACCACTCTCAGCCAGTGTCCGGCTACAC ATTGAGTGGATCCCTTGGCCCCGGCCGTCCTCCATCCCTCTGGCCTTTGATGAGACCTACTACAGCTT TACGGTCATGGAGACGGACCCTGTGAACCACATGGTGGGGGTCATCAGCGTAGAGGGCAGACCCGGAC TCTTCTGGTTCAACATCTCAGGTGGGGATAGCACATGGACTTTGACATTGAGAAGACCACAGGCAGC ATCGTCATTGCCAGGCCTCTTGATACCAGGAGAAGGTCGACTATACTrTGACTGTTGAGGTGACAGA TGGGTCCCGCACCATTGCCACACAGGTCCACATCTTCATGATTGCCACATTACCACCATCGGCCCC AGTTTCTGGAAACTCGTTATGAAGTCAGAGTTCCCCAGGACACCGTGCCAGGGGTAGAGCTCCTGCGA GTCCAGGCCATAGATCAAGACAAGGGCAAAAGCCTCATCTATACCATACATGGCAGCCAAGACCCAGG AAGTGCCAGCCTCTTCCAGCTGGACCCAAGCAGTGGTGTCCTGGTACGGTGGGAAATTGGACCTCG GCTCGGGGCCCTCCCAGCACACACTGACAGTCATGGTCCGAGACCAGGATACCTATCAGAGGAAC TTCGTGTGGGTGACCATTCATGTGGAGGATGGAACCTCCACCCACCCCGCTTCACTCAGCTCCATTA TGAGGCAAGTGTTCCTGACACCATAGCCCCCGGCACAGAGCTGCTGCAGGTCCGAGCCATGGATGCTG ACGGATATCGGTCCATCTCGAAGACGGAGTCTACT AATGCCCTGCTAGGCATCATTACTCTACTCAAGCTTGATCAGGCAALTCATGCCCCACATACTCT GACAGTGAAGGCAGAAGATCAAGGCTCCCCACAATGGCATGACCTGGCTACAGTGATCATTCATGTCT ATCCCTCAGATAGGAGTGCCCCCATCTTTTCAATCTGAGTACTTTGTAGAGATCCCTGATCAATC CCTGTTGGTTCCCCAATCCTCCTTGTCTCTGCTATGAGCCCCTCTGAGTTACCTATGAGTTAAGAGA GGGAATAGGATGGAGTCTTCTCTATGAACTCATATTCTGGCCTTATTTCCACCCAGAGATTGG ACCATGAAAATCTCGTCTTACCAGCTGAAATCCGAGGCAGCATATGGCAGTGCATTTACTGAT GTCATGGTGGTGTTGACATAATTGATGAAATGACATGCTCCTATGTTCTTAGTCAACTTTTGT GGGCCAATTAGTGAAGCAGCTCCACTGTATAGCATGATCATCAAACAACACCCCTTTGTGA TTCATGCCTCTGACAGTGACAA.GAGCTATTCCTTGTTGGTCTATAAATTTTGGAGCCGCACGCC TTGAGTTTTTCAAATTGATCCCAGCATGGGACCCTACCATTGTATCAGAGATGGATTATGAGAG CATGCCCTCTTTCCAATTCTGTGTC-TATGTCCATGACCAAGGAGCCCTGTATTATTTCACCCAGAC CTGCCCAAGTCATCATTCATGTCAGAGATGTGATGATTCCCCTCCCAGATTCTCAGACAGATATAT GAGGTAGCAATAGTCGGGCCTATCCATCCAGGCATGGAGCTTCTCATGGTCCGGGCCAGCGATGA CTCAGAGTCAATTATAGCATCAAAACTGGCAATGCTGATGAGCTGTTACCATCCATCCTGTCACTG GTAGCATATCTGTGCTGAATCCTGCTTTCCTGGGACTCTCTCGGAAGCTCACCATCAGGGCTTCTGAT GGCTTGTATCAAGACACTGCCTGTAAATTCTTTGACCCAGTGCTTGACAAGCTTGCAGTT TGATCAGGATGTCTACTGGGCAGCTGTGAAGGAGACTTCAGACAAAGGCACTGGTGATTCTTG GTGCCCAGGGCAATCATTTGAATGACACCCTTTCCTACTTTCTCTTGAATGGCACAGATATGTTTCAT ATGGTCCAGTCAGCAGGTGTGTTGCAGACAALGAGGTGTGGCGTTTGACCGGGAGCAGCAGGACACTCA TGAGTTGGCAGTGGAAGTGAGGCGACAATCGGACACCTCAGCGGGTGGCTCAGGGTTTGGTCAGAGTCT CTATTGAGGATGTCAATGACAATCCCCCCATTTAAGCATCTGCCCTATTACACALTCATCCAAGAT GGCACAGAGCCAGGGGQATGTCCTCTTTCAGGTATCTGCCACTGATGAGGACTTGGGGACATGGGGC TGTTACATATGAATTTGCAGAAGATTACACATATTTCCGATTGACCCCTATCTTGGGGACATATCAC TCAAGAAACCCTTTGATTATCAAGTTTAATAATATCACCTCAAATCATTGCTCGGGATGGAGGA ACGCCATCCCTCCAGAGTGAGGAGAGGTACTTGTCACTGTGAGAATATCCACCCACTGTTTCA GAGTCCTTATTACAAGTCAGAGTACCTGAAALTATCCCCTCTATACCCCATTCTCCACACCCAGG CCCGGAGTCCAGAGGGACTCCGGCTCATCTACAACATTGTGGAGGAGACCCTTGATGCTGTTCACC ACTGACTTCAAGACTGGTGTCCTAACAGTAACAGGGCCTTTGGACTATGAGTCCAGACCAAACATGT GTTCACAGTCAGAGCCACGCATACAGCTCTGGGGTCATTTTCTGAGCCACAGTGGAAGTCCTAGTCG AGGATGTCAATGATAACCCTCCCACTTTTTCCCAATTGGTCTATACCACTTCCATCTCAGAAGGCTTG CCTGCTCAGACCCCTGTGATCCAACTGTTGGCTTCTGACCAGGACTCAGGGCGGAACCGTGACGTCTC TTATCAGATTGTGGAGGATGGCTCAGATGTTTCCAAGTTCTTCCAGATCATGGGAGCACAGGGGAGA TGTCCACAGTTCAAGAACTGGATTATGAAGCCCACACACTTTCATGTGAAGTCAGGGCCATGGAT AAGGAGATCCCCCACTCACTGGTGAAACCCTTGTGGTTGTCAATGTGTCTGATATCAATGACAACCC CCAA TACA'TATTA7CAGTAT ATGACTT

,CCT'GT

WO 2004/015079 PCT/US2003/024931 TTAAAGTCCAGGCTATTGACCCTGACAGCAGAGACACCTCCCGCCTGGAGTkCCTGATTCTTTCTGGC AATCAGGACAGGCACTTCTTCATTAACAGCTCATCGGGAATAATTTCTATGTTCAACCTTTGCAAAAA * GCACCTGGACTCTTCTTACAATTTGAGGGTAGGTGCTTCTGATGGAGTCTTCCGAGCAACTGTGCCTG TGTACATCAACACTACAAATGCCAACAAGTACAGCCCAGAGTTCCAGCAGCACCTTTATAGGCAGAA TTAGCAGAGAATGCAATGGTTGGAACCAAGGTGATTGATTTGCTAGCCATAGACAAAGATAGTGGTCC CTATGGCACTATAGATTATACTATCATCAATAAACTAGCAAGTGAG3AAGTTCTCCATAAACCCCAATG GCCAGATTGCCACTCTGCAGAAACTCGATCGGGAAAATTCAACACAGAGAGTCATTC'CTATTAAGGTC ATGGCTCGGGATGGAGGAGGAAGAGTAGCCTTCTGCACGGTGAAGATCATCCTCACAGATGAAAATGA CAACCCCCCACAGTTCAAAGCATCTGAGTACACAGTATCCATTCAATCCAATGTCAGTAAAGACTCTC CGGTTATCCAGGTGTTGGCCTATGATGCAGATGAAGGTCAGAACGCAGATGTCACCTACTCAGTGAAC CCAGAGGACCTAGTTAAAGATGTCATTGAAATTAACCCAGTCACTGGTGTGGTCAAGGTGAAAGACAG CCTGGTGGGATTGGAAAATCAGACCCTTGACTTCTTCATCAAAGCCCAAGATGGAGGCCCTCCTCACT GGAACTCTCTGGTGCCAGTACGACTTCAGGTGGTTCCTAAAAAAGTATCCTTACCGAAATTTTCTGAA CCTTTGTATACTTTCTCTGCACCTGAAGACCTTCCAGAGGGGTCTGAAATTGGGATTGTTAAAGCAGT GGCAGCTCAAGATCCAGTCATCTACAGTCTAGTG-CGGGGCACTACACCTGAGAGCAACAAGGATGGTG TCTTCTCCCTAGACCCAGACACAGGGGTCATAAAGGTGAGAAGCCCATGGACCACCAATCCACCAAA TTGTACCAGATTGATGTGATGGCACATTGCCTTCAGAACACTGATGTGGTGTCCTTGGTCTCTGTCAA CATCCAAGTGGGAGACGTCAATGACAATAGGCCTGTATTTGAGGCTGATCCATATAAGGCTGTCCTCA CTGAGAATATGCCAGTGGGGACCTCAGTCATTCAAGTGACTGCCATTGACAAGGACACTGGGAGAGAT GGCCAGGTGAGCTACAGGCTGTCTGCAACCCTGGTACAATTCCATGAGCTCTTITGCCATTGACAG TGAGAGTGGTTGGATCACCACACTCCAGGAACTTGACTGTGAGACCTGCCAGACTTATCATTTTCATG TCTGGCCTATGACCACGGACAGACCATCCAGCTATCCTCTCAGGCCCTGGTTCAGGTCTCCATTACA GATGAGAATGACAATGCTCCCCGATTTGCTTCTGAAGAGTACAGAGGATCTGTGGTTGAGAACAGTGA GCCTGGCGAACTGGTGGCGACTCTAAAGACCCTGGATGCTG.ACATTTCTGAGCAGAACAGGCAGGTCA CCTGCTACATCACAGAGGGAGACCCCCTGGGCCAGTTTGGCATCAGCCAAGTTGGAGATGAGTGGAGG ATTTCCTCAAGGAAGACCCTGGACCGCGAGCATACAGCCAAGTACTTGCTCAGAGTCACAGCATCTGA TGGCAAGTTCCAGGCTTCGGTCACTGTGGAGATCTTTGTCCTCGACOTCAATGATAACAGCCCACAGT GTTCACAGCTTCTCTATACTGGCAAGGTTCATGAAGATGTATTTCCAGGACACTTCATTTTGAAGGTT TCTCCCACAGACTTGGACACTGATACCAATGCTCAGATCACATATTCTCTGCATGGCCCTGGGGCGCA TGAATTCAAGCTGGATCCTCATACAGGGGAGCtGACCACACTCACTGCCCTAGACCGAGAAAGGAAGG ATGTGTTCAACCTTGTTGCCAAGGCGACGGATGGAGGTGGCCCATCGTGCCACGCAGACATCACCCTC CATGTGGAGGATGTGAATGACAATGCCCCGCGGTTCTTCCCCAGCCACTGTGCTGTGGCTGTCTTCGA CAACACCACAGTGAAGACCCCTGTGGCTGTAGTATTTGCCCGGGATCCCGACCAAGGCGCCAATGCCC AGGTGGTTTACTCTCTGCCGGATTCAGCCCAAGGCCACTTTTCCATCGACGCCACCACCGGGCGTGATC CCCCTGGAAAAGCCGCTGCAGGTCAGGCCCCAGGCACCACTGGAGCTCACGGTCCGTGCCTCTGACCT GGGCACCCCAATACCGCTGTCCACGCTGGGCACCGTCACAGTCTCGGTGGTGGGCCTAGAAGACTACC TGCCCGTGTTCCTGAACACCGAGCACAGCGTGCAGGTGCCCGAGGACGCCCCACCTGGCACGGAGGTG CTGCAGCTGGCCACCCTCACTCGCCCGGGCGCAGAGAMGACCGGCTACCGCGTGGTCAGCGGGAACGA GCAAGGCAGGTTCCGCCTGGATGCTCGCACAGGGATCCTGTATGTCAACGCAAGCCTGGACTTTGAGA CAAGCCCCAAGTACTTCCTGTCCATTGAGTGCAGCCGGAAGAGCTCCTCTTCCCTCAGTGACGTGACC ACAGTCATGGTCAACATCACTGATGTCAATGAACACCGGCCCCAATTCCCCCAAGATCCATATAGCAC AAGGGTCTTAGAGAATGCCCTTGTGGGTGACGTCATCCTCACGGTATCAGCGACTGATGAAGATGGAC CCCTAAATAGTGACATTACCTNAGACCTCATAGGAGGGAACCAGCTTGGGCACTTCACCATTCACCCC AAAAAGGGGGAGCTACAGGTGGCCAAGGCCCTGGACCGGGAACAGGCCTCTAGTTATTCCCTGAAGCT CCGAGCCACAGACAGTGGGCAGCCTCCACTGCATGAGGACACAGACATCGCTATCCAAGTGGCTGATG TCAATGATAACCCACCGAGATTCTTCCAGCTCAACTACAGCACCACTGTCCAGGAGAACTCCCCCATT GGCAGCAAAGTCCTGCAGCTGATCCTGAGTGACCCAGATTCTCCAGAGAATGGCCCCCCCTACTCGTT TCGAATCACCAAGGGGAACAACGGCTCTGCCTTCCGAGTGACCCCGGATGGATGGCTGGTGACTGCTG * AGGGCCCTAAGCAGGAGGGCTCAGGAATGGTATCAGCTTCAGATCCAGGCGTCAGACAGTGGCATCCCT CCCCTCTCGTCTTTGACGTCTGTICCGTCTCCATGTCACAGAGCAGAGCCACTATCCACCTTCTGCTCT CCCACTGGAGATCTTCATCACTGTTGGAGAGGATGAGTTCCAGGGTGGCATGGTGGGTAAGATCCATG CCACAGACCGAGACCCCCAGGACACCCTGACCTATAGCCTGGCAGAAGAGGAGACCCTGGGCAGGCAC TTCTCAGTGGGTGCGCCTGATGGCAAGATTATCGCCGCCCAGGGCCTGCCTCGTGGCCACTACTCGTT CAACGTCACGGTCAGCGATGGGACCTTCACCACGACTGCTGGGGTCCATGTGTACGTGTGGCATGTGG GGCAGGAGGCTCTGCAGCAGGCCATGTGGATGGGCTTCTACCAGCTCACCCCCGAGGAGCTGGTGAGT GACCACTGGCGGAACCTGCAGAGGTTCCTCAGCCATAAGCTGGACATCAAACGGGCTAACATTCACTT GGCCAGCCTCCAGCCTGCAGAGGCCGTGGCTGGTGTGGATG2'GCTCCTGGTCTTTGAGGGGCATTCTG GAACCTTCTACGAGTTTCAGGAGCTAGCATCCATCATCACTCACTCAGCCAAGGAGATGGAGCATTCA GTGGGGGTTCAGATGCGGTCAGCTATGCCCATGGTGCCCTGCCAGGGGCCAACCTGCCAGGGTCAAAT CTGCCATAACACAGTGCATCTGGACCCCAAGGTTGGGCCCACGTACAGCACCGGCCAGGCNTTAACAT CCCTAACCCCGCGGCACCACCTGCAGAGGAGCTGCTCCTGCAATGGTACTGCTACAAGGTTCAGTGGT CAGAGCTATGTGCGGTACAGGGTCCCAGCGGCTCGGAACTGGCACATCCATTTCTATCTGAAAACACT CCAGCCACACGCCCATTCTTCTATTCACCAATGAAACAGCGTCCGTCTCCCTGAAGGGCTTTGAAGGCT GCCTGGATGCTGTCGTGGTCAACGAAGAGGCTCTAGATCTGCTGGCCCCTGGCAAGACGGTGGCAGGC TTGCTGGAGACACAAGCCCTCACCCAGTGCTGCCTCCACAGPGACTACTGCAGCCAGAACACATGCCT CAATGGTGGGAAGTGCTCATGGACCCACGGGGCAGGCTATGTCTGCAAATGTCCCCCACAGTTCTCTG GGAAGCACTGTGAACAAGGAAGGGAGAACTGTACTTTTGCACCCTGCCTGGAAGGTGGAACTTGCATC 1AO WO 2004/015079 PCT/US2003/024931 GAGGGGTTGTTCAGAAGGACACTGCCTAGTCACTCCCGAGATCCAAAGGGGGGACTGGGGGCAGCAGG AGTTACTGATCATCACAGTGGCCGTGGCGTTCATTATCA TAAGCACTGTCGGGCTTCTCTTCTACTGC CGCCGTTGCAAGTCTCACAAGCCTGTCCCATGGACGACCCAGACCTCCTGGCCAGGAGTGTTGGTGT TGACACCCAAGCCATGCCTGCCATCGAGCTCAACCCATTGAGTGCCAGCTCCTGCAACAACCTCAACC AACTGCACCCAGCAAGCCCTCTGTTCCAATGAACTCTCACATTTGGACCCAATTCTAAGCAACGG CCAGTGGTCTGCAGTGTGCCCCCCAGACTCCCGCCAGCTGCGGTCCCTTCCCACTCTGACAATGGCC TGTCATTAAGAGAZXCCTGGTCCAGTGAGGAGATGGTGTACCCTCGCCGAGCCATGGTCTGGCCCCCTA CTTACTCCAGGAACGAACGCTGGGAATACCCCCACTCCGAAGTGACTCAGGGCCCTCTGCCGCCCTCG GCTCACCGCCACTCAACCCCAGTCGTGATGCCAGAGCCTAATGGCCTCTATGGGGGCTTCCCCTTCCC CCTGGAGATGGAAAACAAGCGGGCACCTCTCCCACCCCGTTACAGCAACCAGAACCTGGAAGATCTGA TGCCCTCTCGGCCCCCTAGTCCCCGGGAGCGCCTGGTTGCCCCCTGTCTCAATGAGTACACGGCCATC AGCTACTIACCACTGCAGTTCCGGCAGGGAGGGGGAGGGCCCTGCCTGGCAGACGGGGGCTACAAGGG GGTGGGTATGCGCCTCAGCCGAGCTGGGCCCTCTTATGCTGTCTGTGAGGTGGAGGGGGCACCTCTTG C'AGGCCACCCAGCCCCGGGTGCCCCCCAACTIATGAGGGCTCTGACATCGTGGAGAGTGATTATGGC AGCTGTGAGGAGGTCATGTTCTAGCtTCCCATTCCCAGAGCAAGGCACGCGGGAGGCCAAGGACTGGA CTTGGCTTATTTCTTCCTGTCTCGTAGGGGGTGAGTTCAGTGTGGCTCGGAGAGTCGGAGGGAAGCCC TCAGCCCAGGCTGTTGTCCCTTGAAATGTGCTCTTCCAATCCCCCACCTAGTCCCTGAGGGTGGAGGG AAGCTGAGGATACAGCTCCAGAAACAGCACTAGGGTCCCAGCAGACCCGCATTTCTAGAGCAGTGACC CTGGAAAACCAGGAACAATTGACTCCCGGGGTGGGCGAGAGACAGGAGGGCTCCCTGATCTGCCGGCT CTCAGTCCCCGGGGCAGAGCCTGATTGACTGTGCTGGCTCAACTTCACCAAGATGCATTCTCATACCT GCCCACAGCTCCATTTTGGAGGCAGGCAGGTTGGTGCCTGACAGACAACCACTACGCGGGCCGTAA AGGAGCTCTAGAGGGCTGCGTGG3CATCCTCCTAGGGGCTGAGAGGTGAGCACCAGGGGACGCCCACA GTCCCCTCTGCCCCTGCCTCAGTCGAGCACTCACTGTGTCTTTGTCAAGTGTCTGCTCCACGTCAGGC ACTGTGCTTTGCACCGGGGAGAAAATGGTGATGGAGGGCAACAAGGACTCCGAGGAGCACCACCAGGC CTCGGGCCCCAGAGGTCCCACTCCTCAGCCTACACGCAGAGGAACGGGCCCACCTCAGAGTCACACCA CTGGCTGCCAGTCAGGGCCTGCCAGGAGTCTACACAGCTCTAACCTTCTTTGTTAAAGATTCAGAC CTCATGGAACTCTGGTTCTTCATCCCAATTTCCCAGCCACTTTTGAGGAGGAAGAACTA ATTCTTCATTTTAAAAATTCTTAGGCACTTTTTGACCTTGCTGTCTGGATGAGTTTCCTCAATGGGAT TTTTCTTCCCTAGACACAGGAAGTCTGACTCCTATTTAGGCCGGTTGAAGCAGGAGCTGGACC (GCAGTGTCCAGGCTGGACACCTGCCATTGCCTCCTCTCCATTGCAGACGCCTGCCCATCAAGTATTAC TGCGGCGACTCAACCCTATGCATGGAGGGCAATGTGc3CACATGTCTACACATGTGGGTGCCCATG' ATAGTACGTGTGTACACATGTGTAGAGTGTATGTAGCCAGGAGTGGTGGGACCAGAAGCCTCTGTGG CCTTTGGTGACCTCACCACTCCCTCCCACCCAGTCCCTCCCTCTGGTCCACTGCCTTTTCATATGTGT TGTTTCTCOAGACACAAOTCAAAAGGAAGAGCACTGGAGCCTTGCCCACAGGGCTGCTGCTTCATGCG 7AGAGGGAATGTGTGGGCGAGAGCCAATTTGTGTGAGTGGTTTGTGCCTGTGTGTGTGACTGTGAGTG

TGAGTGACAATACATAGTTTCATTGGTCATTTTTTTTTTAACAATAAAGTATCTTTTTTTACTCTT

NOV6n, CG51923-03 rSQ ]ID NO: 66 14264 aa 1Wat 46987 1.7kD Protein SequenceIII MTIALLGFAIFLLHCATCEKPLEGILSSSAWHFTHSHYNATIYENSSPKTYVESFEKMGIYLAEPQWA VRYRI ISGDVANSVFKTEEYWVGNFCFLRIRTKSSNTALLNREVRDSYTLI IQATEKTLELEALTRVVV R-ILDQNDLKPLFSPPSYRVTISEDMPLKSPICKVTATDADLGQNAEFYYAFNTRSEMFAlIHPTSGVVT VAGKLNVTWRGKHELQVLAVDRMRKISEGNGFGSLAALVVHVEPALRKPPAIASVVVTPPDSNDGTTY ATVLVDANSSGAEVESVEVVGGDPGKHFKAIKSYARSNEFSLVSVKDINWM~EYLHGFNLSLQARSGSG PYFYSQIRGFHLPPSKLSSLKFEKAVYRVQLSEFSPPGSRVVMVRVTPAFPNLQYVLKPSSENVOFKL NARTGLITTTKLMDFHDRAlYQLHIRTSPGQASTTVVIDIVDCNNHAPLFNRSSYDGTLDEN~IPPGTS VLAVTATDRDHGENGYVTYSIAGPKALPFSIDPYLGIISTSKPMDYELMKRIYTFRVASDWGSPFRR EKEVSIFLQLRN~LNDNQPMFEVNCTGSIRQDWPVGKSIMTMSAIDVDELQNLKYEIVSGNELEYFDL NHFSGVI SLKRPFINLTAGQPTSYSLKITASDGKNYASPTTLNITVVKDPHFEVPVTCDKTGVLTQFT KTILHFIGLQNQESSDEEFTSLSTYQINHYTPQFEDHFPQSIDVLESVPINTPLARLAADPDAGFNG 7(LVYVIADGNEEGCFDIELETGLhLTVAAPLDYEATNFYILNVTVYDLGTPQKSSWKLLTVNVKDWNDN APRFPPGYQLTISEDTEVGTTIAELTTKDADSEDNGRVRYTLLSPTEKFSLHPLTGELVVTGHLDRE SEPRYILKVEARDQPSKGHQLFSVTDLIITLEDVNDNSPQCITEHNRLKVPEDLPPGTVLTFLDASDP DLGPAGEVRYVLMDGAHGTFRVDLMTGALILERELDFERRAGYNLSLWASDGGRPLARRTLCHVEVIV LDVNENLHPPHFASFVHQGQVQENSPSGTQVIVVAAQDDDSGLDGELQYFLRAGTGLAAFSINQDTGM IQTLAPLDREFASYYWLTVLAVDRGSVPLSSVTEVYIEVT DANDNPPQMSQAVFYPSIQEDAPVGTSV LQLDAWDPDSSSKGKLTFNITSGNYMGFFMIHPVTGLLSTAQQLDRENKDEHILEVTVLDNGEPSLKS TSRVVVGILDVNDNPPIFSHKLFNVRLPERLSPVSPGPVYRLVASDLDEGLNGRVTYSIEDSYEEAFS IDLVTGVVSSNSTFTAGEYNILTIKATDSGQPPLSASVRLHIEWIPWPRPSSIPLAFDETYYSFTvME TDPVNHMVGVISVEGRPGLFWFNISGGDKDMDFDIEKTTGSIVIARPLDTRRRSNYNLTVEVTDGST IATQVHIFMIANINHHRPQLETRYEVRVPQDTVPGVELLRVQAIDQDKGKSLIYTIHGSQDPGSASL FQLDPSSGVTNTVGKLDLGSGPSQHTLTVMVRDQEIPIKRNFVWVTIHVEDGNLHPPRFTQLHYFEASV PDTIAPGTELLQVRAMDADRGVNAEVHYSLLKGNSEGFFNINALLGIITLAQKLDQANHAPHTLTVKA EDQGSPQWHDLATVIIHVYPSDRSAPIFSKSEYFVEIPESIPVGSPILLVSAMSPSEVTYELREGNKD GVFSNNSYSGLISTQKQJDHEKI SSYQLKIRGSNMAGAFWDVMVVVDIIDENDNAPMFLKSTFVGQIS EAAPLYSMIMDKNN~NPFVIHASDSDKEASLLVYKILEPEALKFFKIDPSMGTLTIVSEMDYESMPSF QFCVYVHDQGSPVLFAPRPAQVIIHVRDVNDSPPRFSEQIYEVAIVGPIHPGMELLMVRASDEDSEVN

IYSIKTGNADEAVTIHPVTGSISVLNPAFLGLSRKLTIRASDGLYODTALVKISLTOVLDKSLOFDODVI

WO 2004/015079 PCT/US2003/024931 YWAAVKENLQDRKALVILGAQGNHLNDTLSYFLLNGTDMFHMVQSAGVLQTRGVAFDREQQDTHELAV EVRDNRTPQRVAQGLVRVSIEDVNDNPPKFKHLPYYTIIQDGTEPGDVLFQVSATDEDLGTNGAVTYE FAEDYTYFRIDPYLGDISLKKPFDYQALNKYHLKVIARDGGTPSLQSEEEVLVTVRNKSNPLFQSPYY IVRVPENITLYTPILHTQARSPEGLRLIYNIVEEEPLMLFTTDFKTGVLTVTGPLDYESKTKHVFTVR ATDTALGSFSEATVEVLVEDVNDNPPTFSQLVYTTSISEGLPAQTPVIQLLASDQDSGRNRDVSYQIV EDGSDVSKFFQINGSTGEMSTVQELDYEAQQHFHVKVRAMDKGDPPLTGETLVVNVSDINDNPPEFR QPQYEANVSELATCGHLVLKVQAIDPDSRDTSRLEYLILSGNQDRHFFINSSSGIISMFNLCKKHLDS SYNLRVGASDGVFRATVPVYINTTNANKYSPEFQQHLYEAELAENAMVGTKVIDLLAIDKDSGPYGTI DYTIINKLASEKFSINPNGQIATLQKLDRENSTERVIAIKVMARDGGGRVAFCTVKIILTDENDNPPQ FKASEYTVSIQSNVSKDSPVIQVLAYDADEGQNADVTYSVNPEDLVKDVIEINPVTGVVKVKDSLVGL ENQTLDFFIKAQDGGPPHWNSLVPVRLQVVPKKVSLPKFSEPLYTFSAPEDLPEGSEIGIVKAVAAQD PVTYSLVRGTTPESNKDGVFSLDPDTGVIKVRKPMDHESTKLYQIDVMAHCLQNTDVVSLVSVNIQVG DVNDNRPVFEADPYKAVLTENMPVGTSVIQVTAIDKDTGRDGQVSYRLSADPGSNVHELFAIDSESGW ITTLQELDCETCQTYHFHVVAYDHGQTIQLSSQALVQVSITDENDNAPRFASEEYRGSVVENSEPGEL VATLKTLDADISEQNRQVTCYITEGDPLGQFGISQVGDEWRISSRKTLDREHTAKYLLRVTASDGKFQ ASVTVEIFVLDVNDNSPQCSQLLYTGKVHEDVFPGHFILKVSATDLDTDTNAQITYSLHGPGAHEFKL DPHTGELTTLTALDRERKDVFNLVAKATDGGGRSCQADITLHVEDVNDNAPRFFPSHCAVAVFDNTTV KTPVAVVFARDPDQGANAQVVYSLPDSAEGHFSIDATTGVIRLEKPLQVRPQAPLELTVRASDLGTPI PLSTLGTVTVSVVGLEDYLPVFLNTEHSVQVPEDAPPGTEVLQLATLTRPGAEKTGYRVVSGNEQGRF RLDARTGILYVNASLDFETSPKYFLSIECSRKSSSSLSDVTTVMVNITDVNEHRPQFPQDPYSTRVLE NALVGDVILTVSATDEDGPLNSDITYSLIGGNQLGHFTIHPKKGELQVAKALDREQASSYSLKLRATD SGQPPLHEDTDIAIQVADVNDNPPRFFQLNYSTTVQENSPIGSKVLQLILSDPDSPENGPPYSFRITK GNNGSAFRVTPDGWLVTAEGLSRRAQEWYQLQIQASDSGIPPLSSLTSVRVHVTEQSHYAPSALPLEI FITVGEDEFQGGMVGKIHATDRDPQDTLTYSLAEEETLGRHFSVGAPDGKIIAAQGLPRGHYSFNVTV SDGTFTTTAGVHVYVWHVGQEALQQAMWMGFYQLTPEELVSDHWRNLQRFLSHKLDIKRANIHLASLQ PAEAVAGVDVLLVFEGHSGTFYEFQELASIITHSAKEMEHSVGVQMRSAMPMVPCQGPTCQGQICHNT VHLDPKVGPTYSTGQALTSLTPRHHLQRSCSCNGTATRFSGQSYVRYRVPAARNWHIHFYLKTLQPQA ILLFTNETASVSLKGFEGCLDAVVVNEEALDLLAPGKTVAGLLETQALTQCCLHSDYCSQNTCLNGGK CSWTHGAGYVCKCPPQFSGKHCEQGRENCTFAPCLEGGTCILSPKGASCNCPHPYTGDRCEMEARGCS EGHCLVTPEIQRGDWGQQELLIITVAVAFIIISTVGLLFYCRRCKSHKPVAMEDPDLLARSVGVDTQA MPAIELNPLSASSCNNLNQLEPSKASVPNELVTFGPNSKQRPVVCSVPPRLPPAAVPSHSDNGPVIKR TWSSEEMVYPGGAMVWPPTYSRNERWEYPHSEVTQGPLPPSAHRHSTPVVMPEPNGLYGGFPFPLEME NKRAPLPPRYSNQNLEDLMPSRPPSPRERLVAPCLNEYTAISYYHSQFRQGGGGPCLADGGYKGVGMR LSRAGPSYAVCEVEGAPLAGQGQPRVPPNYEGSDMVESDYGSCEEVMF A ClustalW comparison of the above protein sequences yields the following relationships between the NOV6 sequences. In comparison to NOV6a, CG51923-01, NOV6n is 4264 amino acid residues having the following sequence changes: amino acids 5 3754 to 3759, -ARLSI becomes GQALTS; A3789V; amino acids 3900 to 3907, HSSSNVSQ are deleted; P4117L; E4160G. NOV6m corresponds to amino acid residues 2802 to 4023 of NOV6a with the following sequence changes: V3033A; L3514S; G3591D; M3631I. NOV61 corresponds to amino acid residues1561 to 2233 of NOV6a. NOV6k corresponds to amino acids 1143 to 1733 of NOV6a with the following sequence changes: 10 Y1181H; Y1287D; N1303S. Both NOV6b and NOV6c correspond to amino acids 2561 to 3233 of NOV6a with NOV6b having an amino acid change Q2991H. NOV6e and NOV6f correspond to amino acids 1 to 659 of NOV6a and NOV6e has an amino acid change R574C. NOV6g corresponds to amino acid residues 19-659 of NOV6a with an amino acid change of R574C. NOV6h and NOV6i correspond to amino acids 154-659 of NOV6a and 15 NOV6h has an amino acid change R574C. NOV6d corresponds to amino acids 3559 to 4043 of NOV6a with an amino acid change M363 1. NOV6j corresponds to NOV6a amino acids 570 to 1233 with A1100V and Y1181H amino acid changes. 141~ WO 2004/015079 PCT/US2003/024931 Further analysis of the NOV6a protein yielded the following properties shown in Table 6B. Table 6B. Protein Sequence Properties NOV6a SignalP analysis: Cleavage site between'residues 19 and 20 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 0; pos.chg 0;- neg.chg 0 H-region: length 18; peak value 11.25 PSG score: 6.85 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): -0.05 possible cleavage site: between 18 and 19 >> Seems to have a cleavable signal-peptide (1 to 18) ALOM: Klein et al's method for TM region allocation Init position for calculation: 19 Tentative number of TMS(s) for. the threshold 0.5: 1 Number of TMS-(s) for threshold 0.5: 1 INTEGRAL Likelihood =-10.40 Transmembrane 4049 -4065 PERIPHERAL Likelihood = 1.01l(at 3195) ALOM score: -10.40 (number of .TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 9 Charge difference: -1.5 C(-0.5) - N( 1.0) N >= C: N-terminal side will be inside >>> membrane topology: type la (cytoplasmic tail 4066 to 4349) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 0.99 Hyd Moment(95): 1.82 G content: 1 D/E content: 1 S/T content: 2 Score: -6.08 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: PFRREKE (4) at 541 pat7: PLDTRRR (3) at 1407 bipartite: none content of basic residues: 8.0% NLS Score: 0.13 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none 1 C') WO 2004/015079 PCT/US2003/024931 SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: found KLASGVPQL at 3821 VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: found LL at 4066 LL at 4086 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 44.4 %: endoplasmic reticulum 22.2 %: Golgi 22.2 %: extracellular, including cell wall 11.1 %: plasma membrane >> prediction for CG51923-01 is end (k=9) A search of the NOV6a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6C. I Z'2 WO 2004/015079 PCT/US2003/024931 Table 6C. Geneseq Results for NOV6a NOV6a Identities/ Geneseq Protein/Organism/Length Residues/ Similarities for the Expect Identifier [Patent #, Date] Match Matched Region Value Residues AA026792 Human cadherin (CAD) protein, 1..4349 4349/4349 (100%) 0.0 SEQ ID No 15 - Homo sapiens, 1..4349 4349/4349 (100%) 4349 aa. [W0200299042-A2, 12 DEC-2002] AAU79940 Human protocadherin Fat 2 1..4349 4349/4349 (100%) 0.0 (FAT2) protein NOV2 - Homo 1..4349 4349/4349 (100%) sapiens, 4349 aa. [W0200229038-A2, 11-APR 2002] ABB97540 Novel human protein SEQ ID 1..4349 4346/4349 (99%) 0.0 NO: 808 - Homo sapiens, 4349 1..4349 4347/4349 (99%) aa. [W0200222660-A2, 21 MAR-2002] ABB97541 Novel human protein SEQ ID 1..3821 3819/3821 (99%) 0.0 NO: 809 - Homo sapiens, 4263 1..3821 3819/3821 (99%) aa. [W0200222660-A2, 21 MAR-2002] AA026791 Human cadherin (CAD) protein, 26..4033 1844/4089 (45%) 0.0 SEQ ID No 14 - Homo sapiens, 27..4100 2647/4089 (64%) 4590 aa. [W0200299042-A2, 12 DEC-2002] In a BLAST search of public sequence databases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6D. Table 6D. Public BLASTP Results for NOV6a Protein NOV6a Identities/ Accession Protein/Organism/Length Residues/ Similarities for the Expect Number Residues Matched Portion Q9NYQ8 Protocadherin Fat 2 precursor 1..4349 4349/4349 (100%) 0.0 (hFat2) (Multiple epidermal 1..4349 4349/4349 (100%) growth factor-like domains 1) Homo sapiens (Human), 4349 aa. CAD35056 Sequence 364 from Patent 1..4349 4346/4349 (99%) 0.0 W00222660 - Homo sapiens 1..4349 4347/4349 (99%) (Human), 4349 aa. CAD35057 Sequence 365 from Patent 1..3821 3819/3821 (99%) 0.0 W00222660 - Homo saniens 1.3821 3819/3821 (99%) 1 CA WO 2004/015079 PCT/US2003/024931 (Human), 4263 aa. 088277 Protocadherin Fat 2 precursor 1..4349 3557/4351 (81%) 0.0 (Multiple epidermal growth 1..4351 3915/4351 (89%) factor-like domains 1) - Rattus norvegicus (Rat), 4351 aa. Q9QXA3 Mouse fat 1 cadherin - Mus 33..4167 1890/4317 (43%) 0.0 musculus (Mouse), 4587 aa 35..4315 2701/4317 (61%) (fragment). PFam analysis predicts that the NOV6a protein contains the domains shown in the Table 6E. Table 6E. Domain Analysis of NOV6a NOV6a Match Region Identities/ Pfam NOVn a Matc eion Similarities Expect Domain Amino Acid residues of SEQ ID for the Matched Value NO: 40Rein__ __ Region cadhenn 38..139 25/113 (22%) 0.05 67/113 (59%) cadherin 153..247 28/109 (26%) 2.le-08 69/109 (63%) cadherin 367..449 21/107 (20%) 0.94 54/107 (50%) cadherin 463..553 40/107 (37%) 8.9e-20 69/107 (64%) cadherin 569..659 27/110 (25%) 2.9e-06 64/110 (58%) cadherin 720..811 35/107 (33%) 4.4e-23 70/107 (65%) cadherin 825..916 35/107 (33%) 8.6e-24 75/107 (70%) cadherin 930..1019 33/107 (31%) 2.8e-12 62/107 (58%) cadherin 1037..1128 41/107 (38%) 7.6e-21 70/107 (65%) cadherin 1142..1233 39/107 (36%) 3.7e-20 69/107 (64%) cadherin 1247..1337 33/110 (30%) 2.2e-08 66/110 (60%) cadherin 1354..1438 29/107 (27%) 1.4e-05 63/107 (59%) WO 2004/015079 PCT/US2003/024931 cadherin 1453..1546 29/107 (27%) 4.le-08 67/107 (63%) cadherin 1560..1651 40/107 (37%) 1.8e-21 69/107 (64%) cadherin 1665..1749 26/107 (24%) 6e-13 63/107 (59%) cadherin 1763..1861 23/116 (20%) 8.6e-09 73/116 (63%) cadherin 1877..1959 30/111 (27%) 0.27 53/111 (48%) cadherin 1973..2061 23/108 (21%) 7.le-06 60/108 (56%) cadherin 2075..2164 36/107 (34%) 4.6e-17 64/107 (60%) cadherin 2176..2263 32/107 (30%) 1.5e-09 64/107 (60%)' cadherin 2277..2370 31/109 (28%) 9.3e-27 73/109 (67%) cadherin 2384..2472 34/111 (31%) 3e-09 65/111 (59%) cadherin 2486..2576 34/107 (32%) 3.7e-15 66/107 (62%) cadherin 2590..2682 25/111 (23%) 1.9e-05 66/111 (59%) cadhein 2696..2786 31/112 (28%) 9.8e-07 68/112 (61%) cadherin 2802..2897 36/110 (33%) 2.5e-22 76/110 (69%) cadherin 2911..3002 37/107 (35%) 4.7e-12 63/107 (59%) cadherin 3016..3104 33/107 (31%) 6e-21 69/107 (64%) cadherin 3119..3209 35/107 (33%) 1.3e-13 66/107 (62%) cadherin 3223..3312 30/107 (28%) le-12 69/107 (64%) cadherin 3326..3417 43/107 (40%) 7e-27 69/107 (64%) cadherin 3431..3522 36/108 (33%) 6.9e-20 1 %i~ WO 2004/015079 PCT/US2003/024931 74/108 (69%) cadherin 3536.3620 25/108 (23%) 0.0012 56/108 (52%) lamininG 3800.3924 331156 (21%) 0.0028 76/156 (49%) EGF 3951..3983 18/47(38%) 3.6e-06 27/47 (57%) _ EGF 3990..4021 17/47(36%) 0.00016 26/47 (55%) Various open reading frames of CG51923-01 were cloned as follows: assemblies 317868343 and 317868367, residues 1 to 659; assembly 317871203, residues 19 to 659; assemblies 317871219 and 317871243, residues 154 to 659; assembly 317871246, residues 5 570 to 1233; assembly 317999764, residues 1143 to 1733; assembly 318176301, residues 1561 to 2233; assemblies 305869563 and 305869567 residues 2560 to 3233. The cloned inserts differ from the original sequence as follows: assembly 317868343 has three silent SNPs and one R574C amino acid change; assembly 317868367 has one silent SNP; assembly 317871203 has two silent SNPs and one R574C amino acid change; assembly 10 317871219 has three silent SNPs and one R574C amino acid change; assembly 317871243 has one silent, SNP; assembly 317871246 has two amino acid changes: Al OV and Y1181H; assembly 317999764 has three amino acid changes: Y1181H, Y1287D and N1303S; assembly 318176301 has no changes; assembly 305869563 differs from the original sequence by a single amino acid change: Q2992H while the cloned insert of 15 assembly 305869567 is 100% identical to the original sequence. Example 7. NOV7, CG52919, SEZ-6 The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 7A. Table 7A. NOV7 Sequence Analysis NOV7a, CG52919-06 SEQ ID NO: 67 1694 bp DNA Sequence IORF Start: ATG at 25 ORF Stop: TGA at 1654 CACGGCGCGGCCCCAACCAGCACCATGCGCCCGGTAGCCCTGCTGCTCCTGCCCTCGCTGCTGCGCGCT CCTGGCTCACGGACTCTCTTTAGAGGCCCCAACCGTGGGGAAAGGACAAGCCCCAGGCATCGAGGAGA CAGATGGCGAGCTGACAGCAGCCCCCACACCTGAGCAGCCAGAACGAGGCGTCCACTTTGTCACAACA GCCCCCACCTTGAAGCTGCTCAACCACCACCCGCTGCTTGAGGAATTCCTACAAGAGGGGCTGGAAAA GGGAGATGAGGAGCTGAGGCCAGCACTGCCCTTCCAGCCTGACCCACCTGCACCCTTCACCCCAAGTC CCCTTCCCCGCCTGGCCAACCAGGACAGCCGCCCTGTCTTTACCAGCCCCACTCCAGCCATGGCTGCG GTACCCACTCAGCCCCAGTCCAAGGAGGGACCCTGGAGTCCGGAGTCAGAGTCCCCTATGCTTCGAAT

CACAGCTCCCCTACCTCCAGGGCCCAGCATGGCAGTGCCCACCCTAGGCCCAGGGGAGATAGCCAGCA

WO 2004/015079 PCT/US2003/024931 CTACACCCCCCAGCAGAGCCTGGACACCAACCCAAGAGGGTCCTGAGACATGGGAGGCCGTGGGTT GCAGAGGTTGTGTCCCAGGGCGCAGGGATCGGGATCCAGGGGACCATCACCTCCTCCACAGCTTCAGG AGATGATGAGGAGACCACCACTACCACCACCATCATCACCACCACCATCACCACAGTCCAGACACCAG GCCCTTGTAGCTGGAATTTCTCAGGCCCAGAGGGCTCTCTGGACTCCCCTACAGACCTCAGCTCCCCC ACTGATGTTGGCCTGGACTGCTTCTTCTACATCTCTGTCTACCCTGGCTATGGCGTGGAAATCAAGGT CCAGAATATCAGCCTCCGGGAAGGGGAGACAGTGACTGTGGAAGGCCTGGGGGGGCCTGACCCACTGC CCCTGGCCAACCAGTCTTTCCTGCTGCGGGGCCAAGTCATCCGCAGCCCCACCCACCAAGCGGCCCTG AGGTTCCAGAGCCTCCCGCCACCGGCTGGCCCTGGCACCTTCCATTTCCATTACCAAGCCTATCTCCT GAGCTGCCACTTTCCCCGTCGTCCAGCTTATGGAGATGTGACTGTCACCAGCCTCCACCCAGGGGGTA GTGCCCGCTTCCATTGTGCCACTGGCTACCAGCTGAAGGGCGCCAGGCATCTCACCTGTCTCAATGTC ACCCAGCCCTTCTGGGATTCAAAGGAGCCCGTCTGCATCGCTGCTTGCGGCGGAGTGATCCGCAATGC CACCACCGGCCGCATCGTCTCTCCAGGCTTCCCGCGCAACTACAGCAACAACCTCACCTGTCACTGGC TGCTTGAGGCTCCTGAGGGCCAGCGGCTACACCTGCACTTTGAGAAGGTTTCCCTGGCAGAGGATGAT GACAGGCTCATCATTCGCAATGGGGACAACGTGGAGGCCCCACCAGTGTATGATTCCTATCAGGTGGA ATACCTGCCCATTGAGGGCCTGCTCAGCTCTGGCAAACACTTCTTTGTTGAGCCCCGCCCCCGCCCCC GCCCCTACAACCGCATTACCATAGAGTCAGCGTTTGACAATCCAACTTACGAGACTGGATCTCTTTCC PTTGCAGGAGACGAGAGAATATGAAGTCTCCATCTAGGTGGGGGCAGTCTAGGGAAGTCAAC NOV7a, CG52919-06 SEQ ID NO: 68 543 aa MW at 58351.OkD Protein Sequence7 MRPALIELPSLLALLA';HGLSLE-APTVGKGQAPGIEETDGELTAAPTPEQPERGVHFVTTAPTLKLLN HHPLLEEFLQEGLEKGDEELRPAL PFQPDPPAPFTPSPLPRLANQDSRPVFTSPTPAMAAVPTQPQSK EGPWSPESESPMLRITAPLPPGPSMAVPTLGPGEIASTTPPSRAWTPTQEGPGDMGRPWVAEVVSQGA GIGIQGTITSSTASGDDEETTTTTTIITTTITTVQTPGPCSWNFSGPEGSLDSPTDLSSPTDVGLDCF FYISVYPGYGVEIKVQNISLREGETVTVEGLGGPDPLPLANQSFLLRGQVIRSPTHQAALRFQSLPPP AGPGTFHFHYQAYLLSCHFPRRPAYGDVTVTSLHPGGSARFHCATGYQLKGARHLTCLNVTQPFWDSK EPVCIAACGGVIRNATTGRIVSPGFPGNYSNNLTCHWLLEAPEGQRLHLHFEKVSLAEDDDRLIIRNG DNVEAPPVYDSYEVEYLPIEGLLSSGKHFFVEPRPRPRPYNRITIESAFDNPTYETGSLSLAGDERI NOV7b, 298521010 SEQ ID NO: 69 444 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence TGCCACTTTCCCCGTCGTCCAGCTTATGGAGATGTGACTGTCACCAGCCTCCACCCAG GGGGTAGTGCCCGCTTCCATTGTGCCACTGGCTACCAGCTGAAGGGCGCCAGGCATCTCACCTGTCTC AATGTCACCCAGCCCTTCTGGGATTCAAAGGACCCGTCTGCATCGCTGCTTGCGGCGGAGTGATCCG CAATGCCACCACCGGCCGCATCGtCTCTCCAGGCTTCCCGGGCAACTACAGCAACAACCTCACCTGTC ACTGGCTGCTTGAGGCTCCTGAGGGCCAGCGGCTACACCTGCACTTTGAGAAGGTTTCCCTGGCAGAG GATGATGACAGGCTCATCATTCGCAATGGGGACAACGTGGAGGCCCCACCAGTGTATGATTCCTATCA GGTGGAATACCTGCCCATTGAGGGCCTGCTCAGCTCTGGCAAACAC NOV7b, 298521010 SEQ ID NO: 70 148 aa MWat -16958kD Protein Sequence CHFPRRPAYGDVTVTSLHPGGSARFHCATGYQLKGARHLTCLNVTQPFWDSKEPVCIAACGGVIR NATTGRIVSPGFPGNYSNNLTCHWLLEAPEGQRLHLHFEKVSLAEDDDRLIIRNGDNVEAPPVYDSYE VEYLPIEGLLSSGKH NOV7c, CG52919-09 ISEQ ID NO: 71 1572 bp DNA Sequence JORF Start: -at 1 lORF Stop: at 1583 CTCTCTTTAGAGGCCCCAACCGTGGGGAAAGGACAAGCCCCAGGCATCGAGGAGACAG ATGGCGAGCTGACAGCAGCCCCCACACCTGAGCAGCCAGAACGAGGCGTCCACTTTGTCACAACAGCC CCCACCTTGAAGCTGCTCAACCACCACCCGCTGCTTGAGGAATTCCTACAAGAGGGGCTGGAAAAGGG AGATGAGGAGCTGAGGCCAGCACTGCCCTTCCAGCCTGACCCACCTGCACCCTTCACCCCAAGTCCCC TTCCCCGCCTGGCCAACCAGGACAGCCGCCCTGTCTTTACCAGCCCCACTCCAGCCATGGCTGCGGTA CCCACTCAGCCCCAGTCCAAGGAGGGACCCTGGAGTCCGGAGTCAGAGTCCCCTATGCTTCGAATCAC AGCTCCCCTACCTCCAGGGCCCAGCATGGCAGTGCCCACCCTAGGCCCAGGGGAGATAGCCAGCACTA CACCCCCCAGCAGAGCCTGGACACCAACCCAAGAGGGTCCTGGAGACATGGGAAGGCCGTGGGTTGCA GAGGTTGTGTCCCAGGGCGCAGGGATCGGGATCCAGGGGACCATCACCTCCTCCACAGCTTCAGGAGA TGATGAGGAGACCACCACTACCACCACCATCATCACCACCACCATCACCACAGTCCAGACACCAGCCC CTTGTAGCTGGAATTTCTCAGGCCCAGAGGGTTCTCTGGACTCCCCTACAGACCTCAGCTCCCCCACT GATGTTGGCCTGGACTGCTTCTTCTACATCTCTGTCTACCCTGCCTATGGCGTGGAAATCAAGGTCCA GAATATCAGCCTCCGGGAAGGGGAGACAGTGACTGTGGAAGGCCTGGGGGGGCCTGACCCACTGCCCC TGGCCAACCAGTCTTTCCTGCTGCGGGGCCAAGTCATCCGCAGCCCCACCCACCAAGCGGCCCTGAGG TTCCAGAGCCTCCCGCCACCGGCTGGCCCTGGCACCTTCCATTTCCATTACCAAGCCTATCTCCTGAG CTGCCACTTTCCCCGTCGTCCAGCTTATGGAGATGTGACTGTCACCAGCCTCCACCCAGGGGGTAGTG CCCGCTTCCATTGTGCCACTGGCTACCAGCTGAAGGGCGCCAGGCATCTCACCTGTCTCAATGTCACC CAGCCCTTCTGGGATTCAAACCAGCCCGTCTGCATCGCTGCTTGCGGCGGAGTGATCCGCAATGCCAC

CACCGGCCGCATCGTCTCTCCAGGCTTCCCGGGCAACTACAGCAACAACCTCACCTGTCACTCGCTGC

WO 2004/015079 PCT/US2003/024931 TTGAGGCTCCTGAGGGCCAGCGGCTACACCTGCACTTTGAGAAGGTTTCCCTGGCAGAGGATGATGAC AGGCTCATCATTCGCAATGGGGACAACGTGGAGGCCCCACCAGTGTATGATTCCTATGAGGTGGAATA CCTGCCCATTGAGGGCCTGCTCAGCTCTGGCAAACACTTCTTTGTTGAGCCCCGCCCCCGCCCCCGCC CCTACAACCGCATTACCATAGAGTCAGCGTTTGACAATCCAACTTACGAGACTGGATCTCTTTCCCTT GCAGGAGACGAGAGAATA NOV7c, CG52919-09 SEQ ID NO: 72 1527 aa MW at 56714.8kD Protein Sequence LSLEAPTVGKGQAPGIEETDGLTAPTPEQPERGVHFVTTAPTLKLLNHHPLLEEFLQEGLEKG DEELRPALPFQPDPPAPFTPSPLPRLANQDSRPVFTSPTPAMAAVPTQPQSKEGPWSPESESPMLRIT APLPPGPSMAVPTLGPGEIASTTPPSRAWTPTQEGPGDMGRPWVAEVVSQGAGIGIQGTITSSTASGD DEETTTTTTIITTTITTVQTPGPCSWNFSGPEGSLDSPTDLSSPTDVGLDCFFYISVYPGYGVEIKVQ NISLREGETVTVEGLGGPDPLPLANQSFLLRGQVIRSPTHQAALRFQSLPPPAGPGTFHFHYQAYLLS CHFPRRPAYGUVTVTSLHPGGSARFHCATGYQLKGARHLTCLNVTQPFWDSKEPVCIAACGGVIRNAT. TGRIVSPGFPGNYSNNLTCHWLLEAPEGQRLHLHFEKVSLAEDDDRLIIRNGDNVEAPPVYDSYEVEY LPIEGLLSSGKHFFVEPRPRPRPYNRITIESAFDNPTYETGSLSLAGDERI A ClustalW comparison of the above protein sequences yields the following comparison. NOV7a is a 543 amino acid long protein sequence. NOV7b is the mature protein sequence corresponding to amino acid residues 20 to 543 of NOV7a. NOV7c 5 corresponds to amino acid residues 356 to 504 of NOV7a, which includes the sushi and CUB domain as predicted by pfam, see below. Further analysis of the NOV7a protein yielded the following properties shown in Table 7B. Table 7B. Protein Sequence Properties NOV7a SignalP analysis: Cleavage site between residues 20 and 21 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 2; pos.chg 1; neg.chg 0 H-region: length 20; peak value 8.99 PSG score: 4.59 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: -2.1): 2.15 possible cleavage site: between 17 and 18 >>> Seems to have a cleavable signal peptide (1 to 17) ALOM: Klein et al's method for TM region allocation Init position for calculation: 18 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) .. fixed PERIPHERAL Likelihood = 4.72 (at 267) ALOM score: 4.72 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 8 Charge difference: -1.5 C( 0.5) - N( 2.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq WO 2004/015079 PCT/US2003/024931 R content: 1 Hyd Moment(75): 5.75 Hyd Moment(95): B.42 G content: 1 D/E content: 1 S/T content: 2 Score: -3.74 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 12 MRP|VA NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 6.4% NLS Score: -0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: RPVA none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 55.5 COIL: Lupas's algorithm to detect coiled-coil regions

LI.

WO 2004/015079 PCT/US2003/024931 total: 0 residues Final Results (k = 9/23): 55.6 %: extracellular, including cell wall 33.3 %:mitochondrial 11.1 %:vacuolar >> prediction for CG52919-06 is exc (k=9) A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7C. Table 7C. Geneseq Results for NOV7a NOV7a Identities/ Geneseq Protein/Organism/Length [Patent Residues/ Similarities for Expect Identifier #, Date] Match the Matched Value Residues Region AAB70542 Human PRO12 protein sequence 1..543 518/543 (95%) 0.0 SEQ ID NO:24 - Homo sapiens, 1..526 518/543 (95%) 526 aa. [W0200110902-A2, 15 FEB-2001] AAB70541 Human PRO11 protein sequence 1..533 513/533 (96%) 0.0 SEQ ID NO:22 - Homo sapiens, 1..516 513/533 (96%) 525 aa. [W0200110902-A2, 15 FEB-2001] AAB70540 Human PRO10 protein sequence 1..533 513/533 (96%) 0.0 SEQ ID NO:20 - Homo sapiens, 1.516 513/533 (96%) 525 aa. [W0200110902-A2, 15 FEB-2001] AAU81976 Human secreted protein SECP2 - 1..508 507/508 (99%) 0.0 Homo sapiens, 994 aa. 1..508 507/508 (99%) [W0200198353-A2, 27-DEC-2001] ABP69306 Human polypeptide SEQ ID NO 1..508 507/508 (99%) 0.0 1353 - Homo sapiens, 544 aa. L..508 507/508 (99%) [W0200270539-A2, 12-SEP-2002] In a BLAST search of public sequence databases, the NOV7a protein was found to 5 have homology to the proteins shown in the BLASTP data in Table 7D. Table 7D. Public BLASTP Results for NOV7a Protein . NOV7a Identities/ Expect Protein/Orgamsm/Length RaidnI/ Similaritfieq for Value WO 2004/015079 PCT/US2003/024931 Number Match the Matched Residues Portion CAC33420 Sequence 23 from Patent L..543 518/543 (95%) 0.0 W00110902 - Homo sapiens 1..526 518/543 (95%) (Human), 526 aa. CAC33418 Sequence 19 from Patent 1.533 513/533 (96%) 0.0 WO0110902 -Homo sapiens 1..516 513/533 (96%) (Human), 525 aa. CAC33417 Sequence 17 from Patent 1..533 509/533 (95%) 0.0 WO01 10902 - Homo sapiens 1..516 509/533 (95%) (Human), 525 aa. CAC33416 Sequence 15 from Patent 1..508 503/508 (99%) 0.0 WO01 10902 - Homo sapiens 1..508 504/508 (99%) (Human), 994 aa. CAC33415 Sequence 13 from Patent 1..508 503/508 (99%) 0.0 WOO110902 - Homo sapiens L.508 504/508 (99%) (Human), 993 aa. _ PFam analysis predicts that the NOV7a protein contains the domains shown in the Table 7E. Table 7E. Domain Analysis of NOV7a Identities/ Pfam Domain NOV7a Match Region Similarities Expect Value for the Matched Region sushi 357..412 15/65 (23%) 1.9e-05 41/65 (63%) CUB 416..504 28/116 (24%) 1.3e-05 65/116 (56%) Example 8. NOV8, CG94946, Agrin precursor. 5 The NOV8 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 8A. Table 8A. NOV8 Sequence Analysis NOV8a, CG94946-01 ISEQ ID NO: 73 6224 bp DNA Sequence ORF Start: ATG at 37 ORF Stop: TGA at 6196 CGGCACGGCC CGC GCGCCTCTCCGCGCTGGCCGGCCGGTCCCACCCGGGCC CGCTGCGGGGCGGCCGCTGCTGCCTCTCCTTGTGGTGGCCGCGTGCGTCCTGCCCGGAGCCGGCGGGA CATGCCCGGAGCGCGCGCTGGAGCGGCGCGAGGAGGAGGCGAACGTGGTGCTCACCGGGACGGTGGAG GAGATCCTCAACGTGGACCCGGTGCAGCACACGTACTCCTGCAAGGTTCGGGTCTGGCGGTACTTGAA GGGCAAAGACCTGGTGGCCCGGGAGAGCCTGCTGGACGGCGGCAACAAGGTGGTGATCAGCGGCTTTG GAGACCCCCTCATCTGTGACAACCAGGTGTCCACTGGGGACACCAGGATCTTCTTTGTGAACCCTGCA CCCCCATACCTGTGGCCAGCCCACAAGAACGAGCTGATGCTCAACTCCAGCCTCATGCGGATCACCCT I /' WO 2004/015079 PCT/US2003/024931 GCGGAACCTGGAGGAGGTGAGTTCTGTGTGGAAGATAAACCCGGGACCCACTTCACTCCAGTGCCTC CGACGCCTCCTGATGCGTGCCGGGGATGCTGTGCGGCTTCGGCGCCGTGTCCAGCCCACGGGAG GGCCCGGGCCGGGCGTCCTGCGTCTGCAAGAAGAGCCCGTGCCCCAGCGTGGTGGCGCCTGTGTGTGG GTCGGACGCCTCCACCTACAGCAACGAATGCGAGCTGCAGCGGCGCAGTGCAGCCAGCAGCGCCGCA TCCGCCTGCTCAGCCGCGGGCCGTGCGGCTCGCGGGACCCCTGCTCCAACGTGACCTGCAGCTTCGGC AGCACCTGTGCGCGCTCGGCCGACGGGCTGACGGCCTCGTGCCTGTGCCCCGCGACCTGCCGTGGCGC CCCCGAGGGGACCGTCTGCGGCAGCGACGGCGCCGACTACCCCGGCGAGTGCCAGCTCCTGCGCCGCG CCTGACCCGAGCCGCAGCTGCCGTGTGAZACCCGCGCACGCGGCGCCCTGAGATGCTCCTACGGCCCGA GAGCTGCCCTGCCCGGCAGGCGCCAGTGTGTGGGACGACGGAGTCACCTACGAAAACGACTGTGTCA TGGGCCGATCGGGGGCCGCCCGGGGTCTCCTCCTGCAGAAAGTGCGCTCCGCCCAGTGCCAGCGTCGA GACCAGTGCCCGGAGCCCTGCCGGTTCAATGCCGTGTGCCTGTCCCGCCGTGGCCGTCCCCGCTGCTC CTGCGACCGCGTCACCTGTGACGGGGCCTACAGGCCCGTGTGTGCCCAGGACGGGCCCCACGTATGACA GTGATTGCTGGCGGCAGCAGGCTGAGTGCCGOCACCAGCGTGCCATCCCCAGCAAGCACCAGGGCCCG TGTGACCAGGCCCCGTCCCCATGCCTCGGGGTGCAGTGTGCATTTGGGCGACGTGTGCTGTGAAGAA CGGGCAGGCAGCGTGTGAATGCCTGCAGGCGTGCTCGAGCCTCTACGATCCTGTGTGCGGCAGCGACG GCGTCACATACGGCAGCGCGTGCGAGCTGGAGGCCACGGCCTGTACCCTCGGGCGGGAGATCCAGGTG GCGCGCAAAGGACCCTGTOACCGCTGCGGGCAGTGCCGCTTTGGAGCCCTGTGCGAGGCCGAGACCGG GCGCTGCGTGTGCCCCTCTGAATGCGTGGCTTTGGCCCAGCCCGTGTGTGGCTCCGACGGGCACACGT ACCCCAGCGAGTGCATGCTGCACGTGCACGCCTGCACACACCAGATCAGCCTGCACGTGGCCTCAGCT GGACCCTGTGAGACCTGTGGAGATGCCGTGTGTGCTTTTGGGGCTGTGTGCTCCGCAGGGCAGTGTGT GTGTCCCCGGTGTGAGCACCCCCCGCCCGGCCCCGTGTGTGGCAGCGACGGTGTCACCTACGGCAGTG CCTGCGAGCTACGGGAAGCCGCCTGCCTCCAGCAGACACAGATCGAGGAGGCCCGGGCAGGGCCGTGC GAGCAGGCCGAGTGCGGTTCCGGAGGCTCTGGCTCTGGGGAGGACGGTGACTGTGAGCAGGAGCTGTG CCCGCAGCGCGGTGGCATCTGGGACGAGGACTCGGAGGACGGGCCGTGTGTCTGTGACTTCAGCTGCC AGAGTGTCCCAGGCAGCCCGGTGTCCGGCTCAGATGGGTCACCTACAGCACCGAGTGTGGCTJAAG AAGGCCAGGTGTGAGTCACAGCGAGGGCTCTACGTAGCGGCCCAGGGAGCCTGCCGAGGCCCCGCCTT CGCCCCGCTGCCGCCTGTGGCCCCCTTACACTGTGCCCAGACGCCCTACGGCTGCTGCCAGGACAATA TCACCGCAGCCCGGGGCGTGGGCCTGGCTGGCTGCCCCAGTGCCTGCCAGTGCAACCCCCATCGCTCT TACGGCGGCACCTGTGACCCAGCCACAGGCCAGTGCTCCTGCCGCCCAGGTGTGGGGGGCCTCAGGTG TGACCGCTGTGAGCCTGGCTTCTGGAACTTTCGAGGCATCGTCACCGATGGCCGCAGTGGCTGTACAC CCTGCAGCTGTGATCCCCAA.GGCGCCGTGCGGGATGACTGTGAGCAGATGACGGGGCTGTGCTCGTGT ALAGCCCGGGGTGGCTGGACCCAAGTGTGGCAGTGTCCAGACCGCCGTGCCCTGCGCCCCGCGGGCTG TGAAGCTGACGCTTCTCECCTGCGACCTGTGCGGAGATGCGCTGTGAGTTCGGTGCGCGGTGCGTGG AGGAGTCTGGCTCAGCCCACTGTGTCTGCCCGADGCTCACCTCTCCAGAGGCCAACGCTACCAAGGTC TGTGGGTCAGATGGAGTCACATACGGCAACGAGTGTCAGCTGAAGACCATCGCCTGCCGCCAGGGCCT GCAAATCTCTATCCAGAGCCTGGGCCCGTGCCAGGAGGCTGTTGCTCCCAGCACTCACCCGACATCTG (-GTCCGTGACTGTGACCACCCCAGGGCTCCTCC'rGAGCCAGGCACTOCCGGCCCCCCCCGGCGCCCTC CCCCTGGCTCCCAGCAGTACCGCACACAGCCAGACCACCCCTCCGCCCTCATCGCGACCTCGGACCAC TGCCAGCGTCCCCAGGACCACCGTGTGGCCCGTGCTGACGGTGCCCCCCACGGCACCCTCCCCTGCAC CCAGCCTGGTGGCGTCCGCCTTTGGTGAATCTGGCAGCACTGATGGAAGCAGCGATGAGGAACTGAGC GGGGACCAGGAGGCCAGTGGGGGTGGCTCTGGGGGGCTCGAGCCCTTCGAGGGCAGCAGCGTGGCCAC CCCTGGGCCACCTGTCGAGAGGGCTTCCTGCTACAACTCCGCGTTGGGCTGCTGCTCTGATGGGAAGA CCCCCTCCCTGGACGCAGACGGCTCCAACTGCCCCGCCACCAAGGTGTTCCAGGGCGTCCTGGAGCTG GAGGGCGTCGAGGGCCAGGAGCTGTTCTACACGCCCGAGATGGCTGACCCCAAGTCAGAACTGTTCGG GGAGACAGCCAGGAGCATTGAGAGCACCCTGGACGACCTCTTCCGGAATTCAGACGTCAAGAAGGATT TCCGGAGTGTCCGCTTGCGGGACCTGGGGCCCCGCAAATCCGTCCGCGCCATTGTGGATGTGCACTTT GACCCCACCACAGCCTTCAGGGCACCCGACGTGGCCCGGGCCCTGCTCCGGCAGATCCAGGTGTCCAG GCGCCGGTCCTTGGGGGTGAGGCGGCCGCTGCAGGAGCACGTGCGATTTATGGACTTTGACTGGTTTC CTGCGTTTATCACGGGGGCCACGTCAGGAGCCATTGCTGCGGGAGCCACGGCCAGAGCCACCACTGCA TCGCGCCTGCCGTCCTCTGCTGTGACCCCTCGGGCCCCGCACCCCAGTCACACAAGCCAGCCCGTTGC CAAGACCACGGCAGCCCCCACCACACGTCGGCCCCCCACCACTGCCCCCAGCCGTGTGCCCGGACGTC GGCCCCCCGCCCCCCAGCAGCCTCCAAAGCCCTGTGACTCACAGCCCTGCTTCCACGGGGGGACCTGC CAGGACTGGGCATTGGGCGGGGGCTTCACCTGCAGCTGCCCGGCAGGCAGGGGAGGCGCCGTCTGTGA GAAGGTGCTTGGCGCCCCTGTGCCGGCCTTCGAGGGCCGCTCCTTCCTGGCCTTCCCCACCCTCCGCG CCTACCACACGCTGCGCCTGGCACTGCAATTCCGGGCCCGAGCCTCAGGGGCTGCT-GCTGTACAAT GGCAACGCCCGGGGCAAGGACTTCCTGGCATTGGCGCTGCTAGATGGCCGCGTGCAGCTCAGGTTTGA CACAGGTTCGGGGCCGGCGGTGCTGACCAGTGCCGTGCCGGTAGAGCCGGGCCAGTGGCACCGCCTGG AGCTGTCCCGGCACTGGCGCCGGGGCACCCTCTCGGTGGATGGTGAGACCCCTGTTCTGGGCGAGAGT CCCAGTGGCACCGACOGCCTCAACCTGGACACAGACCTCTTTGTGGGCGGCGTACCCGAGGACCAGGC TGCCGTGGCGCTGGAGCGGACCTTCGTGGGCGCCGGCCTGAGGGGGTGCATCCGTTTGCTGGACGTCA ACAACCAGCGCCTGGAGCTTGGCATTGGGCCGGGGGCTGCCACCCGAGGCTCTGGCGTGGGCGAGTGC GGGGACCACCCCTGCCTGCCCAACCCCTGCCATGGCGGGGCCCCATGCCAGAACCTCOAGGCTGGAAG GTTCCATTGCCAGTGCCCGCCCGGCCGCGTCGGACCAACCTGTGCCGATGAGAAGAGCCCCTGCCAGC CCAACCCCTGCCATGGGGCGGCGCCCTGCCGTGTGCTGCCCGAGCGTGGTGCTCAGTGCGAGTGCCCC CTGGGCGTGAGGGCACCTTCTGCCAGACAGCCTCGGGGCAGGACGGCTCTGGGCCCTTCCTGGCTGA CTTCAACGGCTTCTCCCACCTIGAGCTGAGGCCTGCACACCATTGCACGGGACCTGGGGGAAG ITGGT(-CCC- GTCGCCCGCCAGCTCGTTCA.GCCACAG WO 2004/015079 PCT/US2003/024931 GACGGCAAGGGGGACTTCGTGTCGCTGGCACTGCGGGACCCCCGCCTGGAGTTCCGCTACGACCTGGG CAAGGGGGCAGCGGTCATCAGGAGCAGGGAGCCAGTCACCCTGGGAGCCTGGACCAGGGTCTCACTCG AGCGAACGGCCGCAAGGGTGCCCTGCGTrGTGGGCGACGCCCCCGTGTGTTGGGGGAGTCCCCGAAA TCCCGCAAGGTTCCGCACACCGTCCTCAACCTGAGGAGCCGCTCTACGTAGGGGGCGCTCCCGACTT CAGCAAGCTGGCCCGTGCTGCTGCCGTGTCCTCTGGCTTCGACGGTGCCATCCAGCTGGTCTCCCT CG GAGGCCGCCAGCTGCTGACCCCGGAGCACGTGCTGCGGCAGGT~LGGACGTCACGTCCTTTGCAGGTCAC CCCTGCACCCGGGCCTCAGGCCACCCCTGCCTCATGGGGCCTCCTGCGTcCCGAGGGAGGCTGCCTA TGTGTGCCTGTGTCCCGGGGGATTCTCAGGACCGCACTGCGAGAAGGGGCTGGTGGAGAAGTCAGCGG GGGACGTGGATACCTTGGCCTTTGACGGGCGGACCTTTGTCGAGTACCTCAACGCTGTGACCGAGAGC GAGAAGGCACTGCAGAGCAACCACTTTGAACTGAGCCTGCGCACTGACCCCACGCAGGGGCTGGTGCT CTGGAGTGGCAAGGCCACGGAGCGGGCCGACTATGTGGCACTGGCCATTGTGGACGGGACCTGCAC TGAGCTACAACCTGGGCTCCCAGCCCGTGGTGCTGCGTTCCACCGTGCCCGTCACACCAACCGCTGG TTGCGGGTCGTGGCACATAGGGAGCAGAGGGAAGGTTCCCTGCAGGTGGGCAATGAGGCCCCTGTGAC CGGCTCCTCCCCGCTGGGCGCCACGCAGCTGGACACTGATGGAGCCCTGTGGCTTOGGGGCCTGCCGG AGCTGCCCGTGGGCCCAGCACTGCCCAAGGCCTACGGCACAGGCTTTGTGGGCTGCTTGCGGGATGTG GTGGTGGGCCGGCACCCGCTGCACCTGCTGGAGGACGCCGTCACCAGCCAGAGCTGCGGCCCTGCCC CACCCCATGAGCTGGCACC 4QQCCCGCGCCCGCT NOV8a, CG94946-01 SEQ ID NO: 74 2053 aa M1W at 215628UOD Protein Sequence MRGPPGAGPLLVACLGGTCEAEREAVLGVELVPQT SCKVRVWRYLKGKDVARESLLDGNISGFGDPLICDNQVSTGDTRIFNPAPPLWPHKEL MSSLMRITLRLEEVEFVEDKPGTHFTPVPTPPDACRGMCGFGAVCEPNAEGPGASCVCKK, PCPSVVAPVCGSDASTYSNECELQRAQCSQQRRIRLLSRGPCGSDPCSNTCSFGSTCARSAGLTA SCLCPATCRGAPEGTVCGSDGADYPGECQLLRCARQEVKKFDGPCDPCQGAPDPSRSCRNPR TRRPEMIJLRPESCPARQAPVCGDDGVTYENDCVMGRSGARGLLLQKRSGQCQGRDQCPEPCRFNAV CLSRRGRPRCSCDRVTCDGAYRPVCAQDGRTYDSDCWRQQECRQQAIPSIHQGPCDQAPSPCLGVQ CAFGATCAVKNGQAACECLQACSSLYDPVCGSDGVTYGSACELEATACTLGREIQVAKGPCDRCGQC RFGALCEAETGRCVCPSECVALAQPVCGSDGHTYPSECLVHCTHQISLHASAGPCETCGDAVCA FGAVCSAGQCVCPRCEHPPGPVCGSDGVTGSACELRACLQQTQIEEARGPCEQAECGSGGSGS GEDGDCEQELCRQRGGIWDEDSEDGPCVCDFSCQSVPGSPVCGSDGYSTECELKARESQRGLYV AAQGACRGPAFAPLPPVAPLHCAQTPYGCCQDNITAARGVGLAGCPSACQCNPHGSYGGTCDPATGQC SCRPGVGGLRCDRCEPGFWNFRGIVTDGRSGCTPCSCDPQGAVRDDCEQMTGLCSCKPGVAGPKCGQC PDGRALGPAGCEADASAPATCAEMRCEFGARCVEESGSAHCVCPLTCPAATKCGSDGVTYGNEC QLKTIACRQGLQISIQSLGPCQEAVAPSTHPTSASVVTTPGLLLSQLPAPPGLPLAPSSTAHSQT TPPPSSRPRTTASVPRTTVWPVLTVPPTAPSPAPSLVASAFGESGSTDGSSDEELSGDQEASGGGSGG LEPLEGSSVATPGPPVERASCYNSALGCCSDGKTPSLDAEGSCPATVQGLE:LEGVEGQELFYTP PHPSHTSQPVAKTTAAPTTRRPPTTIAPSRVPGRRPPAPQQPPKPCDSQPCFHGGTCQDWLGGGFTCS CPAGRGGAVCEKVLGAPVPAFEGRSFLAFPTLRAYHTALEFAEPQGLLLYNGNARGKDFLAL LLDGRVQLRFDTGSGPAVLTSAVPVEPGQWHRLELSRHWGTLSDGETPLGESPSGTDGLNLDTD LFVGGVPEDQAAVALERTFVGAGLRG3CIRLLDVNNQRLELGIGPGAATRGSGVGECGDHPCLPNPCHG GAPCQNLEAGRFHCQCPPGRVGPTCADEKSPCQPNPCHGAAPCRVILPEGGAQCECPLGREGTFCQTAS EPLYVGGAPDFSKLAAAAVSSGFDGAIQLVSLGGRQLLTPEVLRQDVTSFAGHPCTRASGHPCLN GASCVPREAVCLCPGGFSGPHCEKGLVEKSAGDVDTLAFDGRTFYAVTESEALQSHFELS AVTKPELRPCPTP NOV8b, 308909220 ~ SEQ ID NO: 75 1935 bp DNA Sequence IORF:Start::atl 1 jRStopenofsqnc TTCCGGGCGCTGGAGCCTCAGGGGCTGCTGCTGTACATGGCAACCCCCGGGGCAAGG ACTTCCTGGCATTGGCGCTGCTAGATGGCCGCGTGCAGCTCAGGTTTGACACAGGTTCGGGGCCGGCG GTGCTGACCAGTGCCGTGCCGGTAGAGCCGGGCCAGTGGCACCGCCTGGAGCTGTCCCGGCACTGGCG CCGGGGCACCCTCTCGGTGGATGGTGAGACCCCTGTTCTGGGCGAGAGTCCCAGTGGCACCGACGGCC TCAACCTGGACACAGACCTCTTTGTGCCCGGCGTACCCGAGGACCAGGCTGCCGTGGCGCTGGAGCGG ACCTTCGTGGGCGCCGGCCTGAGGGGGTGCATCCGTTTGCTGGACGTCACACCAGCGCCTGGAGCT TGGCATTGGGCCGGGGGCTGCCACCCGAGGCTCTGGCGTGGGCGAGTGCGGGGACCACCCCTGCCTGC CCAACCCCTGCCATGGCGGGCCCCATGCCAGAACCTGGAGGCTGGAAGCTTCCATTGCCAGTGCCCG CCCGGCCGCGTCGGACCAACCTGTGCCGATGAGAAGAGCCCCTGTCAGCCCAACCCCTGCCATGGGGC GGCGCCCTGCCGTGTGCTGCCCGAGGGTGGTGCTCAGTGCCAGTGCCCCCTGGGGCGTGAGGGCACCT TCTGCCAGACAGCCTCGGGGCAGGACGGCTCTGGGCCCTTCCTGGCTGACTTCACGGCTTCTCCCAC CTGGAGCTGAGAGGCCTGCACACCTTTGCACGGGACCTCG(GGAGAAGATGGCGCTGGAGGTCGTGTT

CCTGGCACGAGGCCCCAGCGGCCTCCTGCTCTACACGGGCAGAAGACGGACGGCAGGGGGACTTCG

WO 2004/015079 PCT/US2003/024931 TGTCGCTGGCACTGCGGGACCGCCGCCTGGAGTTCCGCTACGACCTGGGCAAGGGGGCAGCCGGTCATC AGGAGCAGGGAGCCAGTCACCCTGGGAGCCTGGACCAGGGTCTCACTGGAGCGAAACGGCCGCAAGGG TGCCCTGCGTGTGGGCGACGGCCCCCGTGTGTTGGGGGAGTCCCCCGTTCCGCACACCGTCCTCAACC TGAAGGAGCCGCTCTACGTAGGGGGCGCTCCCGACTTCAGCAAGCTGGCCCGTGCTGCTGCCGTGTCC TCTGGCTTCGACGGTGCCATCCAGCTGGTCTCCCTCGGAGGCCGCCAGCTGCTGACCCCGGAGCACGT GCTGCGGCAGGTGGACGTCACGTCCTTTGCAGGTCACCCCTGCACCCGGGCCTCAGGCCACCCCTGCC TCAATGGGGCCTCCTGCGTCCCGAGGGAGGCTGCCTATGTGTGCCTGTGTCCCGGGGGATTCTCAGGA CCGCACTGCGAGAAGGGGCTGGTGGAGAAGTCAGCGGGGGACGTGGATACCTTGGCCTTTGACGGGCG GACCTTTGTCGAGTACCTCAACGCTGTGACCGAGAGCGAGAAGGCACTGCAGAGCAACCACTTTGAAC TGAGCCTGCGCACTGAGGCCACGCAGGGGCTGGTGCTCTGGAGTGGCAAGGCCACGGAGCGGGCAGAC TATGTGGCACTGGCCATTGTGGACGGGCACCTGCAACTGAGCTACAACCTGGGCTCCCAGCCCGTGGT GCTGCGTTCCACCGTGCCCGTCAACACCAACCGCTGGTTGCGGGTCGTGGCACATAGGGAGCAGAGGG AAGGTTCCCTGCAGGTGGGCAATGAGGCCCCTGTGACCGGCTCCTCCCCGCTGGGCGCCACGCAGCTG GACACTGATGGAGCCCTGTGGCTTGGGGGCCTGCCGGAGCTGCCCGTGGGCCCAGCACTGCCCAAGGC CTACGGCACAGGCTTTGTGGGCTGCTTGCGGGACGTGGTGGTGGGCCGGCACCCGCTGCACCTGCTGG AGGACGCCGTCACCAAGCCAGAGCTGCGGCCCTGCCCCACC NOV8b, 308909220 SEQ ID NO: 76 645 aa MW at -68813kD Protein Sequence FRLEPQGLLLYNGNARGKDFLALALLDGRVQLRFDTGSGPAVLTSAVPVEPGQWHRLELSHWR RGTLSVDGETPVLGESPSGTDGLNLDTDLFVGGVPEDQAAVALERTFVGAGLRGCIRLLDVNNQRLEL GIGPGAATRGSGVGECGDHPCLPNPCHGGAPCQNLEAGRFHCQCPPGRVGPTCADEKSPCQPNPCHGA APCRVLPEGGAQCECPLGREGTFCQTASGQDGSGPFLADFNGFSHLELRGLHTFARDLGEKMALEVVF LARGPSGLLLYNGQKTDGKGDFVSLALRDRRLEFRYDLGKGAAVIRSREPVTLGAWTRVSLERNGRKG ALRVGDGPRVLGESPVPHTVLNLKEPLYVGGAPDFSKLARAAAVSSGFDGAIQLVSLGGRQLLTPEHV LRQVDVTSFAGHPCTRASGHPCLNGASCVPREAAYVCLCPGGFSGPHCEKGLVEKSAGDVDTLAFDGR TFVEYLNAVTESEKALQSNHFELSLRTEATQGLVLWSGKATERADYVALAIVDGHLQLSYNLGSQPVV LRSTVPVNTNRWLRVVAHREQREGSLQVGNEAPVTGSSPLGATQLDTDGALWLGGLPELPVGPALPKA YGTGFVGCLRDVVVGRHPLHLLEDAVTKPELRPCPT A ClustalW comparison of the above protein sequences yields the following sequence comparisons. NOV8b corresponds to NOV8a protein sequence amino acid residues 1404-2052 with the following changes: 11658F; A1670V; and deletion of 1756 5 1759 of the NOV8a sequence and furthermore includes several laminin G and EGF domains as predicted by pfam, below. Further analysis of the NOV8a protein yielded the following properties shown in Table 8B. Table 8B. Protein Sequence Properties NOV8a SignalP analysis: Cleavage site between residues 34 and 35 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 5; pos.chg 2; neg.chg 0 H-region: length 9; peak value 3.79 PSG score: -0.61 GvH: von Heijne'.s method for signal seq. recognition GvH score (threshold: -2.1): 0.49 possible cleavage site: between 33 and 34 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 WO 2004/015079 PCT/US2003/024931 Tentative number of TMS(s) for the threshold 0.5: Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = -4.35 Transmembrane 17 - 33 PERIPHERAL Likelihood = 0.53 (at 609) ALOM score: -4.35 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 24 Charge difference: -6.5 C(-2.0) - N( 4.5) N >= C: N-terminal side will be inside >> membrane topology: type 2 (cytoplasmic tail 1 to 17) MITDISC: discrimination of mitochondrial targeting seq R content: 3 Hyd Moment(75): 2.17 Hyd Moment(95): 10.07 G content: 6 D/E content:' 1 S/T. content: 1 Score: -4.90 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 25 GRPILL NUCDISC: discrimination of nuclear localization signals pat4: none pat7: PRTRRPE (5) at 339 pat7: PKSRKVP (5) at 1755 bipartite: none content of basic residues: 9.5% NLS Score: 0.39 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: RHGR none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern : none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none WO 2004/015079 PCT/US2003/024931 Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 34.8 %: mitochondrial 34.8 %: nuclear 13.0 %: cytoplasmic 4.3 %: extracellular, including cell wall 4.3 %: vacuolar 4.3 %: Golgi 4.3 %: peroxisomal >> prediction for CG94946-01.is mit (k=23) A search of the NOV8a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 8C. Table 8C. Geneseq Results fo r NOV8a NOV8a Identities/ Geneseq Protein/Organismi/Length Residues/ Similarities for Expect Identifier [Patent #, Date] Match the Matched Value Residues Region ABU52400 Human GPCR related protein 160..2053 1841/1894 (97%) 0.0 NOV40a - Homo sapiens, 1931 51..1931 185311894 (97%) aa. [W0200279398-A2, 10-OCT 20021 ABP43859 Human mRNA precursor - Homo 137..1669 1530/1533 (99%) 0.0 sapiens, 1741 aa. 1..1533 1530/1533 (99%) [W0200231 11 1-A2, 18-APR 20021 AAW26609 Human agrin - Homo sapiens, 1591..2053 460/471 (97%) 0.0 492 na. [WO9721811..A2_ 19- 22..492 146 1/471(97%) WO 2004/015079 PCT/US2003/024931 JUN-1997] AAB93754 Human protein sequence SEQ ID 583..968 381/386 (98%) 0.0 NO:13424 - Homo sapiens, 413 1.386 384/386 (98%) aa. [EP1074617-A2, 07-FEB 2001] AAY73993 Human prostate tumor EST 1634..2053 414/420 (98%) 0.0 fragment derived protein #180 - 1..416 414/420 (98%) Homo sapiens, 416 aa. [DE19820190-Al, 04-NOV 1999] ________ In a BLAST search of public sequence databases, the NOV8a protein was found to have homology to the proteins shown in the BLASTP data in Table 8D. Table 8D. Public BLASTP Results for NOV8a Protein NOV8a Identities/ Expect Accession Protein/Organism/Length R cidues Similarities for the Value Number Residues Matched Portion 000468 AGRIN precursor - Homo 24..2053 2022/2030 (99%) 0.0 sapiens (Human), 2026 aa L.2026 2022/2030 (99%) (fragment). P25304 Agrin precursor - Rattus 160..2053 1558/1914 (81%) 0.0 norvegicus (Rat), 1959 aa. 51..1959 1663/1914 (86%) P31696 Agrin precursor - Gallus gallus 128..2050 1234/1970 (62%) 0.0 (Chicken), 1955 aa. 1..1952 1479/1970 (74%) Q90404 Agrin - Discopyge ommata 716..2051 733/1353 (54%) 0.0 (Electric ray), 1328 aa 1..1325 932/1353 (68%) (fragment). Q961C1 Hypothetical protein - Homo 1562..2053 486/492 (98%) 0.0 sapiens -(Human), 488 aa | 1..488 486/492 (98%) (fragment). PFam analysis predicts that the NOV8a protein contains the domains shown in the Table 8E. Table 8E. Domain Analysis of NOV8a Identities/ Pfarn A NOV8a Match Region Similarities Expect Domain Amino Acid residues of SEQ ID for the Matched Value NO: 74 1Region NtA 34..161 125/135 (93%) 1.le-111 128/135 (95%) WO 2004/015079 PCT/US2003/024931 kazal 201..246 25/61(41%) 7.2e-18 36/61 (59%) kazal 276..321 21/62 (34%) 5.le-13 33/62 (53%) kazal 346.393 18/61 (30%) 7.9e-12 33/61 (54%) kazal 420..465 21/61 (34%) 4.le-16 38/61 (62%) kazal 494..538 24/61 (39%) 3.6e-19 38/61 (62%) kazal 559..603 19/61(31%) 1.4e-18 38/61 (62%) kazal 624..668 26/62 (42%) 1.5e-17 37/62 (60%) kazal 709..754 24/62 (39%) 1.2e-16 40/62 (65%) lamininEGF 797..848 28/61 (46%) 1.le-20 46/61 (75%) lamininEGF 851..895 21/59 (36%) 3.6e-11 37/59 (63%) kazal 927..973 25/62 (40%) 5.2e-18 41/62 (66%) SEA 1134..1256 38/132 (29%) 4.6e-37 111/132 (84%) EGF 1337..1370 16/47 (34%) 0.00055 24/47 (51%) lamininG 1404..1535 70/154 (45%) 4.6e-55 120/154 (78%) EGF 1557..1589 16/47 (34%) 5.2e-06 27/47 (57%) EGF 1596..1628 16/47 (34%) 0.00021 25/47 (53%) lamininG 1672..1807 71/154 (46%) 5.8e-52 122/154 (79%) EGF 1826..1860 14/47 (30%) 4.4e-07 25/47 (53%) lamininG 1905..2036 58/154 (38%) 1.2e-50 125/154 (81%) WO 2004/015079 PCT/US2003/024931 Example B: Sequencing Methodology and Identification of NOVX Clones 1. GeneCalling Technology: This is a proprietary method of performing differential gene expression profiling between two or more samples developed at CuraGen and described by Shimkets, et al., "Gene expression analysis by transcript profiling coupled 5 to a gene database query" Nature Biotechnology 17:198-803 (1999). cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene 10 expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then digested with up to as many as 120 pairs of restriction enzymes and pairs of linker-adaptors specific for each pair of restriction enzymes were ligated to the appropriate end. The restriction digestion generates a mixture of unique cDNA gene fragments. Limited PCR amplification is performed with primers homologous to the linker adapter 15 sequence where one primer is biotinylated and the other is fluorescently labeled. The doubly labeled material is isolated and the fluorescently labeled single strand is resolved by capillary gel electrophoresis. A computer algorithm compares the electropherograms from an experimental and control group for each of the restriction digestions. This and additional sequence-derived information is used to predict the identity of each differentially expressed 20 gene fragment using a variety of genetic databases. The identity of the gene fragment is confirmed by additional, gene-specific competitive PCR or by isolation and sequencing of the gene fragment. 2. SeqCalling Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, 25 and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually 30 and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly WO 2004/015079 PCT/US2003/024931 when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations. 5 3. PathCallings Technology: The NOVX nucleic acid sequences are derived by laboratory screening of cDNA library by the two-hybrid approach. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, are sequenced. In silico prediction was based on sequences available in CuraGen Corporation's proprietary sequence databases or in the public human sequence databases, 10 and provided either the full length DNA sequence, or some portion thereof. The laboratory screening was performed using the methods summarized below: cDNA libraries were derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue 15 cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then directionally cloned into the appropriate two-hybrid vector (Gal4-activation domain (Gal4-AD) fusion). Such cDNA libraries as well as commercially available cDNA libraries from Clontech (Palo Alto, CA) 20 were then transferred from E.coli into a CuraGen Corporation proprietary yeast strain (disclosed in U. S. Patents 6,057,101 and 6,083,693, incorporated herein by reference in their entireties). Gal4-binding domain (Gal4-BD) fusions of a CuraGen Corportion proprietary library of human sequences was used to screen multiple Gal4-AD fusion cDNA libraries 25 resulting in the selection of yeast hybrid diploids in each of which the Gal4-AD fusion contains an individual cDNA. Each sample was amplified using the polymerase chain reaction (PCR) using non-specific primers at the cDNA insert boundaries. Such PCR product was sequenced; sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, 30 sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice WO 2004/015079 PCT/US2003/024931 forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations. Physical clone: the cDNA fragment derived by the screening procedure, covering the entire open reading frame is, as a recombinant DNA, cloned into pACT2 plasmid 5 (Clontech) used to make the cDNA library. The recombinant plasmid is inserted into the host and selected by the yeasthybrid diploid generated during the screening procedure by the mating of both CuraGen Corporation proprietary yeast strains N106' and.YULH (U. S. Patents 6,057,101 and 6,083,693). 4. RACE: Techniques based on the polymerase chain reaction such as rapid 10 amplification of cDNA ends (RACE), were used to isolate or complete the predicted sequence of the cDNA of the invention. Usually multiple clones were sequenced from one or more human samples to derive the sequences for fragments. Various human tissue samples from different donors were used for the RACE reaction. The sequences derived from these procedures were included in the SeqCalling Assembly process described in 15 preceding paragraphs. 5. Exon Linking: The NOVX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each 20 case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or.protein sequence of the target sequence, or by translated 25 homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain - amygdala, brain - cerebellum, brain hippocampus, brain - substantia nigra, brain - thalamus, brain -whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma - Raji, mammary gland, pancreas, 30 pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. 1'72 WO 2004/015079 PCT/US2003/024931 The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were 5 evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein. 6. Physical Clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, 10 BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein. 15 The PCR product derived by exon linking, -covering the entire open reading frame, was cloned into the pCR2.1 vector from Invitrogen to provide clones used for expression and screening purposes. Example C. Quantitative expression analysis of clones in various cells and 20 tissues The quantitative expression of various NOV genes was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell -lines and tissues using real time quantitative PCR (RTQ-PCR) performed on an Applied Biosystems (Foster City, CA) ABI PRISM® 7700 or an ABI PRISM@ 7900 HT Sequence 25 Detection System. RNA integrity of all samples was determined by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s) and the absence of low molecular weight RNAs (degradation products). Control samples to detect genomic DNA contamination included RTQ-PCR 30 reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon. RNA samples were normalized in reference to nucleic acids encoding constitutively expressed genes (i.e., p-actin and GAPDH). Alternatively, non-normalized RNA samples WO 2004/015079 PCT/US2003/024931 were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation, Carlsbad, CA, Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 pg of total RNA in a volume of 20 pl or were scaled up to contain 50 pg of total RNA in a volume of 100 pl and were 5 incubated for 60 minutes at 42"C. sscDNA samples were then normalized in reference to nucleic acids as described above. Probes and primers were designed according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default reaction condition settings and the 10 following parameters were set before selecting primers: 250 nM primer concentration; 58" 60" C primer melting temperature (Tm) range; 590 C primer optimal Tm; 20 C maximum primer difference (if probe does not have 5' G, probe Tm must be 10" C greater than primer Tm; and 75 bp to 100 bp amplicon size. The selected probes and primers were synthesized by Synthegen (Houston, TX). Probes were double purified by HPLC to remove uncoupled 15 dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5' and 3' ends of the probe, respectively. Their final concentrations were: 900 nM forward and reverse primers, and 200nM probe. Normalized RNA was spotted in individual wells of a 96 or 384-well PCR plate (Applied Biosystems, Foster City, CA). PCR cocktails included a single gene-specific 20 probe and primers set or two multiplexed probe and primers sets. PCR reactions were done using TaqMan@ One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 480 C for 30 minutes followed by amplification/PCR cycles: 950 C 10 min, then 40 cycles at 95* C for 15 seconds, followed by 600 C for 1 minute. Results were recorded as CT 25 values (cycle at which a given sample crosses a threshold level of fluorescence) and plotted using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression was the reciprocal of the RNA difference multiplied by 100. CT values below 28 indicate high expression, between 28 and 32 indicate moderate expression, 30 between 32 and 35 indicate low expression and above 35 reflect levels of expression that were too low to be measured reliably. 1'7 A WO 2004/015079 PCT/US2003/024931 Normalized sscDNA was analyzed by RTQ-PCR using 1X TaqMan@ Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification and analysis were done as described above. Panels 1, 1.1, 1.2, and 1.3D 5 Panels 1, 1.1, 1.2 and 1.3D included 2 control vells (genomic DNA control and chemistry control) and 94 wells of cDNA samples from cultured cell lines and primary normal tissues. Cell lines were derived from carcinomas (ca) including: lung, small cell (s cell var), non small cell (non-s or non-sm); breast; melanoma; colon; prostate; glioma (glio), astrocytoma (astro) and neuroblastoma (neuro); squamous cell (squam); ovarian; 10 liver; renal; gastric and pancreatic from the American Type Culture Collection (ATCC, Bethesda, MD). Normal tissues were obtained from individual adults or fetuses and included: adult and fetal skeletal muscle, adult and fetal heart, adult and fetal kidney, adult and fetal liver, adult and fetal lung, brain, spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, 15 colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. The following abbreviations are used in reporting the results: metastasis (met); pleural effusion (pl. eff or pl effusion) and * indicates established from metastasis. Generalscreening-panel-vl.

4 , v1.5, v1.6 and v1.7 Panels 1.4, 1.5, 1.6 and 1.7 were as described for Panels 1, 1.1, 1.2 and 1.3D, above 20 except that normal tissue samples were pooled from 2 to 5 different adults or fetuses. Panels 2D, 2.2, 2.3 and 2.4 Panels 2D, 2.2, 2.3 and 2.4 included 2 control wells and 94 wells containing RNA or cDNA from human surgical specimens procured through the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative 25 (NDRI), Ardais (Lexington, MA) or Clinomics BioSciences (Frederick, MID). Tissues included human malignancies and in some cases matched adjacent normal tissue (NAT). Information regarding histopathological assessment of tumor differentiation grade as well as the clinical stage of the patient from which samples were obtained was generally available. Normal tissue RNA and cDNA samples were purchased from various 30 commercial sources such as Clontech (Palo Alto, CA), Research Genetics and Invitrogen (Carlsbad, CA). HASS Panel v 1.0 WO 2004/015079 PCT/US2003/024931 The HASS Panel vl.0 included 93 cDNA samples and two controls including: 81 samples of cultured human cancer cell lines subjected to serum starvation, acidosis and anoxia according to established procedures for various lengths of time; 3 human primary cells; 9 malignant brain cancers (4 medulloblastomas and 5 glioblastomas); and 2 controls. 5 Cancer cell lines (ATCC) were cultured using recommended conditions and included: breast, prostate, bladder, pancreatic and CNS. Primary human cells were obtained from Clonetics (Walkersville, MD). Malignant brain samples were gifts from the Henry Ford Cancer Center. ARDAIS Panel v1.O and v1.1 10 The ARDAIS Panel v1.0 and v1.1 included 2 controls and 22 test samples including: human lung adenocarcinomas, lung squamous cell carcinomas, and in some cases matched adjacent normal tissues (NAT) obtained from Ardais (Lexington, MA). Unmatched malignant and non-malignant RNA samples from lungs with gross histopathological assessment of tumor differentiation grade and stage and clinical state of 15 the patient were obtained from Ardais. ARDAIS Prostate v1.O ARDAIS Prostate v1.0 panel included 2 controls and 68 test samples of human prostate malignancies and in some cases matched adjacent normal tissues (NAT) obtained from Ardais (Lexington, MA). RNA from unmatched malignant and non-malignant 20 prostate samples with gross histopathological assessment of tumor differentiation grade and stage and clinical state of the patient were also obtained from Ardais. ARDAIS Kidney v1.O ARDAIS Kidney vl.O panel included 2 control wells and 44 test samples of human renal cell carcinoma and in some cases matched adjacent normal tissue (NAT) obtained 25 from Ardais (Lexington, MA). RNA from unmatched renal cell carcinoma and normal tissue with gross histopathological assessment of tumor differentiation grade and stage and clinical state of the patient were also obtained from Ardais. ARDAIS Breast v1.O ARDAIS Breast v1.0 panel included 2 control wells and 71 test samples of human 30 breast malignancies and in some cases matched adjacent normal tissue (NAT) obtained from Ardais (Lexington, MA). RNA from unmatched malignant and non-malignant breast WO 2004/015079 PCT/US2003/024931 samples with gross histopathological assessment of tumor differentiation grade and stage and clinical state of the patient were also obtained from Ardais. Panel 3D, 3.1 and 3.2 Panels 3D, 3.1, and 3.2 included two controls, 92 cDNA samples of cultured human 5 cancer cell lines and 2 samples of human primary cerebellum. Cell lines (ATCC, National Cancer Institute (NCI), German tumor cell bank) were cultured as recommended and were derived from: squamous cell carcinoma of the tongue, melanoma, sarcoma, leukemia, lymphoma, and epidermoid, bladder, pancreas, kidney, breast, prostate, ovary, uterus, cervix, stomach, colon, lung and CNS carcinomas. 10 Panels 4D, 4R, and 4.1D Panels 4D, 4R, and 4.1D included 2 control wells and 94 test samples of RNA (Panel 4R) or cDNA (Panels 4D and 4. 1D) from human cell lines or tissues related to inflammatory conditions. Controls included total RNA from normal tissues such as colon, lung (Stratagene, La Jolla, CA), thymus and kidney (Clontech, Palo Alto, CA). Total RNA 15 from cirrhotic and lupus kidney was obtained from BioChain Institute, Inc., (Hayward, CA). Crohn's intestinal and ulcerative colitis samples were obtained from the National Disease Research Interchange (NDRI, Philadelphia, PA). Cells purchased from Clonetics (Walkersville, MD) included: astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular 20 dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, and human umbilical vein endothelial. These primary cell types were activated by incubating with various cytokines (IL-1 beta -1-5 ng/ml, TNF alpha -5-10 ng/ml, IFN gamma -20-50 ng/ml, IL-4 -5-10 ng/ml, IL-9 -5-10 ng/ml, IL-13 5-10 ng/ml) or combinations of cytokines as indicated. Starved endothelial cells were cultured in the 25 basal media (Clonetics, Walkersville, MD) with 0.1% serum. Mononuclear cells were prepared from blood donations using Ficoll. LAK cells were cultured in culture media [DMEM, 5% FCS (Hyclone, Logan, UT), 100 mM non essential amino acids (Gibco/Life Technologies, Rockville, MD), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5 x 10- M (Gibco), and 10 mM Hepes (Gibco)] and interleukin 30 2 for 4-6 days. Cells were activated with 10-20 ng/ml PMA and 1-2 tg/ml ionomycin, 5-10 ng/ml IL-12, 20-50 ng/ml lFN gamma or 5-10 ng/ml IL-18 for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in culture media with -5 mg/ml PHA (phytohemagglutinin) or PWM (pokeweed mitogen; Sigma-Aldrich Corp., St. Louis, MO).

WO 2004/015079 PCT/US2003/024931 Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from.two donors, isolating the mononuclear cells using Ficoll and mixing them 1:1 at a final concentration of -2x10 6 cells/ml in culture media. The MLR samples were taken at various time points from 1-7 5 days for RNA preparation., Monocytes were isolated from mononuclear cells using CD14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet (Miltenyi Biotec, Auburn, CA) according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culturing in culture media with 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages were 10 prepared by culturing monocytes for 5-7 days in culture media with -50 ng/ml 10% type AB Human Serum (Life technologies, Rockville, MD) or MCSF (Macrophage colony stimulating factor; R&D, Minneapolis, MN). Monocytes, macrophages and dendritic cells were stimulated for 6 or 12-14 hours with 100 ng/ml lipopolysaccharide (LPS). Dendritic cells were also stimulated with 10 Ag/ml anti-CD40 monoclonal antibody (Pharmingen, 15 San Diego, CA) for 6 or 12-14 hours. CD4+ lymphocytes, CD8+ lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet (Miltenyi Biotec, Auburn, CA) according to the manufacturer's instructions. CD45+RA and CD45+RO CD4+ lymphocytes were isolated 20 by depleting mononuclear cells of CD8+, CD56+, CD14+ and CD19+ cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO Miltenyi beads were then used to separate the CD45+RO CD4+ lymphocytes from CD45+RA CD4+ lymphocytes. CD45+RA CD4+, CD45+RO CD4 +and, CD8+ lymphocytes were cultured in culture media at 106 cells/ml in culture plates precoated overnight with 0.5 mg/ml anti 25 CD28 (Pharmingen, San Diego, CA) and 3 /Lg/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8+ lymphocytes, isolated CD8+ lymphocytes were activated for 4 days on anti-CD28, anti-CD3 coated plates and then harvested and expanded in culture media with IL-2 (1 ng/ml). These CD8+ cells were activated again with plate bound anti-CD3 and anti 30 CD28 for 4 days and expanded as described above. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. Isolated NK cells were cultured in culture media with 1 ng/ml IL-2 for 4-6 days before RNA was prepared. 1 '70 WO 2004/015079 PCT/US2003/024931 B cells were prepared from minced and sieved tonsil tissue (NDRI). Tonsil cells were pelleted and resupended at 106 cells/ml in culture media. Cells were activated using 5 pg/ml PWM (Sigma-Aldrich Corp., St. Louis, MO) or -10 pig/ml anti-CD40 (Pharmingen, San Diego, CA) and 5-10 ng/m 1IL-4. Cells were harvested for RNA preparation after 24, 5 48 and 72 hours. To prepare primary and secondary Thl/Th2 and Tr1 cells, umbilical cord blood CD4+ lymphocytes (Poietic Systems, German Town, MD) were cultured at 10 5 -10 6 cells/ml in culture media with IL-2 (4 ng/ml) in 6-well Falcon plates (precoated overnight with 10 pg/ml anti-CD28 (Pharmingen) and 2 tg/ml anti-CD3 (OKT3; ATCC) then washed twice 10 with PBS). To stimulate ThI phenotype differentiation, IL-12 (5 ng/ml) and anti-IL4 (1 pg/ml) were used; for Th2 phenotype differentiation, IL-4 (5 ng/ml) and anti-lFN gamma (1 pxg/ml) were used; and for Tr1 phenotype differentiation, IL-10 (5 ng/ml) was used. After 4-5 days, the activated Thl, Th2 and Tr1 lymphocytes were washed once with DMEM and 15 expanded for 4-7 days in culture media with IL-2 (1 ng/ml). Activated ThI, Th2 and Tr1 lymphocytes were re-stimulated for 5 days with anti-CD28/CD3 and cytokines as described above with the addition of anti-CD95L (1 pg/ml) to prevent apoptosis/After 4-5 days, the Thl, Th2 and Tr1 lymphocytes were washed and expanded in culture media with IL-2 for 4-7 days. Activated ThI and Th2 lymphocytes were maintained for a maximum of three 20 cycles. RNA was prepared from primary and secondary Thl, Th2 and Tr1 after 6 and 24 hours following the second and third activations with plate-bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures. Leukocyte cells lines Ramos, EOL-1, KU-812 were obtained from the ATCC. EOL 1 cells were further differentiated by culturing in culture media at 5 x 105 cells/ml with 0.1 25 mM dbcAMP for 8 days, changing the media every 3 days and adjusting the cell concentration to 5 x10 5 cells/ml. RNA was prepared from resting cells or cells activated with PMA (10 ng/ml) and ionomycin (1 pg/ml) for 6 and 14 hours. RNA was prepared from resting CCD 1106 keratinocyte cell line (ATCC) or from cells activated with -5 ng/ml TNF alpha and 1 ng/ml IL-i beta. RNA was prepared from resting NCI-H292, 30 airway epithelial tumor cell line (ATCC) or from cells activated for 6 and 14 hours in culture media with 5 ng/ml IL-4, 5 ng/ml IL-9, 5 ng/ml IL-13, and 25 ng/ml TFN gamma. RNA was prepared by lysing approximately 107 cells/ml using Trizol (Gibco BRL) then adding 1/10 volume of bromochloropropane (Molecular Research Corporation, WO 2004/015079 PCT/US2003/024931 Cincinnati, OH), vortexing, incubating for 10 minutes at room temperature and then spinning at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was placed in a 15 ml Falcon Tube and an equal volume of isopropanol was added and left at -20* C overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min and washed in 70% ethanol. 5 The pellet was redissolved in 300 pd of RNAse-free water with 35 ml buffer (Promega, Madison, WI) 5 pd DTT, 7 Al RNAsin and 8 ptl DNAse and incubated at 370 C for 30. minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with 1/10 volume of 3 M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down, placed in RNAse free water and stored at -80* C. 10 Alcomprehensive panel_vl.O Autoimmunity (AI) comprehensive panel vl.O included two controls and 89 cDNA test samples isolated from male (M) and female (F) surgical'and postmortem human tissues that were obtained from the Backus Hospital and Clinomics (Frederick, MD). Tissue samples included: normal, adjacent (Adj); matched normal adjacent (match control); joint 15 tissues (synovial (Syn) fluid, synovium, bone and cartilage, osteoarthritis (OA), rheumatoid arthritis (RA)); psoriatic; ulcerative colitis colon; Crohns disease colon; and emphysmatic, asthmatic, allergic and chronic obstructive pulmonary disease (COPD) lung. Pulmonary and General inflammation (PGI) panel v1.O Pulmonary and General inflammation (PGI) panel v1.0 included two controls and 20 39 test samples isolated as surgical or postmortem samples. Tissue samples include: five normal lung samples obtained from Maryland Brain and Tissue Bank, University of Maryland (Baltimore, MD), International Bioresource systems, IBS (Tuscon, AZ), and Asterand (Detroit, MI), five normal adjacent intestine tissues (NAT) from Ardais (Lexington, MA), ulcerative colitis samples (UC) from Ardais (Lexington, MA); Crohns 25 disease colon from NDRI, National Disease Research Interchange (Philadelphia, PA); emphysematous tissue samples from Ardais (Lexington, MA) and Genomic Collaborative Inc. (Cambridge, MA), asthmatic tissue from Maryland Brain and Tissue Bank, University of Maryland (Baltimore, MD) and Genomic Collaborative Inc (Cambridge, MA) and fibrotic tissue from Ardais (Lexinton, MA) and Genomic Collaborative (Cambridge, MA). 30 Cellular OA/RA Panel Cellular OA.RA panel includes 2 control wells and 35 test samples comprised of cDNA generated from total RNA isolated from human cell lines or primary cells representative of the human joint and its inflammatory condition. Cell types included It Onl WO 2004/015079 PCT/US2003/024931 normal human osteoblasts (Nhost) from Clonetics (Cambrex, East Rutherford, NJ), human chondrosarcoma SW1353 cells from ATCC (Manossas, VA)), human fibroblast-like synoviocytes from Cell Applications, Inc. (San Diego, CA) and MHI7A cell line (a rheumatoid fibroblast-like synoviocytes transformed with SV40 T antigen) from Riken Cell 5 bank ( Tsukuba Science City, Japan). These cell types were activated by incubating with various cytokines (IL-1 beta -1-10 ng/ml, TNF alpha -5-50 ng/ml, or prostaglandin E2 for Nhost cells) for 1, 6, 18 or 24 h. All these cells were starved for at least 5 h and cultured in their corresponding basal medium with - 0.1 to 1 % FBS. Minitissue OA/RA Panel 10 The OA/RA mini panel includes two control wells and 31 test samples comprised of cDNA generated from total RNA isolated from surgical and postmortem human tissues obtained from the University of Calgary (Alberta, Canada), NDRI (Philadelphia, PA), and Ardais Corporation (Lexington, MA). Joint tissue samples include synovium, bone and cartilage from osteoarthritic and rheumatoid arthritis patients undergoing reconstructive 15 knee surgery, as well as, normal synovium samples (RNA and tissue). Visceral normal tissues were pooled from 2-5 different adults and included adrenal gland, heart, kidney, brain, colon, lung, stomach, small intestine, skeletal muscle, and ovary. AI.05 chondrosarcoma AI.05 chondrosarcoma plates included SW1353 cells (ATCC) subjected to serum 20 starvation and treated for 6 and 18 h with cytokines that are known to induce MIP (1, 3 and 13) synthesis (e.g. ILibeta). These treatments included: IL-1beta (10 ng/ml), IL-1beta + TNF-alpha (50 ng/ml), IL-1beta + Oncostatin (50 ng/ml) and PMA (100 ng/ml). Supernatants were collected and analyzed for MMP 1, 3 and 13 production. RNA was prepared from these samples using standard procedures. 25 Panels 5D and 51 Panel 5D and 51 included two controls and cDNAs isolated from human tissues, human pancreatic islets cells, cell lines, metabolic tissues obtained from patients enrolled in the Gestational Diabetes study (described below), and cells from different stages of adipocyte differentiation, including differentiated (AD), midway differentiated (AM), and 30 undifferentiated (U; human mesenchymal stem cells). Gestational Diabetes study subjects were young (18 - 40 years), otherwise healthy women with and without gestational. diabetes undergoing routine (elective) Caesarean section. Uterine wall smooth muscle (UT), visceral (Vis) adipose, skeletal inuscle (SK), WO 2004/015079 PCT/US2003/024931 placenta (Pl) greater omentum adipose (GO Adipose) and subcutaneous (SubQ) adipose samples (less than 1 cc) were collected, rinsed in sterile saline, blotted and flash frozen in liquid nitrogen. Patients included: Patient 2, an overweight diabetic Hispanic not on insulin; Patient 7-9, obese non-diabetic Caucasians with body mass index (BMI) greater than 30; 5 Patient 10, an overweight diabetic Hispanic, on insulin; Patient 11, an overweight nondiabetic African American; and Patient 12, a diabetic Hispanic on insulin. Differentiated adipocytes were obtained from induced donor progenitor cells (Clonetics, Walkersville, MD). Differentiated human mesenchymal stem cells (HuMSCs) were prepared as described in Mark F. Pittenger, et al., Multilineage Potential of Adult 10 Human Mesenchymal Stem Cells Science Apr 2 1999: 143-147. mRNA was isolated and sscDNA was produced from Trizol lysates or frozen pellets. Human cell lines (ATCC, NCI or German tumor cell bank) included: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells and adrenal cortical adenoma cells. Cells were cultured, RNA extracted and sscDNA was 15 produced using standard procedures. Panel 51 also contains pancreatic islets (Diabetes Research Institute at the University of Miami School of Medicine). Human Metabolic RTQ-PCR Panel Human Metabolic RTQ-PCR Panel included two controls (genomic DNA control 20 and chemistry control) and 211 cDNAs isolated from human tissues and cell lines relevant to metabolic diseases. This panel identifies genes that play a role in the etiology and pathogenesis of obesity and/or diabetes. Metabolic tissues including placenta (PI), uterine wall smooth muscle (Ut), visceral adipose, skeletal muscle (Sk) and subcutaneous (SubQ) adipose were obtained from the Gestational Diabetes study (described above). Included in 25 the panel are: Patients 7 and 8, obese non-diabetic Caucasians; Patient 12 a diabetic Caucasian with unknown BMI, on insulin (treated); Patient 13, an overweight diabetic Caucasian, not on insulin (untreated); Patient 15, an obese, untreated, diabetic Caucasian; Patient 17 and 25, untreated diabetic Caucasians of normal weight; Patient 18, an obese, untreated, diabetic Hispanic; Patient 19, a non-diabetic Caucasian of normal weight; Patient 30 20, an overweight, treated diabetic Caucasian; Patient 21 and 23, overweight non-diabetic Caucasians; Patient 22, a treated diabetic Caucasian of normal weight; Patient 23, an overweight non-diabetic Caucasian; and Patients 26 and 27, obese, treated, diabetic Caucasians.

WO 2004/015079 PCT/US2003/024931 Total RNA was isolated from metabolic tissues including: hypothalamus, liver, pancreas, pancreatic islets, small intestine, psoas muscle, diaphragm muscle, visceral (Vis) adipose, subcutaneous (SubQ) adipose and greater omentum (Go) from 12 Type II diabetic (Diab) patients and 12 non diabetic (Norm) at autopsy. Control diabetic and non-diabetic 5 subjects were matched where possible for: age; sex, male (M); female (F); ethnicity, Caucasian (CC); Hispanic (H); African American (AA); Asian (AS); and BMI, 20-25 (Low BM), 26-30 (Med BM) or overweight (Overwt), BMI greater than 30 (Hi BMI) (obese). RNA was extracted and ss cDNA was produced from cell lines (ATCC) by standard 10 methods. CNS Panels CNS Panels CNSD.01, CNS Neurodegeneration V1.O and CNS Neurodegeneration V2.0 included two controls and 46 to 94 test cDNA samples isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean 15 Hospital). Brains were removed from calvaria of donors between 4 and 24 hours after death, and frozen at -80' C in liquid nitrogen vapor. Panel CNSD.01 Panel CNSD.01 included two specimens each from: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy (PSP), 20 Depression, and normal controls. Collected tissues included: cingulate gyrus (Cing Gyr), temporal pole (Temp Pole), globus palladus (Glob palladus), substantia nigra (Sub Nigra), primary motor strip (Brodman Area 4), parietal cortex (Brodman Area 7), prefrontal cortex (Brodman Area 9), and occipital cortex (Brodman area 17). Not all brain regions are represented in all cases. 25 Panel CNS Neurodegeneration V1.O The CNS Neurodegeneration V1.0 panel included: six Alzheimer's disease (AD) brains and eight normals which included no dementia and no Alzheimer's like pathology (control) or no dementia but evidence of severe Alzheimer's like pathology (Control Path), specifically senile plaque load rated as level 3 on a scale of 0-3; 0 no evidence of plaques, 3 30 severe AD senile plaque load. Tissues collected included: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), occipital cortex (Brodman area 17) superior temporal cortex (Sup Temporal Ctx) and inferior temporal cortex (Inf Temproal Ctx).

WO 2004/015079 PCT/US2003/024931 Gene expression was analyzed after normalization using a scaling factor calculated by subtracting the Well mean (CT average for the specific tissue) from the Grand mean (average CT value for all wells across all runs). The scaled CT value is the result of the raw CT value plus the scaling factor. 5 Panel CNS Neurodegeneration V2.0 The CNS Neurodegeneration V2.0 panel included sixteen cases of Alzheimer's disease (AD) and twenty-nine normal controls (no evidence of dementia prior to death) including fourteen controls (Control) with no dementia and no Alzheimer's like pathology and fifteen controls with no dementia but evidence of severe Alzheimer's like pathology 10 (A13), specifically senile plaque load rated as level 3 on a scale of 0-3; 0 no evidence of plaques, 3 severe AD senile plaque load. Tissues from the temporal cortex (Brodman Area 21) included the inferior and superior temporal cortex that was pooled from a given individual (Inf & Sup Temp Ctx Pool). A. NOV1 CG121992: CHORDIN 15 Expression of NOVla gene CG121992-03 was assessed using the primer-probe set Ag8269, described in Table AA. Results of the RTQ-PCR runs are shown in Table AB. Table AA. Probe Name Ag8269 Start SEQ ID Primers Sequences Length Position No Forward 5' -gagaaggttagggagagcacct'-3' 22 1255 85 TET-5'-ccttgcaggactaacccaggttc-3'- 2 328 Probe TMA23 1302 86 TAMRA Reverse ^gtagaatctggagcctcaag-3' 22 1326 87 Table AB. Probe Name Ag7203 Primers' Sequences Length Start SEQ ID Pie S e L h Position No Forward 5'-aggagagggggggcact-3 17 2379 88 Probe FAM-5'-acactgcaccttctcacagtgcacctc- 27 2399 89 3' -TAMRA Reverse 5'-actgtttgcagcagtcggt-3 19 2465 90 20 Table AC. General-screening-panel vl.7 Column A - Rel. Exp.(%) Ag8269, Run 325595059 Tissue Name A Tissue Name A Adipose 10.2 Gastric ca. (liver met.) NCI-N87 0.0 N 0.2 Stomach 0.5 Melanoma* Hs688(A).T 0.0 Colon ca. SW-948 0.0 1 O A WO 2004/015079 PCT/US2003/024931 M0la.ma Hs688(B).T .1 Colon ca. SW480 0.0 Melanoma (met) SK-MEL-5 0.3_ Colon ca. (SW480 met) SW620 0.0 Testis 0.5 Colon ca. HT29 3.3 Prostate ca. (bone met) PC-3 0.0 ColonCa.HCT-116 0.0 Prostate ca. DU145 0.8 Colon cancer tissue 0.0 Prostate pool 1.2 Colon ca. SW1116 0.8 us poo 1.9 Colon ca. Colo-205 0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. SW-48 0.0 Ovarian ca. (ascites) SK-OV-3 0.0 Colon 1.0 Ovarian ca. OVCAR-4 0.2 Small Intestine 3.0 Ovarian ca. OYCAR-5 1.5 Fetal Heart 0.3 Ovarian ca. IGROV-1 3.8 Heart 1.5 Ovarian ca. OVCAR-8 0.9 Lymph Node Pool 0.0 Ovary 2.6 Lymph Node pool 2 6.6 Breast ca. MCF-7 0.6 Fetal Skeletal Muscle 1.3 Breast ca. MDA-MB-231 0.1 Skeletal Muscle poo 0.4 Breast ca. BT 549 0.0 kel tal Muscle 1.6 Breast ca. T47D 1.8 Spleen 1.7 113452 mammary gland 0.0 Thymus 0.9 Trachea 3.7 CNS cancer (glio/astro) SF-268 0.1 Lung 2.5 CNS cancer (glio/astro) T98G 0.0 Fetal Lung 6.7 CNS cancer (neuro;met) SK-N-AS 0.0 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 0.7 Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0 Lung ca. NCI-H146 6.8 CNS cancer (glio) SNB-19 0.7 Lung ca SBP-77 - 57 CNS cancer (glio) SF-295 0.1 Lung ca. NCI-H23 0.9 Brain (Amygdala) 4.7 Lung ca. NCI-H460 0.0 Brain (Cerebellum) 100-0 Lung ca. HOP-62 0.0 Brain (Fetal) 16.4 Lung ca. NCI-H522 1.6 Brain (Hippocampus) 3.5 Lung ca. DMS-114 1.2 Cerebral Cortex pool 3.8 Liver -0.6 Brain (Substantia nigra) 2.8 Fetal Liver 7.2 Brain (Thalamus) 4.9 Kidney pool 7.2 Brain (Whole) 84.7 Fetal Kidney 0.8 Spinal Cord 1.2 Renal ca. 786-0 4.7 Adrenal Gland 5.2 Renal ca. A498 0.0 pituitary Gland 0.9 Renal ca. ACHN 02Saliv Gland Renal ca. UO-31 00Thyroid 2.2 Renal ca. TK-10 0.1 Pancreatic ca. PANC-1 0.1 Bladder 1.5 Pancreas pool WO 2004/015079 PCT/US2003/024931 Generalscreening-panel_vl.7 Summary: Results using probe-primer sets Ag8269 and Ag7203 showed similar expression profile. This gene was highly expressed in brain (CT=25.27) and adipose (CT=28.57). This gene encodes a human chordin polypeptide. The chordin polypeptides have homology to Xenopus chordin, a secreted 5 molecule that functions as a dorsalizing factor in early embryo development. Chordin binds and antagonizes BMP-4, a member of the transforming growth factor (TGF)-beta superfamily. Therapeutic modulation of the activity of this gene is useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes, and central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, 10 multiple sclerosis, schizophrenia and depression. B. NOV2 CG186275: ADAM 22 Expression of gene CG186275-03 was assessed using the primer-probe sets Ag7761 and Ag8175, described in Tables BA and BB. Results of the RTQ-PCR runs are shown in Table 15 BC. Table BA. Probe Name Ag7761 Pr r SStart SEQ ID Primers Sequences Length Position No Forward 5atataccagatacagttgactcatgttg-3 28 329 91 Probe TET-5-accaagcaagcttccaggttgatgc-3'- 25 357 92 TAMRA Reverse .5 -gagaatgaatgacgttccaaag-3 22 382 93 Table BB. Probe Name Ag8175 Start SEQ ID Primers Sequences Length Position No Forward 5s'--cattategatgtegtgtaaat-3 22 397 94 Probe TET-5'-catgatttgctgtcctctgaatacataga-3 - 29 419 95 TAMRA Reverse 5Icttgcctccatgttcaatgt-31 20 453 96 Table BC. General_screening-panel-vl.7 Column A - Rel. Exp.(%) Ag7761, Run 318349329 Tissue Name A Tissue Name A Adipose 3.8 [Gastric ca. (liver met.) NCI-N87 0.0 HUVEC 0.7 Stomach Melanoma* Hs688(A).T 10.0 Colon ca. SW-948 2.6 Melanoma* Hs688(B).T 11.1 Colon ca. SW480 0.2 Melanoma (met) SK-MEL-5 2.2 Colon ca. (SW480 met) SW620 14.5 Testis 1.1 Colon ca. HT29 8.8 1 Oe: WO 2004/015079 PCT/US2003/024931 Prostate ca. (bone met) PC-3 0.0 [Colon C a. HCT-116 9.7 Prostate ca. DU145 4.9 Colon cancer tissue Prostate pool 1.0 Colon ca. SW1116 2.6 Uterus 0.4 Colon ca. Colo-205 0.8 Ovarian ca. OVCAR-3 1.3 Colon ca. SW-48 0.2 Ovarian ca. (ascites) SK-OV-3 0.2 Colon 0.9 Ovarian ca. OVCAR-4 0.3 Small Intestine 0.5 Ovarian ca. OVCAR-5 Fetal Heart 0.5 Ovarian ca. IGROV-1 4.6 Heart 0.4 ovarian ca. OVCAR-8 1.6 Lymph Node Pool 0.6 Ovary 2.6 Lymph Node pool 2 2.9 Breast ca. MCF-7 1.1 Fetal Skeletal Muscle 0.9 Breast ca. MDA-MB-231 3.1 Skeletal Muscle pool Breast ca. BT 549 Skeletal Muscle 0.4 Breast ca. T47D 0.8 Spleen 1.5 113452 mammary gland 0.0 Thp us 151 Trachea E1.2 CNS cancer (glio/astro) SF-268 Lung 1.2 CNS cancer (glio/astro) T98G 1.4 Fetal Lung 3.4 CNS cancer (neuro;met) SK-N-AS J0.6 Lung ca. NCI-N417 2.9 CNS cancer (astro) SF-539 1.0 Lung ca. LX-1 0.7 CNS cancer (astro) SNB-75 1.0 Lung ca. NCI-H146 9.7 CNS cancer (glio) SNB-19 1.2 Lung ca. SHP-77 35.8 CNS cancer (glio) SF-295 0.3 Lung ca. NCI-H23 2.9 Brain (Amygdala) 13.8 Lung ca. NCI-H460 2.6 Brain (Cerebellum) 100.0 Lung ca. HOP-62 0.9 Brain (Fetal) 21.5 Lung ca. NCI-H522 6.9 Brain (Hippocampus) ._ ung ca. DMS-114 1.2 Cerebral Cortex pool 5.7 Liver 0.0 Brain (Substantia nigra) 3.5 Fetal Liver Brain (Thalamus) 2.0 Kidney pool 7.5 Brain (Whole) 82.4 Fetal Kidney 27SpinaCord J 2.8 Renal ca. 786-0 Adrenal Gland 5.5 Renal ca. A498 10 Pituitary Gland 2 Renal ca. ACIN -- Salivary Gland 0.3 Renal a. UO-31 0.4 Thyroid 4.5 Renal ca. TK-10 10.9 Pancreatic ca. PANC-1 0.2 IBladder 0.9 IPancreas pool Generalscreening-panel_vl.7 Summary: Ag7761 The highest expression of this gene was detected in cerebellum (CT=24). Generally, this gene is ubiquitously WO 2004/015079 PCT/US2003/024931 expressed at moderate to low levels. It was upregulated in some colon and lung cancers and therefore is useful as a marker for these cancers and to differentiate between cancerous and normal tissue of these organs. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product is 5 useful in the treatment of colon and lung cancer. C. NOV3, CG50586: Beta-secretase Expression of gene CG50586-03 and NOV3b, 260368280, were assessed using the primer-probe set Ag43, described in Table CA. Results of the RTQ-PCR runs are shown in Table CB. 10 Table CA. Probe Name Ag43 Start SEQ ID Primers Sequences Length Position No Forward 5 -aaatcgcaagacattcactgtca-3 23 558 97 Prob TET-5'-cagcacactggacttccgagtggacc-3 - 26 582 98 TAMRA Reverse 5 -ccgccactccatcatcact- 3 19 610 Table CB. Panel 1 Column A - Rel. Exp.(%) Ag43, Run 87354406 Tissue Name A Tissue Name A Endothelial cells 0.0 Renal ca. 786-0 10.0 Endothelial cells (treated) 0.0 Renal ca. A498 0.0 Pancreas 0.2 Renal ca. RXF 393 [0.0 Pancreatic ca. CAPAN 2 0.0 Renal ca. ACHN [0.0 Adrenal gland 0.6 Renal ca. UO-31 0.0 Thyroid 0.2 Renal ca. TK-10 0.0 Salivary gland 0.3 Liver 0.1 Pituitary gland 0.1 Liver (fetal) 0.0 Brain (fetal) 11.5 Liver ca. (hepatoblast) HepG2 0.0 Brain (whole) 0.0 Lung 0.0 Brain (amygdala) 18.9 Lung (fetal) 0.1 Brain (cerebellum) 100.0 Lung ca. (small cell) LX-1 0.0 Brain (hippocampus) 57.0 Lung ca. (small cell) NCI-H69 1.0 Brain (substantia nigra) 23.2 Lung ca. (s.cell var.) SHP-77 0.0 Brain (thalamus) 12.6 Lung ca. (large cell)NCI-H460 0.0 Brain (hypothalamus) 4.3 Lung ca. (non-sm. cell) A549 0.0 Spinal cord 2.8 Lung ca. (non-s.cell) NCI-H23 1.0 glio/astro U87-MG 0.0 Lung ca. (non-s.cell) HOP-62 0.1 glio/astro U-118-MG 0.0 Lung ca. (non-s.cl) NCI-H522 0.3 1 00 WO 2004/015079 PCT/US2003/024931 astrocytoma SW1783 0.0 Lung ca. (squam.) SW 90 0.8 neuro*; met SK-N-AS 0 Lung ca. (squam.) NCI-H596 1.2 astrocytoma SF-53977 Mamr an1. astrocytoma SNB-75 0.0 Breast ca.* (pl.et) MCF-7 0.0 glioma SNB-19 0.0 Breast ca.* (pl.et) MDA-MB-231 0.0 glioma U251 0.0 Breast ca.* (pl. ef) T47D 0.0 glioma SF-295 .0 Breast ca. BT-549 0.0Breast ca. MDA-N 0.8 Skeletal muscleM ary 1 Bone marrow 0.1 Ovarian ca. OVCAR-3 0.0 0.3 Ovarian ca. OVCAR-4 0.0 0.1 Ovarian ca. OVCAR-5 0. Lymph node 0.1 Ovarian ca. OVCAR-8 0. Colon (ascending) 1.1 Ovarian ca. IGROV-i 0.0 2omaro 0.1 Ovarian ca. (ascites) SK-OV-3 10.0 Small intestine 0.8 Uterus 0.1 Colon ca. OW480 V R P-acent4 0. Colon ca.* SW620 (SW480 met)____ T0.0 state 0.7 l n 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Testis 1.8 Colon ca. CaCo-2 0.0 Melanoma Hs688(A).T t0.2 Colon ca. HCT-15 0.0 Me oma* (met) Hs688(B).T 0.0 Colon ca HCC-2998 0.1 Melanoma UACC-62 Gastric ca. (liver met) NCI-N87 .0 _ Melanoa M14 0.1 1.3 Melanoma LOX IMVI 0.0 Trachea 0.7 Melanoma* (met) SK-MEL-5 10.2 Kidney 0.1 Melanoma SK-MEL-28 0.0 Kidney (fetal) 0.2 I Panel 1 Summary: Ag43 Highest. expression of this gene was detected in brain tissues (CT=21.7) and spinal cord (CT=26.68). This gene encodes the human beta-secretase enzyme polynucleotide. Beta-secretase is capable of cleaving the beta-amyloid precursor protein (APP) (AAY33742;swedish mutant APP). This enzyme is useful in detecting 5 human beta-secretase cleavage of polypeptides and for identifying beta-secretase inhibitors. Therapeutic modulation of the activity of this gene is useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. 1 OA WO 2004/015079 PCT/US2003/024931 D. NOV4 CG50637: T-CELL SURFACE GLYCOPROTEIN CD1B PRECURSOR Expression of gene NOV4a, CG50637-01; NOV4b 277577082; and NOV4c 277577094 were assessed using the primer-probe set Ag2828, described in Table DA. 5 Results of the RTQ-PCR runs are shown in Tables DB, DC and DD. Table DA. Probe Name Ag2828 e SStart SEQ ID Sequences Length Position No Forward 5' -ctgaggctgtctccttgatg-3 20 1401 100 Probe TET-5'-ctggaaggcttctctacaccccgg-3'- 24 j 1376 101 TAMRA Reverse 5'-gtggtcctggtcetcatatacc-3' 22 1326 102 Table DB. General screening-panelvl.5 Column A - Rel. Exp.(%) Ag2828, Run 254396109 Tissue Name A Tissue Name A Adipose 2.0 Renal ca. TK-10 2.2 melanoma* Hs688(A).T 1.9 Bladder 2.7 Melanoma* 1s688(B).T 1.3 Gastric ca. (liver met.) NCI-N87 14.4 Melanoma* M14 4.5 Gastric ca. KATO III 11.4 Melanoma* LOXIMYI 1.3 Colon ca. SW-948 1.7 Melanoma* SK-MEL-5 1.8 Colon ca. SW480 4.7 Squamous cell carcinoma SCC-4 0.6 Colon ca.* (SW480 met) SW620 1.5 Testis Pool 37 Colon ca. HT29 0.7 Prostate ca.* (bone met) PC-3 5.2 Colon ca. HCT-116 0.1 Prostate Pool 6.9 Colon ca. CaCo-2 1.3 Placenta 3.3 Colon cancer tissue 2.6 Uterus Pool 3.2 Colon ca. SW1116 1.3 Ovarianca. OVCAR-3 6.3 Colon ca. Colo-205 3.1 Ovarian ca. SK-OV-3 15.6 Colon ca. SW-48 2.7 Ovarian ca. OVCAR-4 1.0 Colon Pool 6.4 Ovarian ca. OVCAR-5 6.0 Small Intestine Pool 4.9 Ovarian ca. IGROV-1 4.9 Stomach Pool 2.5 Ovarian ca. OVCAR-8 7.4 Bone Marrow Pool 2.9 0var 4.7 Fetal Heart 2.7 Breast ca. MCF-7 18.4 Heart Pool 2.9 Breast ca. MDA-MB-231 6.9 Lymph Node Pool 6.1 Breast ca. BT 549 7.3 Fetal Skeletal Muscle 5.2 Breast ca. T47D 1.9 Skeletal Muscle Pool 18.0 Breast ca. MDA-N Spleen Pool 3.9 Breast Pool 6.0 Thymus Pool 4.5 inn~t WO 2004/015079 PCT/US2003/024931 Trachea 4.6 CNS cancer (glio/astro) U87-MG 1.8 Lung 1.7 CNS cancer (glio/astro) U-1 18-MG 0.4 Fetal Lung 3.1 CNS cancer (neuro;met) SK-N-AS 3.5 Lung ca. NCI-N417 2.6 CNS cancer (astro) SF-539 0.1 Lung ca. LX-1 0.5 CNS cancer (astro) SNB-75 1.6 Lung ca. NCI-H146 1.3 CNS cancer (glio) SNB-19 7.7 Lung ca. SHP-77 5.5 CNS cancer (glio) SF-295 2.7 Lung ca. A549 1.3 Brain (Amygdala) Pool 15.5 Lung ca. NCI-H526 0.9 Brain (cerebellum) 100.0 Lung ca. NCI-H23 14.2 Brain (fetal) 19.2 Lung ca. NCI-H460 3.5 Brain (Hppocampus) Pool 11.'7 Lung ca. HOP-62 0.9 ,Cerebral Cortex Pool 20.0 Lung ca. NCI-H522 9.8 |Brain (Substantia nigra) Pool 20.7 Liver 10.8 Brain (Thalamus) Pool 26.1 Fetal Liver 1.8 Brain (whole) 33.0 Liver ca. HepG2 1.2 Spinal Cord Pool 6.2 Kidney Pool [12.1 Adrenal Gland 23.0 Fetal Kidney 2.1 Pituitary gland Pool 3.0 Renal ca. 786-0 0.2 Salivary Gland 3.1 Renal ca. A498 0.9 Thyroid (female) 5.8 Renal ca. ACHN 1.1 Pancreatic ca. CAPAN2 0.2 Renal ca. UO-31 2.8 Pancreas Pool 3.5 Table DC. Panel 4D Column A - Rel. Exp.(%) Ag2828, Run 162350533 Tissue Name A Tissue Name A Secondary Th1 act 0.0 HUVEC IL-Ibeta 0.0 Secondary Th2 act 2.9 HUVEC IFN gamma 2.0 Secondary Tr1 act - 28 HUVEC TNF alpha + IFN gamma 0.0 Secondary ThI rest 9.5 HUVEC TNF alpha + IL4 0.8 Secondary Th2 rest 11.1 IHUVEC IL-1 0.0 Secondary Tr1 rest 11.9 ILung Microvascular EC none 2.3 Primary ThI act 10.8 Lung Microvascular EC TNFalpha + IL-1beta 0.0 Primary Th2 act 9.3 Microvascular Dermal EC none 12.2 Primary Tr1 act 4.5 Microsvasular Dermal EC TNFalpha + IL- 3.5 beta Primary Th1 rest 100.0 Bronchial epithelium TNFalpha + ILbeta 0.2 Primary Th2 rest 75.8 Small airway epithelium none 2.3 Primary Tr1 rest 47.3 Small airway epithelium TNFalpha + IL- 79 beta CD45RA CD4 lymphocyte act 6.2 Coronery artery SMC rest 2.5 CD45RO CD4 lymphocyte act 11.9 Coronery artery SMC TNFalpha + IL-1beta 1.0 101 WO 2004/015079 PCT/US2003/024931 CD8 lymphocyte act 13.9 Astrocytes rest 11.5 Secondary CD8 lymphocyte rest 22.5 Astrocytes TNFalpha + IL-1beta 17.8 Secondary CD8 lymphocyte act 0.4 KU-812 (Basophil) rest.5 CD4 lymphocyte none 47.0 KU-812 (Basophil) PMA/ionomycin 5.8 2ry ThlIrh2/Trl anti-CD95 27.5 CCD 1106 (Keratinocytes),none 11.5 CH11 LAK cells rest 8.9 CCD 1106 (Keratinocytes) TNFalpha + IL- 6.2 LAK ellsrest8 9 beta LAK cells IL-2 27.4 Liver cirrhosis 6.0 LAK cells IL-2+IL-12 14.9 Lupus kidney 3.2 LAK cells IL-2+IFN gamma 28.7 NCI-H292 none 46.7 LAK cells JL-2± IL-i 18-6.5 NCI-H292 LL-4 81.8 LAK cells P ionomycin 2.6 NCI-H292 69.7 NK Cells IL-2 rest 27.2 NCI-11292 1-13 37.6 Two Way 1.R 3 day 28. NCI-H292 ILN gamma 44.8 Two Way MLR 5 day 11.2 HPAEC none 7.8 Two Way MLR 7 day 5.7 BPAEC TNF alpha + 11-l beta 0.0 PBMC rest 42.6 Lung fibroblast none 14.6 27.9 ELung fibroblast TNF alpha + L -1 beta 6.5 PBMC PHA-L 21.6 Lung fibroblast IL-4 5.3 Ramos (B cell) none 0.0 Lung fibroblast 11-9 8.2 Ramos (B cell) ionomycin 0.0 L fIL13 4.8 B lymphocytes PWM 9.2 Lung fibroblast IFN gamma 61 B lymphocytes CD40L and IL-4 5.6 Dermal fibroblast CCD1070 rest 147 EOL-1 dbcAMP 1.5 Dermal fibroblast CCD1070 TNF alpha 17.3 EOL-1 dbcAMP 2.8 Dermal fibroblast CCD1070 IL-1 beta 2.7 PMA/ionomycin___________________ Dendritic cells none 3.5 Dermal fibroblast IFN gamma 3.3 Dendritic cells LS 1.1 Dermal fibroblast IL-4 25.7 Dendritic cells anti-CD40 6.0 ID Colitis 2 2.4 Monocytes rest 1.9 IBD Crohn's 3.7 on0 ccolon 54. Monocytes LPS ___________________ 54. 3 Macrophages rest 1 9Lug27.7 Macrophages LPS 17 Thymus 75.8 HUVEC none 5.6 Kidney 77.9 _________________j4.5 Table DD. Panel 5 Islet Column A - Rel. Exp.(%) Ag2828, Run 253721040 Column B - Rel. Exp.(%) Ag2828, Run 254275034 Tisu-NmeAA Tissue NameA B Tissue Name A B 97457 Patient-2go adipose 22.1 127.7 194709 Donor 2 AM - A adipose _ 8.5 7.6 s un ii i WO 2004/015079 PCT/US2003/024931 97476 Patient-07sk skeletal 18.3 20.6194710 Donor 2 AM - B adipose 3.1 5.O muscle 97477 Patiqnt-17ut uterus 17.6 39.2 94711 Donor 2 AM - C adipose 45 7.5 97478 Patient-07pl placenta 24.1 49.7 94712 Donor 2 AD - A adipose 14.1 9.9 99167 Bayer Patient 1 68.8 59.0 94713 Donor 2 AD - B adipose 10.6 26.2 97482 Patient-08ut uterus 12.1 24.7 94714 Donor 2 AD - C adipose 25.5 20.9 97483 Patient-O8pi placenta 7.1 5.1 94742 Donor 3 U - A 97483 Patient-08pl placenta 7.1 -5.1 Mesenchymal Stem Cells 2.2 3.4 97486 Patient-09sk skeletal 94743 Donor 3 U - B muscle Mesenchymal Stem Cells 97487 Patient-09ut uterus 39.8 60.7 94730 Donor 3 AM - A adipose 6.2 9.1 97488 Patient-09p1 placenta 13.2 13.2 94731 Donor 3AM - B adipose 3.9 4.0 97492 Patient-10ut uterus 25.5 31.6 94732 Donor 3 AM - C adipose 2.9 3.4 97493 Patient-10pl placenta 45.4 953 94733 Donor 3 AD - A adipose 10.823.2 97495 Patient-1Igo adipose 30.1 30.8 94734 Donor 3 AD - B adipose 4.0 3.0 97496 Patient-i1 sk skeletal 5551859 94735Donor3AD -Cadipose 3 muscle 97497Patient- ut uterus A77 ad 6.3 9.7 13.2 13.2 73556 Heart Cardiac stromal cells 4. 97498 Patient-25. placenta 472 (prim r 0a.04.7 97500 Patient-l2o adipose 20.9 7.5 81735 Small Intestine 40.82.9 97501 Patient-32sk skeletal 47 72409 Kidney Proximal 6.0 14.0 muscle 55.5 Convoluted Tubule 97502 Patient-12ut uterus 26.4 18.8 82685 Small intestine Duodenum 23.3 53.2 990650 Adrenal Adrenocortical 97503 Patient-12p placenta 27.4 48.3 16.533.2 9751_Ptiet-1skmkelta 94721 Donor 2U-1A 6.4 9.7 72410 KidneyRCE 17.428.5 M esenchym al Stem Cells st o a cells 0.0 4.7 94722 Donor 2 U-B 10.1 72409 Kidney PRE 8. 17.0 Mesenchymal Stem CellsA6.6 94723 Donor 2 U - 6.4 . 73139 Uterus Uterine smooth. 8 Mesenchymal Stem Cells J muscle cells General-screening.panel_vl.5 Summary: Ag2828 The highest expression of this gene was detected in cerebellum (CT=26). Generally this gene was ubiquitously expressed. Among tissues with metabolic or endocrine function, this gene was expressed at high to moderate levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, 5 skeletal muscle, heart, liver and the gastrointestinal tract. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

WO 2004/015079 PCT/US2003/024931 Panel 4D Summary: Ag2828 The highest expression of this gene was detected in resting primary ThI cells (CT=30). This gene was expressed in thymus, colon, lung and kidney. The expression of this gene was downregulated in Crohn's disease and colitis. Unstimulated T lymphocytes (Thl, Th2, and Tr1) expressed this gene at higher 5 levels than anti-CD28 + anti-CD3-stimulated T cells. The gene or protein product therefore is useful as a marker of resting vs activated T cells. Thus, this gene may be involved in T lymphocyte function. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of T cell-mediated autoimmune and inflammatory diseases. 10 Panel 5 Islet Summary: Ag2828 The highest expression of this gene was detected in skeletal muscle from a diabetic patient (CT=30). It was also expressed in adipose, uterus and placenta from both diabetic and non-diabetic individuals. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of endocrine/metabolically related 15 diseases, such as obesity and diabetes. E. NOV5, CG51117, Nephronectin Expression of gene NOV5a through 5f, CG51117 were assessed using the primer probe sets Ag2505, Ag2667, Ag2767, Ag2831 and Ag7237, described in Tables EA, EB, EC, ED and EE. Results of the RTQ-PCR runs are shown in Tables EF, EG, EH, El, EJ, 20 EK, EL and EM. Table EA. Probe Name Ag2505 -rir SStart SEQ ID Primers Sequences Length Position No Forward, 5-aaagaaggataccagggtgat-3 103 TET-5'-atgattgaaccttcaggtccaattca- 3 '- 26 1031 104 TAMRA Reverse 5 1 ggtaccatttccctttggtaca- 3 1 22 105 105 Table EB. Probe Name Ag2667 Primers Sequences Length Sit No Forward 5 '-gcagagaatagccaggataagg- 3 ' 2 391 106 Probe TET-5 -caaccacgatgcaaacatggtgaat-3- 25 107 TAMRAI I Reverse 5'-cacttgtttggcccgatac- 3 ' 19 459 Table EC. Probe Name Ag2767 WO 2004/015079 PCT/US2003/024931 Start SEQ ID Primers Sequences Length Position No Forward 5' -gcagagaatagccaggataagg-3' 391 109 Probe TET -5-caaccacgatgcaaacatggtgaat-3 25 4 110 TAMRA Reverse 51-cacttgtttggeccgatac-3, 19 459 111 Table ED. Probe Name Ag2831 Start SEQ ID Primers Sequences Length Position No Fowr gaaaaacagtag3 22 391 112 Probe TET-'-aaccacgatgcaaacatggtgaat-31- 25 434 113 TAMRA______a____ Reverse 5'-cacttgtttggcccgatac- 3 ' 19 459 114 Table EE Probe Name Ag7237 Primers SequencesLegh Sat EQI Start ISEQ ID Length Position No Forward 5 -gtgttcattccacggcaac-3' 19 1406 115 TET-5'-catcgtctgcactgactcctcttcta 3455 116 k~oe TAMRA __a3- 27 15 1 Reer gtgtaccagaacacetggat ca-31 22 1427 1221ers 1492 117 Table EF. AI-comprehensive panelvl.0 Column A - Rel. Exp.(%) Ag2505, Run 248588456 Column B - Rel. Exp.(%) Ag2831, Run 244570250 Tissue Name A B Tissue Name A B 110967 COPD-F 15.3 9.3 112427 Match Control Psoriasis-F 16.7 18.9 110980 COPD-F 11.8 7.0 112418 Psoriasis-M 14.0 13.9 110968 COPD-M 8.9 5.8 112723 Match Control Psoriasis-M 0.2 0.2 110977 COPD-M 28.1 14.1 112419 Psoriasis-M 18.2 8.7 110989 Emphysema-F 9.6 12.2 112424 Match Control Psoriasis-M 6.8 6.7 110992 Emphysema-F 1.9 4.1 112420 Psoriasis-M 13.9 15.5 110993 Emphysema-F 7.7 9.3 112425 Match Control Psoriasis-M 13.6 16.6 110994 Emphysema-F 5.2 4.1 104689 (MID OA Bone-Backus 25.3 38.4 110995 Emphysema-F 3.6 4.3 104690 (W) Adj "Normal" Bone- 27.9 21.2 IBackus 110996 Emphysema-F 0.410.2 104691 (MID OA Synovium- 2.9 3.0 -- Backus 110997 Asthina-M 4.6 3.0 104692 (BA) OA Cartilage-Backus 0.0 0.0 111001 Asthma-F .3 15.0 694(BA)OABone-Backus 5.8 18.7 111002 Asthma-F 13.5 7.2 104695 (BA) Adj "Normal" Bone- 14.1 19.8 *Backus 111003 Atopic Asthma-F . 0.2 10469 (BA) OA Synovium-Backus 2.3 3.6 111004 Atopic Asthma-F 20.411.4 104700 (SS) OA Bone-Backus 28.9 122. 111005 Atopic Asthma-F 7.3 9.4 104701 (SS) Adi "Normal" Bone- 125.51 18.7 -1 n WO 2004/015079 PCT/US2003/024931 -__Backus 111006 Atopic Asthma-F 1.6 1.4 104702 (SS) OA Synovium-Backus 11.7 7.1 111417 Allergy-M 5 2.8 117093 OA Cartilage Rep7 75 7.5 112347 Allergy-M 1.4 0.2 112672 OA Bone5 19.2 17.2 112349 Normal Lung-F 0.7 0.21112673 OA Synovium5 6.4 3.8 112357 Normal Lung-F 7.1 6.4 112674 OA Synovial Fluid cells5 6.8 4.2 112354 Normal Lung-M 7.6 6.0 117100 OA Cartilage Rep14 1.9 2.1 112374 Crohns-F 9.0 3.2 112756 OABone9 126.4 31.6 112389 Match Control Crohns- 11.2 6.6 112757 OA Synovium9 2.8 1.3 112375 Crohns-F 10.2 6.0 112758 OA Synovial Fluid Cells9 8.1 6.3 112732 Match Control Crohns- 1.2 2.1 117125 RA Cartilage Rep2 14.8 9.2 F- 112725 Crohns-M 0.9 1.6 113492 Bone2 RA 84.7 47.0 112387 Match Control Crohns- 11.4 13.0 113493 Synovium2 RA 40.9 25.3 112378 Crhns-M 1.3 2.0 113494 Syn Fluid Cells RA ~ 61.1 49.3 112390 Match Control Crohns- 16.7 4.3 113499 Cartilage4 RA 90.1 73.2 112726 Crohns-M 21.8 17.0 113500 Bone4 RA 100.0 100.0 112731 Match Control Crohns- 15.3 6.3 113501 Synovium4 RA 71.2 59.5

M

112380 Ulcer Col-F 5.8 7.0 113502 Syn Fluid Cels4 RA 48.6 -37.9 112734 Match Control Ulcer 3.7 5.0 113495 Cartilage3 RA 77.9 47.0 Col-F t rI2 - ... 112384 Ulcer Col-F 19.2 15.0 113496 Bone3 RA 92.0 41.8 112737 Match Control Ulcer 13.5 12.0 113497 Synovium3 RA 53.6 24.0 112386 Ulcer Col-F 8.4 6.0 113498 Syn Fluid Cells3 RA 98.6 57.0 112738 Match Control Ulcer 3.8 2.1 117106 Normal Cartilage Rep20 3.0 1.6 11381 Ulcer Col-M 5-0 9.9 1 ne3 ormal 2. 0 0.7 112735 Match Control Ulcer 9.7 5.8 113664 Synovium3 Normal 0.5 0.4 Col-M 112382 Ulcer Col-M 11.7 12.6 113665 Syn Fluid Cells3 Normal 1.6 1.4 112394 Match Control Ulcer 3.1 3.4 117107 Normal Cartilage Rep22 3.7 5.5 112383 Ulcer Col-M 5.1 13.7 113667 Bone4 Normal 4.3 6.0 112736 Match Control Ulcer 5.0 6.3 113668 Synovium4 Normal 9.1 7.4 112423 Psoriasis-F 14.0110.3 113669 Syn Fluid Cells4 Normal 6.6 6.6 Table EG. CNSneurodegeneration_vl.0 Column A - Rel. Exv.(%) A22505, Run 208123723 WO 2004/015079 PCT/US2003/024931 Column B - Rel. Exp.(%) Ag2505, Run 224116291 Column C - Rel. Exp.(%) Ag2667, Run 206955569 Column D - Rel. Exp.(%) Ag2767, Run 206985756 Column E - Rel. Exp.(%) Ag2831, Run 208699692 Column F - Rel. Exp.(%) Ag7237, Run 296423778 Tissue Name IAIBIC DJ E F 38.7 51.1 75.3 75.8 59.9 32.1 AD 2 Hippo 48.0 64.2 61.1 61.6 68.8 59.9 AD 3 Hippo 18.8. 30.4 21.8 21.3 7.9 28.7 AD 4ippo 34.6 32.8 30.8 76.8 21.9 38.2 37.1 39.2 30.4 32.5 25.5 36.6 AD 6 Hippo 100.0 97.3 62.4 100.0 59.0 100.0 Control 2 Hippo 26.8 33.4 5.8 35.6 7.2 19.2 CEontrol 4 Hip 98 52.1 27.0 40.3 49.03 83.5 Control (Path) 3ippo 16 21.8 570.8 12.9 25.0 AD 1 Tempora Ctx 48.6 58.2 61.1 36.9 _41.5 50.3 AD 2Tempral tx 45.1 42.9 56.3 45.7_ 100.0 56.6 AD 4 Temporal Ctx 503 66.0 j76.8 -37.4 44.4 56.3 AD 5 Inf Temporal Ctx 23.2 26.4 20.9 22.5 j 29.5 29.7 AD 5 Sup Temporal Ctx 42.6 43.8 16.6 19.6 45.4 50.7 AD 6 Inf Temporal Ctx 88.9 100.0 68.8 72.2 79.6 100.0 AD SupTemporal Ctx '0.2 7 64.6 448 46.3 82.4 Control 1 Temporal Ctx 16.7 16.3 44.8 31.6 9.2 7.5 Control 2 Temporal Ctx 16.7 1 23 41.2 219 24.5 Control 3 Temporal Ctx 7.2 12.8 1.6 1.8 6.3 25.3 Control 3 Temporal Ctx 19.8 43.2 25.5 58.6 43.8 [ 50.7 AH3 3975 206 40 332 32.3 16.5 25.0 AH3 3954 20.6 31.9 25.9 66.4 46.7 31.9 4.0 17.7 12.6 31.9 38.2 20.0 21.0 23.3 27.9 36.3 I16.2 30.8 AD 1 Occp t 31. 35.1 44.1 19 28.7 32.1 AD 2 Occipital Ctx singn) 5.2 4.8 27.9 30.8 31.4 8.7 AD 3 Occipital Ctx 16.7 23.3 .212.9 30.6 12.4 AD 4 Occipital Ctx 39.8 46.3 24.3 20.3 63.3 56.3 AD 5 Occipital Ctx 24.7 22.7 26.4 34.6 18.2 27.2 AD 5 Occipital Ctx 59.9 87.1 50.7 56.6 20.2 66.9 Control I Occipital Ctx 19.91 14.9 46.7 3.7 49.0 14.3 Control 2 Occipital Ctx 26.2 29.7 1.8 36.6 _15.9 39.0 Control 3 Occipital Ctx 15.3 44.4 11.8 11.7 20.2 Control 4 Occipital Ctx 34.2 33.7 35.1 47.6 64.2 Control (Path) 1 Occipital Ctx 25I 24.1 21.9 27.0 31.4 30.1 I Y~7 WO 2004/015079 PCT/US2003/024931 Control (Path) 2 Occipital Ctx 15.1 20.2 12.9 16.2 19.1 15.7 Control (Path) 3 Occipital Ctx 9.5 14.1 100.0 21.5 3.8 14.0 Control (Path) 4 Occipital Ctx 30.6 37.4 29.9 32.3 22.8 27.2 Control 1 Parietal Ctx 13.3 13.9 25.0 88.3 19.2 13.5 Control 2 Parietal Ctx 46.7 57.8 42.0 44.8 53.6 66.9 Control 3 Parietal Ctx 10.1 12.8 1.6 8.4 6.3. 12.9 Control (Path) I Parietal Ctx 24.5 29.3 17.0 23.3 33.2 31.6 Control (Path) 2 Parietal Ctx 28.3 35.4 55 .9 22.7 53.2 37.1 Control (Path) 3 Parietal Ctx 12.8 18.9 49.7 19.6 11.1 11.9 Control (Path) 4 Parietal Ctx 28.3 32.3 F44.1 j 28.7 49.0 33.9 Table EH. General_screening-panelv 1.6 Column A - 1el. Exp.(%) Ag7237, Run 296433071 Tissue Name A Tissue Name A Adipose 199 Renal ca. TK-10 2.4 Melanoma* Hs688(A).T 02 Bladder 192 Melanoma* Hs688(B).T 00 Gastric ca. (liver met.) NCI-N87 45.7 Melanoma* M14 0.0 Gastric ca. KATO 111 11.7 Melanoma* LOXIMVI 0.0 9.1 Melanoma* SK-MEL-5 00Colon ca. SW480 0.5 Squa mous cell carcinoma SCC-4 1.9 ;Colon ca.* (SW480 met) SW620 f0.0 Testis Pool 5.0 Colon ca. HT29 12.4 Prostate ca.* (bone met) PC-3 G03 Colon ca. HCT- 16 110.0 state Pool 144.1 Colon ca. CaCo-2 117.4 Placenta 1.0 Colon cancer tissue 5.9 Uterus Pool 2.0 Colon ca. SW4116 4.8 Ovarian ca. OVCAR-3 5.0 Colon ca. Colo-205 4.2 Ovarian ca. SK-OV-3 118.0 Colon ca. SW-48 10.1 Ovarian ca. OVCAR-4 0.0 Colon Pool u 5.9 Ovarian ca. OVCAR-5 4.7 Small Intestine Pool 6.3 Ovarian ca. IGROV-i 10.9 Pool 4.3 Ovarian ca. OVCAR-8 0.9 Bone Marrow Pool 6.4 Ovary 12.3 Fetal Heart 6.0 Breast ca. MCF-7 571.7 Heart Pool 4.5 Breast ca. MIDA-MB-231 0.Lymph Node Pool 18.0 Breast ca. BT 549 112.2 'Fetal Skeletal Muscle 112.8 Breast ca. T47D 6.2 Skeletal Muscle Pool 0.6 Breast ca. MDA-N 0.0 Spleen Pool 5.8 Breast Viol 7.7 Thymus Pool 6.9 Trachea 10.7 CNS cancer (glio/astro) U87-MG 0.0 Lung 24 CNS cancer (glio/astro) U-I 18-MG Fetal Lung 100.0 CNS cancer (neuro;met) SK-N-AS 0.1 .1 no WO 2004/015079 PCT/US2003/024931 Lung ca. NCI-N417 0.0 CNS cancer (astro) SF-539 1.7 Lung ca. LX-1 5.2 CNS cancer (astro) SNB-75 0.7 un .NI-1 7.9 CNS cancer (glio) SNB-19 12.7 Lung ca. SHP-77 0.7 CNS cancer (glio) SF-295 0.2 Lung ca. A549 0.7 Brain (Amygdala).Pool 3.0 Lung ca. NCI-H526 0.3 Brain (cerebellum) .

0.6 Lung ca. NCI-H23 4.5 Brain (fetal) 124.8 Lung ca. NCI-H460 0.5 Brain (Hippocampus) Pool 7.5 Lung ca. HOP-62 0.0 Cerebral Cortex Pool 3.7 Lung ca. NCI-H522 00 Brain (Substantia nigra) Pool 11.9 Liver 0.0 Brain (Thalamus) Pool 15.5 Fetal Liver 1.3 Brain (whole) 16.1 Liver ca. HepG2 2.7 Spinal Cord Pool 1.0 Kidney Pool 0.0 Adrenal Gland 3.1 Fetal Kidney 23.2 Pituitary gland Pool 5.8 Renal ca. 786-0 0.0 Salivary Gland 0.7 Renal ca. A498 0.0 Thyroid (female) 47.3 Renal ca. ACHN 47.6 Pancreatic ca. CAPAN2 4 0.7 Renal ca. UO-3 1 0.0 Pancreas Pool 9.6 Table El. PGI1.0 Column A -Rel. Exp.(%) Ag2505, Run 406107081 Tissue Name A Tissue Name A 162191 Normal Lung 1 (IBS) 9.2 162185 Emphysema Lung 12 (Ardais) 48.0 160468 MID lung 19.2 162184 Emphysema Lung13 (Ardais) 14.5 156629 MD Lung 13 7.9 162183 Emphysema Lung 14 (Ardais) 59.5 162570 Normal Lung 4 (Aastrand) 9.5Emphysema Lung 15 (Genoic 77.9 162571 Normal Lung 3 (Aastrand) 5.2 1162177 NAT UC Colon 1(Ardais) 4.8 162187 Fibrosis Lung 2 (Genomic 89.5 162176 UC Colon 1(Ardais) 2.3 Collaborative) 8 151281 Fibrosis lung 11(Ardais) 100.0 162179 NAT UC Colon 2(Ardais) 6.7 162186 Fibrosis Lung 1 (Genomic 79.0 162178 UC Colon 2(Ardais) 3.6 Collaborative) 162190 Asthma Lung 4 (Genomic 60.7 162181 NAT UC Colon 3(Ardais) 4.1 160467 Asthma Lung 13 (MD) 11.8 162180 UC Colon 3(Ardais) 1.8 137027 Emphysema Lung 1 (Ardais) 11.3 162182 NAT UC Colon 4 (Ardais) 7.5 137028 Em ysemaLung 2 dais) 11.7 37042 UC Colon 1108 1.2 137040 Emphysema Lung 3 (Ardais) 26.4 137029 UC Colon 8215 1.8 137041 Emphysema Lung 4 (Ardais) 23.7 137031 UC Colon 8217 1.4 137043 Emphysema Lung 5 (Ardais) 293 137036 UC Colon 1137 3.3 WO 2004/015079 PCT/US2003/024931 142817 Emphysema Lung 6 (Ardais) 48.0 137038 UC Colon 1491 2.7 142818 Emphysema Lung 7 (Ardais) 33.4 137039 UC Colon 1546 5.8 142819 Emphysema Lung 8 (Ardais) 50.3 162593 Crohn's 47751 (NDRI) 0.4 142820 Emphysema Lung 9 (Ardais) 9.5 162594 NAT Crohn's 47751 (NDRI) 1.9 142821 Emphysema Lung 10 27.4 (Ardais) Table EJ. Panel 1.3D Column A - Rel. Exp.(%) Ag2505, Run 165531061 Column B - Rel. Exp.(%) Ag2667, Run 162554578 Column C - Rel. Exp.(%) Ag2767, Run 165527179 Column D - Rel. Exp.(%) Ag2831, Run 165517578 Tissue Name A B C D Liver adenocarcinoma 1.8 0.0 0.0 1.3 13.7 8.9 35.4 14.1 Pancreatic ca. CAPAN 2 1.5 2.0 0.0 2.0 -de|| la.n3.6 2.9 2.8 4.6 Thyroid 100.0 52.5 100.0 67.8 Salivary gland Pituitary gland 37.6 9.9 18.7 19.8 Brain (fetal) 44.1 6.8 40.9 28.5 Brain (whole)0.6 11 0.0 Brain (amygdala) 8.1 4.4 8.2 2.6 Brain (cerebellum) 1.8 0.8 0.0 4.4 Brain (hippocampus) 10.2 1.6 6.4 2.2 Brain substantiala nigra) 29.3 3.7 12.5 11.0 Brain (thalamus) 3.6 1.9 8.7 7.2 Cerebral Cortex 7.7 8.8 3.8 1.3 Spinal cord 15.2 14.4 13.3 10.4 glio/astro U87-MG 0.0 0.0 0.0 0.0 glio/astro U-i 18-MG 0.0 0.0 0.0 0.0 astrocytoma SW1783 0.3 0.6 0.0 1.0 neuro*; met SK-N-AS 0.4 0.0 0.0 0.0 astrocytoma SF-539 1.8 1.2 2.5 1.2 astrocytoma SNB-75 2.7 0.6 0.0 2.0 glioma SNB-19 0.0 0.0 00 0.0 glioma U251 9.3 2.0 12.2 9.1 glioma SF-295 0.4 0.0 2.6 1.3 Heart (Fetal) 100 247 9.6 7.4 Heart 3.1 0.0 2A 2.4 Skeletal muscle (Fetal) 12.8 66.4 7.7 1.3 Skeletal muscle 20.9 ]2.1 7.5 13.1 WO 2004/015079 PCT/US2003/024931 Bone marrow 1:2 1.9 4.5 0.9 6.0 24.0 17.8 4.9 Spee1 6.7F 5.0 -19.81 9.2 Lymph node 6.7 1.4 2.6 Colorectal 23 19.3 6.5 9.9 Stomach - 120 1.8 4.5 2.5 Small intestine 4.3 13.3 .69.7 43.2 clnc.S401.1 05 .0 0.0 Colon ca.* SW620 (SW480 met) 1.4 0.0 2.8 3.1 Colon ca. HT29 _73 28.3 11.3 5.3 Colon ca. HCT-116 7.3 9.0 12.4 10.2 Colon ca. CaCo-2 10.7 29.7 19.6 11.1 CC Well to Mod Diff (OD03866) 8.5 14.6 10.6 10.6 Colon ca. HCC-2998 2.9 6.3 19. 2.9 Gastric ca. (liver met NCI-N87 71.7 -c49.7 95.3 100.0 Bladder 14.8 44.4 29.7 20.4 [rachea 13.9 18.6 5.5 Kidney 38.2 74.2 56.3 67.4 ey (fetal) 27.5 37.1 40.1 33.9 Renalca.786-0 0.0 0.0 0.0 0.0 R90.2 1.7 3.7 2.9 3en c XF 393 5.9 20.3 10.8 Renal a. ACHN 6.8 20.2 7.2 Renal ca. UO-31 0.2 0.0 0.0 0.0 lca. TK-10 0 0.0 0.0 0.0 Lir. 0.7 0.0 3.5 ver (fetal) 0.0 1.2 Liver ca. (hepatoblast) HepG2 11.8 4.7 19.5 10.8 Lung 75.3 46.0 91.4 84.1 Lung (fetal) 54.7 100.0 92.0 64.6 Lung ca. (small cell) LX-1 5.5 2.5 - 5.8 - 4.1 Lung ca. (small cell) NCI-H69 5.6 6.2 10.1 5.3 Lung ca. (s.cell var.) SHP-77 0.2 0.6 0.0 0.0 Lung ca. (large cell)NCI-H460 1.2 0.0 0.0 0.0 Lung ca. (non-sm. cell) A549 1.2 0.7 3.1 1.3 Lung ca. (non-s.cell) NCI-H23 3.2 4.7 8.2 4.5 Lung ca. (non-s.cell) HOP-62 00 0.0 00 0.0 Lung ca. (non-s.cl) NCI-H522 0.0 0.0 0 0 0 Lung ca. (squam.) SW 900 1.8 0.0 34 2.0 Lung ca. (squam.) NCI-11596 14.6 10.9 31.6 53.6 lyammary gland 11- j49 4.9 23.8 17.4 WO 2004/015079 PCT/US2003/024931 Breast ca.* (pl.ef) MCF-7 89.5 92.7 84.1 80.1 Breast ca.* (pl.ef) MDA-MB-231 0.0 .0.0 0.0 Breast ca.* (pl. ef) T47D 247 7.6 Breast ca. BT-549 23 0.0 1.2 Breast ca. MDA-N 0.0 10.0 0.0 0.0 Ovary -8 3.5 20.3 8.5 4.9 Ovarian ca. OVCAR-3 6.4 1 2.6 8.2 4.5 Ovarian ca. OVCAR-4 J0(10 OA) 0.0 0.0 Ovarian ca. OVCAR-5 0.0 C 0.0 0.0 0.0 Ovarian ca. OVCAR-8 0.2 1.0 0.0 0.0 Ovarian ca. IGROY-1 14.5 17.6 31.6 33.7 Ovarian ca. (ascites) SK-OV-3 9.3 5.4 '20.7 22.5 Uterus 27.7 3.5 39.0 46.3 Placenta 2.9 4.9 6.4 8.9 Prostate [ 25.0 8.8 16.7 16.7 Prostate ca.* (bone met) PC-3 0.0 0.0 0.0 0.0 Testis 2.5 0.7 4.4 2.7 Melanoma Hs688(A).T 0.0 0.0 f0.0 0.0 Melanoma* (met) Hs688(B).T 0.0 0.0 0.0 Melanoma UACC-62 0.0 0.0 0.0 0.0 Melanoma M14 0.0 0.0 0.0 0.0 Melanoma LOX IMVI 00 0.0 0.0 0.0 Melanoma* (met) SK-MEL-5 0.0 0.0 0.0 0 Adipose 19.3 .5 41 Table EK. Panel 2.2 Column A - Rel. Exp.(%) Ag2831, Run 175063921 Tissue Name IA - ~ Tissue Name - A Normal Colon -7Kidney Margin (0D04348), 100.0 Colon cAncer (0D067T4) 24.7 Kidney -malignant cancer (0D06204B) 0.0 Colon Margin (0D06064) 112.0 Kinynormal adjacent tissue. (D06204E).0 Colon cancer (0D06159) 1.1 Kidney Cancer (0D04450-01) 11.2 Colon Margin (0D06 159) 16.2 Kidney Margin (0D04450-03) 116.6 Colon cancer (0D06297-04) 11.9 jKidney Cancer 8120613 [1.8 Colon Margin (QD06297-05) 6.9 jKidney Margin 8120614 15.7 CC Gr.2 ascend colon (0D03921) __0.4 Kidney Cancer 9010320 [0.6 CC Margin (0D03921) 12.7 Kidney Margin 9010321 {2.6 Colon cancer metastasis (0D06104) 2.4 Kidney Cancer 8120607 46.2 Lung Margin (0D06 104) 10.2 Kidney Margin 81206082. ,Colon mets to lung (0D0445 1-0 1) 17.0 INormal Uterus I13.4 Lug ari (0D04451-02) 120.4,Uterine Cancer 064011 02. ^n0.0 WO 2004/015079 PCT/US2003/024931 Normal Prostate 4.9 Normal Thyroid 6.1 Prostate Cancer (OD04410) 5.9 IThyroid Cancer 28.5 Prostate Margin (OD04410) 8.3 IThyroid Cancer A302152 46.3 Normal Ovary 1.9|Thyroid Car 1.3 Ovarian cancer (OD06283-03) 1.2 Normal Breast 10.2 Ovarian Margin (OD06283-07) 3.6 Breast Cancer 1.5 Ovarian Cancer 7.8 Breast Cancer 4.6 Ovarian cancer (OD06145) 0.9 Breast Cancer (OD04590-01) 62.0 Ovarian Margin (OD06145) 10.9 Breast Cancer Mets (OD04590-03) 98.6 Ovaranancer OD064 0.0 Breast Cancer Metastasis 70.7 Ovarian Margin (OD06455-07) 7.3 Breast Cancer 3.6 Normal Lung__ 14.2 Breast Cancer 9100266 3.4 Invasive poor diff. lung adeno2.9 (ODO4945-01 Lung Margin (0D04945-03) 15.5 Breast Cancer A209073 1.7 Lung Malignant Cancer (OD03126) 4.2 Breast Margin A209073 2.5 Lung Margin (OD03126) 8.3 Breast cancer (0D06083) 497 Lung Cancer (OD05014A) 5 Breast cancer node metastasis __________jDD683) 14 Lung Margin (OD05014B) Lung cancer (OD06081) 3.8 Liver Cancer 1026 0.5 Lung Margin (OD06081) 376 Liver Cancer1025 1.8 Lung Cancer (0D04237-01) 1.6 Liver Cancer 6004-T 0.0 Lung Margin (OD04237-02) 33 Lv Tissue 6004-N 1.3 Ocular Mel Met to Liver (0D043 10) 0.0 Liver Cancer 6005-T 0.5 Liver Margin (0D143 10) 0B0 Liver Tissue 6005-N 1.4 Melanoma Metastasis 0.0 Liver Cancer 0.0 Lung Margin (0D04321) 37.9 Normal Bladder 2.8 Normal Kidney 5.5 Bladder Cancer 2.5 Kidney Ca, Nuclear grade 2 (0D04338) 26.6 Bladder Cancer 56.2 Kidney Margin (0D04338) 0.9 Normal Stomach 2.8 Kidney Ca Nuclear grade 1/2 2.0 Gastric Cancer 9060397 0.0 (OD04339) eettivr(DO30_00Lveace_05-_ . Kidney Margin (OD04339) 0v3eStomachMargin 9060396 11.4 Kidney Ca, Clear cell type (OD04340) 4.5 lGastric Cancer 9060395 2 Kidney Margin (OD04340) 12.6 Stomach Margin 9060394 4.1 Kidney Ca, Nuclear grade 3 (D04348) 1.4 Gastric Cancer 064005 5.7 Table EL. Panel 3D Column A -Rel. Exp.(%) Ag2831, Run 164843468 D issue Name (A ITissue NameA 92.0 Gaoyast Can 94Cer 060 WO 2004/015079 PCT/US2003/024931 Medulloblastoma/Cerebellum carcinoma (metastasis 94906 TE671 94955 ES-2 Ovarian clear cell 0.0 Medulloblastom/Cerebellum carcinoma 94907 D283 Med 6.7 94957 Ramos Stimulated with 0.0 Medulloblastoma/Cerebellum PMA/ionomycin 6h 94908 PFSK-1 Primitive 0.0 94958 Ramos Stimulated with 0.0 Neuroectodermal/Cerebellum PMA/ionomycin 14h 94909 XF-498 CNS 1.

2 94962 MEG-01 Chronic myelogenous 0.7 94909__XF-498 __CNS_1.2 j leukemia (megokaryoblast) 94910 SNB-78 CNS/glioma 1.7 94963 Raji Burkitt's lymphoma 0.0 94911 SF-268 CNS/glioblastoma 0.0 94964 Daudi Burkitt's lymphoma 0.0 94912 T98G Glioblastoma 0.0 U266 B-cell 0.0 plasmacytoma/myeloma 96776 SK-N-SH Neuroblastoma 0.0 94968 CA46 Burkitt's lymphoma 0.0 (metastasis) 94913 SF-295 CNS/glioblastoma 0.0 94970 RL non-Hodgkin's B-cell 0.0 9491 SF295CNSgliolasoma 0.0lymphoma 94972 JM1 pre-B-cell 0.0 94914 Cerebellum 0 lymphomalleukemia 96777 Cerebellum 0.0 94973 Jurkat T cell leukemia 0.0 94916 NCI-H292 Mucoepidermoid 23.7 94974 TF-i Erythroleukemia 0.0 lung carcinoma 94917 DMS-i 14 Small celllung dance 94975 HUT 78 T-cell lymphoma 0.0 94918 DMS-79 Small cell lung 1.1 94977 U937 Histiocytic lymphoma 0.0 cancer/neuroendocrine 94919 NCI-H146 Small cell lung 100.0 94980 KU-812 Myelogenous leukemia 0.6 cancer/neuroendocrine 94920 NCI-H526 Small cell lung 5.6 769-P- Clear cell renal carcinoma 3.2 cancer/neuroendocrine 94921 NCI-N417 Small cell lung .94983 Caki-2 Clear cell renal 0.8 cancer/neuroendocrine carcinoma 94923 NCI-H82 Small cell lung 00 94984 SW 839 Clear cell renal 0.9 cancer/neuroendocrine carcinoma 94924 NCI-H157 Squamous cell lung 00194986G401 Wilms' tumor 0.0 cancer (metastasis) ___ 0.0_9986_G01 ___________ 0. 94925 NCI-H1155 Large cell lung 14.6 94987 Hs766T Pancreatic carcinoma 0.0 cancer/neuroendocrine (LN metastasis) 94926 NCI-H1299 Large cell lung 94988 CAPAN-1 Pancreatic cancer/neuroendocrine 0.0 adenocarcinoma (liver metastasis) 0.0 94927 NCI-H727 Lung carcinoid 14.8 94989 SU86.86 Pancreatic carcinoma (liver metastasis) 0.0 94990 Bx.PC-3 Pancreatic 94928 NCI-UMC-11 Lung carcinoid 84.1 90 x inoma 0.0 -~ j adenocarcinoma 94929 LX-l Small cell lung canceri I.5 194991 HPAC Pancreatic . 9429 X 1 mal cel lug cacer 7.5adenocarcinoma WO 2004/015079 PCT/US2003/024931 94930 Colo-205 Colon cancer 18.7 94992 M A PaCa-2 Pancreatic 0.0 94935 W-48 olon aenrcacinom 94931 KM12 Colon cancer 66.4 94903 CFPAC-1 Pancreatic ductal 0.0 adenocarcmnoma 94932 KM2OL2 Colon cancer 8.4 94 PANC-1 Pancreatic epithelioid 0.6 ductal carcinoma 94933 NCI-H716 Colon cancer 23.2 94996 T24 Bladder carcinma 0.0 (transitional cell 94935 SW-48 Colon adenocarcinoma 63.7 5637- Bladder carcinoma 0.0 94936 SW1116 Colon adenocarcinoma 15.5 94998 HT-1197 Bladder carcinoma 3.2 94937 LS 174T Colon adenocarcinoma 62.9 4999 UM-UC-3 Bladder carcinma 0.0 (transitional cell) 94938 SW-948 Colon adenocarcinioma 2.7 95000 A204 Rhabdomyosarcoma 0.0 94939 SW-480 Colon adenocarcinoma 39.2 95001 HT-1080 Fibrosarcoma 0.0 94940 NCI-SNU-5 Gastric carcinoma 0.0 95002 MG-63 Osteosarcoma (bone) 0.0 95003 SK-LMS-1 Leiomyosarcoma 0.0 (vulva) 94943 NCI-SNU-16 Gastric carcinoma 0.0 95004 SJRH30 Rhabdomyosarcoma 27.7 (met to bone marrow) 94944 NCI-SNU-1 Gastric carcinoma 35.6 95005 A431 Epidermoid carcinoma 17.8 94946 RF-1 Gastric adenocarcinoma 0.0 '95007 WM266-4 Melanoma 0.0 -7 -8 GDU 145- Prostate carcinoma (brain 0.0 94947 RF-48 Gastric adenocarcinoma 0.7 metastasis) 96778 -KN-45 Gastric carcinoma 96.6 95012 MDA-MB-468 Breast adenocarcinoma 94949 SCC-4- Squamous cell carcinoma of 0.0 9NCI-N87 Gastric carcnoma 79.6 tongue 94951 OVCAR-5 Ovarian carcinoma 0.0 SCC-9- Squamous cell carcinoma of 0.0 94951_OVCAR-5_Ovariancarcinoma_ 0.0_ tongue .0SCC-15- Squamous cell carcinoma of 00 94952 RL95-2 Uterine carcinoma 00 tongue 0.0 94953 HelaS3 Cervical 0.0 195017 CAL 27 Squamous cell 1.2 adenocarcinoma Icarcinoma of tongue Table EM. Panel 5 Islet Column A -Rel. Exp.(%) Ag2505, Run 248045752 Tissue Name A Tissue Name A 97457 Paient-)2go adipose 32.3 94709 Donor 2 AM - A adipose 0.0 97476 Patient-07sk skeletal muscle 8.2 94710 Donor 2 AM - B adipose 0.0 97477 Patient-07ut uterus 31.4 94711 Donor 2 AM - C adipose 0.0 97478 Patient-07pl placenta 3.5 94712 Donor 2 AD - A adipose 0.0 99167 Bayer Patient 1 9.5_94713 Donor 2 AD -B adipose 0.0 97482 Patient-08ut uterus 90.1 94714 Donor 2 AD - C adipose 0.0 97483 Patient-08pl placenta 7.4 94742 Donor 3 U - A Mesenchymal 10.0 WO 2004/015079 PCT/US2003/024931 Stem Cells 94743 Donor 3 U - B Mesenchymal 97486 Patient-09sk skeletal muscle 1.4 Ste Cel 0.0 97487 Patient-09ut uterus 78.5 94730 Donor 3 AM - A adipose 0.0 97488 Patient-09pl placenta 0.6 94731 Donor 3 AM - B adipose 0.0 97492 Patient-10ut uterus 66.0 94732 Donor 3 AM - C adipose 0.2 97493 Patient-10p1 placenta 3.1 94733 Donor 3 AD - A adipose 0.0 97495 Patient-11go adipose 28.3 94734 Donor 3 AD - B adipose 0.0 97496 Patient-11sk skeletal muscle 5.8 94735 Donor 3 AD - C adipose 0.0 97497 Patient-1 lut uterus 35.4 77138 Liver HepG2untreated 21.2 97498 Patient-1 pl placenta 2.0 73556 Heart Cardiac stromal cells 0.0 ____________________ (primary) 97500 Patient-2go adipose 35.1, 81735 Small Intestine 36.9 97501 Patient-l2sk skeletal muscle 9.9 72409 Kidney Proximal Convoluted 4.6 Tubule 97502 Patient-l2ut uterus ~ 100.0182685 Small intestine Duodenum 27.0 97503 Patient-12pL placenta 4.1 90650 Adrenal Adrenocortical adenoma 0.3 94721 Donor 2 U - A Mesenchymal 10.0 72410 Kidney LRCE7. Stem Cells j _ _ _ _ _ 94722 Donor 2 U - B Mesenchymal 0.0 72411 Kidney LIRE 1. Stem CellsHeartCardiacstromalcells 94723 Donor 2 U - C Mesenchymal 0.j 33 trsUein mohmsl . IStem Cellsr cellsUl I Allcomprehensive panel-vl.( Summary: Ag2505/Ag2831 The highest expression of this gene was seen in bone from a rheumatoid arthritis patient (CT=27-29). While the gene showed ubiquitous expression, expression was clearly higher in bone, synovium, cartilage and synovial fluid from RA patients as compared to expression in 5 samples from OA patients, normal and diseased lung and therefore is useful for differentiating these disease states. Expression of this gene was modulated in Crohn's samples as compared to the corresponding control samples. This gene encodes a novel adhesion molecule which is homologous to mouse POEM (preosteoblast epidermal growth factor-like repeat protein with meprin)or nephronectin. Marine nephronectinfunctions in 10 multiple biological processes including development of the kidney (Miner JH. J Cell Biol 2001 Jul 23;154(2):257-9, PMID: 11470814) and bone (Morimura Net al., 2001, J. Biol. Chem. 2000 Nov 9;276(45):42172-42181, PMID: 11546798) and contribute to liver and lung fibrosis (Levine et al., 2000, Am J Pathol 2000 Jun;156(6):1927-35, PMID: 10854216). Therapeutic modulation of this gene, expressed protein and/or use of antibodies 15 or small molecule drugs targeting the gene or gene product are useful in the treatment of WO 2004/015079 PCT/US2003/024931 autoimmune and inflammatory diseases such as rheumatoid and osteoarthritis, Inflammatory bowel disease, COPD, asthma, psoriasis, liver and lung fibrosis. CNS_neurodegeneration_vL.O Summary: Ag2505/Ag2667/Ag2767/Ag2831/Ag7 2 37 This panel confirms the expression 5 of this gene at low levels in the brain in an independent group of individuals. This gene was found to be upregulated in the temporal cortex of Alzheimer's disease patients. This gene codes for a homolog of mouse POEM (Nephronectin short isoform), a cell adhesion molecule with EGF domains. Alpha secretase activity, which is generally believed to be a beneficial processing alternative to beta secretase, is increased by EGF in neuronal cells 10 (Slack BE, Breu J, Muchnicki L, Wurtman RJ, 1997, Biochem J 327 ( Pt 1):245-9). The increased expression of this gene reported here is a compensatory action in the brain to counter the mechanisms of Alzheimer's Disease. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of Alzheimer's disease and other neurodegenerative 15 diseases. EGF is also known to facilitate long term potentiation (LTP) in the hippocampus, a process thought to underlie learning and memory (Abe K, Ishiyama J, Saito H, 1992, Brain Res 593(2):335-8). Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in treating 20 disorders of memory, such as neurodegenerative diseases and aging, when used alone or incombination with other growth factors such as but not limited to bFGF. In addition, EGF supports the growth and differentiation of dopaminergic neurons (Storch A, Paul G, Csete M, Boehm BO, Carvey PM, Kupsch A, Schwarz J, 2001, Exp Neurol 170(2):317-25), which are selectively vulnerable to loss in Parkinson's disease. 25 Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in treating Parkinson's Disease. Generalscreening-panel_vl.6 Summary: Ag7237 Highest expression of this gene was detected in fetal lung (CT=27) and was higher in fetal (CTs=27-33) than in 30 corresponding adult lung, kidney, liver and skeletal muscle tissues (CT=32-40). The relative overexpression of this gene in fetal tissue suggests that the protein product may enhance growth or development of these tissues in the fetus and thus may also act in a regenerative capacity in the adult. Therapeutic modulation of this gene, expressed protein WO 2004/015079 PCT/US2003/024931 and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of lung, liver, kidney and muscle related diseases. Moderate to low levels of expression of this gene were also seen in cancer cell lines derived from squamous cell carcinoma, brain, colon, renal, lung, breast, and ovarian 5 cancers. Expression of this gene is useful as diagnostic marker for detection of these cancers or for differentiating cancerous from normal tissue. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of carcinomas including but not limited to: squamous cell carcinoma, brain, colon, renal, lung, breast, and ovarian cancers. 10 Moderate to low levels of expression of this gene was also seen in tissues with metabolic/endocrine functions and also in all the regions of brain. PGI1.O Summary: Ag2505 The highest expression of this gene was detected in a lung fibrosis sample (CT=22). This gene was upregulated in several lung fibrosis and emphysema samples, and also in one asthma sample. Therapeutic modulation of this-gene, 15 expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of lung diseases including fibrosis, emphysema, and asthma. Panel 1.3D Summary: Ag2505/Ag2667/Ag2767/Ag2831 Highest expression of this gene was detected in the thyroid and fetal lung (CTs=29-3 1). Moderate to low levels of 20 expression of this gene was also seen in other tissues with metabolic/endocrine functions, including skeletal muscle, fetal skeletal muscle, small intestine, stomach, pancreas, adipose and fetal heart. Very low levels were also seen in heart and placenta. Nephronectin is the ligand for the alpha8betal integrin. Integrins are known to mediate development and organogenesis. Nephronectin can bind integrins including alpha5beta3, alpha5beta5, 25 alpha5beta6 and alpha4beta7, but not alpha4betal, alpha3betal, alpha2betal or alphalbetal. Nephronectin interacts with integrins via the RGD sequence, but RGD alone is not sufficient for binding, the MAM domain is also required. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of disorders involving alpha8betal integrin 30 signaling including inflammatory diseases. Obesity has also been linked to inflammatory condition (Das UN, 2001, Nutrition 17(11-12):953-66, PMID: 11744348) and thus humanized antibodies are therapeutically relevant in treating this condition and related complications such as type II diabetes.

WO 2004/015079 PCT/US2003/024931 Panel 2.2 Summary: Ag2831 Highest expression of this gene was detected in kidney (CT=30.3). Expression of this gene was down regulated in kidney, lung and colon cancer as compared to the corresponding normal adjacent tissue. Conversely, increased expression of this gene was seen in breast cancer samples. Therefore, expression of this 5 gene may be used to distinguish between cancer and normal kidney, lung, colon and breast. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of kidney, lung, colon and breast cancer. Panel 3D Summary: Ag2831 Highest expression of this gene was detected in a 10 small cell lung cancer NCI-H146 cell line (CT=29.7). Moderate to low levels of expression of this gene was also seen in cancer cell lines derived from epidermoid carcinoma, rhabodomyosacoma, gastric, colon and small cell lung cancers. The expression of this gene can be used as diagnostic marker for detection of these cancers or for differentiating cancerous from normal tissue. Therapeutic modulation of this gene, expressed protein 15 and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of epidermoid carcinoma, rhabodomyosacoma, gastric, colon and small cell lung cancers. Panel 5 Islet Summary: Ag2505 The highest expression of this gene was detected in uterus (CT=30). Moderate expression of this gene was also seen in adipose and skeletal 20 muscle of gestational diabetic patients requiring and not requiring daily injections of insulin. This gene was also expressed in samples derived from pregnant and a nondiabetic, but overweight patient. In addition, this gene is also expressed in islet beta cells (those that are insulin producing) and small intestine. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product 25 are useful in the treatment of metabolically related diseases including obesity, Type I and Type II diabetes. F. NOV6, CG51923: FAT tumor suppressor homolog 2 Expression of gene NOV6a, 6m, 6n, CG51923 were assessed using the primer probe sets Ag395, Ag'706, Ag888, Ag944 and Ag945, described in Tables FA, FB, FC, FD 30 and FE. Results of the RTQ-PCR runs are shown in Tables FF and FG. Table FGA. Probe Name Ag395 Primers Sequences Length Start Position SEQ ID No WO 2004/015079 PCT/US2003/024931 Forward 5 -caggaagaaataagcca agtcca- 3 ' 23 13104 118 Probe TET-5'-tccttggcctcccgcctgc-3-TAMR 19 13084 119 Reverse 5'-gaggtcatgttctagcttcccatt- 3 24 13049 120 Table FB. Probe Name Ag706 Start SEQ ID Primers Sequences Length Position No Forward 5 -tatgtggagagcttcgagaaaa- 3 22 121 Probe TET-5-atctacctcgcggagccacagtg-3 23 191 122 -TAMRA Reverse 5'-agagatgatccggtacctcact- 3 ' 22 217 123 Table FC. Probe Name Ag888 Start SEQ ID Primers Sequences Length Position No Forward 5 1-caatgaccgcatetgaa-3' 20 11160 124 Probe TET-5'-aatgctccatctccttggetgagtga-3 - 26 11125 125 TAMRA - Reverse15l-ggagctagcatccatcatcac-3 21 11104 126 Table FD. Probe Name Ag944 .,.-- - e-"-"--r'., ineieieeei~iel."itS tart S E Q ID Primers Sequences Length Position No Fowad51-gccacaagacatt-'22 10296 127 Probe TET-5'-cagcaaagtcctgcagctgatcctg-3'- 25 10339 128 TAMRA Reverse 5' -cttggagaatctgggtcact- 3 21 10364 129 Table FE. Probe Name Ag945 Y Start SEQ ID Primers Sequences Length Sit No ____________________________Cfl Position No Foard 1 -ccaagtcatcattcatgtcaga- 3 ' 22 5581 130 Probe TET-5'tcccctcccagattctcagaacaga- 3 '~ 26 5614 131 Reverse 5-atggataggcccgactattg- 3 20 5652 132 5 Table FF. Panel 1.1 Column A - Rel. Exp.(%) Ag395, Run 109668522 Tissue N eA Tissue Name A Adrenal gland 0.1 Renal ca. UO-31 0.1 1.4 Renal ca. RXF 393 0.0 Bri aydl)01Lver 0.5 Brain (cerebellum) 1 (fetal) 0.5 Brain (hippocampus) ver ca. (hepatoblast) HepG2 0.0 Brain (substantia nigra) 1.2 Lung 0.1 Brain (thalamus) Lung (fetal) Cerebral Cortex 1.5 Lung ca. (non-s.cell) HOP-62 1.0 WO 2004/015079 PCT/US2003/024931 Brain (fetal) 0.9 Lung ca. (large cell)NCI-H460 0.8 Brain (whole) 4.5 Lung ca. (non-s.cell) NCI-H23 0.2 glio/astro U--118-M 0.1 Lung ca. (non-s.cl) NCI H522 0.7 astrocytoma SF-539 0.3 Lung ca. (non-sm. cell) A549 0.3 astrocytoma SNB-75 0.3 Lung ca. (s.cell var.) SHP-77 [0.2 astrocytoma SW1783 0.1 Lung ca. (small cell) LX-1 1.2 glioma U251 0.1 Lung ca. (small cell) NCI-H69 0.4 glioma SF-295 0.4 Lung ca. (squam.) SW 900 0.1 glioma SNB-19 0.1 Lung ca. (squam.) NCI-H596 0.5 glio/astro U87-MG 0.8 Lymph node 0.3 neuro*; met SK-N-AS 1.2 Spleen [0.1 Mammary gland 1.4 Thymus 1.1 Breast ca. BT-549 0.2 Ovary 0. _estca. MOA-N 0.7 Ovarian ca. IGROV-1 0.1 Breast ca.* (p]. ef) T47D 0.5 Ovarian ca. OVCAR-3 - 7.7 Breast ca.* (pl.ef) MCF-7 0.3 Ovarian ca. OVCAR-4 6.4_ Breast ca.* (pl.ef) MDA-MB-231 01 Ovarian ca. OVCAR-5 1.5 all intestine 0.6 Ovarian ca. OVCAR-8 0.5: Colorectal 0.2 Ovarian ca. (ascites) SK-OV-3 0.7 Colon ca. HT29 0.1 Pancreas 0.9 Colon ca. CaCo-2 1.0 Pancreatic ca. CAPAN 2 0.0 Colon ca. HCT-15 0.3 Pituitary gland 0.5 Colon ca. HCT-116 0.3 Placenta 0.6 Colon ca. HCC-2998 [1.1 Prostate 2.4 Colon ca. SW480 0.3 Prostate ca.* (bone met) PC-3 0.2 Colon ca.* SW620 (SW480 met) [1.0 Salivary gland [2.4 [oah0.3 Trachea 11.9 Gastric ca. (liver met) NCI-N87 0.5 Spinal cord 0.4 art T estis 2.0 Skeletal muscle (Fetal) 0.5 Thyroid [0.1 Skeletal muscle 0.8 Uterus 0.1 Endot-elial cells 0.2 Melanoma M14 0.4 Heart (Fetal) ' 0.0 Melanoma LOX IMVI 0.1 Kidney 0.7 Melanoma UACC-62 10.1 Kidney (fetal) -T 0.7 Melanoma SK-MEL-28 1.6 Renal ca. 786-0 10.1 Melanoma* (met) SK-MEL-5 0.1 Renal ca. A498 0.3 Melanoma Hs688(A).T 0.1 Renal ca. ACHN 0.3 Melanoma* (met) Hs688(B).T 0.1_ Renal ca. TK-10 0.5 Table FG. Panel 2D Column A - Rel. Exn.(%) A2395. Run 144794701 ,-I1 I WO 2004/015079 PCT/US2003/024931 Column B - Rel. Exp.(%) Ag888, Run 144791434 Column C - Rel. Exp.(%) Ag888, Run 145420466 Tissue Name A B C Tissue Name A B C Normal Colon 20.2 10.7 5.6 Kidney Margin 8120608 1.1 0.4 1.9 CC Well to Mod Diff6. 05 CC ellto8 od if 6.0 0.5 10.5 Kidney Cancer 8120613 0.9 0.0 0.4 CC Margin (OD03866) 5.8 0.0 0.0 Kidney Margin 8120614 2.0 0.0 0.3 CC Gr.2 rectosigmoid1. 07 (0D03868)toigroi 1.8 0.7 0.2 Kidney Cancer 9010320 13.1 2.4 0.9 (OD03868 CC Margin (OD03868) 19 0.6 0.7 Kidney Margin 9010321 11.5 2.3 3.1 CC Mod Diff (OD03920) 2.2 2.0 0.7 Normal Uterus 2 0 1 CC Margin (OD03920) 5.6 1.1 1 Uterine Cancer 064011 21.3 23.2 21.2 CC Gr.2 ascend colon 1.2 0.3 (OD03921) 1. - 0.3 I N CC Margin (OD03921) 0.9 0.8 7 Thyroid Cancer 25 3.2 1.5 CC from Partial Hepatectomy 0.9 0.7 0.2 Thyroid Cancer A302152 3:0 0.7 1.5 (OD04309) Mets Liver Margin (OD04309) 1.3 0.9 0.0 Thyroid Margin A302153 0.0 0.4 0.5 Colon mets to lung 2.2 0.7 0.4 Normal Breast (0D04451-01) Lung Margin (0D04451-02) 5.4 0.6 K neast Cancer 5.3 1.7 3.8 Breast Cancer Nonnal Prostate 6546-1 43.8 29.3 21.0 Kidey 10.8 1.2 1.2 __ __ _r7 1 Breast Cancer Mets Prostate Cancer (0D04410) 17.3 9.3 5.2 6.4 3.1 3.3 0.7tKidneyiMargin(D04590103) 0 Pr(0D04410) 12.2 Breast Cancer Metastasis 2.9 0.2 1.4 Prostate Cancer (0D04720- j41.2~ 37.9 41.2 Breast Cancer 13.1 13.7. 5.5 Prostate Margin e22.8 37.1 33.2 Breast Cancer 62.0 55.9 23.3 2.m78 4.5 3.0 Breast Cancer 9100266 10.0 22.4 14.4 Lung Met to Muscle 0.0 1.3 1.3 Breast Margin 9100265 12.9 36.6 28.5 Muscle Margin (0D04286) 66.0 24.0 16.7 Breast Cancer A209073 25.2 43.8 44.8 Lung Malignant Cancer 3.5 4. 2.4 Breast Margin A209073 61.1100.0 20.7 (0D03 126) __________ Lung T Margin (AD03126) 29 .8 15.4 0.0 0.4 Lung Cancer ((D04404) 146.0 1)0.0f30. river Cancer 12.6 1.0 0.0 Lung Margin (OD04404) 16.6 5.9 1.7 Liver Cancer 1025 1. 0.7 03 Lung Cancer (0D04565) 1100.0 65.5 100.0 Liver Cancer 1026 10.9 0.0 0.0 Lung Margin (D04565) 3.0 0.8 2.0 Liver Cancer 6004-T 9.7 0.0 0.0 Lung Cancer (D04237-01) .2 3.9 41.2 LiverTissue 6004-N 13.1 13.7 0.2 Lung Margin (D04237-02) 3 0.6 0.933.2 BLiver Cancer 6005- 62.0 50 .3 WO 2004/015079 PCT/US2003/024931 Ocular Mel Met to Liver 1 0 0 6005-N (ODO4310) 1.0 0.7 0.9 Liver Tissue 6 0.0 0.0 0.0 Liver Margin (ODO43 10) 0.0 0.0 0.0 Normal Bladder 9.0 2.5 3.1 Melanoma Metastasis 3.5 1.1 0.3 Bladder Cancer 2.4 0.4 0.3 Lung Margin (OD04321) 0.8 1.2 0.5 Bladder Cancer 21.8 33.4 11.9 Normal Kidney 11.3 10.3 3.0 Bladder Cancer 46.7 75.3 68.3 ____________________ - -(0D04718-01) 4. 536. Kidney Ca, Nuclear grade 2 6.3 2.3 2.4 Bladder Normal Adjacent 4.1 1.6 0.5 (OD04338) (OD04718-03) idney Margin (0D04338) 3.6 {3.4 1.4 Normal Ovary ~ 0.0 0.4 0.0 Kidney Ca Nuclear grade 1/2 23.8 4.5 3.3 Ovarian Cancer 65.1 91.4 50.3 (OD04339) Kidney Margin (OD04339) 15.0 5.8 5 5 Ovarian Cancer 33.0 17.9 10.8 ___________________ - - - 0D04768-07) 3. 791. Kidney Ca, Clear cell type 3.2 1.0 2.4 Ovary Margin 0.0 0.0 0.2 (OD04340) (OD04768-08) Kidney Margin (OD04340) 11.9 9.8 4.0 Normal Stomach 2.4 2.1 1.6 Kidney Ca, Nuclear grade 3 1.3 2.0 1.9 Gastric Cancer 9060358 1.5 0.7 0.0 (0D04348)0. 00 Kidney Margin (OD04348) 12.2 2.7 3.0 Stomach Margin 1.4 0.4 0.4 Kidney Cancer (OD04622- 4.9 2.5 4.8 Gastric Cancer 9060395 2.3 0.4 0.2 01) Kidney Margin (OD04622- 3.1 3.2 4.4 Stomach Margin 0.8 0.3 0.7 03) 9060394 Kidney Cancer (OD04450 01)y C0.5 1.6 0.1 Gastric Cancer 9060397 6.6 2.8 0.8 01) 1 Kidney Margin (OD04450- 7.4 3.0 0.8 Stomach Margin 0.0 0.0 0.2 03) 1 . 0 9060396 0 Kidney Cancer 8120607 J3.0 2.72 0.4 Gastric Cancer 064005 R4.5 1.5 10.3 Panel 1.1 Summary: Ag395 Highest expression of NOV6 was detected in cerebellum (CT=21). High to moderate levels of expression of this gene were also seen in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebral cortex, and spinal cord. This gene encodes 5 protocadherin Fat 2 protein, a homolog of the Drosophila tumor suppressor gene fat. Protocadherins are transmembrane glycoproteins belonging to the cadherin superfamily of molecules, which are involved in many biological processes such as cell adhesion, cytoskeletal organization and morphogenesis. Protocadherins generally exhibit only moderate adhesive activity and are highly expressed in the nervous system. FAT2 is unique 10 among the cadherin superfamily because it contains EGF domains together with the classical cadherin repeats (Nollet et al., 2000, J Mol Biol 299(3):551-72, PMID: WO 2004/015079 PCT/US2003/024931 10835267). Cadherins can act as axon guidance and cell adhesion proteins, specifically during development and in the response to injury (Ranscht B., 2000, Int. J. Dev. Neurosci. 18: 643-651, PMID: 10978842). Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product is 5 useful in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss. Moderate to high levels of expression of this gene was also seen in certain cancer 10 cell lines derived from gastric, colon, lung, renal, breast, ovarian, prostate, melanoma and brain. Therefore expression of this gene is useful in differentiating the cancer cells from normal counterparts. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule- drugs targeting the gene or gene product is useful in the treatment of gastric, colon, lung, renal, breast, ovarian, prostate, melanoma and brain 15 cancers. Among tissues with metabolic or endocrine function, this gene was expressed at high to moderate levels in pancreas, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product 20 is useful in the treatment of endocrine/metabolically related diseases, such as obesity obesity, diabetes, hypercholesterolemia and hypertension. Panel 2D Summary: Ag395/Ag888 Highest expression of the CG51923-01 gene was detected in two lung cancer cell lines and a control breast sample (CTs=29-32). Moderate expression of this gene was also seen in samples derived from ovarian, bladder, 25 breast, uterine, lung, and prostate cancers. Expression of this gene was higher in ovarian, bladder and lung cancers as compared to their corresponding control samples. Therefore, expression of this gene can be used to differentiate these cancers from the normal tissue counterparts. Furthermore, therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product is useful in the 30 treatment of ovarian, bladder, breast, uterine, lung, and prostate cancers. G. NOV7 CG52919: secreted sushi and CUB sez-6 WO 2004/015079 PCT/US2003/024931 Expression of gene CG52919-06 was assessed using the primer-probe set Ag90, described in Table GA. Results of the RTQ-PCR runs are shown in Table HB. Table GA. Probe Name Ag90 Start SEQ ID Sequences Length Position No Forward 5 -ttggcctggactgcttcttc- 3 ' 20 824 133 Probe TET-5' -catctctgtctacCctggCtatggcgtg- 3 '- 28 846 134 TAMRA Reverse 5'-aggctgatattctggaccttgatt-3 24 876 135 Table GB. Panel 1 Colum A - Re]. Exp.(%) Ag90, Run 87586258 Tissue Name A Tissue Name A Endothelial cells 0.0 Renal ca. 786-0 0.0 Endothelial cells (treated) 0 Renal ca. A498 10.0 Pancreas 0.1 Renal ca.RX393 0.0 Pancreatic ca. CAPAN 2 0.0 Renal ca. ACHN 0.0 Adrenal gland 10.0 Renal ca. UO-31 1. Tyod0.0 Renal ca. TK-10 0o.0 Salivary gland 0.0 Liver 0.0 Pituitary gland 0.0 Liver (fetal) 0.0 Brain (fetal) f37.1 Liver ca. (hejpatoblast) HepG2 0.0 Brain (whole) 22.5 Lung 0.0 Brain (amygdala) 24 Lung (fetal) 0.0 Brain (cerebellum) 100.0 Lung ca. (small cell) LX-1 0.0 Brain (hippocampus) 29.5 Lung ca. (small cell) NCI-H69 33.7 Brain (substantia nigra) 7.6 Lung ca. (s.cell var.) SBP-77 10.0 Brain (thalamus) 13.7 Lung ca. (large cell)NCI-H460 0.0 Brain (hypothalamus) 7.7 Lung ca. (non-sm. cell) A549 0.0 Spinal cord 1.4 Lung ca. (non-s.cell) NCI-H23 0.0 glio/astro U87-MG 0.0 Lung ca. (non-s.cell) HOP-62 0.0 gilo/astro U-118-MG 0.0 Lung ca. (non-s.cl) NCI-H522 0.0 astrocytoma SW1783 0.0 Lung ca. (squam.) SW 900 0.0 neuro*; met SK-N-AS .4 Lung ca. (squam.) NCI-H596 20.0 astrocytoma SF-539 0.0 Mammary gland 0.1 astrocytoma SNB-75 0.0 Breast ca.* (pl.ef) MCF-7 0.0 glioma SNB-19 1.8 Breast ca.* (pl.ef) MDA-MB-231 0.0 glioma U251 0.4 Breast ca.* (pl. ef) T47D 0.0 glioma SF-295 0.0 Breast ca. BT-549 0.0 Heart 0.0 Breast ca. MDA-N 0.0 Skeletal muscle 0.0 Ovary 0.0 Bone marrow 0.0 Ovarian ca. OVCAR-3 0.0 WO 2004/015079 PCT/US2003/024931 Thymus 0.1 Ovarian ca. OVCAR-4 0.0 Spleen 0.0 Ovarian ca. OVCAR-5 0.0 Lymph node 0.0 Ovarian ca. OVCAR-8 0.0 Colon (ascending) 0.1 Ovarian ca. IGROV-1 0.0 omac 0.1 ovarian ca. (ascites) SK-OV-3 0.0 nal estine 0.3 s 0.0 Colon ca.VS480 0.0 Placenta 10.0 Colon ca.* SW620 (SW480 met) 0.0 Prostate 0.0 Colon ca. HT29 .0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-1 16 0.0 Testis 1.3 Colon ca. CaCo-2 0.0 Melanoma Hs688(A).T 0.0 Colon ca. HCT-15 0.0 Melanoma* (met) Hs688(B).T 0.0 Colon ca. HCC-2998 0.0 Melanoma UACC-62 0.0 Gastric ca. (liver met) NCI-N87 0.0 Melanoma M14 0.0 Bladder 0.0 Melanoma LOX IMVI 0.0 0F 0 Melanoma* (met) SK-MEL-5 0.0 d 0.0 IMelanoma SK-MEL-28 0.0 Kidney (fetal) 0 0 Panel 1 Summary: Ag90 Highest expression of this gene was detected in brain cerebellum (CT=25). High expression of this gene was seen in all the regions of brain including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. In addition, moderate levels of expression of this gene were also seen in 5 two lung cancer cell lines and a glioma cell line. Differential NOV7 gene expression is useful for differentiating lung and glioma cancerous tissues or cells from normal counterparts. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's 10 disease, epilepsy, multiple sclerosis, schizophrenia, depression, lung and brain cancers. H. NOV8 CG94946: agrin precursor Expression of gene CG94946-01 was assessed using the primer-probe sets Ag3605 and Ag3974, described in Tables HA and BB. Results of the RTQ-PCR runs are shown in Tables HC and HD. 15 Table HA. Probe Name Ag3605 Start SEQ ID Primers Sequences Length Position No Forward 5' accaagte actgtte-3 21 3514 137 WO 2004/015079 PCT/US2003/024931 Poe TET-5-ttgagagcaccctggacgacctctt-26 3518 IProbe TL 26 3553 .3 TAMRA Reverse 5'-gaaatccttcttgacgtctgaa-3 22 3585 139 Table HB. Probe Name Ag3974 Start SEQ ID Primers Sequences Length Position No Forward 5 '-gacaccaggatcttctttgtga-3' 22 379 :140 Probe TET-5 -catacctgtggccagcccacaag- 3 ' TAMRAI everse 5,-gttgagcatcagtgtt-3' 20 436142 Table HC. Generalscreening-panel-vl.4 Column A - Rel. Exp.(%) Ag3605, Run 213406184 Column B - Rel. Exp.(%) Ag3974, Run 217508632 Tissue Name A B Tissue Name A B Adipose 1.4 1.5 Renal ca. TK-10 19.3 16.4 Melanoma* Hs688(A).T 2.6 3.2 Bladder 8.4 9.0 Melanoma* Hs688(B).T 4.6 4.2 Gastric ca. (liver met.) NCI-N87 87.7 80.7 Melanoma* M14 6.7 6.4 Gastric ca. KATO III 17.8 17.7 Melanoma* LOXIMVI 4.8 4.0 Colon ca. SW-948 9.2 7.8 Melanoma* SK-MEL-5 2.6 4.2 Colon ca. SW480 25.032.3 Squamous cell carcinoma SCC-4 9.0 8.4 Colon ca.* (SW480 met) SW620 5.0 4.6 Testis Pool 1.3 1.1 Colon ca. HT29 Prostate ca.* (bone met) PC-3 21.0 24.8 Colon c_ 1 4.9 58 Prostate Pool 0.9 0.8 Colon ca. CaCo-2 13.6104 Placenta 0.9 1.3 Colon cancer tissue 10.210.0 Uterus Pool 0.4 0.4 Colon ca. SW 16 5. 16 Ovarian ca. OVCAV-3 77. 66.: 9 Colon ca. Colo-20 1._ . Ovarian ca. OV -3 4277.4 66.9 Colon ca. SW-948 1.2 7 O4.a Colon Pool W8 2 .3 Ova1 3 .1 Small Intestine Pool 0.6 1.0 22. Stomach Pool 5.8 0.8 Bone Marrow Pool .6 0.4 1. oo Fetal Heart 1.4 1.0 Breast ca. MCF-7 17.7 6.9 Heart Pool 0.7 j0.

8 Breast ca. MDA-MB-231 122 31.2 Lymph Node Pool 21 1.3 Breast ca. BT 549 13.2110.1 Fetal Skeletal Muscle 0.9 . Breast ca. T47D -18.0 14.9 oSkletal Muscle Pool 0.4 0.5 Breast ca. MDA-N 4.8 4.2 Spleen Pool 0.7 0.7 Brest Pool 1.6 1.6 Thymus Pool _1.812.2 Trachea 2.8 2.6 CNS cancer (glio/astro) U87-MG 5.9 16.0 Lung 0.2 0.1 ICNS cancer (glio/astro) U-118-MG 11.7111.2 Fetal Lung 11.4 8.3 CNS cancer (neuro;met) SK-N-AS 1.2 0.9 WO 2004/015079 PCT/US2003/024931 Lung ca. NCI-N417 1.4 0.7 CNS cancer (astro) SF-539 6.7 5.0 Lung ca. LX-1 10.5 11.0 CNS cancer (astro) SNB-75 22.8 32.3 Lung ca. NCI-H146 0.1 0.1 CNS cancer (glio) SNB-19 25.0 20.2 Lung ca. SHP-77 1.1 0.8 CNS cancer (glio) SF-295 35.1 38.2 Lung ca. A549 15.6110.4 Brain (Amygdala) Pool J1.7 1.3 Lung ca. NCI-H526 5.4 1.6 Brain (cerebellum) 1.4 1.0. Lung ca. NCI-H23 18.9 0.6 Brain (fetal) 7.02.8 Lung ca. NCI-H460 11.5 9.3 Brain (Hippocampus) Pool 11.6 10.9 Lung ca. HOP-62 123.7 23.0 Cerebral Cortex Pool 1.9 0.9 Lung ca. NCI-H522 1.8 2.3 Brain (Substantia nigra) Pool 2.8 1.7 Liver 0.5 0.6 Brain (Thalamus) Pool 2.7 1.6 Fetal Liver 0.8 1.4 Brain (whole) 3.411.1 Liver ca. HepG2 15.5 12.6 Spinal Cord Pool 1.8 1.4 Kidney 1.5 2.5 Adrenal Gland 0.2 0.4 Fetal Kidney 5.8 4.6 Pituitary gland Pool 0.3 0.2 Renal ca. 786-0 46.3 39.5 Salivary Gland 1.111.3 Renal ca. A498 13.8 7.9 Thyroid (female) 3137 Renal ca. ACHN 14.3 15.9 Pancreatic ca. CAPAN2 23.7 27.7 Renal ca. UO-31 41.5 38.7 Pancreas Pool 3.014.1 Table HD. Panel 4.1D Column A - Rel. Exp.(%) Ag3605, Run 169943454 Column B - Rel. Exp.(%) Ag3974, Run 170739806 Tissue Name A B Tissue Name A B Secondary Th1 act 1.0 1.2 HUVCIL-lbeta 1 18.9 Secondary Th2 act 5.1 8.0 HUVEC IFN gamma 12.9 16.7 Secondary Tr1 act 2.5 3.5 HUVEC TNF alpha + IFN gamma 37.6134.9 Secondary Th1 rest 10.0 0.7 HUVEC TNF alpha + IL4 131.4131.4 Secondary Th2rest 0.4 0.2 HUVEC IL-11 14.9113.9 Secondary Tr1 rest 0.4 1.2 Lung Microvascular EC none 79.0 100.0 Lung Microvascular BC TN~alpha + Primary Th1 act 3.6 3.2 L-1bea 00.0 97.9 IL-ibeta Primary Th2 act 1.1 2. Microvascular Dermal EC none 49.7 48.3 Primary n act 34 2.9 Microsvasular Dermal EC TNFalpha +5664. Primary Tr actIL-beta Primary Th et0904Bronchial epithelium TNFalpha + 78.5 90.1 Thi rst 0. 0.4 Llbeta Primary Th2 rest 0.5 .2 Small airway epithelium none 31.0 32.5 PrimaryTn rest0.2 0.3Small airway epithelium TNFalpha + 8189. Primary Th2 rest 0203I-bt 189. acD4RA CD4 lymphocyte 43.5 22.7 Coronery artery S EC rest 17.2 28.5 3D5R y t . 2.9 Mcrosartery SMC TNFalpha + iL- 22.2028.7 WO 2004/015079 PCT/US2003/024931 act 1betaE CD8 lymphocyte act 3.9 3.3 Astrocytes rest Secondary CD8 lymphocyte 3.7 3.3 Astrocytes TNFalpha + IL-1beta 82.9 66.4 rest Secondary CD8 lymphocyte 3.3 3.5 KU-812 (Basophil) rest 2.6 1.9 act CD4 lymphocyte none 0.3 0.1 KU-812 (Basophil) PMA/ionomycin 0.6 2.8 2ry Thl/Th2/Tr1 anti-CD95 0.3 0.4 CCD1106 (Keratinocytes) none 70.7 82.4 CH11_-_-_ LAK cells rest 6.4 (Keratinocytes) TNFalpha + 77.4 72.7 LAK ellsres 5 06.4IL-1beta LAK cells IL-2 2.8 1.7 Liver cirrhosis 13.2 14.4 LAK cells IL-2+]L-12 1.4 L8 NCI-H292 none 57.8 54.0 LAK cells IL-2+IFN gamma 2.311.1 NCI-H292 IL-4 62.4 78.5 L cellslM-2+IL-18 2.9 1.6 NCI-H292 IL-9 61.6 79.6 LAK cells PMA/ionomycin 6.8 4.6 NCI-11292 IL-13 53.6 59 NK Cells LL-2 rest 1161 1.9 NCI-Hl292 IFN gamma 67.4 71.7 Two Way MER 3 day 10( 12.4 HPAEC none 21.5 21.3 Two Way 1LR 5 day 6.5 5.3 |PAEC TNF alpha + IL-1 beta 37.6 45.4 Two Way MLR 7 day 4.3 4.0 Lung fibroblast none 22.4 29.3 PBMC rest 0.0 0.6 Lung fibroblast TNF alpha + IL-i beta 71.2 87.7 3 5.0 4.9 Lung fibroblast IL-4 16.2 23.3 PBMC PIIA-L 5.5 3.4 Lung fibroblast IL-9 31.9 30.4 Ramos (B cell) none 0.4 04 Lung fibroblast IL-13 18.7 36.6 Ramos(B cell) ionomycin 0.2 0.2 Lung fibroblast IFN gamma 23.0 29.7 B lymphocytes PWM 3.0 Dermal fibroblast CCD1070 rest 15.9 27.2 B lymphocytes CD40L and 1.5 3.7 Dermal fibroblast CCD 1070 TNF 15.9 20.6 IL-4 Ialpha OL-1 dbcAMP 3.4 3.1 Dermal fibroblast CCD1070 IL-1 beta 17.2 22.4. EOL-1 dbcAMP 18.3 8.0 Dermal fibroblast IFN gamma 7.2 10.3 PMA/ionomycin Dendritic cells none 14.8 9.0 Dermal fibroblast IL-4 7.2 8.0 Dendritic cells LPS 48.3 32.8 Dermal Fibroblasts rest 4.3 6.3 Dendritic cells antiCD4O 9.7 8.8 Neutrophils TNFa+LPS 0.0 0.9 Monocytes rest 0.9 1.4 Neutrophils rest 0.2 1.0 Monocytes LPS 66.4 81.2 Colon 7.0 5.8 Macrophages rest 16.2 9.7 Lung 23 Macrophages LPS 5 43.8Thymus 5. HUVEC none ~ 9.3 12.6 Kidney2323. HUVEC starved 14.4125.2 General-screening-panel-vl.4 Summary: Ag3605/Ag3974 The highest expression of the CG94946-01 gene was detected in breast cancer cell line T47D WO 2004/015079 PCT/US2003/024931 (CTs=22.5-25.3). In addition, there was substantial expression in other samples derived from breast, ovarian cancer, renal, lung, colon and brain cancer cell lines. Thus, the expression of this gene is useful as a marker for cancer and for differentiating cancerous from normal tissues or cells. Therapeutic modulation of this gene, expressed protein and/or 5 use of antibodies or small molecule drugs targeting the gene or gene product is in the treatment of breast, ovarian, kidney, lung, colon and brain cancer. Among metabolic tissues, this gene showed low-to-moderate levels of expression in adrenal, pituitary, adult and fetal heart, adult and fetal liver, adult and fetal skeletal muscle, and adipose. High expression of this gene was detected (CT values = 27) in pancreas and thyroid. Decreased 10 glomerular expression of agrin has been observed in diabetic nephropathy (Yard BA, Exp. Nephrol 2001;9(3):214-22 ). Thus, this gene product is useful for the differentiation, diagnosis and treatment of metabolic and endocrine diseases, including obesity, Types 1 and 2 diabetes and thyroidopathies. This gene was expressed at moderate levels in all regions of the central nervous system examined, including amygdala, hippocampus, 15 substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression. 20 Panel 4.1D Summary: Ag3605/Ag3974 Highest expression of NOV9 was detected in lung microvascular endothelial cells (CTs=27.3-28.5), microvascular dermal endothelial cells, mucoepidermoid cell line NCI-H292, astrocytes, and keratinocytes. Thus therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product are useful in the treatment of 25 symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis. Example D: Gene Expression analysis using CuraChip in human tissues from 30 tumors and from equivalent normal tissues Background: CuraGen has developed a gene microarray (CuraChip 1.2) for target identification. It provides a high-throughput means of global mRNA expression analyses of WO 2004/015079 PCT/US2003/024931 CuraGen's collection of cDNA sequences representing the Pharmaceutically Tractable Genome (PTG). This sequence set includes genes which can be developed into protein therapeutics, or used to develop antibody or small molecule therapeutics. CuraChip 1.2 contains -11,000 oligos representing approximately 8,500 gene loci, including (but not 5 restricted to) kinases, ion channels, G-protein coupled receptors (GPCRs), nuclear hormone receptors, proteases, transporters, metabolic enzymes, hormones, growth factors, chemokines, cytokines, complement and coagulation factors, and cell surface receptors. The CuraChip eDNAs were represented as 30-mer oligodeoxyribonucleotides 10 (oligos) on a glass microchip. Hybridization methods using the longer CuraChip oligos are more specific compared to methods using 25-mer oligos. CuraChip oligos were synthesized with a linker, purified to remove truncated oligos (which can influence hybridization strength and specificity), and spotted on a glass slide. Oligo-dT primers were used to generate cRNA probes for hybridization from samples of interest. A biotin-avidin 15 conjugation system was used to detect hybridized probes with a fluorophore-labeled secondary antibody. Gene expression was analyzed using clustering and correlation bioinformatics tools such as Spotfire@ (Spotfire, Inc., 212 Elm Street, Somerville, MA 02144) and statistical tools such as multivariate analysis (MVA). 20 Expression analysis of NOVI, CG121992-01 using PTG Chip 1.2: Approximately 234 samples of RNA from tissues obtained from surgically dissected disease- and non-disease tissues, and treated and untreated cell lines, were used to generate labelled nucleic acid which was hybridized to PTG Chip 1.2. An oligo (optg21002018, 25 TTGGAGAGATGAGCTGTATCACCTGCAGAT (SEQ ID NO:143)) that corresponds to CG121992-01 on the PTG Chip 1.2 was analyzed for its expression profile. Signal Definition value G1 C4D21 B11-01 _Lung cancer(35C) 18.72 G1C4D21B11-02_-Lung NAT(36A) 27.29 G1C4D21B1 1-03-Lung cancer(35E) 150.11 G1 C4D21 B1 1-04-Lung cancer(365) 47.21 G 1 C4D21 B 1-05_Lung cancer(368) 46.04 G1 C4D21 B1 1-06_Lung cancer(369) 33.28 WO 2004/015079 PCT/US2003/024931 G1 C4D21 B 1-07_Lung cancer(36E) 20.46 G1C4D21B1 1-08_Lung NAT(36F) 121.31 G1 C4D21 B 1-09--Lung cancer(370) 57.42 G1 C4D21 B 1-1 0_Lung cancer(376) 24.03 Gi C4D21 B 1-11 Lung cancer(378) 16.67 G1 C4D21 B1 1-1 2_Lung cancer(37A) 12.85 GlC4D21B11-13_Normal Lung 4 61.34 GIC4D21B11-14_Normal Lung 5 99.72 G1C4D21B11-16_5.Melanoma 52.01 G1C4D21B11-17_6.Melanoma 71.46 G1C4D21B1 1-18_Melanoma (19585) 28.82 G1C4D21B11-19_Normal Lung 1 38.72 G1C4D21B1 1-20_Lung cancer(372) 34.2 G1C4D21B11-21 _Lung NAT(35D) 73.14 G1C4D21 B1 1-22_Lung NAT(361) 20.95 G1C4D21B11-23_1.Melanoma 42.94 G1C4D21B11-24_Normal Lung 2 56.04 G1 C4D21 B 1-25_Lung cancer(374) 76.78 G1C4D21B1 1-26_Lung cancer(36B) 12.72 G1 C4D21 B 1-27_Lung cancer(362) 51.13 G1 C4D21 Bi 1 -28_Lung cancer(358) 101.83 G1C4D21B11-29_2.Melanoma 57.33 G1 C4D21 B 1-30_Normal Lung 3 42.9 G1 C4D21 B 1-31_Lung NAT(375) 87.42 G1 C4D21 B11-32_Lung cancer(36D) 23.39 G1 C4D21 B 1-33_Lung NAT(363) 26.15 G1 C4D2i Bi 1 -34-Lung cancer(35A) 35.39 G1C4D21B11-35_4.Melanoma 92.98 GiC4EO9B12-54_Prostate cancer(B8B) 115.79 G1 C4EO9B 2-55_Prostate cancer(B88) 66.13 G1C4EO9B12-56_Prostate NAT(B93) 129.17 G1C4E09B12-57-Prostate cancer(B8C) 133.03 G1C4EO9B12-58-Prostate cancer(AD5) 80.36 G1C4E09B12-59_Prostate NAT(AD6) 121.97 Gi C4EO9B1 2-60_Prostate cancer(AD7) 65.73 G 1 C4EO9B1 2-61 Prostate NAT(AD8) 91.17 G1C4EO9B12-62_Prostate cancer(ADA) 242.14 GIC4EO9B12-63_Prostate NAT(AD9) 151.25 WO 2004/015079 PCT/US2003/024931 G1 C4E09B12-64_Prostate cancer(9E7) 5.51 G1 C4EO9B12-65_Prostate NAT(AOB) 92.72 G1 C4EO9B1 2-66_Prostate cancer(AOA) 75.96 G1C4E09B12-67_Prostate cancer(9E2) 18.05 G1C4EO9B12-68_Pancreatic cancer(9E4) 55.06 G1 C4E09B12-69_Pancreatic cancer(9D8) 5.02 G1 C4E09B12-70_Pancreatic cancer(9D4) 9.04 G1C4EO9B12-71_Pancreatic cancer(9BE) 38.09 G1 C4EO9B1 2-73_Pancreatic NAT(ADB) 172.23 G1 C4EO9B1 2-74_Pancreatic NAT(ADC) 327.48 G1C4EO9B12-76_Pancreatic NAT(ADD) 103.04 G1C4EO9B12-77_Pancreatic NAT(AED) 31.82 G1 C4E1 9B1 3-10_Colon NAT(8B6) 53.85 G1 C4E1 9B1 3-12_Colon NAT(9F1) 61.04 G1C4E19B13-13_Colon cancer(9F2) 31.11 G1C4E19B13-14_Colon NAT(A1D) 122.69 G1 C4E19B13-15_Colon cancer(9DB) 0 GI C4E1 9B1 3-16_Colon NAT(A1 5) 78.49 G1 C4E1 9B1 3-17_Colon cancer(A1 4) 23.69 G1 C4E1 9B1 3-18_Colon NAT(ACB) 57.87 G1 C4E1 9B1 3-19_Colon cancer(ACO) 19.08 G1C4E19B13-2_Colon cancer(8A4) 94.14 G1C4E19B13-20_Colon NAT(ACD) 58.43 G1C4E19B13-21_Colon cancer(AC4) 17.46 G1C4E19B13-22_Colon NAT(AC2) 17.37 G1C4E19B13-23_Colon cancer(AC1) 24.09 G 1 C4E1 9B1 3-24_Colon NAT(ACC) 31.75 G1 C4E1 9B1 3-25_Colon cancer(AC3) 12.67 G1C4E19B13-26_Breast cancer(9B7) 841.73 G1C4E19B13-27_Breast NAT(9CF) 33.19 G1 C4E1 9B1 3-28_Breast cancer(9B6) 453.74 G1 C4E1 9B1 3-29-Breast cancer(9C7) 5.87 G1C4E19B13-3_Colon cancer(8A6) 23.75 G1C4E19B13-30_Breast NAT(A11) 187.73 Gi C4E1 9B1 3-31_Breast cancer(A1A) 52.65 G1C4E19B13-32_Breast cancer(9F3) 56.05 G1C4E19B13-33_Breast cancer(9B8) 13.06 G1C4E19B13-34_Breast NAT(9C4) 184.99 'V)2 WO 2004/015079 PCT/US2003/024931 G1 C4E1 9B1 3-35.Breast cancer(9EF) 139.47 G1C4E19B1 3-36_Breast cancer(9F0) 32.54 G1C4E19B1 3-37_Breast cancer(9B4) 77.88 G1C4E19B13-38_Breast cancer(9EC) 36.65 G1C4E19B13-4_Colon cancer(8A7) 5.41 G1C4E19B13-44_Colon cancer(8B7) 47.59 G1C4E19B13-5_Colon cancer(8A9) 12.73 G1C4E19B13-6_Colon cancer(8AB) 50.86 Gi C4E1 9B1 3-7_Colon cancer(8AC) 9.22 G1C4E19B13-8_Colon NAT(8AD) 97.98 Gi C4E1 9B1 3-9_Colon cancer(8B5) 43.83 G1C4E21B14-1_Cervical cancer(B08) 0 Gi C4E21 B1 4-10_Brain cancer(9F8) 0 G1 C4E21 B14-11 _Brain cancer(9CO) 0 G1 C4E21B14-12_Brain cancer(9F7) 0 G1C4E21B14-13_Brain cancer(AOO) 0 G1C4E21B14-14_Brain NAT(AO1) 0 G1C4E21B14-15_Brain cancer(9DA) 0 G1 C4E21 B1 4-16_Brain cancer(9FE) 0 G1C4E21B14-17_Brain cancer(9C6) 0 G1C4E21B14-18_Brain cancer(9F6) 0 G1C4E21B14-2_Cervical NAT(AEB) 0 G1 C4E21 B1 4-21._Bladder NAT(23954) 0 G1 C4E21 B1 4-22_Urinary cancer(AF6) 0 G1 C4E21 B1 4-23_Urinary cancer(BOC) 0 G1 C4E21 B1 4-24_Urinary cancer(AE4) 0 G1C4E21B14-25_Urinary NAT(B20) 0 G1 C4E21 B1 4-26-Urinary cancer(AE6) 0 G1 C4E21 B1 4-27-Urinary NAT(B04) 0 G1C4E21B14-28_Urinary cancer(B07) 0 G1C4E21B14-29_Urinary NAT(AF8) 0 G1 C4E21 B14-3_Cervical cancer(AFF) 0 G1C4E21B14-30_Ovarian cancer(9D7) 0 G1 C4E21 B14-31_Urinary cancer(AF7) 0 G1C4E21B14-32-Ovarian cancer(9F5) 0 G1 C4E21 B1 4-33_Ovarian cancer(A05) 0 Gi C4E21 B1 4-34_Ovarian cancer(9BC) 0 GiNCE21 Bi4-35 _Ovarian cancer(9C2) 0 WO 2004/015079 PCT/US2003/024931 G1 C4E21 B1 4-36_Ovarian cancer(9D9) 0 G1 C4E21 B1 4-37_Ovarian NAT(AC7) 0 G1 C4E21 B1 4-38_Ovarian NAT(AC9) 0 G1 C4E21 B1 4-39_Ovarian NAT(ACA) 0 G1C4E21B14-4-Cervical NAT(B1E) 0 G1C4E21 B14-40-Ovarian NAT(AC5) 0 G1 C4E21 B1 4-6-Cervical NAT(AFA) 0 G1 C4E21 B1 4-7_Cervical cancer(B1 F) 0 G1C4E21B14-8_Cervical NAT(B1C) 0 G1C4E23B15-32_Breast cancer(D34) 41.24 G1 C4E23B1 5-33 Breast cancer(D35) 21.19 G1C4E23B15-34_Breast cancer(D36) 102.07 G1C4E23B15-35_Breast cancer(D37) 83.94 G1C4E23B15-36_Breast cancer(D38) 25.2 G1 C4E23B1 5-37_Breast cancer(D39) 1.62 G1 C4E23B1 5-38-Breast cancer(D3A) 96.28 G1 C4E23B1 5-39_Breast cancer(D3B) 81.09 G1 C4E23B1 5-40_Breast cancer(D3C) 71.32 G1C4E23B15-41_Breast cancer(D3D) 56.37 G1C4E23B15-42_Breast cancer(D3E) 283.29 G1C4E23B15-43_Breast cancer(D3F) 1141.66 G1C4E23B15-44_Breast cancer(D40) 157.32 G1 C4E23B1 5-45_Breast cancer(D42) 58.84 G1 C4E23B1 5-46_Breast cancer(D43) 223.65 G1C4E23B15-47_Breast cancer(D44) 778.17 G1 C4E23B1 5-48_Breast cancer(D45) 278.05 G1 C4E23B1 5-49_Breast cancer(D46) 1191.16 G1C4E3OB16-1_2.SK-MES 0 G1C4E3OB16-10_40.HLaC-79 64.5 G1C4E3OB16-11_43.H226 0 G1C4E3OB16-12_45.HCT-116 94.63 G1C4E30B16-13_53.lGROV-1 0 G1C4E3OB16-14_59.MX-1 0 G1 C4E3OB1 6-15_63.C33A 229.24 G1C4E3OB16-16_65.Daudi 0 G1C4E3OB16-17_71.MV522 68.41 G1C4E30B16-18_76.RWP-2 0 GI C4E3OB1 6-1 9_7.BON 3.86 WO 2004/015079 PCT/US2003/024931 Gi C4E30B1 6-2_6.MiaPaCa 0 G1C4E30B16-20_82.H82 176.67 G1C4E30B16-21-86.H69 0 G1C4E30B16-22_95.Caki-2 0 G1C4E3OB16-23_100.LNCaP 5.77 G1C4E30B16-24_101.A549 0 G1C4E30B16-25_1. DU145 96.91 G1C4E30B16-26_6. OVCAR-3 0 G1 C4E3OB1 6-27_11. HT-29 135.28 G1C4E3OB16-28_13. DLD-2 0 .G1C4E30B16-29_18. MCF-7 24.47 G1C4E3OB16-3_9.H460 0 G1 4E30B1 6-4-15.SW620 3.28 G1C4E30B16-5_20.SK-OV-3 0 G1C4E30B16-6_23.MDA-231 0 G1C4E30B16-7_27.Caki-1 0 G1C4E30B16-8_31.PC-3 0 G1C4E30B16-9_35.LoVo 0 G1C4111B20-10 Kidney NAT(1 0B1) 206.25 G1 C411 1 B20-1 1 Kidney cancer(1 0B2) 103.55 G1 C4111B20-12_Kidney NAT(10B3) 194.23 G1C411 1 B20-13_Kidney cancer(10B4) 0 G1 C4111 B20-14_Kidney NAT(10B5) 191.62 G1C411 1 B20-15_Kidney cancer(10B6) 0.84 G1 C4111 B20-16_Kidney NAT(10B7) 222.1 G1 C4111B20-17_Kidney cancer(1 OBA) 0 G1C4111B20-18_Kidney NAT(1OBB) 216.02 G1 C4111 B20-1 9_Kidney cancer(10CO) 13.27 G1 C4111 B20-20Kidney NAT(10C1) 149.04 G1 C4111 B20-21_Kidney cancer(10C4) 309.45 G 1C4111 B20-22_Kidney NAT(10C5) 217.97 G1 C4111 B20-23_Kidney cancer(10A8) 0 G1 C4111 B20-24_Kidney NAT(10A9) 265 G 1C4111 B20-25_Kidney cancer(1 OAA) 106.33 G1 C4111 B20-4_Kidney NAT(10 AB) 246.18 G1 C4111 B20-5_Kidney cancer(1 OAC) 219.37 G1 C4111 B20-6_Kidney NAT(10 AD) 226.44 G10C411 I1B20-7_Kidney cancer(1 OAE) 251.5 WO 2004/015079 PCT/US2003/024931 G1C411 1 B20-8_Kidney NAT(1 OAF) 238.33 G1C4111 B20-9_Kidney cancer(1 OBO) 129.29 G1C4112B21-66_Ardais Lung 4 115.55 G1C4112B21-67_Ardais Lung 6 24.5 G1C4112B21-68_Ardais Lung 7 74.81 G1C4112B21-69_Ardais Lung 10 51.67 G1C4112B21-70_4169B1 normal lung 1.11 G1C4112B21-71_4267B1 normal lung 4.99 G1C4112B21-72_#689 Control Lung 34.21 G1C4112B21-73_#812 Asthma Lung 82.58 G1C4112B21-74_#1078 Control Lung 104.81 G1C4117B22-10 Lymphoma(9BF) 0 Gi C4117B22-1 1-Lymphoma(9D2) 0 G1C4117B22-12_Lymphoma(A04) 0 G1C4117B22-13_Lymphoma(9DD) 0 G1C4117B22-14-Lymphoma(F68) 0 G1 C4117B22-15_Lymphoma(F6A) 0 G1C4117B22-16_Lymphoma(F6B) 0 G1 C4117B22-17_Lymphoma(F6C) 0 Gi C4117B22-18_Lymphoma(F6D) 0 G1C4117B22-19_Lymphoma(F6E) 0 G1C4117B22-20_Lymphoma(F6F) 0 G1C4117B22-21_Lymphoma(F70) 0 G1C4117B22-22_Lymphoma(F71) 0 G1C4117B22-23-jLymphoma(F72) 0 G1C411 7B22-24_-Lymphoma(F73) 0 G1C4117B22-25-Lymphoma(F74) 0 G1 C4117B22-26_Lymphoma NAT(1 002) 41.6 G1C4117B22-28_Lymphoma NAT(1004) 3.63 G 1C411 7B22-29_Lymphoma NAT(1 005) 0 G1 C4117B22-30_Lymphoma NAT(1 007) 0 G1C4117B22-32_Lymphoma NAT(1003) 0 G1C4117B22-4_Lymphoma(9E3) 135.17 G1 C4117B22-5_Lymphoma(9DO) 0 G1 C4117B22-6_Lymphoma(9E1) 0 G1C4117B22-7-Lymphoma(AOD) 65.22 G1C4117B22-8-Lymphoma(9B5) 0 G1C4117B22-9_Lymphoma(9D3) 0 WO 2004/015079 PCT/US2003/024931 Gene expression analysis using CuraChip revealed that the expression level of this gene was elevated in breast cancer tissues and reduced in kidney cancer tissues as compared with normal adjacent tissues. Therefore this gene is useful as a specific marker 5 for differentiating cancerous from normal tissue in these disease states. Therapeutic modulation of this gene, expressed protein and/or use of antibodies or small molecule drugs targeting the gene or gene product would be useful in the treatment of breast cancer and kidney cancer. 10 OTHER EMBODIMENTS Although particular embodiments are disclosed herein in detail, this is done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications will be made to the 15 invention without departing from the spirit and scope of the invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. Other aspects, advantages, and modifications considered to be within the scope of the following claims. The claims presented are 20 representative of the inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims.

Claims

1. An isolated polypeptide comprising the mature form of an amino acid sequenced selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38.

2. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38.

3. A composition comprising the polypeptide of claim 1 and a carrier.

4. A kit comprising, in one or more containers, the composition of claim 4.

5. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising: (a) providing said sample; (b) introducing said sample to an antibody that binds immunospecifically to the polypeptide; and (c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

6. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the polypeptide of claim 1 in a first mammalian subject, the method comprising: a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and b) comparing the expression of said polypeptide in the sample of step (a) to the expression of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease, 110 WO 2004/015079 PCT/US2003/024931 wherein an alteration in the level of expression of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

7. A method of identifying an agent that binds to the polypeptide of claim 1, the method comprising: (a) introducing said polypeptide to said agent; and (b) determining whether said agent binds to said polypeptide.

8. The method of claim 7 wherein the agent is a cellular receptor or a downstream effector.

9. A method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of the polypeptide of claim 1, the method comprising: (a) providing a cell expressing the polypeptide of claim 1 and having a property or function ascribable to the polypeptide; (b) contacting the cell with a composition comprising a candidate substance; and (c) determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition in the absence of the substance, the substance is identified as a potential therapeutic agent.

10. A method for screening for a modulator of activity of or of latency or predisposition to a pathology associated with the polypeptide of claim 1, said method comprising: (a) administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of claim 1, wherein said test animal recombinantly expresses the polypeptide of claim 1; (b) measuring the activity of said polypeptide in said test animal after administering the compound of step (a); and WO 2004/015079 PCT/US2003/024931 (c) comparing the activity of said polypeptide in said test animal with the activity of said polypeptide in a control animal not administered said polypeptide, wherein a change in the activity of said polypeptide in said test animal relative to said control animal indicates the test compound is a modulator activity of or latency or predisposition to, a pathology associated with the polypeptide of claim 1.

11. The method of claim 10, wherein said test animal is a recombinant test animal that expresses a test protein transgene or expresses said transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein said promoter is not the native gene promoter of said transgene.

12. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38 or a biologically active fragment thereof.

13. An isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38.

14. An isolated nucleic acid molecule encoding the mature form of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 38.

15. A vector comprising the nucleic acid molecule of claim 13.

16. A cell comprising the vector of claim 15.

17. An antibody that immunospecifically binds to the polypeptide of claim 1. n'), 1 WO 2004/015079 PCT/US2003/024931

18. The antibody of claim 17, wherein the antibody is a human monoclonal antibody.

19. A method of producing the polypeptide of claim 1, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 38.

20. The method of claim 19 wherein the cell is chosen from the group comprising a bacterial cell, an insect cell, a yeast cell and a mammalian cell.