CA2218741A1 - Nucleotide sequence of the haemophilus influenzae rd genome, fragments thereof, and uses thereof - Google Patents

Abstract

The present invention provides the sequencing of the entire genome of Haemophilus influenzae Rd, SEQ ID NO:1. The present invention further provides the sequence information stored on computer readable media, and computer-based systems and methods which facilitate its use. In addition to the entire genomic sequence, the present invention identifies over 1700 protein encoding fragments of the genome and identifies, by position relative to a unique Not I restriction endonuclease site, any regulatory elements which modulate the expression of the protein encoding fragments of the Haemophilus genome.

Description

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DEMANI:~ES OU ~3R~V~TS VOLUMINEIJX

I A PRES~NTE PARTIE DE CEl~E DEMANDE OU CE BREVEr COMPREND PLUS D'UN TOME. -CECI FST LE TOnnE ¦ DE 5 NOTE: Pour les tomes add;tionels, veuillez c~ntacler le Bureau canadien desbrevets ~2,/,~7S//

JIJ~VIBO APPLICAT~ONS/PATENTS - -THIS SECTION OF THE APP~ICATION/PATENT ~ONTAINS MORE
THAN ONE VOLUME

THIS 5S VOLUME ~ / OF

.

NO~E: For addit~-onal vnlumes-please c~nt~ict~the Canadlan Patent (:)ff~c~ -. . .
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W 096133276 PCTnUS96/05320 Nucleotide Sequence of the Haemophilus influenzae Rd Genome, Fragments Thereof, and Uses Thereof ~, .

Part of the work pelrc,l...ed during development of this invention utilized U.S. Gov~rnm~nt funds. The gov~,rnm~nt may have certain rights in this invention. NIH-5ROlGM4825 1 Field of the Invention The present invention relates to the field of mol~o~ r biology. The present invention discloses co---posilions comprising the nucleotide sequence of Haemophilus influenzae, fr~gmP.ntc thereof and usage in in~1nctri~1 fermPnt~tion and ph~rm~ceutir~l development.

Background of the Invention The co~pl-~tn genome sequence from a free living cellular organism has never been det~,rmin~i. The first mycobacterium sequence should be completed by 1996, while E. coli and S. cerevisae are expected to be completed before 1998. These are being done by random and/or directed sequencing of o~/t;lld~ g cosmid clones. No one has ~lLt;.~.pled to determine ences of the order of a ...~-,~h~, or more by a random shotgun approach.
H. influenzae is a small (a~pluAilllalely 0.4 x 1 micron) non-motile, non-spore forming, germ-negative b~ct.q,ri~-m whose only natural host is human. It is a resident of the upper le~ildtOly mucosa of children and adults and causes otitis media and lr~jl.i-"l.. ,~ tract infectinn~ mostly in children. The most serious comrli~tinn is ...~ ;c, which produces neurological sequelae SUBS 1 l l UTE SHFET (RULE 2~i~

W 096/33276 PCTrUS96/05320 in up to 50% of affected children. Six H. infl~uenzae s~o~y~es (a through f) have been id~ntifi~l based on immllnnl~ir~lly distinct c~rsul~r poly~rch~ri(l~
antigens. A number of non-typeable strains are also known. Serotype b accounts for the majority of human ~ P~P
Interest in the mrf1ir~lly~l~ L~lL aspects of H. influenzae biology has focused particularly on those genes which dettormine virulence rh~r~cteri~tics of the org~ni~m. A number of the genes responsible for the capsular poly.~r~h~ri~ have been m~d and sequenced (Kroll et al., Mol. Microbiol.
5(6):1549-1560 (1991)). Several outer membrane protein (OMP) genes have been identifi~l and sequenced (Langford et al., J. Gen. Microbiol. 138: 155-159 (1992)). The lipoligo~rrh~r~ (LOS) component of the outer membrane and the genes of its synthetic ~ W~y are under intensive study (Weiser et al., J. Bacteriol. 172:3304-3309 (1990)). While a vaccine has been available since 1984, the study of outer membrane components is motivated to some extent by the need for improved v~r-cin~-s. Recently, the ç~t~ e gene was ~h~rz~r.trri7~1 and ses~uenced as a possible virulence-related gene (Bishni et al., in press) . Flllr~ tic)n of the H. influenzae genome will enh~n~ e the un~lçrst~nflin~ of how H. inffuenzae causes invasive disease and how best to combat infection.
H. irffluen2ae po~_ ~s a highly çfficient natural DNA tran~ro~ aLion system which has been intensively studied in the non-encapsulated (R), ~u~y~e d strain (Kahn and Smith, J. Membrane Biology 81:89-103 (1984)).
At least 16 ~ r .. ~ion-spe~ific genes have been idPntifi~l and sequenced.
Of these, four are regulatory (RPAfiel~, J. Bacteriol. 173:5612-5618 (1991), and C~h~n~ r, Proc. Natl. Acad. Sci. USA 89:1626-1630 (1992)), at least two are involved in recombination piocesses (Barouki and Smith, J. Bacteriol.
163(2):629-634 (1985)), and at least seven are targeted to the membranes and ~ h,~ir space (Tomb etal., Gene 1~4:1-10 (1991), and Tomb, Proc. Natl.
Acad. Sci. USA 89:10252-10256 (1992)), where they appear to function as structuIal colllpo~ ls or in the ~Pmhly of the DNA transport m~rhin~-.ry, H.
ir~luen~ae Rd ~ rO~ ;ol. shows a number of in~;ie~ g r~atu,~s inclll~in~

SU8~ TUTE S~E~T (RULE 26 W 096/33276 PCTrUS96/05320 sequence-specific DNA uptake, rapid uptake of several double-str~nded DNA
molecules per co,..~;lenl cell into a membrane col"~ ent called the I,d"sr,.~ om~-7 linear translocation of a single strand of the donor DNA into the cytoplasm, and synapsis and recombination of the strand with the chromosome by a single-strand displ~emPnt m~-~h~ni~m The H. influenzae Rd ~ r~ l ion system is the most thoroughly studied of the gram-negative systems and distinct in a number of ways from the gram-positive systems.
The size of H. influenzae Rd genome has been determined by pulsed-field agarose gel electrophoresis of restriction digests to be a~ru~i",~l~ly 1.9 Mb, making its genome a~l)r~,~i"lately 40% the size of E.
coli (Lee and Smith, J. Bacteriol. 170:4402-4405 (1988)). The restriction map of H. influenzae is circular (Lee et al., J. Bacteriol. 171:3016-3024 (1989), and Redfield and Lee, "Haemophilus influenzae Rd", pp. 2110-2112, In O'Brien, S.J. (ed), Genetic Maps: Locus Maps of Complex Genomes, Cold Spring Harbor Press, New York). Various genes have been mapped to restriction fr~gm~nt~ by Southern hybri-li7~tion probing of restriction digest DNA bands. This map will be valuable in verific~tion of the assembly of a complete genome sequence from randomly sequenced fr~mPnt~ GenR~nk ~;ullerllly cont~in~ about 100 kb of non-rçdl-n~l~nt H. influenzae DNA
sequences. About half are from seir~ly~e b and half from Rd.

Summa y of the Invention The present invention is based on the sequen~ ing of the Haemophilus influen~ae Rd genome. The primary n~ oti~le sequence which was gen~r~t~l is provided in SEQ ID NO: 1.
The present invention provides the ~~~r~l~ nucleotide sequence of the Haemophilus influenzae Rd genome, or a lc~les~--t~tive fragment thereof, in a form which can be readily used, analyzed, and inlel~l~led by a skilled artisan. In one embodiment, present invention is provided as a contiguous SUBSmUTE S~EE~ tRULE 26) W 096/33276 PCTrUS96/05320 string of primary sequence information collG~onding to the nucleotide sequence depicted in SEQ ID NO: 1.
The present invention further provides nucleotide sequences which are at least 99.9% idPn*c~l to the nucleotide sequence of SEQ ID NO:l.
The nucleotide sequence of SEQ ID NO: 1, a lc~lect~-t~tive fr~gmPnt thereof, or a nucleotide sequence which is at.least 99.9% identic~l to the nucleotide sequence of SEQ ID NO:l may be provided in a variety of mediums to f~ilit~tP its use. In one applic~tinn of this emb(!AimPnt the Se~lucllCeS of the present invention are recorded on colllyulcl readable media.
Such media in~ d~Ps, but is not limited to: m~gnetic storage media, such as floppy discs, hard disc storage mP51inm, and m~gnPtic tape; optical storage media such as CD-ROM; el~P~tn~l storage media such as RAM and ROM;
and hybrids of these categ(jlies such as m~gnptic/optical storage media.
The present invention further provides systems, particularly colllpuLcl-based systems which contain the sequence information herein described stored in a data storage means. Such systems are d~P~ignP~1 to identify commercially illl~l kulL f~mPnt~ of the Haemophilus influenzae Rd genome.
Another embodiment of the present invention is directed to i~ol~tP~
frz~gmPnt~ of the Haemophilus in~uenzae Rd genome. The fr~gmPnt~ of the Haemophilus influenzae Rd genome of the present invention include, but are not limited to, fr~gmPnt~ which encode peptides, hereinafter open reading frames (ORFs), fra~mPnt~ which modulate the c~lc~ion of an operably linked ORF, h~lcinarL~r c~lc~ ion modlll~*ng fr~gmPnt~ (EMFs), fr~pmPnt~
which mediate the uptake of a linked DNA fr~gmPnt into a cell, hclcinarLcl uptake mod~ *n~ fr~gmPnt~ (UMFs), and fr~gmPnt~ which can be used to gn~)sP the ~lcs~ce of Haemophilus influenzae Rd in a c~mplP, hereinafter, gnostic fr~gmPnt.~ (DFs).
Each of the ORF fr~gmPnt~ of the Haemophilus influenzae Rd genome o~l in Tables l (a) and 2, and the EMF found 5 ' to the ORF, can be used in numerous ways as polynucleotide reagents. The sequences can be used as noStiC probes or ~ ,nostic amplific~tion primers for the presence of a SUBS 111 UTE S~{E~T tRULE 2~i) W 096133276 PCTrUS96/05320 sperific microbe in a ~mple, for the production of commercially i...po~ t pharm~re~ltir~l agents, and to selectively control gene c;~Lples~iom The present invention further inch~ Ps recombinant constructs cnmri~ing one or more fr~gmPnt~ of the Haemophilus influenzae Rd genome " S of the present invention. The recombinant constructs of the present invention c~...l.. ;~ vectors, such as a pl~mi~l or viral vector, into which a fr~gmPnt ofthe Haemophilus influenzae Rd has been inserted.
The present invention further provides host cells cont;~ g any one of the isolated r.~ of the Haemophilus influen2~e Rd gPnomP of the present invention. The host cells can be a higher eukaryotic host such as a ~ n cell, a lower eukaryotic cell such as a yeast cell, or can be a L.r~yc Lic cell such as a b~rtp-ri~l cell.
The present invention is further directed to i~ol~tP~ proteins encoded by the ORFs of the present invention. A variety of methodologies known in the art can be utilized to obtain any one of the proteins of the present invention. At the cimr~est level, the amino acid sequence can be synthPci7~1 using c~.. ~ ;ally available peptide synthP-~i7P,rs. In an ~lLf~ e method, the protein is purified from b~rtP~ l cells which n~tllr~lly produce the protein.
Lastly, the ploL~uls of the present invention can ~ ely be purified from cells which have been altered to express the desired protein.
The invention further provides mPtho~ of obl~ilLu~g homologs of the r,~g...~ of the Haemophilus influenzae Rd genome of the present invention and homologs of the proteins encoded by the ORFs of the present invention.
Sptorifir~lly, by using the nllrl~ti~lP and amino acid sellu~ es ~ r-losp~l herein as a probe or as primers, and techniques such as PCR cloning and colony/plaque hybritii7~ti~ n, one skilled in the art can obtain homologs.
The invention further provides antibodies which selectively bind one of the proteins of the present invention. Such antibodies include both monoclonal and polyclonal antibodies.

SU8S 111 UTE SHEET ~RULE 26) W 096/33276 PCTrUS96/OS320 The invention further provides hybridomas which produce the above-described antibodies. A hybridoma is an immortalized cell line which is capable of s~.c~ g a specific monoclonal antibody.
The present invention further provides methods of identifying test samples derived from cells which express one of the ORF of the present invention, or homolog thereof. Such mPth~ comprise inc~lb~ting a test sample with one or more of the antibodies of the present invention, or one or more of the DFs of the present invention, under con~lition~ which allow a skilled artisan to delt;l-l--l-e if the sample conf~in~ the ORF or product produced the.Gr ~
In another embo limPnt of the present invention, kits are provided which contain the n~ ~ y reagents to carry out the above-described assays.
Specifically, the invention provides a cOIllp~l .~..ont~li7F~1 kit to receive, in close confinPment, one or more cont~iners which comrri~çs: (a) a first con~illcr compri~ing one of the antibodies, or one of the DFs of the present invention; and ~o) one or more other c~ ".l~in~ com~i~ing one or more of the following: wash r~gFnt~, reagents capable of ~letFecting presence of bound antibodies or hybridiAd DFs.
Using the i~ol~tçd p-~,~eins of the present invention, the present invention fur~er provides .. ~ll.o~l~ of ~ining and identifying agents capable of binding to a protein encoded by one of the ORFs of the present invention.
Specifically, such agents include antibodies (described above), peptides, I~llydldk~s, ph~rm~rP~tir~l agents and the like. Such methods comprise the steps of:
(a) cnn~rtin~ an agent with an isnl~tF~ protein encoded by one of the ORFs of the present invention; and (b) del~.lllining wh~ . the agent binds to said protein.
The complete ~em~mir s~u~l~ce of H. influen~ae will be of great value to all lab~ ., ;F-~ ~vc, hu-g with this organism and for a variety of commerciall,u.~o~s. Many r,~g.. ~ of the Haemophilus influ~nzae Rd genome will be immP1i~trly identified by ~imil~rity searches against GPnR~nk or protein SUBST117.~TE 5~EET tRULE 2~i~

W 096/33276 PCTrUS96/05320 ~t~h~PS and will be of immPAi~tP value to Haemophilus lesealcllers and for immPAi~tP cx~ ;dl value for the production of proteins or to control gene c~ion. A specific PY~mrl~ a n~Prn~ PHA synthase. It has been reported that polyhy~uAyl.u~yldL~ is present in the membranes of H. influenzae Rd and S that the amount correlates with the level of cc~ ence for tran~rolllldLion.
The PHA synthase that synthP~i7Ps this polymer has been i(lPntifieA. and sequenced in a number of bact~P-ri~, none of which are evolutionarily close to H. influenzae. This gene has yet to be i~ol~tPA. from H. influenzae by use of hybrirli7~tic)n probes or PCR techniques. However, the genomic sequence of the present invention allows the identifi~tiQn of the gene by ~tili7ing search means described below.
Developing the mPtho~lology and technology for el~ ting the entire genomic sequence of b~ctP-ri~l and other small genomes has and will greatly enh~n~e the ability to analyze and understand chromosomal org~ni7~tinn In particular, sequenced g~nn.. --s will provide the models for developing tools for the analysis of chromnsome structure and function, inl~h--ling the ability to identify genes within large s~ of genomic DNA, the structure, position, and spacing of regulatory PkPmPnts, the identifi~tion of genes with potential indllstri~l appli~tinn~ and the ability to do co~ te genomic and molP~c~ r phylogeny.

Des~ ion of the Figures Figure 1 - restriction map of the Haemophilus in~uenzae Rd genome.
Figure 2 - Block ~ gr~m of a colll~ul~r system 102 that can be used to implement the colll~u~l-based systems of present invention.
Figure 3 - A col.. r~ on of eYrerimPnt~l coverage of up to ay~rux~ ely 4000 random sequence fr~gmPnt~ assembled with AutoAssembler (squares) as colll~c;d to Lander-Waterlllall prediction for a 2.5 Mb genome (tri~nglP-s) and a 1.6 Mb genome (circles) with a 460 bp average sequence length and a 25 bp overlap.

SUBS i 11 UTE SHEET tRULE ;~

W 096133276 PCT~US96/05320 Figure 4 - Data flow and col,lpulel programs used to manage, q~Pmhle, edit, and annotate the H. influenzae genome. Both MqrintrJsh and Unix ~laLrulll.s are used to handle the AB 373 sequence data files (Kerlavage et al., Proceedings of the Twenty-Sixth Annual Hawaii International Conference on System Sciences, IEEE Colll~ulel Society Press, W~q.~hington D.C., 585 (1993)). Factura (AB) is a Mqrintosh plO~ UI~ ~P.~ipn~l for au~alic vector sequence removal and end l ~ g of sequence files. The program esp runs on a M~qrintc)sh platform and parses the feature data rYtr.qr~d from the sequence files by Factura to the Unix based H. influenzae rrlqtinnql d-qt~qhq-ee Assembly is acco",~lished by retrieving a specific set of~qluPnr~ files and their q~ f~alules using stp, an X-windows ~r.qphirql interface and control program which can retrieve sequences from the H.
irffluenzae ~IAI;-h~, using user-defined or standard SQL queries. The sequence files were q~PmhlP~l using TIGR ~~~' ler, an assembly engine de~igne~i at TIGR for rapid and qccnr~te q~sPmhly of thousands of sequence frqgmPnt~.
TIGR Editor is a grqphicql int~rfqr~ which can parse the aligned sequence files from TIGR ~ m'~' output and display the qlignmPnt and Lqc~oci-qtrA
ele~llu~h~ l~,,s for contig editing. T~iPntifir~tir,n of putative coding regionswas ~- r~..... ~ with C ~ 3orodovsky and MrTninrh, Computers Chem.
17~J:123 (1993)), a Markov and Bayes modPl~d pr~ for pre lirting gene lor~tin,n~, and trained on a H. influer~ae sequence data set. Peptide searches were ~f . r~.. rd against the three reading frames of each G~n-m ~rk predicted coding region using blaze (Brutlag et al., Computers Chem. 17:203 (1993)) run on a Maspar MP-2 massively parallel cc,n.~uLei with 4096 mi~ Results from each frame were combined into a single output file by mblzt. Optimal protein ~ ?nm~-.nt~ were obtained using the program praze which extends ~lipnm~.nt~ across potential fr~mPchift~ The output was in~pPct~ using a custom graphic viewing program, gbyob, that inter~rts directly with theH. ir~quenzae ~l~t~h~5P The ~ nn~ent.~ were further used to identify ~e~ fr~mP~hift errors and were targeted for ~ ition~l editing.

SUBSTITUTE SH E~T (RULE 2~) W 096/33276 PCTnUS96/05320 Figure S - A circular rc~leselltation of the H. inf~uenzae Rd ~;lllu.~losolllP illn~tr~ting the location of each predicted coding region contain-ing a ~ ~ match as well as s~l~t~ global r~;alu.~s of the genome. Outer pc.~el~.. The location of the unique NotI restriction site (~le~ign~t~ as S nucleotide 1), the Rsr~ sites, and the SmaI sites. Outer concentric circle: The location of each identifi~ coding region for which a gene identific~tion was made. P~rh coding region location is coded as to role according to the color code in Fig. 6. Second concentric circle: Regions of high G/C content ( >
42%, red; > 40%, blue) and high A/T content (> 66%, black; > 64%, green). High G/C content regions are spe~ifit~lly ~o~i~tt~ with the 6 ribosomal operons and the mu-like prophage. Third co~ ;c circle:
Coverage by lambda clones (blue). Over 300 lambda clones were sequenced from each end to c~. . ri .. . . the overall sh ucture of the genome and identify the 6 ribosomal operons. Fourth coLc~ ;c circle: The locations of the 6 ribosomal operons (green), the tRNAs (black) and the cryptic mu-like prophage (blue). Flfth concentric circle: Simple tandem repeats. The lc~tic-n~ of the following repeats are shown: CTGGCT, GTCT, ATT, AATGGC, TTGA, TTGG, TTTA, TTATC, TGAC, TCGTC, AACC, TTGC, CAAT, CCAA. The putative origin of re~lit~hr n is illustrated by the outward pointing arrows (green) ori~in~hng near base 603,000. Two potel,Lial It-- ...i,. .~;rm St;Llu~;llc~s are shown near the c~osi~ midpoint of the circle (red).

Figures 6(A)-6(D)- Complete map of the H. in~?uenzae Rd genome.
Predicted coding regions are shown on each sh~nd. rRNA and tRNA genes are shown as lines and fri~nglt-s, ~espe~ ely. Genes are color-coded by role ca~guly as described in the legend. GeneID nulllbel~ colle~ d to those in Tables l(a), l(b) and 2. Where possible, three-letter ~ecign~tionC are also provided.

Figure 7 - A colllp~ison of the region of the H. inf~uenzae chromo-some cot.l~;nillg the 8 genes of the fimbrial gene cluster present in H.

SUBS 111 UTE S~EET tRULE 2~) --~ =

W 096133Z76 PCTrUS96/05320 influenzae type b and the same region in H. influenzae Rd. The region is flanked by the pepNand purE genes in both org~ni~m~. However in the non-inf~cti-nls Rd strain the 8 genes of the fimhri~l gene cluster have been excised.
A 172 bp spacer region is located in this region in the Rd strain and continllPs to be flanked by the pepN and purE genes.

Figure 8 - H~ hobicity analysis of five predicted ch~nnPl-proteins.
The amino acid sequences of five predicted coding regions that do not display homology with known peptide se4uences (GenR~nk release 87), each exhibit multiple hydrophobic domains that are ch~r~rteri~tic of channel-forming ~ ;uls. The predicted coding region sequences were analyzed by the Kyte-Doolittle algorithm (Kyte and Doolittle, J. Mol. Biol. 157:105 (1982)) (with a range of 11 residues) using the GeneWor_s sorLw~c package (~ntf~lligPnptirs) .

Def~7i1e~l D~sc,~lion of the Preferred Embodiments The present invention is based on the seqmPn~ing of the Haemophilus iry'luenzae Rd ~PnomP The ~linldL~ "~ sequence which was gen~Pr~tP~
is provided in SEQ ID NO: 1. As used herein, the "~linlaly sequence" refers to the nucleoti-lP- sequence ~c~r~sell~ed by the IUPAC nomencl~h-re system.
The ~uen~ provided in SEQ ID NO: 1 is ~ rd relative to a unique Not I restriction en-lom--le~e site found in the Haemophilus influenzae Rd f~n~lm~., A skilled artisan will readily r~og.~ that this startlstop point was chosen for conveniPm~e and does not reflect a structural si~nific~nre The present invention provides the nucleotide sequence of SEQ ID
NO:l, or a lc~l4se .~;.li~e fragment thereof, in a form which can be readily used, analyzed, and intt;l~rcl~d by a skilled artisan. In one embc~limPnt the sequence is provided as a contiguous string of primary sequence in~llllation colrcs~nding to the nucleotide sequence provided in SEQ ID NO: 1.

SUBSTtTUTE SHE~ tRULE 2fi) W 096/33276 ~ PCTAUS96/05320 As used herein, a "lc~ s~ ;ve fragment of the nucleotide sequence ~le~ict~P~d in SEQ ID NO:l" refers to any portion of SEQ ID NO:l which is not ~leselllly r~,esellt;ed within a publicly available ~l~t~h~e P-ert; -ed r~.eselll~ e fr~gmPnt~ of the present invention are Haemophilus influenzae open reading frames, e~ ;,;,ion mod~ ting fr~mPnt~, uptake mo~ ting fragments, and fr~gmPnt~ which can be used to ~ nose. the presence of Haemophilus influenzae Rd in sample. A non-limitinf~ id.ontific~tion of such pr~r~ d .~res~ e fr~mPnts is provided in Tables l(a) and and 2.
The nucleotide sequence information provided in SEQ ID NO: 1 was obtained by seqllencing the Haemophilus influenzae Rd genome using a meg~h~e shotgun sequP-ncing method. Using three parameters of accuracy CU~d in the FY~mrl-, below, the present inventors have calculated that the sequence in SEQ ID NO:l has a ~ xi~ ." ~rcur~y of 99.98%. Thus, the nucleotide sequence provided in SEQ ID NO:lis a highly accurate, although not neces~rily a 100% perfect"~L~.es.~ lion of the nucleotide sequence of the Haemophilus influenzae Rd genome.
As r~i~cll~ in detail below, using the inÇo.lll;lLion provided in SEQ
ID NO:l and in Tables l(a) and 2 together with routine cloning and se~lut;,l- ~.Ig methods, one of ordina. y skill in the art will be able to clone and sequence all "re~.~s~ e fr~gmPnt~" of interest inclu-1ing open reading frames (ORFs) encoding a large variety of Haemophilus influenzae proteins.
In very rare in.ct~nces, this may reveal a nucleotide sequence error present in the nucleotide sequence ~ rlr,sed in SEQ ID NO: 1. Thus, once the present invention is made available (i.e., once the information in SEQ ID NO: 1 and Tables l(a) and 2 have been made available), resolving a rare seql~en~ing error in SEQ ID NO: 1 will be well within the skill of the art. Nucleotide sequence editing surlw~ is publicly available. For e~ la, Applied Biosystem's (AB) Auto~PmhlPrTM can be used as an aid during visual inspection of nucleotide ~ sequences.

SUB5T~TIJTE S~EE~ (RULE 2~i) W 096133276 ~ PCTrUS96/05320 Even if all of the very rare seqllPneing errors in SEQ ID NO: 1 were corrected, the rçsl-lting nucleotide sequence would still be at least 99.9%
i~Pntic~l to the nucleotide sequence in SEQ ID NO: 1.
The nucleotide sequences of the genomes from dirr~e,lt strains of S Haemophilus influenzae differ slightly. However, the nucleotide sequence of the ~ ollles of all Haemophilus influenzae strains will be at least 99.9%
denti~l to the nll-lf oti~lP sequence provided in SEQ ID NO: 1.
Thus, the present invention further provides nucleotide sequences which are at least 99.9% i-lPnti-~l to the nucleotide sequence of SEQ ID NO: 1 in a form which can be readily used, analyzed and hl~ ed by the skilled artisan. Methods for delelll~ g whether a nucleotide sequence is at least 99.9% idPnti~l to the nucleotide sequence of SEQ ID NO:1 are routine and readily available to the skilled artisan. Por ~ , the well known fasta algvlh.i~l,m OEearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988)) can be used to generate the percent identity of nucleotide sequences.

Ca , ~.er Re~ated F bo~ Jff~

The mlrl~?tirlP sequence provided in SEQ ID NO:l, a l~r~;sce~ e fr~mPnt thereof, or a nuckoti~lp ~u~ nce at least 99.9% identic~l to SEQ ID
NO:l may be "provided" in avariety of r..P11il....~ to f~rilit~t~ use thereof. As used herein, provided refers to a m~nllf~rt~lre, other than an isolated nucleic acid mf'-clllP, which c~ a n~ leotidp sequence of the present invention, i.e., the mlçl~oti~lp sequence provided in SEQ ID NO:l, a l~r~senl~ e r.~ thereof, or a nu l~lide sequence at least 99.9% idPnti~-~l to SEQ ID
NO: 1. Such a m~nllf~tllre provides the Haemophilus influenzae Rd genome or a subset thereof (e.g., a Haemophilus Influenzae Rd open reading frame (ORF)) in a form which allows a skilled artisan to PY~mine the manufacture using means not dil~;Lly applicable to ~i,...;.)i,-g the Haemophilus influenzae Rd genome or a subset thereof as it eYists in nature or in purified form.

SUBSTrTUTE S~E~T tRULE 26') W 096/33276 PCTrUS96/05320 In one applic~tic)n of this embc~imPnt, a nucleotide sequence of the present invention can be recorded on col"pu~r readable media. As used herein, "co~ uLe readable media" refers to any mPAillm which can be read and ~"CPe~d directly by a colll~llltl. Such media include, but are not limited to: m~gnPtic storage media, such as floppy discs, hard disc storage mPAillm, and ",~g"~l;c tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categolies such as m~gnPti~/optical storage media. A skilled artisan can readily a~l"~iale how any of the ~ ly known COI,,~uL~, readable mPAiume can be used to create a m~nllf~ meco,~p~ g co.~ ul~ readable ".t~ ... having recorded thereon a nucleotide sequence of the present invention.
As uscd herein, "recorded" refers to a process for storing inr~"".aLion on co~ uL~l readable mPAillm A skilled artisan can readily adopt any of the presently know methods for ,~co~u~g information on colll~uL~l readable medium to ~Pner~tP manufactures comprieing the nucleotide sequence information of the present invention.
A variety of data storage structures are available to a skilled artisan for creating a cûlll~-lLel readable mPAillm having recorded thereon a nucleotide sequence of the present invention. The choice of the data storage structure will gPnPr~lly be based on the means chosen to access the stored information.
In addition, a variety of data p,ucessor LlU~ldlllS and fc"lllaL~ can be used tostore the nu~ o.otitlP, sP~uence il~r~ 1;nn of the present invention on computerreadable mPAi~lm The sequence inform~fion can be represented in a word pr~cPeein~ text file, Çû~ LUed in collllll~,,ially-available software such as WordPerfect and MicroSoft Word, or l~,~,s~llPd in the form of an ASCII
file, stored in a d; I; h~. appli~ti~m, such as DB2, Sybase, Oracle, or the like.
A skilled artisan can readily adapt any number of dataprocessor structllring formats (e.g. text file or 11~t~h~ee) in order to obtain CO~llpuL~ readable mPAillm having recorded thereon the nucleotide sequence information of the present invention.

SUBS 11 l UTE S~tE~T tRULE 26) W 096133276 PCTrUS96/05320 By providing the nucleotide sequence of SEQ ID NO: 1, a repres~-nt~five fragmPnt thereof, or a nucleotide sequence at least 99.9%
nti~l to SEQ ID NO:1 in cu.l-~uLel readable form, a skilled artisan can l~wLinely access the s~ut;nce ulr~ I;nn for a variety of ~ul~oses. Co...~uleL
s~rLw~e is publicly available which allows a skilled artisan to access sequence lion provided in a colll~ul~r readable m.~ m. The eY~mrles which follow de.mon~tr~tP how sorlw;~e which imrl~-nPnt~ the BLAST (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) and BLAZE (Brutlag et al., Comp.
Chem. 17:203-207 (1993)) search alg..l;~1....~ on a Sybase system was used to identify open reading frames (ORFs) within the Haemophilus influenzae Rd genomt-. which contain homology to ORFs or proteins from other orp~ni~m~
Such ORFs are protein t-n~rling r.,.g...~ within the Haemophilus infl~uenzae Rd genome and are useful in producing commercially important proteins such as enzymes used in fermpnt~tic)n r~t tinn~ and in the production of commercially useful metabolites.
The present invention fur~er provides systems, particularly colll~u~
based systems, which contain the ~.~ e ;nr~ lir)n described herein. Such systems are de-~ign~d to identify c(~ lcially illl~l~lt fr~gmP.nt.c of the Haemop*ilus influen~e Rd genome.
As used herein, "a colll~ulel-based system" refers to the hal.lw~
means, sonw~ means, and data storage means used to analyze the nucleotide ~uence ~nr -- ~ l;nn of the present invention. The Inil).illlUIII h~udw~e means of the co~ ult;l-based systems of the present invention compri~es a central pl~-~ g unit (CPU), input means, output means, and data storage means.
A skilled artisan can readily a~lc;ci~le that any one of the ~;ullc;l-lly available colllpuler-based system are suitable for use in the present invention.
As stated above, the cc,lll~uL~r-based systems of the present invention cnmrri.~- a data storage means having stored therein a nucleotide sequence of the present invention and the nf~ry ha(.lw~e means and software means for :iU~J~lLing and implem~n*np a search means. As used herein, "data storage means" refers to memory which can store nucleotide sequence SUBSTJTUTE SHEET tRULE 26~

W O 96/33276 PCTrUS96/05320 information of the present invention, or a memory access means which can access manufactures having recorded thereon the nucleotide sequence information of the present invention.
As used herein, "search means" refers to one or more programs which ~ S are impl~PmPntP11 on the co~ uLe -based system to co",pale a target sequence or target ~Llu~;~uldl motif with the sequence info.",ation stored within the data storage means. Search means are used to identify fr~gm~nte or regions of the Haemophilus influenzae Rd genome which match a particular target sequence or target motif. A variety of known algo. ilh,..e are disclosed publicly and a variety of commercially available sorLw~u~; for condl1cting search means are and can be used in the co",~uL~-based systems of the present invention.
Examples of such software in~ des, but is not limited to, MacPattern (EMBL), BLASTN and BLASIX (NCBIA). A skilled artisan can readily recognize that any one of the available algo. ;II....e or implemPnting software packages for conducting homology searches can be adapted for use in the present co",pule.-based ~ IIS.
As used herein, a "target sequence" can be any DNA or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily l~O~ that the longer a target sequence is, the less likely a target s~u~ce will be present as a random occurrence in the d~t~h~ ee The most pr~r~ d sequence length of a target sequence is from about 10 to 100 amino acids or from about 30 to 300 nucleotide reeitl-les However, it is well recognized that searches for commercially i",~- l~u~ fr~gmente of the Haemophilus infl~uenzae Rd genome, such as sequence fr~gmente involved in gene ~A~.~ssion and protein proceeeing, may be of shorter length.
As used herein, '!a targei structurai motif, !! or !!target motif,!! refers to any r~tion~lly SPl~ctP~i sequence or colllbi"~lion of sequences in which the sequence(s) are chosen based on a three-~limpnei~nal configuration which is formed upon the folding of the target motif. There are a variety of target motifs known in the art. Protein target motifs int~lnde, but are not limited to,enzymic active sites and signal sequences. Nucleic acid target motifs include, SUBSTTTUTE SH EET tRULE ~6) W 096/33276 PCTrUS96/05320 but are not limited to, promoter sequences, hairpin structures and inducible c~plcs~ion elP-ment~ (protein binding sequences).
A variety of structural Çolll,at~ for the input and output means can be used to input and output the i,.rt.. ~ n in the col"~uLcl-based systems of the present invention. A ~lCrcll~d format for an output means ranks fr~gmPnts of the Haemophilus influenzae Rd genome possç~ing varying degrees of homology to the target sequence or target motif. Such ~lcsP-n~ on provides a skilled artisan with a ranl~ng of .~luP-~I PS which contain various amounts ofthe target sequence or target motif and identifiP.s the degree of homology cont~in~l in the i-lPntifiPA fr~gm~Pnt A variety of co---p~ g means can be used to COlllp~hc a target sequence or target motif with the data storage means to identify sequence fragments of the Haemophilus influenzae Rd genome. In the present examples, implPmPnting sorlw~c which implPmPnt the BLAST and BLAZE
~lgorithm~ (Altschul et al., J. Mol. Biol. 215:403-410 (1990)) was used to identify open reading frames within the Haemophilus inffuenzae Rd genome.
A skilled artisan can readily recognize that any one of the publicly available hn~ l~y search pl~l~LIlls can be used as the search means for the co",~uLcr-based systems of the present invention.
One ~ 1if-~l;on of this embodiment is provided in Figure 2. Figure 2 provides a block fli~gr~m of a co,,ll.u~c~ system 102 that can be used to implement the present invention. The co",~uler system 102 incl~ldPs a processor 106 connected to a bus 104. Also connPctell to the bus 104 are a main memory 108 (l~cr~ ly ~ ~' ~PntPA as random access memory, RAM) and a variety of secondary storage devices 110, such as a hard drive 112 and a removable mP~ m storage device 114. The removable m~ m storage device 114 may lc~ ,l, for ~ ..l,le, a floppy disk drive, a CD-ROM drive, a m~gnPtic tape drive, etc. A removable storage mPAi~lm 116 (such as a floppy disk, a compact disk, a m~gnPtic tape, etc.) CO~ control logic and/or data recorded therein may be inserted into the removable mf~ lm storage device 114. The CO~ JU~C1 system 102 in~ des a~pLu~liatc software SU85 l l I UTE ~{EET tRULE 2~i) W 096/33276 PCTrUS96/05320 for reading the control logic and/or the data from the removable mPAillm storage device 114 once inserted in the removable mt-Ai~lm storage device 114.
A n~ ooti~le ~lu~n~e of the present invention may be stored in a well known manner in the main Illellluly 108, any of the secondary storage devices 110, and/or a removable storage mPAillm 116. Software for ~ ccing and pl~c~-~.c;ng the ~enomic s~lPn~e (such as search tools, co...p~ -g tools, etc.) reside in main memory 108 during PY~utinn Biochemicn~ Embodimen~s Another embodiment of the present invention is directed to i.c~ tPA
fr~gmP.ntc of the Ha~mophilus inyquenzae Rd genome. The fr~gmto.ntc of the Haemophilus inyquenzae Rd genome of the present invention inl~.h-dç, but are not limited to fr~gmP.nt.c which encode peptides, hereinafter open reading frames (ORFs), fr~gm~ntc which mod~ t~ the cA~ies~ion of an operably linked ORF, he.ci,~LrLcr cApl~;,;,ion m-xilll~ting fr~m~.ntc (EMFs), fr~m~.nt.c is which m~ii~t.o. the uptake of a linked DNA fr~gm~nt into a cell, hclein~rLcr uptake mod~ ting fr~gm~ntc (IJMFs), and fr~gm.q.ntc which can be used to gnose the prcsc,lce of Haernophilus influenzae Rd in a .c~mI~Iç, hercillarLc diagnostic fr~gm~ntc (DFs).
As used herein, an "icol~t~ nucleic acid molecule" or an "icol:~ted f~3~m~.nt of the Haemophilus influenzae Rd genome" refers to a nucleic acid ml~leclll~. ~ossçs~i.-g a spe~-ific nucleotide sequence which has been subjectedto purifi~fi~n means to reduce, from the composition, the number of co..l~ullds which are norm~lly ~ d with the composition. A variety of purific~tinn means can be used to gen~r~tçd the isolated fr~gmP.ntc of the ~-csent invention. These incl~lde, but are not limited to methods which se~ - conctitlllontc of a solution based on charge, solubility, or size.
In one embo~lim~-nt~ Haemophilus in~uenaze Rd DNA can be m ~.h~nic~lly sheared to produce fr~g m ~.nt.c of 15-20 kb in length. These - f~ g m~.ntc can then be used to generate an Haemophilus influenzae Rd library SUBSmUTE SHEET tRULE 26) W 096133276 PCTrUS96/OS320 by inserting them into labda clones as described in the Examples below.
Primers fl~nking, for eY~mip1~, an ORF provided in Table l(a) can then be grn~ ~ using m~ ~ti~e sequence information provided in SEQ ID NO: l.
PCR cloning can then be used to isolate the ORF from the lambda DNA
library. PCR cloning is well known in the art. Thus, given the av~ hility of SEQ ID NO:l, Table l(a) and Table 2, it would be routine to isolate any ORF or other nucleic acid fr~ment of the present invention.
The i~ol~t~d nucleic acid mol~c~ s of the present invention include, but are not limited to single st~n-le~l and double st~n~lYl DNA, and single str~n-1çd RNA.
As used herein, an "open reading frame," ORF, means a series of triplets coding for amino acids without any lel.l-il-aLion codons and is a sequence tr~n~1~t~hle into protein. Tables la, lb and 2 identify ORFs in the Haemophilus infl!uenzae Rd genome. In particular, Table la in-lic~tes the lo-~tinn of ORFs within the Haemophilus influenzae genome which encode the recited protein based on homolngy ~ ing with protein sequences from the organism ~I?e~; in ~arç-.l~ (see the fourth column of Table l(a)).
The first column of Table l(a) provides the "GeneID" of a particular ORF. This i..r.,....;.I;f~n is useful for two reasons. First, the complete map of the Haemophilus influen~ae Rd genome provided in Figures 6(A)-6(D) refers to the ORFs acculd..~g to their GeneID numbers. Second, Table l(b) uses the GeneID ~~u~nl~l~ to in-lic~tf~ which ORFs were provided previously in a public .l~t~h~
The second and third cnlllmn~ in Table l(a) in~ te an ORFs position in the nucleotide sequence provided in SEQ ID NO: l. One of O~i~ skill will reco~,.~i~e that ORFs may be oriented in o~o~ directions in the Haemophilus in;fluenae genome. This is rçflect~ in columns 2 and 3.
The fifth column of Table l(a) inr1i~t~s the percent identity of the protein en-~or1~1 for by an ORF to the collcs~nding protein from the orgaism al)~uulg in ~.,11.~tir~1~ in the fourth coll-mn SUB5T~TUTE ~i~tE~ tRuLE

W 096/33276 PCTrUS96/OS320 The sixth column of Table l(a) inriic~tps the percent cimil~rity of the protein encoded for by an ORF to the co~ .di~g protein from the organism appearing in parenthPti~le in the fourth column. The concepts of percent identity and percent eimil~rhy of two polypeptide sequences is well understood - S in the art. For PY~mpl~P, two polypeptides 10 amino acids in length which differ at three amino acid poeitit~ne (e.g., at positions 1, 3 and 5) are said to have a percent identity of 70 % . However, the same two polypeptides would be deemed to have a percent ~imil~rity of 80% if, for eY~mple at position 5, the amino acids moieties, although not identir~l, were "similar" (i.e., poseeee~d similar biorh~mic~l ch~r~rtPrietir,e).
The seventh column in Table l(a) in-lir~t~.s the lenth of the amino acid homology match.
Table 2 provides ORFs of the Haemophilus influenzae Rd genome which encode poly~ Lide ~uenrp~s which did not elicit a "homology match"
with a known protein sequence from another org~niem Further details concPrning the alg~ e and criteria used for homology searches are provided in the Examples below.
A skilled artisan can readily identify ORFs in the Haemophilus in~uenzae Rd genome other than those listed in Tables l(a), l(b) and 2, such as ORFs which are ovella~ping or encoded by the opposite strand of an identifiP~ ORF in ~ iti~m to those ascc~lLi~ihlable using the col,-pu~ based sy~Le".s of the present invention.
As used herein, an "eA~lession mod~ ting fr~gmP-nt " EMF, means a series of l~llr~ lP molPclllPs which modlll~tPe the eAplc~ssion of an operably linked ORF or EMF.
As used herein, a sequence is said to "modulate the ~A~ession of an operably linked sequence" when the eA~ression of the sequence is altered by the presence of the EMF. EMFs inclll(le, but are not limited to, promoters, - and pl~ IlluL~l m~ ting sequences (inducible ~lPm~nte) . One class of EMFs are fragments which induce the eA~ s~ion or an operably linked ORF in response to a sper-ific regulatory factor or physiological event. A review of SUBST~TUTE SHEET ~RUL~ 26~

W 096133276 PCT~US96/05320 known EMFs from Haemophilus are ~e~rrihed by ~romb et al. Gene 104:1-10 (1991), ~h~n-1lPr, M. S., Proc. Natl. Acad. Sci. USA 89:1626-1630 (1992).
EMF se l~ellces can be i~1PntifiP~i within the Haemophilus influenzae Rd genome by their pruAilniLy to the ORFs provided in Tables l(a), l(b) and 2.
S An inL~l~;enic sP.gmPnt, ûr a fr~gmPnt of the hlt~l~;ellic segmPnt from about 10 to 200 nucleotides in length, taken 5' from any one of the ORFs of Tables 1{a), 1(b), or 2 will mod~ fP the ~Al,lc~ion of an operably linked 3' ORF in a fashion similar to that found with the n~tllr~lly linked ORF
sequence. As used herein, an "h~L~l~ ellic segmPnt" refers to the fr~gment~ of the Haemophilus gPnome which are bcLwc~ell two ORF(s) herein described.
~ltPrn~tively~ EMFs can be irlPntifi~ using known EMFs as a target sequence or target motif in the colll~uLt;l-based systems of the present invention.
The ~,l~cll~ and activity of an EMF can be conr,lllled using an EMF
trap vector. An EMF trap vector contains a cloning site 5' to a marker sequence. A marker sequence enc~xles an id~Pntifi~hle phenotype, such as antibiotic rÇ~i~t~nre or a comr'~-nPnting nutrition auxotrophic factor, which can be identifie~1 or assayed when the EMF trap vector is placed within an ~ploLliate host under approl~liaLt; cQn~liti~n~. As described above, a EMF
will m~lll~te the ~Ayl~S~ of an operably linked marker sequence. A more ~et~ile~ cll~ n of various marker sequences is provided below.
A sequence which is sn~peot~l as being a EMF is cloned in all three reading frames in one or more restrir*on sites u~Ll~a~ll from the marker sequence in the EMF trap vector. The vector is then transforrned into an applupli~L~ host using known p~c~dnrP-~ and the ~lle,loLyl,e of the transformed host in PY~minPfl under ~lu~liat~ con-litions. As described above, an EMF
will modulate the ~;AL,le~,ion of an operably linked marker sequence.
As used herein, an "uptake mo~ ting fr~pment " UMF, means a series of nucl~Qti~ie moleclllPs which mPAi~tP the uptake of a linked DNA
f~gmPnt into a cell. UMFs can be readily i~PntifiPll using known UMFs as a target sequence or target motif with the colll~Lel-based systems described above.

SUBSTrrUTE S~tEET (RULE 26 W 096/33276 PCTrUS96/05320 The ~l~se lce and activity of a UMF can be confirmed by ~tt~hing the s..~ ~ UMF to a marker sequence. The res--lting nucleic acid molecule is then in~ub~tpcl with an al~p~ liale host under ~ liat~ conditions and the uptake of the marker sequence is determined. As described above, a UMF
~ 5 wiU i-lc~se the frequency of uptake of a linked marker sequence. A review of DNA uptake in Haemophilus is provided by Goodgall, S.H., et al., J. Bact.
172:5924-5928 (1990).
As used herein, a "~ gnostic fr~gmPnt " DF, means a series of nucleotide molecules which selectively hybridize to Haemophilus influenzae sequences. DFs can be readily idPntifiPIl by idell~iryillg unique sequences within the Haemophilus in~quenzae Rd genome, or by generating and testing probes or amplific~ti~ n primers con~i~ting of the DF sequence in an a~yl~lial~ g~ format which determines ~mplifi~ ~tion or hybrilli7~tion selectivity.
The sç~l-up-nrp~s faUing within the scope of the present invention are not limited to the spe~fic sequences herein described, but also include allelic and species v~ri~ti-~n~ thereof. Allelic and species v~ri~tion~ can be routinely de~e~l,lined by co...~ g the sequence provided in SEQ ID NO:l, a reprçsç.~ e fragment thereof, or a nucleotide sequence at least 99.9%
idçnti-~l to SEQ ID NO: 1 with a sequence from another isolate of the same species. Furthermore, to accommodate codon variability, the invention in~lll(les nucleic acid m~ l~cl~lps coding for the same amino acid sequences as do.the .spe~-ifiG ORFs disclosed herein. In other words, in the coding region of an ORF, substitlltion of one codon for another which encodes the same amino acid is expressly c~'~ tP~
Any s~ific sequence disclosed herein can be readily screened for errors by reseq~-çncing a particular fr~gm~-nt such as an ORF, in both directions (i.e., s~uPn~ both strands). Alternatively, error screening can be ~;lÇol"led -by sequencing collc~ndil~g poly.. ~ Ps of Haemophilus influenzae origin isolated by using part or all of the fr~gmP-nt~ in question as a probe or primer.

SUB5~11 UTE SHEET tRULE ~

-W 096/33276 PCTrUS96/05320 Each of the ORFs of the Haemophilus influenzae Rd genome disclosed in Tables l(a), l(b) and 2, and the EMF found 5' to the ORF, can be used in numerous ways as polynucleotide r~gent~ The sequences can be used as gnosti~ probes or rli~gnnst~ mplific~tion primers to detect the presence of a specific microbe, such as Haemophilus in~uenzae RD, in a sample. This is especially the case with the f~mP.nt~ or ORFs of Table 2, which will be highly selective for Haemophilus influenzae.
In ~iition, the fr~gm~-nt~ of the present invention, as broadly described, can be used to control gene e~ c~sion through triple helix formation or ~nti~-n~e DNA or RNA, both of which methods are based on the binding of a poly.,ucle~Lide sequence to DNA or RNA. Polynucleotides suitable for use in these m~.thotl~ are usually 20 to 40 bases in length and are de-~ign~l to be complem--nt~ry to a region of the gene involved in tr~n~c-rirtion (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251:1360 (1991)) or to the mRNA
itself (~ ~, - Okano, J. Neurochem. 56:560 (1991); Oligodeo~nl~cleot7~
as Antisense Inhibitors of Gene E~cpression, CRC Press, Boca Raton, FL
(1988))-SUBS 111 UTE S~E~ tRULE 2~i) W 096/33276 PCTrUS96/05320 Triple helix- formation optimally results in a shut-off of RNA tr~n~crirtion from DNA, while ~ ~ RNA hybritli7~ti-)n blocks t~n.~l~tion of an mRNA
molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems. Information cont~in~l in the sequences of the present invention is n~s~ry for the design of an ~ntieçnee or triple helix oligonucleotide .
The present invention further provides recombinant constructs a~mrrieing one or more fr~gm-onte of the Haemophilus influenzae Rd genome of the present invention. The recombinant constructs of the present invention c ~ p~ a vector, such as a pl~emi(l or viral vector, into which a fr~gmPnt of the Haemophilus iny?uenzae Rd has been inserted, in a Çulvv~d or reverse o. ;~ l;on In the case of a vector comprieing one of the ORFs of the present invention, the vector may further c~..,l.. ;~ regulatory sequences, inrlllrling for ~-Y~mplP, a ~,lulllO~, operably linked to the ORF. For vectors comprieing the EMFs and UMFs of the present invention, the vector may further comprise a marker sequence or heterologous ORF operably linked to the EMF or UMF.
Large IlUlllbel:i of suitable vectors and promoters are known to those of skill in the art and are commercially available for gent;,~ g the recombinant constructs of the present invention. The following vectors are provided by way of PY~mplP R~- tçri~l: pBs, ph~g~sc.;l.l, PsiX174, pRluescrirt SK, pBs KS, pNH8a, pNH16a, pNH18a, pNH46a (Stratagene); pTrc99A, pKK223-3, pKK233-3, pDR540, pRlT5 (Pharmacia). Eukaryotic: pWLneo, pSV2cat, pOG44, pXTl, pSG (str~enp) pSVK3, pBPV, pMSG, pSVL (Pharmacia).
Plulllo~l regions can be ~1~t~ from any desired gene using CAT
(chlo.~.. l.l.r-~ nl l.,~ rr~,.~) vectors or other vectors with sPl~-~t~hle m~rkPrs Two a~ "dL~ vectors are p~-8 and pCM7. Particular named ~ t-o.ri~l promoters include lacI, lacZ, T3, T7, gpt, lambda PR~ and trc. Eukaryotic promoters include CMV imm~Ai~t~ early, HSV thymidine kinase, early and - late SV40, LTRs from retrovirus, and mouse metallothionein-I. Selection of the appr~,iate vector and promoter is well within the level of o,.linaly slcill m the art.

SUBSmUTE ~H~ET tRULE 2'6) The present invention further provides host ceUs cn~ h-g any one of the isolated fr~gmPntc of the Haemophilus inf~uen~ae Rd genome of the present invention, wherein the fr~mPnt has been introduced into the host cell using known transformulation methods. The host cell can be a higher eukaryotic S host cell, such as a m~mm~ n cell, a lower eukaryotic host cell, such as a yeast cell, or the host cell can be a pn~c~yl)~ic cell, such as a b~c tPri~l cell.
Intro~ rtion of the lcco~-~bin~t construct into the host ceU can be effected by calcium phnsrh~tP transfection, DEAE, dextran mP~ tP~ transfection, or el~;L.~"~ol~lion (Davis, L. et al., Basic Methods in Molecular Biology (1986)).
The host cells col.f;~;nil-g one of the fr~f~mPnt~ of the Haemophilus inyquenzae Rd genome of the present invention, can be used in conventional ...~1-l-~. . to produce the gene product encoded by the i~ol~tP~ fr~gmPnt (in the case of an ORF) or can be used to produce a heterologous protein under the control of the EMF.
The present invention further provides i~l~tPd polypeptides enrod~
by the nucleic acid fr~gmPnt~ of the present invention or by ~e~enPr~t~
variants of the nucleic acid r, ~ ; of the present invention. By "degr.~
v~iant" is int~-n~ nucleotide fr~mPnt~ which differ from a nucleic acid r.,.~ ..l of the present invention (e.g., an ORF) by nucleotide sequence but, due to the ~1te~ n~ry of the Genetic Code, encode an idPntic~l polypeptide sequence. Plcrt;lled nucleic acid fr~gmPnt~ of the present invention are the ORFs depicted in Table 1(a) which encode proteins.
A variety of mPth- dologies known in the art can be utilized to obtain any one of the i~ol~tp~1 polypeptides or plo~ehls of the present invention. At the ~implPst level, the amino acid sequence can be sy.. ll.P-~i7~1 using commercially available peptide synth~i7p-r~ This is particularly useful in prodllring smaU peptides and fr~gmPnt~ of larger polypepfi-les Fr~gmt-nt~ are useful, for Py~mple, in gPnPr~ting antibodies against the native polypeptide.
In an ~ltp-rn~tive mPth~xl, the polypeptide or protein is purified from b~rtPri~l ceUs which naturally pl~lUCe the poly~;~tide or protein. One skilled in the art can readily follow known m~thn~s for i~ol~ting polpeptides and proteins in SUBSTITUTE S}~ FET ~RULE 26) order to obtain one of the i~ t~l polypeptides or proteins of the present invention. These in~ d~p~ but are not limited to, immunochlvlna~o~ld~l.y, HPLC, size-eYclll~ion cl~ alogld~lly, ion-eYch~nge cl,lo...~ gr~phy, and immuno-affinity ci~ la~ogl~ y.
S The pOly~e~!;rlP-s and ~ teu,s of the present invention can ~ltPrn~tively be purified from cells which have been altered to express the desired polypeptide or protein. As used herein, a cell is said to be altered to express a desired polypeptide or protein when the cell, through genetic manipulation, is made to pl~luce a polypeptide or protein which it normally does not produce or which the ceil normally produces at a lower level. One skilled in the art can readily adapt ~r~lules for introducing and eAples~ing either reco"lbinallt or synthetic seguences into eukaryotic or prokaryotic cells in order to ge~ a cell which produces one of the polypeptides or proteins of the present invention.
Any host/vector system can be used to express one or more of the ORFs of the present invention. These inr~ e, but are not limited to, eukaryotic hosts such as HeLa cells, Cv-l cell, COS cells, and Sfg cells, as well as prokaryotic host such as E. coli and B. subtilis. The most pl~relled cells are those which do not normally express the particular polypeptide or protein or which eApl~s the polypeptide or protein at low natural level.
"Recombinant," as used herein, means that a polypeptide or protein is derived from ,~...hi~ (e.g., microbial or ~-~....-.~li~n) ~Aples~ion systems.
"Microbial" refers to recombinant polypeptides or proteins made in b~teri~l or fungal (e.g., yeast) eA~,es~ion systems. As a product, "recombinant microbial" defines a polypeptide or protein e-~i~e~ lly free of native o~nVu~ subst~n~-s and u~ i~ by associated native glycosylation.
Polypeptides or proteins eA~,es~ in most b~-t~--ri~l cultures, e.g., E. coli, will be free of glycosylation mn~ifi~tion~; polypeptides or proteins eA~lessed in yeast will have a glycosylation pattern diLre cnt from that eA~le~sed in ... ~ n cells.

SVBSTlTUTE S~tEET (RULE 2~) = CA 02218741 1997-10-21 W O 96133276 PCTnUS96/05320 "Nucleotide sequence" refers to a heteropolymer of deoxyribom~c~ tides. Generally, DNA se~ .L~ çnc~ling the polypeptides and proteins provided by this invention are assembled from fragmPnt~ of the Haenwp~ulus i~?flu~nz~e Rd gPnnmP and short oligonucleotide linkers, or from S a series of oligon~lcl~.o~tides, to provide a ~7ylltheLic gene which is capable of being t;~ ;ssed in a recomhin~nt tr~n~criptional unit compnsing regulatory el~mPnt~ derived from a microbial or viral operon.
"Recomhin~nt ~ ssion vehicle or vector" refers to a pl~mirl or phage or virus or vector, for ~ g a polypeptide from a DNA (RNA) sequence.
The eAples~ion vehicle can comprise a t~n~ riptional unit compri~ing an ~Pmhly of (1) a genetic e1emPnt or plPmPnt~ having a regulatory role in gene t;A~,ession, for eY~mrle, promoters or enh~n~prs~ (2) a structural or coding sequence which is tr~n~rihed into mRNA and tr~n~l~tP~ into protein, and (3) a~pro~,iat~ t~ S~ Lion initizltion and l~. ---i,-~l;nn sequences. Structuralunits intendPll for use in yeast or eukaryotic t;Aples~,ion systems preferably include a leader s~u~nce en~h1in~ PYtracP~ r secretion of tr~n~l~tP~ protein by a host cell. Alternatively, where lccolllh~ protein is c~lessed without a leader or transport sequence, it may include an N~ l mPthioninP
residue. This residue may or may not be subsequently cleaved from the eA~r~ssed ieco.. l ;--~nt protein to provide a final product.
"Recombinant ~AL"~e.,sion system" means host cells which have stably ;~lr.~,l, lrl~ a l~...l)i.~i.t tr~n~rirtional unit into chromosomal DNA or carrythe recolllbillant transcriptional unit extra chromosomally. The cells can be prokaryotic or eukaryotic. Reco,llbinant t;A~les.,ion systems as defined herein will express heterologous polypeptides or proteins upon induction of the regulatory el~mPnt~ linked to the DNA s~PgmPnt or synthetic gene to be ~,Aplessed.
Mature p,~ s can be ~Ap~ sed in m~mm~ n cells, yeast, b~teri~
or other cells under the control of a~prup,iaLe promoters. Cell-free tr~n~1~tionsystems can also be employed to produce such proteins using RNAs derived from the DNA constructs of the present invention. A~r~,~,iate cloning and SUBST~TUTE SHEET tRULE 26) W 096/33276 PCTrUS96/05320 cAylèS~iOn vectors for use with prokaryatic and eukaryotic hosts are described by Sambrook, et al., in Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, New York (1989), the rlic~losllre of which is hereby incolyuld~d by reference.
- 5 Gener~lly, recombinant cAyre~ion vectors will include origins of replir~tion and select~hle Illa,kcl~ ye~ illing tran~Çullllalion of the host cell, e.g., the ~mpicillin reci~t~nce gene of E. coli and S. cerevisiae TRP1 gene, and a promoter derived from a highly-cAylessed gene to direct tr~n~crirtion of a downstream structural sequence. Such promoters can be derived from operons çnco~ing glycolytic enzymes such as 3-phosphoglycerate kinase (PGK), a-factor, acid phn~yh~ or heat shock proteins, among others. The heterologous structural sequence is assembled in apylvyliate phase with tr~n~l~tinn initi~tion and tcl~l~inalion sequences, and preferably, a leader sequence capable of directing secretion of tr~n~l~t~ protein into the peripl~mic space or eytr~ r m~Ainm. Optionally, the heterologous sequence can encode a fusion protein inr~ ing an N-t~llllihlal ic~entific~tiQn peptide illly~hLillg desired çh~r~-~t~ri~ties, e.g., stabilization or simplifiedpllrifie~tiQn of eAylc:,sed lcco",binalll product.
Useful c~yle~ion vectors for b~ tPri~l use are constructed by inserting a structural DNA sequence en~ ing a desired protein together with suitable tr~n~l~tinn initi~tinn and l~ ;nn signals in operable reading phase with a functional ylulllolel. The vector will comprise one or more phenotypic selectable Ill~l~ and an origin of rep~ tinn to ensure m~int~n~nce of the vector and to, if desirable, provide ~mplific~tion within the host. Suitable prokaryotic hosts for transfnrm~tion include E. coli, R(7cilll/~ su~ilis, Salmonella typ~umurium and various species within the genera Pseudomonas, SLI~y~llly~s, and Staphylococc~-~, although others may, also be employed as a matter of choice.
As a leylc~lll~ re but n--nlimiting ~Y~mple, useful ~ ylc;~ion vectors for b~ t~ri~l use can comprise a s~loct~hle marker and b~ct~ri~l origin of re.pli~tinn derived from commercially available pl~mirl~ compri~in~ genetic SUBSTITUTE S~EET (RULE 2~) W 096/33276 PCTrUS96/05320 çlemPnt~ of the well known cloning vector pBR322 (ATCC 37017). Such commercial vectors in~ de., for PY~mrle, pKK~ 3 OEh~rm~ Fine Chemicals, Uppsala, Sweden) and GEM 1 (P-ulllega Biotec, M~ on, WI, USA). These pBR322 "bac~l~ne" sçctic n~ are combined with an a~pro~-iaLG
promoter and the structural sequence to be ~ A~.essed.
Following L~ srul-nation of a suitable host strain and growth of the host strain to an appi~p idl~ cell density, the sçl~ctPd promoter is derepressed by a~ LG means (e.g., ~ G shift or f hPmic~l inductiQn) and cells are cultured for an ~ iticm~1 period. Cells are typically harvested by centrifugation, disrupted by physical or ~ hPmiç~l means, and the rPsu1ting crude extract retained for further pnrific~tion Various m~mm~ n cell culture systems can also be employed to eA~ress recombinant protein. Fy~mrlps of n ,~",...~ n c AplG:i~ion systems include the COS-7 lines of monkey kidney fibroblasts, described by Gl~-7m~n, Cell 23:175 (1981), and other cell lines capable of GA~les~il-g a cc,lllpalible vector, for PY~mI)le, the C127, 3T3, CHO, HeLa and BHK cell lines.
M~mm~ n GA~lG:~:iion vectors will comprise an origin of reI~lic~ti-n, a suitable promoter and ~--h~n~. .., and also any ~ y ~il~osollle binding sites, polyadenylation site, splice donor and acceptor sites, tr~n~crirtional te.. i~ n sequences, and 5' fl~nking nontr~n~çrihed sequences. DNA
sequences derived from the SV40 viral genome, for PY~m~le, SV40 origin, early promoter, enh~n~Pr, splice, and polyadenylation sites may be used to provide the required nc-nt~n~rrihed genetic elements.
Recombinant polypeptides and ~roL~ins produced in b~ tPri~l culture is usually i~ol~tP~1 by initial P.tr~çtion from cell pellets, followed by one ormore salting-out, aqueous ion eY,--h~nge or size eYcl~ n chlo...~tugr~rhy StGps. Protein refolding steps can be used, as n~ç~ry, in completing configuration of the mature protein. Finally, high l?e r~ lance liquid chro...~lc)p..~ .y (HPLC) can be employed for final pllrific~tion steps.
Microbial cells employed in GA~lession of proteins can be disrupted by any SUBSTrrUTE ~}~FET ~RULE 26~

W 096/33276 PCTnUS96/05320 convenient method, in~ rling freeze-thaw cycling, sonication, mPrh~nic~l disruption, or use of cell lysing agents.
The present invention further inc1~des i~ol~tPc~ polypeptides, proteins and nucleic acid molP~u1Ps which are subsf~nti~11y equivalent to those herein S described. As used herein, subst~nti~11y equivalent can refer both to nucleic acid and amino acid sequences, for example a mutant sequence, that varies from a reference sequence by one or more substitlltionc~ dP1Ptionc, or z~ litionc, the net effect of which does not result in an adverse functional ~liccimi1~rity between reference and subject sequences. For pul~oses of the plcselll invention, sequences having equivalent biological activity, and equivalent cA~lc~ion ch~r~tericti~s are con~ pred subct~nti~lly equivalent.
For pul~oses of dc~c~mi~ g equivalence, truncation of the mature sequence should be disregarded.
The invention further provides mPthods of obt~u~ g homologs from lS other st~ains of Haemophilus influenz~e, of the fr~gm~ntc of the Haemophilus influenzae Rd genome of the present invention and homologs of the proteins ~nro~Pd by the ORFs of the present invention. As used herein, a sequence or protein of Haemophilus influen~e is defined as a homn1Og of a fr~gm~nt of the Haemophilus influenza~ Rd genome or a protein encoded by one of the ORFs of the present invention, if it shares cignifi~nt homology to one of the r.~g...~ of the Haemophilus infl~uenzae Rd genome of the present invention or a protein encoded by one of the ORFs of the present invention.
~SpPnifi-~11y, by using the sequence disclosed herein as a probe or as primers, and techniques such as PCR cloning and colony/plaque hybril1i7~tinn, one skilled in the art can obtain homologs.
As used herein, two nucleic acid mo1ec111Ps or proteins are said to "share ~i~nifi~nt h- ...o1~y" if the two contain regions which process greater than 85 % sequence (amino acid or nucleic acid) homology.
- Region specific'primers or probes derived from the nucleotide sequence provided in SEQ ID NO:l or from a nucleotide sequence at least 99.9%
identi~1 to SEQ ID NO:l can be used to prime DNA synthesis and PCR
~mp1ifi~tion, as well as to identify colonies U)nli inil-g cloned DNA encoding SUBSTI~UTE SH EET tRULE 26) W 096/33276 PCTrUS96tO5320 a homolog using known m.otho le (Innis et al., PCR Protocols, Ac~ omic Press, San Diego, CA (1990)).
When using primers derived from SEQ ID NO: 1 or from a nucleotide sequence at least 99.9 % identi~ to SEQ ID NO: 1, one skilled in the art will rt~COg~ that by employing high stringency con-liti~-ne (e.g., ~nnP~linp at 50-60~C) only sequences which are greater than 75% homologous to the primer will be ~mrlifi~l By employing lower string~n~y con-iitinne (e.g., ~nnP~lin~
at 35-37~C), sequences which are greater than 40-50% homologous to the primer will also be ~mplifi~d When using DNA probes derived from SEQ ID NO:l or from a nucleotide sequence at least 99.9 % i~l~ntir~l to SEQ ID NO: 1 for colony/plaque hybri~li7~tion, one skilled in the art will recogni_e that by employing high stringency con-iiti~ ne (e.g., hybri~i7in~ at 50-6S~C in 5X
SSPC and 50% r~ e, and washing at 50-65~C in 0.5X SSPC), s~u~nces having regions which are greater than 90% homologous to the probe can be obl~ined, and that by employing lower stringency contliti~ns (e.g., hybri~i7in~ at 35-37~C in 5X SSPC and 40-45% ior...~...i-le, and washing at 42~C in SSPC), sequences having regions which are greater than 35-45%
homologous to the probe will be o~ ed.
Any organism can be used as the source for homologs of the present invention so long as the organism n~t~ lly t;A~r~sses such a protein or cc nt~ine genes ~I lI',~i~p the same. The most pr~rc;ll~d organism for i eol~ting homologs are b~cteri~e which are closely related to Haemophilus influen~ae Rd.

Usesfor the 1~ ns of fhe Inventwn Each ORF provided in Table l(a) was ~eeipn~d to one of 102 biological role ca~egolies adapted from Riley, M., Microbiology Reviews 57(4J:862 (1993)). This allows the skilled artisan to determine a use for each i~lentifi~
coding s~~ - Tables l(a) further provides an icl.ontifi~tion of the type of polypeptide which is ~nt~4ded for by each ORF. As a result, one skilled in the art can use the polypeptides of the present invention for commercial, SUBSTITUTE SHEET (RULE 26) W 096/33276 PCTrUS96/05320 rld~ulic and indll~triAl purposes con~i~tent with the type of putative ntifi~ti~n of the polypeptide.
Such ~ ntifi~ Ati~ n~ permit one sl~led in the art to use the Haemophilus influen~ae OJ~s in a manner similar to the known type of sequences for which - 5 the idetltificAtinn is made; for example, to ferment a particular sugar source or to produce a particular metabolite. (For a review of enzymes used within the commercial industry, see Biochemical Engineering and Biotechnology Handbook 2nd, eds. Macmillan Publ. Ltd., NY (1991) and Biocatalysts in Organic Syr.ll.P.ses, ed. J. Tramper et al., Elsevier Science Publishers, Am~le,.la,l" The NethPrlAntl~ (1985)).

1. Bwsynthetzc Enz~ymes Open reading frames encoding proteins involved in mt~liAting the catalytic reactions involved in intermediary and macromnle~ulAr metabolism, the biosynthesis of small molPcllles, cellular plucesses and other functions in~hl~es enzymes involved in the de~rAtlAtion of the intermp~liAry products of metabolism, elLGyl"es involved in central intermPAiAry metabolism, enzymes involved in r~i.dtion, both aerobic and anaerobic, enzymes involved in ferm~ntAtiQn, enzymes involved in ATP proton motor force conversion, enzymes involved in broad regulatory function, enzymes involved in amino acid synthesis, el~yl"es involved in nucleotide synthto~i~, enzymes involved in cofactor and vitamin synth~ , can be used for in~ triAl biosynthesis. The vanous metabolic pathways present in Haemophilus can be iclentifi~ based on Ahsnlllto "~ as well as by r~ g the various enzymes i~ientifi~d in Table l(a).
I~entifi~ within the ca~goly of intermediary metabolism, a number of the ~lu~ills en~l~ by the i~l.ontifi~i ORPs in Tables l(a) are particularly - involved in the degrA-l~tion of intermediary metabolites as well as non-macromc-leculAr metabolism. Some of the enzymes i~entifi~d include amylases, glucose oxi~lA~es, and cAtAlA~e SUBS i i I UTE S~E T tRULE 2~) W 096133276 PCTrUS96/05320 Proteolytic e";cy"les are another class of commercially i"lpol~nt enzymes. Proteolytic enzymes find use in a number of in~ stri~1 processes inr~ linfr the ~,locess~,lg of flax and other vegetable fibers, in the extraction, rl~rific~tion and ~le~ l;on of fruit juices, in the eYtr~tion of vegetables' oil and in the m~.-Pr~ti--n of fruits and vegetables to give unicPlllll~r fruits. A
~et~ile~ review of the proteolytic enzymes used in the food industry is provided by Rombouts et a~., Symbiosis 21:79 (1986) and Voragen et al. in Biocatalyst in Agricultural Biotechnology, edited J.R. Whitaker et al., American Chemical Society Symposium Series 389:93 (1989)).
The metabolism of gl~lcQse~ g~ tose, fructose and xylose are t parts of the ~lill~y metabolism of Haemophilus. Fn7ymes involved in the degradation of these sugars can be used in inrillstri~l ferm~nt~ti~ n.
Some of the illl~?o~ sugar tran~L~ll"ing en_ymes, from a commercial viewpoint, include sugar isc,~ s such as glucose isomP-r~P Other IIlG~bolic en_ymes have found CO""~G1- ial use such as glucose oxidases which produces l~P-tQ~I~lonic acid (KGA). KGA is an intermPAi~tP in the commercial production of ascorbic acid using the R~i~h~tPin's procedure (see Krueger etal.,Biotechnology6(A), Rhine, H.J. etal., eds., VerlagPress, WPinh~Pim, G~.lll~ly (1984)).
Glucose o~ e (GOD) is comlllGl~ially available and has been used in purified form as well as in an immobilized form for the deoxygenation of beer. SeeHartmeiretal.,BiotechnologyLettersl:21 (1979). Themost applic~tion of GOD is the in~ tri~l scale f~ n of gluconic acid. M~rk~t for pll-c~nic acids which are used in the detergent, textile, leather, photographic, pharm~ ti~l, food, feed and concrete industry (see Bigelis in Gene Maruplda~ions and Fungi, Benett, J.W. et al., eds., Ac~-lemic Press, New York (1985), p. 357). In ~ liti~n to in~ stri~l applications, GOD
has found applic~tinn~ in m.oAi~ ine for ~lu~n~ e det~...i.~i.l;o~ of glucose in body fluids l~cen~ly in biot~hnok)gy for analyzing syrups from starch and cellulose hydrosylates. See Owusu et al., Biochem. et Biophysica. Acta.
872:83 (1986).

SUBST~TUTE ~ E:ET tRULE 2~3 W 096133276 PCTrUS96/05320 The main sweetener used in the world today is sugar which comes from sugar beets and sugar cane. In the field of in~ stri~l enzymes, the glucose isol"cld~e process shows the largest exr~n~ n in the market today. Initially, soluble enzymes were used and later immobilized enzymes were developed S (Krueger et al., Biotechnology, The Textbook of Industrial Microbiology, Sinauer ~ 1~1 Incc, ~ Sun~lPrl~n-l, M~rhll~ett~ (1990)). Today, the use of glucose-produced high rlu~;~se syrups is by far the largest in-lustri~l business using immobilized enzymes. A review of the in-1u~tri~1 use of these enzymes is provided by Jolgensc,l, Starch 40:307 (1988).
Protein~ps~ such as ~ll~linP serine ~ e;~ P~s, are used as de~cl~;
additives and thus lcl~lcsellt one of the largest volumes of microbial el~y",es used in the industrial sector. Re~ e of their in-i~lstri~l i"l~ol~lce, there is a large body of published and unpublished information lCgaL-lillg the use of these enzymes in in~ tri~ S. (See F~ tm~n et al., Acid Proteases Structure Function and Biology, Tang, J., ed., Plenum Press, New York (1977) and Godfrey et al., In~strial Enzymes, ~rMi11~n Pllkli~hpr~ Surrey, UK (1983) and Hepner et al., Report Industrial Enzymes by 1990, Hel Hepner &.A.cs~-i~les~ T~n-lon (1986)).
Another class of co.. ~-~;ally usable proteins of the present invention are the microbial lipases i-lPntifip~l in Table 1 (see Macrae et al., Philosophical Transactions of the Chiral Society of Lon~lon 310:227 (1985) and Poserke, Jou~l of the American Oil C/iemist Society 61: 1758 (1984). A major use of lipases is in the fat and oil industry for the production of neutral glycerides using lipase catalyzed inter-estPrifir~tion of readily available triglycPri~1p~
Appli~til n of lipases include the use as a de~l~ell~ additive to f~rilit~te theremoval of fats from fabrics in the course of the washing procedures.
The use of enzymes, and in particular microbial enzymes, as catalyst for key steps in the ~yll~hesis of complex organic molecules is gaining - popula~ity at a great rate. One area of great interest is the ~ n of chiral ;--I~ S. P~ n of chiral intr.rmP~ t~ is of interest to a wide range of synthetic chemi~t~ particularly ~ose sri~onticte involved with the ~l~d~ion SUBSmUTE 5~ E~T (RULE

W 096/33276 PCT~US96/05320 of new ph~rmaçelltif~lc, agroGhP-mic~lc, fr~r~nrps and flavors. (See Davies et al., Recent Advances in the Generation of Chiral lntermediates Using En~ymes, CRC Press, Boca Raton, Florida (1990)). The following re~ctions catalyzed by enzymes are of interest to organic çhPmictc hydrolysis of carboxylic acid esters, phnsph~tP esters, amides and nitrileC, çstprific-~tinn re~r*onc, trans-ect~p-rific~tion re~rtionc~ ~,ynLlle~is of ~mi~les, reduction ofz~lk~nc~nPs and ox~ D.n~tPs" oxidation of ~l~hc~lc to carbonyl c~,.l~unds, cxitl~ti-)n of sulfides to slllfoxi~l~ps~ and carbon bond forming rP~ctionC such as the aldol r~o~rtion When cnn~ Prin~ the use of an enzyme encoded by one of the ORFs of the present invention for biotran~ru",laLion and organic synthesis it is somPfimPs nP~P~y to con~ er the respective advantages and disadvantages of using a microorganism as opposed to an icol~tPA enzyme.
Pros and cons of using a whole cell system on the one hand or an icol~tP~i partially purified enzyme on the other hand, has been ~esçribe~ in detail by Bud et al., Chemistry in Britain (1987), p. 127.
Amino tr~ncfer~cps~ enzymes involved in the biosynthesis and metabolism of amino acids, are useful in the catalytic pr~ucfion of amino acids. The advantages of using microbial based enzyme systems is that the amino tr~ncfPr~cP enzymes catalyze the stereo-selective synthesis of only l-amino acids and generally possess ~ll~ir~llllly high catalytic rates. A
description of the use of amino transferases for amino acid production is provided by Roselle-David, Methods of Er~ymology 136:479 (1987).
Another ~l~gUly of useful ~)luk;~lS encoded by the ORFs of the present invention include enzymes involved in nucleic acid synthPci~, repair, and lcco~l~binaLion. A variety of c~ ;ally illll~Ull~lllt enzymes have previously been icol~tP~l from members of Haemophilus sp. These include the Hinc II, Hind III, and Hinf I restriction enrlnnl~r1~ces. Table l(a) iclPntifiPs a wide array of enzymes, such as restriction enzymes, ligases, gyrases and metnylases, which have i.. Pfli~e use in the biotPrlmolQgy industry.

2. Generation of ~r~trbo~ies SUBSTITUTE S~tE~T tRULE 2~i~

W 096/33276 PCTrUS96/05320 As described here, the proteins of the present invention, as well as hnmnlogc thereof, can be used in a variety procedures and methods known in the art which are ~;ul~nlly applied to other proteins. The proteins of the present invention can further be used to gp~ an antibody which selectively binds the protein. Such antibodies can be either mono~lon~l or polyclonal antibodies, as well fr~gm~nt.c of these antibodies, and h~ P.1 forms.
The invention further provides antibodies which selectively bind to one of the proteins of the present invention and hybridomas which produce these antibodies. A hybridoma is an immortalized cell line which is capable of se;lt;Ling a c~ific mnnoclonal antibody.
In general, techniques for p~ g polyclonal and monoclonal antibodies as well as hybridomas capable of ~lu.h~ g the desired antibody are well known in the art (Campbell, A.M., Monoclonal Antibody Technology:
Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers, Am~l~lda"" The ~h~rl~ntls (1984); St. Groth et al., J.
Irrununol. Methods 35:1-21 (1980); Kohler and Milct~in, Nature 256:495-497 (1975)), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., Immunology Tod~y 4:72 (1983); Cole et al., in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985), pp. 77-96).
Any animal (mouse, rabbit, etc.) which is known to produce antibodies can be immlmi7Pcl with the pseudogene polypeptide. Methods for i..",..-..;,~l;nn are well known in the art. Such mPthorls include subcutaneous or in~e.~.;l~ l injection of the polypeptide. One skilled in the art will recognize that the amount of the protein en~ocled by the ORF of the present invention used for immllni7~tinn will vary based on the animal which is i.. -.. ~i,~d, the antigenicity of the peptide and the site of injection.
The protein which is used as an immunogen may be modified or z~iminictt-red in an adjuvant in order to increase the protein's antigenicity.
- Methods of increasing the ~ntig~nicity of a protein are well known in the art and include, but are not limited to coupling the antigen with a heterologous SUBS~TTUTE St~ EET tRULE ;~6) W 096/33276 PCTrUS96/05320 protein (such as globulin or ,B-g~ tc s~ cP) or through the inclusion of an adjuvant during i,.,.."..~ inn.
For monoclonal antibodies, spleen cells from the immlmi7PA ~nim~ls are removed, fused with myeloma cells, such as SP2/0-Agl4 myeloma cells, and allowed to become monoclonal antibody producing hybridoma cells.
Any one of a number of mPthol1c well known in the art can be used to identify the hybridoma cell which produces an antibody with the desired h~r~-tPrictics. These include s~ g the hybridomas with an ELISA assay, weslelll blot analysis, or radi~ c~y (Lut~ et al., Exp. Cell Res.
1 75: 109-124 (1988)) .
Hybridomas secreting the desired antibodies are cloned and the class and subclass is determined using procedures known in the art (Campbell, A.M., Monoclonal Antibo~ Technology: Laboratory Techniques in Bioc~,.~lr~ and MolecularBiology, Elsevier Science Publishers, Am~l~ul"
The NethPrl~n-1s (1984)).
Techniques dçc~rihed for the production of single chain antibodies (IJ.S. Patent 4,946,778) can be ~ rtPA to produce single chain antibodies to proteins of the present invention.
For polyclonal antibodies, ~nlil,~<xly c4..'~ hlg ~nhcPr~ is isolated from the ;~ A animal and is screened for the presence of antibodies with the desired specificity using one of the above-described procedures.
The present invention further provides the above-described antibodies in ~etprt~hly l~hellPA form. Antibodies can be ~etP~t~hly labelled through the use of radioisotopes, affinity labels (such as biotin, avidin, etc.), en~y,llaLic labels (such as hl~rcPr~-lieh peroYi~l~cP-~ ~lk~linP phosphatase, etc.) fluoL~sccllt labels (such as FITC or rh~mine, etc.), p~r~m~gnPtic atoms, etc.
Procedures for accompliching such labelling are well-known in the art, for example see (Sternberger, L.A. et al., J. Histochem. Cytochem. 18:315 (1970); Bayer, E.A. et al., Meth. Er~:ym. 62:308 (1979); Engval, E. et al., Inununol. 1~.129 (1972); Goding, J.W. J. Immunol. Meth. 13:215 (1976)).

SU8S l l l UTE S}tEET ~RULE 2~) W 096/33276 PCTrUS96105320 The labeled antibodies of the present invention can be used for in vitro, in vivo, and in situ assays to identify cells or tissues in which a fragment of the Naemophilus influenzae Rd genome is ~Aples.,ed.
The present invention further provides the above-described antibodies immobilized on a solid support. Examples of such solid ~u~ , include plastics such as polycarbonate, complex carbohydrates such as agarose and seyharose~ acrylic resins and such as polyacrylamide and latex beads.
Techniques for coupling antibodies to such solid ~711~)1ki are well known in the art (Weir, D.M. et al., "Handbook of Experimental Immunology" 4th Ed., Blackwell S~ ientific Publi~tinn~7 Oxford, P.ngl~nfl, Chapter 10 (1986);
Jacoby, W.D. et al., Meth. Enzym. 34 ~c~(lemic Press, N.Y. (1974)). The immobilized antibodies of the present invention can be used for in vitro, in vivo, and in situ assays as well as for immlmo~ffinity p~-rifi~tinn of the proteins of the present invention.

lS 3. D~ , r ~ Assays and Kits The present invention further provides m.-th~s to identify the ~Al,r~ssion of one of the ORFs of the present invention, or homolog thereof, in a test sample, using one of the DFs or antibodies of the present invention.
In detail, such methods comri~e inc~lb~ting a test sample with one or more of the antibodies or one or more of the DFs of the present invention and assaying for binding of the DFs or antibodies to co.nl)onents within the test sample.
Cnn-lition~ for i~u ub~t;l~g a DF or antibody with a test sample vary.
Incubation conditions depend on the format employed in the assay, the ~le-tection methods employed, and the type and nature of the DF or antibody used in the assay. One skilled in the art will recognize that any one of the - co-.. -.. only available hybri-1i7~ti~ n, amplific~tion or imm~mological assay formats can readily be adapted to employ the DFs or antibodies of the present invention. Examples of such assays can be found in Chard, T., An SUBSmUTE S~E~T (RULE 26) =

W 096133276 PCTrUS96/05320 Introduction to Radioimrnunoassay and Related Techniques, Elsevier Science Publishers, Am~L~ld~l" The Nt;~ lAn-l~ (1986); Bullock, G.R. et al., Techniques in Im~nunocytochemistry, Ac~-lPmic Press, Orlando, FL Vol. 1 (1982), Vol. 2 (1983), Vol. 3 (1985); Tijssen, P., Practice and Theory of Enyme Imm~oassays: L~,~ci,~ Techniques in Biochemistry and Molecular Biology, Elsevier Science Publi~hP-~, All~sLel-lalll, The NethPrl~n-l~ (1985).
The test ~AmplPs of the present invention include cells, protein or ~.dl~e extracts of cells, or binlngi~l fluids such as sputum, blood, serum, plasma, or urine. The test sample used in the above-described method will vary based on the assay format, nature of the detection method and the tissues, cells or eYtr~-t~ used as the sample to be assayed. MethfKl~ for p.el,~,ng protein extracts or membrane extracts of cells are well known in the art and can be readily be adapted in order to obtain a sample which is co...l)AIihlP with the system utili7P~
In another embo limpnt of the present invention, kits are provided which contain the n~-C~A~ reagents to carry out the assays of the present invention.
S~-;l;CA11Y, the invention provides a ~Il~ Ali7Pd kit to receive, in close co..l;,~ n(, one or more CO~IA;ne~:~ which comprises: (a) a first COj~IA;I~Pr compri~ing one of the DFs or antibodies of the present invention;
and (b) one or more other c~ ;n~:. CCi---~ ;ng one or more of the following:
wash reAgPnt~, reagents capable of ~etP~ting presence of a bound DF or antibody.
In detail, a colll~l...PntAli7Pd kit in.-ludPs any kit in which reagents are cnntAinPA in S~.~AIAI~.CnnlA;~ j. Such COnIA;nPI~ include small glass containers, plastic contAinPrs or strips of plastic or paper. Such contAinPr~
allows one to efficiently transfer reagents from one co~ lllent to another colll~alLIllent such that the ~mplPs and reagents are not cross-col-l~",il-~tP11, and the agents or soll-tion~ of each container can be added in a 4llAntilAI;~re fashion from one colll~llllellt to another. Such cont~inPrs will include a conlaill~r which will accept the test ~mp1P, a contAinPr which cont~in~ the SU85T~UTE S~ E~:T tRULE ~

- = :

W O 96/33276 PCTrUS96/05320 antibodies used in the assay, cont~int~rs which contain wash reagents (such as pl~ urr~lcd saline, Tris-buffers, etc.), and cont~inprs which contain the reagents used to detect the bound antibody or DF.
Types of det~ti~ n reagents include l~hP~led nucleic acid probes, S l~hPIl~ s~n~1~ry antibodies, or in the ~ltern~tive~ if the ~ ll~y antibody is labelled, the el~llldLiC, or antibody binding reagents which are capable of reacting with the labelled antibody. One skilled in the art will readily recognize that the disclosed DFs and antibodies of the present invention can be readily incc,l~uldLed into one of the established kit folllldl~ which are well known in the art.

4 Screening Assay for Ri~ g Agents Using the isolated proteins of the present invention, the present invention further provides methods of obta~ing and idellLiryillg agents which bind to a protein ~nc(KI~ by one of the ORFs of the present invention or to one of the fr~gmPnt~ and the Haemophilus genome herein described.
In detail, said method compri.~s the steps of:
(a) conf~ ~ting an agent with an icol~t~ protein encoded by one of the ORFs of the present invention, or an i~ol~tPA fr~gml-nt of the Haemophilus genome; and (b) determining whether the agent binds to said protein or said fragm~nt The agents screened in the above assay can be, but are not limited to, peptides, carbohydldl~s, vitamin derivatives, or other pharm~re~ltir~l agents.
The agents can be sPl~ted and screened at random or r~tion~lly s~--lrcteA or ~le~ nrA using protein modeling techniques.
For random sclcel~ing, agents such as peptides, carbohydrates, - pl~ r~ ;r~l agents and the like are selected at random and are assayed for their ability to bind to the protein encoded by the ORF of the present invention.

SUBSTITVTE St{EET (RULE 2~) W 096/33276 PCTrUS96/05320 ~ltPrn~tively, agents may be r~ti( n~lly selected or de~ipn-P~ As used herein, an agent is said to be "r~ti~n~lly ~PlPct~l or de~ign-F~l" when the agent is chosen based on the configuration of the particular protein. For eY~mrle, one skilled in the art can readily adapt curlGlllly available procedures to S gen~ P peptides, pharm~eutic~l agents and the like capable of binding to aspecific peptide sequence in order to generate rationally de~ignF~ lLi~ide peptides, for example see Hurby et al., Applic~ti~ n of Synthetic Peptides:
~nti~Pn~e Peptides," In Synthetic Peptides, A User's Guide, W.H. Fl~~n~
NY (1992), pp. 289-307, and K~7~k et al., Bio~7~,~lr~ 28:9230-8 (1989), or l,hal~ eutic~l agents, or the like.
In ~lflitinn to the rolt;goillg, one class of agents of the present invention, as broadly /1es(~ril~ed~ can be used to control gene eApres~ion through binding to one of the ORFs or EMFs of the present invention. As described above, such agents can be randomly screened or r~*on~lly de~ignP~l/sel~Pct-P~ Targeting the ORF or EMF allows a skilled artisan to design s~u~n~ specific or P1F..~n~ specific agents, m~~ ting the e~?res~ion of either a single ORF or mlll*rlF~ ORFs which rely on the same EMF for t;A~l~s~ion control.
One class of DNA binding agents are agents which contain base r~ lues which hybridi_e or form a triple helix formation by binding to DNA
or RNA. Such agents can be based on the classic phosphodiester, ribonll~lpic acid backbone, or can be a variety of sulfhydryl or polymeric derivatives which have base ~tt~hment capacity.
Agents suitable for use in ~ese mPtho ls usually contain 20 to 40 bases and are de~i~n-F~ to be comp'~ to a region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res. 6:3073 (1979);
Cooney et al., Science 241:456 (1988); and Dervan et al., Science 251: 1360 (1991)) or to the mRNA itself (~n*~Pn~e - Okano, J. Neurochem. 56:560 (1991); Oligodeoxym~c~eon~es as An~isense Inhibitors of Gene Expression, CRC Press, Boca Raton, FL (1988)). Triple helix- formation optimally results in a shut-off of RNA transcription from DNA, while ~nti~Pn~P RNA

SU85TrrUTE S~E~T tRULE 2~i) W 096/33276 PCTrUS96/05320 hyhrilli7~ti- n blocks ~ jo~ of an mRNA molecule into polypeptide. Both techniques have been demonstrated to be effective in model systems.
Information cnnt~in~l in the sequences of the present invention is ne~e~ry for the design of an ~nti~n~e or triple helix oligonucleotide and other DNA
S binding agents.
Agents which bind to a protein encoded by one of the ORFs of the present invention can be used as a diagnostic agent, in the control of b~r te infection by mod~ ting the activity of the protein encoded by the ORF.
Agents which bind to a protein encoded by one of the ORFs of the present invention can be formlll~t~ using known techniques to gene~; a pharm~-eutir~l co~ osilion for use in controlling Haemophilus growth and infection.

5. Vaccine and P*a~ a~ev~n~ ,6~ n The present invention further provides ph~rm~ uti~l agents which can be used to ".~ the growth of Haemophilus inJquenzae, or another related or~ni~m, in vivo or in vitro. As used herein, a "ph~...~-euti-~l agent" is dPfinPA as a co...posilion of matter which can be formlll~t~cl using known techniques to provide a ph~rm~ellti~l compositions. As used herein, the "pharm~reuti~l agents of the present invention" refers the ph~rm~-euti~
agents which are derived from the ~l~ins ~n~ ~ by the ORFs of the present invention or are agents which are irl~ntifi~l using the herein described assays.As used herein, a pharm~ceutir~l agent is said to "mocllll~t~1 the growth of Haemophilussp., or a related or~ni~m, in vivo or in vitro," when the agent reduces the rate of growth, rate of division, or viability of the organism in ~lue~liun. The ph~rm~euti~l agents of the present invention can modulate the growth of an organism in many f~hinn~, although an - ... u3~ g of the ul~ g m~h~ni~m of action is not needed to practice the use of the ph~rm~eutic~l agents of the present invention. Some agents will m~ tp the growth by binding to an i---pc,ll~lt protein thus blocking the SUB5 i I i UTE SHEET tRULE 26) W 096133276 PCTrUS96/0',320 binlngi~1 activity of the protein, while other agents may bind to a col-lpollentof the outer surface of the organism blocking ~tt~hmPnt or rPn~lPnng the organism more prone to act the bodies nature immlmP system. .A1lr~ rely, the agent may be comprise a protein encoded by one of the ORFs of the present invention and serve as a vaccine. The development and use of a vaccine based on outer membrane cu-l~pollents, such as the LPS, are well known in the art.
As used herein, a "related organism" is a broad term which refers to any organism whose growth can be mo~ tecl by one of the ph~r-m~c-eut~
agents of the present invention. In genP~1, such an organism will contain a homolog of the protein which is the target of the pharm~ceutif ~1 agent or the protein used as a vaccine. As such, related organism do not need to be b~cteri~1 but may be fungal or viral p~thogt~n~.
The pharm~ccl1ti~1 agents and compo~itic n~ of the present invention may be ~-lmini~t~Pred in a convel~ient manner such as by the oral, topical, intravenous, i~ pe~ ;lo~ r, subc 1t~npous~ ~1 or int~-lPnm~1 routes. The ph~nm~-~euti~1 co-l.posilions are ~lmini$tPred in an amount which is effective for treating and/or prophylaxis of the specific intli~tinn In genP~1, they are ~ t d~d in an amount of at least about lO
~ug/kg body weight and in most cases they will be ~lmini~tpJed in an amount not in excess of about 8 mg/Kg body weight per day. In most cases, the dosage is from about lO ~g/kg to about l mg/kg body weight daily, taking into account the routes of ~(lmini~tr~tic~n, sy...~l~,...s, etc.
The agents of the present invention can be used in native form or can be m~lifiPcl to form a chP-mic~1 derivative. As used herein, a mnlP~ulP is said to be a "chemic~1 derivative" of another mc-lPc111e when it contains additional chPmic~1 mnietiPs not normally a part of the molp~llle. Such moieties may improve the molecule's solubility, absorption, bic-1Ogic~1 half life, etc. The mc ~~iPS may ~1tPrn~tively decrease the toxicity of the mo1ec1-1P, P1imin~te or ;.ll~.. l.;.l~ any ~ hle side effect of the mo1ec111e, etc. MniPtips capable of SUB5TTTUTE SHEET (RULE 26 W O 96/33276 PCTrUS96/05320 lg such effects are disclosed in Remington's Pharm~7c.elltic~71 Sciences (1980).
For; , '-, a change in the imm1-n~1ngi~ h~ ~ of the fim~ti~n:~l derivative, such as affinity for a given antibody, is measured by a co,.,pc;~ e S type imm1mo~c~y. Changes in immlmnmodulation activity are measured by the a~propliate assay. M~lifi~ti~ne of such protein p~ ies as redox or thPrm~1 stability, biological half-life, hydrophobicity, susceptibility to proteolytic ~le~r~ ti~ n or the ten~lency to aggregate with c~rriP-rc or into mn1tim~-rs are assayed by ",~lh~ylc well known to the or~ hily skilled artisan.
The th~pe~l;c effects of the agents of the present invention may be obtained by providing the agent to a patient by any suitable means (i.e., inh~1~tion, intravenously, intr~m1-~cu1~r1y, subcutaneously, enterally, or ~ellt~ldlly). It is ~lc;fell~d to ~lmini~t~3r the agent of the present inventionso as to achieve an effective con-~nt-~tion within the blood or tissue in which the growth of the organism is to be controlled.
To achieve an effective blood conce-ntr~ti~n~ the plert;lled method is to ~ l the agent by ;.~je~l;fu- The ~ ;on may be by continuous infusion, or by single or mlll~iple injecti- n~.
Ir~ providing a patient with one of the agents of the present invention, the dosage of the ~ d agent will vary depen-ling upon such factors as the patient's age, weight, height, sex, general m.oAic~1 condition, previous mt~ 1 history, etc. In general, it is desirable to provide the recipient with a dosage of agent which is in the range of from about l pg/kg to lO mg/kg (body weight of patient), although a lower or higher dosage may be admin-istered. The th~ 11y effective dose can be lowered by using co",bil,~iions of ine agents or tne present invention or anotner agent.
As used herein, two or more uJlllpoul-ds or agents are said to be ~rlmini~t.ored "in combination" with each other when either (l) the - physiological effects of each colll~und, or (2) the serum concentrations of each compound can be measured at the same time. The composition of the SU8STITUTE S~ EE~ tRULE 2~i) W 096/33276 PCTrUS96/05320 present invention can be ~lministpred concullc l~y with, prior to, or following the Atlminietration of the other agent.
The agents of the present invention are intPn(le~d to be provided to recipient subjects in an amount sllffiçi~ont to decrease the rate of growth (as S dPfin~P~l above) of the target org~niem.
The A~lminiet~tinn of the agent(s) of the invention may be for either a hyl~ctic" or ' ~ A~ ose. When provided ~rophylA~ticAlly, the agent(s) are provided in advance of any ~y~ tOIllS in~ Ative of the or~niem~
growth. The prophylactic A-lminietrAti~n of the agent(s) serves to prevent, Allel~llA~P, or decrease the rate of onset of any subs_quent infection. When provided thplApculic-Ally~ the agent(s) are provided at (or shortly after) the onset of an inf~ tion of infç~tion The th~.Al~.lic A~lminietrAtion of the coll-~u.ld(s) serves to AI~cl~llAl~- the PAI1IO1~;~'A1 ~y--~---s of the infection and to increase the rate of recovery.
The agents of the present invention are ~llminietPred to the mAmmAl in a phArmAc-p~utir~lly acceptable form and in a l]le.ld~JC~ lly effective cnn~--l-AI;- -- A composition is said to be ''yhA~lllArologically acceptable" ifits A~lminietrAti~n can be tcl---At~i by a recipient patient. Such an agent is said to be ~minietPred in a l'th~G-Apc-ll;~Ally effective amount" if the amount AtlminietPred is physiologically ei~nifi~Ant An agent is physiologically eignifi-~Ant if its presence results in a ~PtectAhle change in the physiology of a recipient patient.
The agents of the present invention can be formulated according to known methods to ~JlC~llC pharmA~ -ti~Ally useful compositions, whereby these mAtPriAle, or their functional derivatives, are co---bined in A.l.. ixl.. c with a phArm~ lti~Ally acceptable carrier vehicle. Suitable vehicles and their f~rmlllAti~n, inclusive of other human proteins, e.g., human serum albumin, are c~P-~ih~ for ~ -, in Remington's Pha~mnrel~cn7 Sciences (16th ed., Osol, A., Ed., Mack, Far~ton PA (1980)). In order to form a phArm~ceutifAlly Al c~1AhlP co~ ;nn suitable for crr~;Live A~lmini~fr~tion, such compositions ~4-SUBSTJ~JTE S~tEET (RULE 2~3 W 096/33276 PCT~US96/05320 will contain an effective amount of one or more of the agents of the present invention, together with a s~lit~hle amount of carrier vehicle.
Additional pharm~l~ellti~-~l methods may be employed to control the rlllr~tit~n of action. Control release ~ ns may be achieved through the use of polymers to ~ o ~ Y or absorb one or more of the agents of the present invention. The controlled delivery may be exercised by se~ting al)pl~liate macrom~ lP~IIlPs (for eY~mplP polyesters, polyamino acids, polyvinyl, pyrr~ lone, ethylenevinyl~cet~tP, methylcP~ se, carboxymethylcellulose, or ~n~1~.ni,-P., sulfate) and the concentr~ti()n of macromolP~lps as well as themetholi~ of inc~ in order to control release. Another possible method to control the d--r~tion of action by controlled release p~A-,Iion~ is to incol~ldLe agents of the present invention into particles of a polymeric m~tPri~l such as polyesters, polyamino acids, hydlogels, poly(lactic acid) or ethylene vinylacetate copolymers. AlL~ ly, instead of incol~Ql~ing these agents into polymeric particles, it is possible to entrap these m~teri~l~ in micror~rsulPs ~r~p~;d, for PY~mple, by coacervation techniques or by interf~ l polymPri7~ti( n, for eY~mrl~P, hydn.,-y",ethylcellulose or gelatine-llli~;ç~ lP-s and poly(,,,c;Lhylln~lh~cylate) micf~a~ les, le~ecLi~ly, or in colloidal drug delivery systems, for eY~mrle, liposo",es, albumin micros~h~les, microem~ ion~, nanoparticles, and nanor~rs--l~s or in macroem--l~i~.n~. Such techniques are ~i~close~l in Remington's Pharm~lc~l~ncn~ Sciences (1980).
The invention further provides a ph~rm~rPllti~l pack or kit compri.~ing one or more ~nl~inf.~ filled with one or more of the ingredients of the pharm~eu*r~l composition~ of the invention. ~soci~tP~ with such . (s) can be a notice in the form prescribed by a government~l agency regulating the mamlfact~lre~ use or sale of pharmace~1tic~1~ or biological U~ i, which notice reflects approval by the agency of man11fa~t11re, use or - sale for human a-i-,.;.. ;.~l., I;~n In ~ li*on, the agents of the present invention may be employed in conjunction with other th~ lic compounds.

SUBST~l'UTE SHEET (RULE ~) W 096/33276 PCTrUS96/05320 6. Shot-Gun Approach to Megabase DNA Seque~ci~g The present invention further provides the first ~lemon~tr~tiQn that a sequence of greater than one m~g~h~ can be sequenced using a random shotgun approach. This procedure, described in detail in the eY~mrles that S follow, has Pl;.. ;l-~t~d the up front cost of i~o1~ting and ordering o~/e~ ing or contiguous subclones prior to the start of the seqllen- ing protocols.
Certain aspects of the present invention are described in greater detail in the non-limitin~ Examples that follow.

~6-SU85TrrUTE S~EET tRULE 26) E~ ~les Expen~e~f~71 Design and Mef~
..
1. Shotgun .~equ~nri~Jg Strategy The overall ~ e~;Y for a shotgun approach to whole genome se~lue". ~g is outlined in Table 3. The theory of shotgun seqllPnring follows from the Lander and W~P....~ n-l.orrn~n and Wat~l-"an, Genomics 2: 231 (1988)) applir~ti~ n of the equation for the Poisson distribution p" = mXe~n'/x!, where x is the number of oc-;ulle"ces of an event, m is the mean mlmb~r of oc.;ull~nces, and Px is the probability that any given base is not sequenced after a cer~in amount of random sequence has been ge~ PA If L is the genome length, n is the llull~b~l of clone insert ends se luei-rRcl, and w is the seqll~nring read length, then m = nw/L, and the ~rl~bability that no clone origin~t~s at any of the w bases pl~ce/ling a given base, i.e., the probability that the base is not se~luc;l~ed, is pO = e~. Using the fold coverage as the unit for m, one sees that after 1.8 Mb of sequence has been randomly gçn.or~t~, m = 1, Lepres~ ;ng lX covesge. In this case, pO = e~' = .37, thus a~luxim~t~ly 37% is unsequenced. For example, 5X coverage (ap~ i",ately 9500 clones sequenced from both insert ends and an average sequence read length of 460 bp) yields pO = e~5 = 0.0067, or 0.67%
unsequf~-nr-e~. The total gap length is Le~, and the average gap size is L/n.
SX coverage would leave about 128 gaps averaging about 100 bp in size. The I l r;1l 1 l Ir.~ I~ iS P~nti~lly ~at of Lander and W~ IP. ~ .-, Genomics 2:231 (1988) .
Table 4 ill~ s the coverage for a 1.9 Mb genome with an average fragment size of 460 bp.

SU85mUTE St~EET tRULE 26 W 096/33276 PCTrUS96105320 2. Rnn~ Libr~uy Construction In order to approximate the random model described above during actual seq~len~ing, a nearly ideal library of cloned genomic fr~gm~nt is required. The following library construction procedure was developed to achieve this.
H. influen2~e Rd KW20 DNA was pl~?aled by phenol extr~ctinn A
IlliX.LUit; (3.3 ml) c~ .;..g 600 ~g DNA, 300 mM sodium ~t~t~7 10 mM
Tris-HCl, 1 mM Na-EDTA, 30% glycerol was sQnic~t~l (Branson Model 450 Sonir~tnr) at the lowest energy setting for 1 min. at 0~ using a 3 mm probe The DNA was ethanol precipitated and redissolved in 500 ~41 TE buffer. To create blunt-ends, a 100 ~Ll aliquot was digested for 10 min at 30~ in 200 ,ul BAL31 buffer with 5 units BAL31 nuclease (New F.n~l~n~ BioLabs). The DNA was phenol-extracted, ethanol-~l~;pil~l~d, redissolved in 100 ,ILl TE
buffer, electrophoresed on a 1.0% low mPlting agarose gel, and the 1.6-2.0 kb size fr~rtion was eYr,i~ll, phenol-~Yt~ted, and redissolved in 20 ~l TE
buffer. A two-step li~fi~n p-~lur~ was used to produce a pl~mid library with 97% insert of which >99% were single inserts. The first ligation Illi~LUle (50 ~1) coi.l;~ ~ 2 ~g of DNA fr~gm~nt~, 2 ~g SmaI/BAP pUC18 DNA (ph~ ), and 10 units T4 ligase (GIBCO/BRL), and incub~tion was at 14~ for 4 hr. After phenol PYtr~tion and ethanol p~ i~lion, the DNA
was dissolved in 20 ~Ll 1~ buffer and electrophoresed on a 1.0% low melting agaro~ gel. A ladder of ethi~ m bromide-stained linear bands, ici~ntifi~d by si_e as in~rt (i), vector (v), v+i, v+2i, v+3i, ... was vi~ 1i7~d by 360 nm W light, and the v+i DNA was excised and recovered in 20 ~Ll TE. The v +i DNA was blunt-ended by T4 polymerase tre~tm~o-nt for 5 min. at 37~ in a reaction mixture (50 ~ul) conl;~ the v+i linears, 500 ~M each of the 4 dNTP's, and 9 units of T4 polymerase (New Fngl~n-l BioLabs) under recommt--nded buffer conditions. After phenol extraction and ethanol pl~ ;p; I;.tinn the ~e~ d v+i linears were dissolved in 20 ~1 TE. The final ligation to produce circles was carried out in a 50 ~1 reaction cont;.in;.)g S ~1 of v+i linears and S units of T4 ligase at 14~ ov~rni~ht After 10 min. at 70~
the reaction IllixLulc was stored at -20~. 48 SU8STTTUTE S~E~ tRULE 2 W 096/33276 PCTnUS9610S320 This two-stage procedure resulted in a m~lec~ rly random collection of single-insert pl~mi~ ,ecol,lbinallL~ with minim~l cont~min~ti~n from double-insert cl~ ( < 1 %) or free vector ( < 3 %). Since deviation from r~n~1OmnP~ is most likely to occur during cloning, E. coli host cells dPficient in all recombination and restriction fimetion~ (A. Greener, Strategies 3 (1):5 (1990)) were used to prevent rearrangem~-nt~, deletions, and loss of clones by restriction. Transformed cells were plated directly on antibiotic diffusion plates to avoid the usual broth recovery phase which allows mllltiI)lic ~tinn and selection of the most rapidly growing cells. Plating occured as follows:
A 100 ~1 aliquot of Epicurian Coli SURE II Su~~ico.. ~ Cells (Stratagene 200152) was thawed on ice and transferred to a chilled Falcon 2059 tube on ice. A 1.7 ~1 aliquot of 1.42 M ,B-mercaptoeth~nol was added to the aliquot of cells to a final C~ - of 25 mM. Cells were inc~lb~tPJi on ice for 10 min. A 1 ~1 aliquot of the final lig~tion was added to the cells and in~lb~tP~ on ice for 30 min. The cells were heat pulsed for 30 sec. at 42~
and placed back on ice for 2 min. The ouL~ wLh period in liquid culture was ~1;",;"~ from this protocol in order to minimi7P the ~lcÇclcllLial growth of any given L,~ulsrulll,ed cell. Instead the tran~roll~lalion were plated diiccLly on a nutrient rich SOB plate co..l;~ i.-g a S ml bottom layer of SOB agar (1.5% SOB agar: 20 g lly~Lunc, 5 g yeast extract, 0.5 g NaCl, 1.5% Difco Agar/L). The S ml bottom layer is supplemP-ntP~I with 0.4 ml ampicillin (50 mg/ml)/100 ml SOB agar. The 15 ml top layer of SOB agar is supplemPnt~ with 1 ml X-Gal (2%), 1 ml MgCl2 (1 M), and 1 ml MgSO4/100 ml SOB agar. The 15 ml top layer was poured just prior to plating. Our titer was ay~ ,lllaLcly 100 colonies/10 ,ul aliquot of tran~Çu~ ion.
All colonies were picked for tPmpl~tP p~c~aldLion regardless of si_e.
Only clones lost due to "poison" DNA or dP-ietPriQus gene products would be deleted from the library, r~s-llting in a slight increase in gap number over that eYpe~t~

SUBSTErUTE SHEET tRULE 26) W 096/33276 PCTrUS96/05320 In order to evaluate the quality of the H. influenzae library, sequence data were obtained from approximately 4000 templ~tes using the M13-21 primer. The r~ndom sequence fr~gmPntc were ~ccpmhled using the AutoAssembler~M sor~w~e (Applied Biosy~lc,,,s division of Perkin-Elmer (AB)) after ol,~i.. ng 1300, 1800, 2500, 3200, and 3800 sequence fr~gmP.nt.c, and the IIUIIII~Cl of unique ~c~Pmhl~A. base pairs was detçrminpA Based on the equations des~.nhed above, an ideal plot of the l~umbel of base pairs ~ i n i ~gto be sequenced as a function of the .~Y of sequenced fr~gmP.ntc obtained with an average read length of 460 bp for a 2.5Xl06 and a l.9Xl06 bp genome was detel",il,ed (Figure 3). The ~lOgl~ ion of ~ccPmhly was plotted using the actual data ol,l~il,ed from the as_embly of up to 3800 sequence fr~gmPntc and co"-pa.~d the data that is provided in the ideal plot (Figure 3). Figure 3 .ctr~tes that there was e~ lly no deviation of the actual assembly data from the ideal plot, ;nriic~ting that we had cor.sL-u. ~1 close to an ideal random library with minim~l cont~min~ti~ n from double insert çhim~r~c and free of vector.

3. P~ DNA Seq1~e~ g High quality double st~nded DNA p1~cmid If-"~ t~s (19,687) were ~lc~aled using a "boiling bead" method developed in collaboration with Advanced Genetic Technology Corp. (Gaithersburg, MD) (Adams et al., Scien~e 252:1651 (1991); Adams et al., Nature 355:632 (1992)). Plamid prc~ l ion was pclrol.--ed in a 96-well format for all stages of DNA
ylc~ n from b~c f~ri~l growth through final DNA pl~rific~tion TPmplz3t col-c~ .dLion was del~ A using ~oe~hct Dye and a Millipore Cytofluor.
DNA concpntr~tions were not adjusted, but low-yielding tpm~ tec were identifi.-A where possible and not sequenced. Templates were also plc~alcd from two H. influenzae lambda genomic libraries. An ~mplifiPA library was constructed in vector Lambda GEM-12 (Promega) and an nn~mrlifiPA library was constructed in Lambda DASH II (Stratagene). In particular, for the e SUB5TITUTE S~{F~T tRULE ~

W 096t33276 PCTnUS96/05320 l~n~mplifi~ lambda library, H. in,7?uenzae Rd KW20 DNA (> 100 kb) was partially digested in a reaction IlLU~lulG (200 ~1) cnn~ in_ 50 ~g DNA, lX
Sau3AI buffer, 20 units Sau3AI for 6 min. at 23~. The digested DNA was phenol-extracted and elecLrophoresed on a 0.5% low mPltinp agarose gel at ~ 5 2V/cm for 7 hours. I~l,.g.. ~ from 15 to 25 kb were excised and recovered in a final volume of 6 ~1. One ~ul of f~pmPnte was used with 1 ~1 of DASHII
vector (str~t~gpnp-) in the ~G~.. Pnrled 1i~tinn re~-~tion One ~1 of the ligation mixture was used per p~ ging reaction following the recommP-nrle~
plùtocol with the Gi_~p~rl~ II XL p~cl~ginp Extract (Stratagene, #227711).
Phage were plated d-lccLly without ~mrlific~tinn from the p~ ping ~ ulc;
(after dilution with 500 ~1 of lGcGI.. Pn~iP~1 SM buffer and chlororol--.
tre~tmPnt). Yield was about 2.5x103 pfu/,ul. The ~mrlified library was pl~alGd ç~Pnti~lly as above except the lambda GEM-12 vector was used.
After ~;.~ , about 3.5x104 pfu were plated on the restrictive NM539 host.
The lysate was harvested in 2 ml of SM buffer and stored frozen in 7%
dimethylsulfoxide. The phage titer was approxim~tP-ly lx109 pfu/ml.
Liquid lysates (10 ml) were ~lc~d from randomly s~l~ct~P~l plaques and ~ was ~lG~Gd on an anion-eYch~npe resin (Qiagen). Sequ~Pncinp reactions were carried out on pl~mi~1 ~e-..~ s using the AB Catalyst LabStation with Applied Biosy~G --s PRISM Ready Reaction Dye Primer Cycle SequP-ncinP Kits for the M13 rol~ l (M13-21) and the M13 reverse (M13RPl) ~lilllCl~ (Adams et al., Nature 368:474 (1994)). Dye lelll~ aLol seque-ncing re~t-tion~ were carried out on the lambda tpmpl~tp~s on a Perkin-Elmer 9600 Thcl.llo~;ycler using the Applied Bio~y~LG.IIs Ready Reaction Dye Tf .. . . ; n~ , Cycle Se4uG ~cing kits. T7 and SP6 primers were used to sequence the ends of the inserts from the Lambda GEM-12 library and T7 and T3 primers were used to s~uG,~ce the ends of the inserts from the Lambda DASH
II library. Se~uGl- ing rP~.-tinnc (28,643) were ~GlÇol,l,ed by eight individuals using an average of ruul L~ en AB 373 DNA .S~ lPn~-r~ per day over a 3 month period. All sequencing r~ fion~ were analyzed using the Stretch m~ifir~tic)n of the AB 373, primarily using a 34 cm well-to-read distance. The overall SUBS 111 UTE St{EET (RULE 2~

W 096/33276 PCTrUS96/05320 sequencing success rate was 84% for M13-21 sequences, 83% for M13RPl sequences and 65% for dye-~~ .. reactions. The average usable read length was 485 bp for M13-21 se lue,l~es, 444 bp for M13RPl sequences, and 375 bp for dye-l~ fillal~r ~rl;,~n~ Table S s~ . ;7PS the high-throughput S sequPnrin~ phase of the invention.
Richards et al. (Richards et al., Automated DNA sequencing and Analysis, M.D. Adams, C. Fields, J.C. Venter, Eds. (Academic Press, London, 1994), Chap. 28.) ~lescrihe~ the value of using sequence from both ends of seqU~pnrinE tP-~pl~tçs to f~rilit~tP ordering of contigs in shotgun :l~Pmhly plu; e :t~ of lambda and cosmid clones. We b~l~nr~ the desirability of both-end sequPnr-in~ (inrlurlinE the reduced cost of lower total number of ~r.l~pl ll~s) against shorter read-lengths for s~upncinE rP~rti~ n~ ~lrulllled with the M13RPl (reverse) primer con~ d to the M13-21 (folw~d) primer.
A~r~ ly one-half of the templates were sequenced from both ends. In tûtal, 9,297 M13RPl sequpnr-inE re~rfion~ were done. Random reverse sequPnrinE re~rtinn~ were done based on succ~s~ful folw~d seqnPnrinE
Some M13RPl se~u~lce~ were obtained in a semi-directed f~hi~n M13-21 se~lu~llces pointing uutw~d at the ends of contigs were chosen for M13RPl sequ~nrinE in an effort to speoifir~lly order contigs. The semi-directed ~lld~gy was effective, and clone-based ordering formed an intP.~r~l part of assembly and gap clûsure (see below).

4 Protocolfor~ D~ Cycle SDql ~7ci~g The seqnpnrinE c~n~i~tP~1 of using eight ABI Catalyst robots and fuulLeell AB 373 Autulll~d DNA Seq--PnrP-rs. The Catalyst robot is a publicly available s~phistic~tpcl ~ipc;~ g and Ir~ llle control robot which has been developed spec-ific~lly for DNA sequPncinE re~rti~)n~ The Catalyst coll~ -s pre-aliquoted l~-..P1 ~IP-S and reaction mixes con~i~tinE of deoxy- anddideoxynucleotides, the Taq thprrnost~hle DNA polymP~ee, fluulesc~ ly-labelled sequPnr-in~ primPrs, and reaction buffer. l~P~rti-)n mixes and SUBSTrrUTE ~EET tRULE 2~i) f W 096133276 PCTrUS96/05320 L~ s were combined in the wells of an aluminum 96-well thermocycling plate. Thirty con~ tive cycles of linear amplific~tion (e.g., one primer synthesis) steps were pc.rollned incl~lAing dendLu,dLion, ~nn~ling of primer and templ~te, and eYt~neinn of DNA synthP~i.c A heated lid with rubber gaskets on the L1~ cling plate prevented evaporation without the need for an oil overlay.
Two sequen---ing ~luLocols were used: dye-labelled primers and dye-labelled dideoxy chain Icl---;n~ol~. The shotgun sequPn.-ing involves use of four dye-labelled seqll~nr-ing primers, one for each of the four t~ll..in~JI
nucleotide. Each dye-primer is labelled with a dirrc~cnt fluorcscel-t dye, pcl~ ing the four individual reactions to be combined into one lane of the 373 DNA Sequencer for electrophoresis, det~tion, and base-calling. AB
cullcllLly ~u~lies pre-mixed reaction mixes in bulk p~e~ ge~ cnn~;.i.-il-g all the n~ .~- y non ~ "~ reagents for s~u~ Seql~enring can be done with both plasmid and PCR-generated templates with both dye-primers and dye-~el...il-~-tc)rs with a~ vxi...;~ y equal fidelity, although plasmid templ-t,s generally give longer usable sequences.
Thirty-two re~ tion~ were loaded per 373 Sequencer each day, for a total of 960 ~mrlPs Elcctrophoresis was run overnight following the manufacture's p,~,l~ols, and the data was c~ ll~te~A. for twelve hours.
Following electrophoresis and fluorescen-~ det~ctinn, the AB 373 pclrOllllS
automatic lane traclring and base-calling. The lane-tracking was confirmed visually. Each sequence elecl~ hcl~ -dlll (or nuo-esc~ e lane trace) was A, visually and ~ A for quality. Trailing sequences of low quality were removed and the se.l~ence itself was loaded via software to a Sybase h~ (a~h,,~" A A~;ly ~0 a 8mm ~pe). T P ~Ain~ v~tor polylu-ker sequence was removed ~11tom~tir~11y by sorLwale program. Average edited lengths of sequences from the standard ABI 373 were around 400 bp and depended mostly on the quality of the temr1-~t~ used for the sequçn---ing reaction. All of the ABI 373 Sequencers were converted to Stretch Liners, which provided a SUE~S 111 UTE S}~EET tRULE 2~;) W 096/33276PCTrUS96/05320 longer ~ L~ophoresis path prior to fluoresc~nce det~ti~ n, thus increasing the average number of usable bases to 500-600 bp.

Infonnatics 1. Data Mana~ e~tt 5A number of information m~n~gtem~.nt systems (LIMA) for a large-scale s~ g lab have been developed (Kt;ll~v~e et al., Proceedings of the Twenly-Sixth Annual Nawaii International C~r~f~,~, ce on System Sciences, IEEE Co~ uL~ir Society Press, W~hing~n D.C., 585 (1993))~ The system used to collect and assemble the s~.lu~ P data was developed using the Sybase relational data m~n~p;em~nt system and was clP-~igne~1 to auLu,,.aLe data flow whereever possible and to reduce user error. The cl~t~h~e stores and cc,llclalt;s all infoll..alion collected during the entire oppr~tion from lemplale n to final analysis of the genomP. Re~ sP the raw output of the AB
373 .Se~ue~ was based on a M~tintf-~h platform and the dat~ management system chosen was based on a Unix platform, it was nf~.s~. ~ to design and implP.ment a variety of multi-user, client server applic~tinn~ which allow the raw data as well as analysis results to flow se~m~ 1y into the ~t~h~e with a minimum of user effort. A d~;,i~Lion of the sorLw~e pl'Ogl~lllS used for large sequence assembly and m~n~pm~.nt is provided in Figure 4.

2. ,4.. !s~mblY

An assembly engine mGR A~cPm' ler) was developed for the rapid and accurate assembly of thousands of sequence fr~gmP.nt.~ The AB
AutoA! ~ ~- TM was mollifi~ (and named TIGR Editor) to provide a gr:~phi<~l infPrf~l~e to the electrophelugla~,l for the purpose of editing data ~ f~ with the aligned sequence file output of TIGR A~cPmhler TIGR
Editor ...~in~;n~ synchrony belwwl~ the electropherogram files on the SUBSTrrUTE ~;~EET tRUEE

W 096/33276 PCTrUS96/05320 M~intrlsh ~ r... and the se lu~lce data in the H. influenzae ~1~t~h~e on the Unix platform.
The T~GR: ~ ~im~ ..~.u~1y clusters and ~ mh1es fr~gmt-nt~
of the genome. In order to obtain the speed n~es~ry to assemble more than 104 fr~gmPnt~, the algc,~ " builds a hash table of lO bp oligonucleotide subsequences to gent;l~ a list of potential sequence fr~gmPnt overlaps. The number of potential ov~l~s for each fr~gm~nt determines which fr~gm~nt~
are likely to fall into repeLiLi~e e1emPntC Re~inning with a single seed ~uellce fr~gm~nt TIGR Assembler extends the current contig by ~LL~;IIIpLillg to add the best .. ~ h;.. g fr~gm~nt based on oligonucleotide content. The current contig and c~n~ t~ fr~gm.ont are aligned using a modified version of the Smith-Wat~ll"an algoliLh~ (Waterman, M.S., Methods in Enzymology l64:765 (1988)) which provides for optimal gapped ~ nmPnt~ The current contig is ~oYten-l~ by the fragment only if strict criteria for the quality of the match are met. The match criteria include the Illill;llllllll length of overlap, the ...;.~i..~-.... length of an u~ cl-~l end, and the minimllm ~rcel,L~ge match.
These criteria are autom~tic~11y lowered by the algorithm in regions of minim~1 coverage and raised in regions with a possible repetitive e1~m~-nt The number of poLe,lLial overlaps for each fr~gmPnt determines which fr~f~mPnt~
are likely to fall into re~K;LiLi~e e1em~nt~. Fr~gmPnt~ lt;plesPI.L;l-g the bo-..-~ s of repetitive "1_",~ and ~I~"Lially ~~himPric fr~gm~nt~ are often rejected based on partial mi~m~t~ s at the ends of ~1ignmPnt~ and ~Y~c1~ ed from the current contig. TIGR Assembler is deeignecl to take advantage of clone size inrol,l,a~ion coupled with sequenting from both ends of each ~ It ~ r~es the c~tl~ in~ that sequence fr~gmt-nt~ from two ends of the same template point toward one another in the contig and are located within a certain ranged of base pairs (definable for each clone based on the known clone size range for a given library). Assembly of 24,304 sequence r. ~ of H. iry~uenzae required 30 hours of CPU time using one processor on a SPARCenter 2000 with 512 Mb of RAM. This process resulted in a~lu,~im~tt--ly 210 contigs. Re~use of the high string~-ncy of the TIGR

SU~ST~UTE SH E~T tRULE ~) A~ , all contigs were searched against each other using grasta (a modified fasta (Person and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85:2444 (1988)). In this way, ~ 1iti~n~1 overlaps were dptrctç~ which en~hl~i co~ ion oof the data set into 140 contigs. The location of each fragment S in the contigs and extensive inr~ ion about the con~Aon~us sequence itself were loaded into the H. influenzee r~l~tion~ t~h~P

3. Ordenng ~ bl~d Cont~gs After ~c~Pmhly the relative positions of the 140 contigs were unknown.
The contigs were ordered by asm align. Asm align uses a number of relationships to identify and align contigs that are ~ rPnt to each other.
Using this algc,lilh..., the 140 contigs were placed into 42 groups tota1ing 42 physical gaps (no templ~t~-- DNA for the region) and 98 sequence gaps (tc~.mp1~t~ available for gap closure).

Ordenng Contigs Separated by Physical Gaps and Achieving Closure Four i~ p-, ~ lt'.E;;f-S were developed to order contigs S~ f~ by physical gaps. Oligonllr~l~tide primers were ~le~iFn~i and synth~ i7P~ from the end of each contig group. These ~llilllCl~ were then available for use in one or more of the st~trgies outlined below:
1. Southern analysis was done to develop a unique "fingcl~li-.L"
for a subset of 72 of the above oligonllrl~t~ o-s. This procedure was based upon the supposition that labeled oligon~clr-oti~ies homologous to the ends of nt contigs should hybridize to common DNA restriction fr~gmPnt~, and thus share a similar or i~lonti-~l hybridization pattern or "fingt;lL.fin~".
Oligonucleotides were labeled using 50 pmoles of each 20 mer and 250 mCi of [y 32P]ATP and T4 polyn~-cl~ti-lr kinase. The labeled oligonucleotides were purified using Seph~ley G-25 ~u~lfille (Pharmacia) and 107 cpm of each was used in a Southern hybri~1i7~tinn analysis of H. influen2ae Rd SUBSTtTUTE SHE~ tRULE 263 W 096133276 PCTrUS96/05320 chromosomal DNA digested with one frequent cutters (AseI) and five less Lle luellt cutters (Bgm, EcoRI, PstI, XbaI, and PvuII). The DNA from each digest was fractionated on a 0.7% agarose gel and transferred to Nytran Plus nylon membranes (Schleich~r & Schuell). Hybri~li7~tinn was carried out for 16 hours at 40~. To remove non-specific signals, each blot was sequentially washed at room 1~ with increasingly stringent conditions up to 0. lX
SSC + 0.5~ SDS. Blots were exposed to a Phosph~rTm~ger c~ccettP, (Molecular Dynamics) for several hours and hybri~li7~tinn p~ttPrnC were visually co,~,~ed.
Adjacent contigs i~lentifipci in this manner were targeted for sperific PCR reactions.
2. Peptide links were made by sea-clling each contig end using blastx (Altschul et al., J. Mol. Biol. 215:403 (1990)) against a peptide ~l~t~h~ce, If the ends of two contigs m~trh~ the same ~l~t~h~ce sequence in an a~ manner, then the two contigs were tentatively considered to be rPnt to each other.
3. The two lambda libraries constructed from H. in~uenaze genomic DNA were probed with oligomlrl~ooti~e,s clPsi~nP~ from the ends of contig groups (~irknP.cc et al., Genomics 10:985 (1991)). The positive plaques were then used to ~lC;~, templates and the sequence was delell,lilled from each end of the larnbda clone insert. These sequence fr~gmPntc were searched using grasta against a ~t~h~ce of all contigs. Two contigs that ~l the sequence from the opposite ends of the same lambda clone were ordered. The lambda clone then provided the temrl~tP- for closure of the se~ut;llce gap bc~lw~ll the ~ rPnt contigs. The lambda clones were esperi~lly valuable for solving repeat structures.
4. To confirm the order of contigs found by the other approaches and ~t~hliCh the order of non-ordered contigs, standard and long range (XL) PCR re~rtionC were ~l~>ll"ed as follows.
Standard PCR was ~ r~ll"ed in the following manner. Each reaction C4~ ~ a 37 ~l cocktail; 16.5 ~l H2O, 3 ~l 25 mM MgCl2, 8 ~l of a dNTP

SuBsmuTE S~EET (RULE 2~i~

W 096/33276 PCTrUS96/05320 mix (1.25 mM each dNTP), 4.5 ~1 lOX PCR core buffer II (Perkin Elmer), 25 ng H. influenzae Rd KW20 genomic DNA. The a~lu~liate two primers (4 ,ul, 3.2 pmole/~l) were added to each reaction. A hot start was pclr~,l"led at 95~ for S min followed by a 75~ hold. During the hold ~mplitA-l DNA
S polymerase (Perkin Elmer) 0.3 ~Ll in 4.3 ~1 H20, 0.5 ~1 lOX PCR core buffer II, was added to each reaction. The PCR profile was 25 cydes of 94~/45 sec., denAhlre; 55~/1 min., anneal; 72~/3 m~n, eYt~-n~inn. All reactions were ~clrolll,ed in a 96 well format on a Perkin Elmer GeneAmp PCR System 9600.
Long range PCR (XL PCR) was pelrolllled as follows: Each reaction C~ P,l a 35.2 ~1 cocktail; 12.0 ~1 H2O, 2.2 ~1 25 mM Mg(OAc)2, 4 ~cl of a dNTP mix (200 ~M final con~nh~ation), 12.0 ~1 3.3X PCR buffer, 25 ng H. infCuenza~ Rd KW20 genomic DNA. The a~ ,plia~c two primers (5 ~Ll, 3.2 pmoles/~l) was added to each reaction. A hot start was pclrulllled at 94~
for 1 minute. rTth polym~-~, 2.0 ~1 (4 U/reaction) in 2.8 ~1 3.3X PCR
buffer II was added to each reArtion. The PCR profile was 18 cycles of 94~/15 sec., denaLulc; 62~/8 min., anneal and extend followed by 12 cycles 94~/15 sec., dellalulc; 62~/8 min. (in~ilCi3~C 15 sec./cycle), anneal and extend;
72~/10 min., final ~Yten~inn All reA~tion~ were pclr~lllled in a 96 well format on a Perkin Elmer GeneAmp PCR System 9600.
Although a PCR reaction was pclrulll,ed for e~.liAlly every c~---hi--Alinn of physical gap ends, techniques such as Southern fingel~ g~
tAhA~e IllA~l~hi~g, and the probing of large insert clones were particularly valuable in orde~ing contigs A~j~cent to each other and re~ ing the number of combi~-Ato. ;Al PCR reArtion~ n~Ary to achieve complete gap closure.
Employing these ~ AI~ to an even greater extent in future genome projects will illl.ilC~sC the overall effici~n~,y of complete genome closure. The number of physical gaps ordered and closed by each of these techniques is s-lmmAri7t-~1in Table 5.
Sequence ;-~ r~.. ~AI inn from the ends of 15-20 kb clones is particularly suitable for gap closure, solving repeat structures, and providing general SU~S 111 UTE S~~~ tRULE 26) W 096/33276 PCTnUS96/05320 confirmation of the overall genome ~sPmhly. We were also con~PrnPA that some fr~gmPntc of the H. influena~e genome would be non-clonable in a high copy plasmid in E. coli. We reasoned that lytic lambda clones would provide the DNA for these segmPntc. A~ IP1Y 100 random plaques were picked from the ~mplifiPcl lambda library, temrl~tPs y~ d, and sequence i.~r~,....,.l;nn o~il.ed from each end. These sequences were searched (grasta) agaulst the contigs and linked in the d~t~h~e to their a~lopliate contig, thus providing a scaffolding of lambda clones contributing additional support to the accuracy of the genome assembly (Fig 5). In z~rlr1ition to confirmation of the contig structure, the lambda clones provided closure for 23 physical gaps.
Approxim~tPly 78% of the genome is covered by larnbda clones.
T~mhl~ clones were also useful for solving repeat structures. Repeat structures i~lPntifip~1 in the genome were small enough to be sp~nnP~I by a single clone from the random insert library, except for the six ribosomal RNA
operons and one repeat (2 copies) which was 5,340 bp in length.
Oligo,.~c~ P- probes were rlPqignPd from the unique flanks at the beg;~
of each repeat and hybridized to the lambda lihr~rips. Positive plaques were identifiP~l for each flank and the sequence fr~gmPnt~ from the ends of each clone were used to cu~ ly orient the repeats within the genome.
The ability to distinguish and ~qqPmhlP the six ribosomal RNA (rRNA) operons of H. influena2e (16S subunit-23S subunit-5S subunit) was a test of our overall ~LId~y to ~quPn~ and assemble a complex genome which might contain a qignifi~nt l~u-~hr~.~ of repeat regions. The high degree of sequence qimil~rity and the length of the six operons caused the assembly process to cluster all the underlying sequences into a few in-liqtinguishable contigs. To delel...ine the correct pl~PmPrlt of the operons in the sequence, a pair of unique fl~nking sequences was required for each. No unique fl~nking sequences could be found at the left (16S rRNA) ends. This region contains the ribosomal promoter and a~ ed to be non-clonable in the high copy number pUC18 pl~cmi~ However, unique sequences could be idPntifiP~l at the right (5S) ends. Oligonucleotide primers were d~P~ignPcl from these six SUBST~TUTE S~EEr (RULE 26) W 096t33276 PCTrUS96/0~320 fl~nking regions and used to probe the two lambda libraries. For each of the six rRNA operons at least one positive plaque was i~ ntifi~A which completely ~l~n~ the rRNA operon and contained unique fl~nking sequence at the 16S
and 5S ends. These plaques provided the temrl~tPc for obtaining the unique sequence for each of the six rRNA operons.
An ~ litinn~1 confirmation of the global structure of the assembled circular genome was obtained by col..l.~. ;ng a co~ ulel gent;,dt~d restrictionmap based on the assembled sequence for the enzymes Apal, SmaI, and RsrII
with the predicted physical map of l?~Afi~l(l and Lee (Genetic Maps: locus 0 maps of complex genomes, S.J. O'Brien, Ed. Cold Spring Harbor Laboratory Press, New York, N.Y., 1990, 2110.). The restriction fr~gm~ntc from the sequence-derived map m~tch~d those from the physical map in size and relative order (Figure 5).

Editing ~im~ .n~us with the final gap filling process, each contig was edited visually by re~c~mhling o~ ll~pil.g 10 kb s~tionc of contigs using the AB
AntQA~P~blerTM and the Fast Data F~derTM ha~w~;. AntoA~seml~lerTM
provides a gr~phic~l int~rf~ce to electropher~,gl~un data for editing. The ele.;lropll~v~ n data was used to assign the most likely base at each position.
Where a discrepancy could not be resolved or a clear ~ccipnm~nt made, the k,---~;c base calls were left lln-~h~nged Individual sequence changes were written to the el~L-opllerogram files and a reFli~tion protocol (crash) was used to m~int~in the ~yl~hl~ny of sequence data between the H. inf~uenzae ~ t:lh~ce and the electropherogram files. Following e~liting, contigs were re~cc~mhled with TIGR Assembler prior to annotation.
Potential r.~ h;r,.~; identifi~l in the course of annotating the genome were saved as reports in the ~l~t~h~cP These reports include the coo~linales in a contig which the ~ nm~nt ~rlWal~ (p~e) predicts to be the most likely location of a mic.cing or ins~;l~d base and a leprese~ ion of the sequence SUB5TITUTE 5~EET tRULE 26 -zllignmf nt co..~ g the fr~m~ehift. A~hcnt fr~mf ehifts were used to in~1ir~tf areas of the sequence which may require further editing. Fr~mPehifte were not c~,,ccLed in cases where clear electrophelogl~l- data disagreed with a fr~meshift. Fr~mf ~hifit editing was ~lr~ I-ed with TIGR Editor.
The rRNA and other repeat regions precluded cu. . .~ 'e assembly of the circular genome with TIGR Acc~ml-ler. Final assembly of the genome was accomI-liehf~A using comb_ssm which splices together contigs based on short ov~laps.

Ac~u~~.~, of the Genome Seqr~en~e The ~rC~ ry of the H. influena~e genome sequence is difficult to quantitate because there is very little previously determined H. influena~e sequence and most of these sequences are from other strains. There are, however, three parameters of accuracy that can be applied to the data. First, the ~-u---ber of app~cll~ r.,....~h;rl~ in predicted H. influer~e genes, based on ~ h~ imil~ritif~s, is 148. Some of these ~u~c ~L fr~mPehifts may be in the b~ s~lllf ~ s rather than in ours, particularly coneitlçring that 49 of the aL~ f ~l r. ,....f ~I.; rl~ are based on ...;.k-1.PS to hypothetical proteins from other org~ni.em.~. .Se~ond, there are 188 bases in the g.onomP that remain as N
ambiguities (1/9,735 bp). Comhining these two types of "known" errors, we can calculate a maximum sequence ~cur~ y of 99.98 % . The average coverage is 6.5X and less than 1% of the genome is single-fold coverage.

Identifying Genes An attempt was made to predict aU of the coding regions of the H.
irffluenzae Rd genome and identify genes, tRNAs and rRNAs, as well as other fealu.~s of the DNA sequence (e.g., repeats, regulatory sites, replication origin sites, nucleotide composition). A descli~lion of some of the readily a~l,~e.lt sequence fea~ules is provided below.

SUBSTITUTE S~E~ (RULE 2~) TheH. in,fluena~e Rd genome is a circular chromosome of 1,830,121 bp. The overall G/C nucleotide content is ayy~ ldL~ly 38% (A = 31 %, C
= 19%, G = 19%, T = 31%, IUB = 0.035%). The G/C content of the genome was ~ .in?~A with several window lengths to look for global structural r~alul~. With a window of 5,000 bp, the G/C content is relatively even except for 7 large G/C-Ach regions and several A/T-rich regions (Fig.
5). The G/C rich regions CO11QYOI d to six rRNA operons and the location of a cryptic mu-like prophage. Genes for several pl~,~ins with ~imil~rity to proteins encoded by b~r-teriophage mu are located at ayyl~x~ t~ly position 1.56-1.59 Mbp of the genome. This area of the genome has a m~rkrAly higher G/C content than average for H. influena2e (~50% G/C colllyaled to ~38% for the rest of the genome). No ~ignifi~nre has yet been asc~lL~ined for the source or illlyc~ ce of the A/T rich regions.
The minim~l origin of replir~fion (oriC) in E. coli is a 245 bp region defined by three copies of a LhilL~Il base pair repeat co~ ini~g a GATC core sequence at one end and four copies of a nine base pair repeat co~ ining a TTAT core s~uenee at the other end. The GATC sites are Ill~;Lhylation targets and control re~lic~tion while the TTAT sites provide the binding sites for DnaA, the first step in the l~li- ~I;oi~ process (Genes v, B. Lewin Ed. (Oxford University Press, New York, 1994), chap. 18-19). An ayylo~ y 281 bp sequence (602,483 - 602,764) whose limits are defined by these same core sequences ay~al~ to define the origin of re~lir~tion in H. inflluena~7e Rd.
These coc,l~]inaL~s lie b~l sets of ril~osoll,al operons r7nF, rrnE, mzD and m2~, rrnB, mnC. These two groups of ribosomal o~r~lls are tr~n~crihed in opyosite directions and the pl~c~m~nt of the origin is con~i~t~nt with their yGlaliLy for 1., ,.~-;l,lion. Tf-.. ;n~ ,- of E. coli replic~tion is marked by two 23 bp termin~tic-n sequences located -100 kb on either side of the midway point at which the two repli~tion forks meet. Two ~enLial le ...ii.~ion ~ nr~ sha~ing a 10 bp core s~llonre with the E. coli L~l,ninaLion sequence were id~ntifi~d in H. influeno~e at cool-lirldL~s 1,375,949-1,375,958 and 1,558,759-1,558,768. These two sets of coordinates are offset a~r~x;...~tely SUBSTIl~UTE SHE~T (RULE 2~i) W 096/33276 PCTrUS96105320 100 kb from the point 180~ opposite of the proposed origin of H. influenaze repli~ tinn.
Six rRNA operons were i~l~ntifie(l Each rRNA operon contains three rRNA ~ubu~ and a variahle spacer region in the order: 16S subunit - spacer region - 23S subunit -5S subunit. The subunit lengths are 1539 bp, 2653 bp, and 116 bp, respectively. The G/C content of the three ribosomal subunits (50%) is higher than the genome as a whole. The G/C content of the spacer region (38%) is coneiet~nt with the rçm~in~er of the genome. The nucleotide sequence of the three rRNA subunits is 100% identic~l in all six ribosomal operons. The rRNA operons can be gluuped into two classes based on the spacer region between the 16S and 23S sequences. The shorter of the two spacer regions is 478 bp in length (rrnB, rrnE, and rrnF) and cont~ine the gene for tRNA Glu. The longer spacer is 723 bp in length (~7n4, rrnC, and rrnD) and contains the genes for tRNA Ile and tRNA Ala. The two sets of spacer regions are also 100% i~lentirzll across each group of three operons. tRNA
genes are also present at the 16S and 5S ends of two of the rRNA operons.
The genes for tRNA Arg, tRNA His, and tRNA Pro are located at the 16S end of rrnE while the genes for tRNA Trp, and tRNA Asp are located at the 5S
end of rrnA.
The predicted coding regions of the H. ir~fluenaze genom~ were initially defin~cl by evaluating their coding potential with the program G~n~m~rk (Borodovsky and ~rcTninc~h, Computers Chem. 1 7(2): 123 (1993)) using codon frequency m~tric~s derived from 122 H. influena~e coding sequences in GenR~nk The predicted coding region sequences (plus 300 bp of fl~nking ~5 sequence) were used in ~rches against a ~l~t~h~e.o of non-rec~lln~l~nt b~ct~ri~l proteins (NRRP) creat~d spel~-ifir~lly for the annotation. ~llnrl~ncy was removed from NRBP at two stages. All DNA coding sequences were extracted from (3~nR~nk (release 85), and sequences from the sarne species - were searched against each other. Sequences having >97% eimil~rity over regions > 100 nucleotides were combined. In addition, the sequences were tr~n~l~ted and used in protein co...p~. i eons with all sequences in Swiss-Prot SUB5mUTE 5HEET tRULE 2~i) W 096/33276 PCTrUS96/05320 (release 30). Sequences belc-nging to the same species and having >98%
~imilArity over 33 amino acids were combined. N~RP is composed of 21,445 sequences eYtrA~ted from 23,751 GPnRAnk sequences and 11,183 Swiss-Prot sequences from 1,099 dirr~ -- s~i~s.
A total of 1,749 predicted coding regions were i~1e-n*fi-P~l Searches of the H. infilenz~e predicted coding regions were ~ ro~llled using an algorithm that I I A ~ '~ the query DNA s~quPn/ ~ in the three plus-strand reading frames for sear~llillg against NRBP, idPntifiPs the protein sequences that match the query, and aligns the protein-protein mAt hPs using praze, a mn-lifiPA Smith-Waterman (Pearson and TipmAn, Proc. Na~l. Acad. Sci. U.S.A. 85:2444 (1988)) algorithm. In cases where insertion or rlPl~*on~ in the DNA sequence produced a frAm~chift error, the AlignmPnt algorithm started with protein regions of Ill~ imilArity and eYtende~ the AlignmPnt to the same tlAtAhA~P match in alternative frames using the 300 bp fl~nking region.
Regions known to contain frameswft errors were saved in the .iAt~hA~P and evaluated for possible co,recLion. Uni~pnt*fie~ predicted coding regions and the ~e.~ining inl~,ellic sequences were s~uclled against a dataset of all available peptide sequences from Swiss-Prot, PIR, and GPnRAnk TdPntific~tion of operon structures will be f~rilitAtP~1 by ~,~. ;.--Pnt~l dt;l~ aLion of tr~n~l~ription ~."lllo~l and t~ n sites.
Each putatively identifip~1 H. influena2e gene was A~eignP~l to one of 102 biological role catc~olies adapted from Riley (Riley7 M., Microbiology Reviews 57(4):862 (1993)). ~ignmentc were made by linking the protein ~uence of the predicted coding regions with the Swiss-Prot sequences in the ~5 Riley ~iAtAh~e Of the 1,749 predicted coding regions, 724 have no role A~ignment. Of these, no rlAtAhA~e match was found for 384, while 340 m~trhP~1 "hypothetical proteins" in the ~l~tAhA~P Role Ac~ignmPnts were made for 1,025 of the predicted coding regions. A compilAti~ n of all the predicted coding regions, their unique i~1pntifiers~ a three letter gene idPntifier, percent identity, ~lce~ imilArity, and amino acid match length are ~ sented in Table l(a).

SUBSTITUTE ~EET (RULE 26) W 096/33276 PCT~US96/05320 An annotated complete genome map of H. influenaze Rd is ~,csell~ed in Figures 6(A)-(D). The map places each predicted coding region on the H.
inf~uenaze chromosome, in~ tPc its direction of tr~nccription and color codes its role ~cci~nmPnt Role ~ccignmf ntc are also lc~lcscl~Lcd in Figure 5.
S A survey of the genes and their chromosomal o~ t;l n in H.
influenaze Rd make possible a description of the metabolic pn,cesses H.
influenaze requires for survival as a free living org~nicm, the mltrhion~l requirements for its growth in the laboratory, and the charactprictic-s which make it unique from other or~nicmc c~ifi~lly as it relates to its p~thOgr~ y and virulence. The genome would be l_A~ ed to have complete complementc of certain classes of genes known to be eccenti~l for life. For PY~mp'-, there is a one-to-one ~lle:,~on-len~e of published E. coli ribosomal protein sequences to potential homologs in the H. influenaze ~l~t~h~ce Likewise, as shown in Table l(a), an aminoacyl tRNA-synth~-t~ce is present in the genome for each amino acid. Finally, the location of tRNA genes was mapped onto the ~enom~ There are 54 i-lentifi~d tRNA genes, inclutlin~
s~ es of all 20 amino acids.
In order to survive as a free living org~nicm, H. influenaze must ~l~luce energy in the form of ATP via r~ ;nn and/or electron transport.
As a f~yllt~tive anaerobe, H. influenaze Rd is known to ferment glucose, fructose, g~l~ctosp7 ribose, xylose and fucose (Dorocicz et al., J. Bacteriol.
175:7142 (1993)). The genes ide-ntified in Table l(a) in~ te that transport systems are available for the uptake of these sugars via the phosphoenolpyruvate-phosphotransferase system (PTS), and via non-PTS
,~ ---C Genes that specify the co----- ~ hc~ ~carriers Enzyme I and Hpr (ptsl and ptsH) of the PTS system were identifie~ as well as the glucose specific crr gene. The ptsH, ptsl, and crr genes c~ the pts operon. We have not however identifif-ci the gene Pn-~ling membrane-bound glucose specific ~y~-le Il. The latter enzyme is r~uilt;d for transport of glucose by the PTS system. A complete PTS system for fructose was idP~tifie l.

SvBsmuTE St~EET (RULE ~6) W 096/33276 PCTrUS96/05320 Genes ~nr~lin~ the c~....pl~ ~ . glycolytic ~.~v~ and for the production of fprmpnt~tive end products were id~ntifipl1 Growth utili7.ing anaerobic r~ y m~h~ni.~m~ were found by ide,~lifyi,lg genes encoding filnl~tion~l electron t~ systems using inol~,~nic electron ~ccel~lo. ~ such as nit~t~s, S nitrites, and dimethylsulfoxide. Genes encoding three enzymes of thetric~l,~,Aylic acid (TCA) cycle appear to be absent from the genome. Citrate synthase, i.~;l.,.lt~ d~l~y~,ge~, and acordtase were not found by searclling the predicted coding regions or by using the E. coli enzymes as peptide queries against the entire genome in tr~n~l~tit~n This provides an explanation for the very high level of ~,l."~ (lg/L) which is l~ui~ed in ~lefin~d culture media (E~lein and L~ul~ul~l, J. Gen. Microbiol. 113:409 (1979)). (~lut~m~tt~ can be dil~;l~d into the TCA cycle via cc"l~/t;l:,;oll to alpha-ketogh~ te by gl,.
dehydrogenase. In the absence of a complete TCA cycle, p;~ t~
~r~;,~l...~hly serves as the source of carbon for biosynthesis of amino acids using pl~;UlS~ i which branch from the TCA cycle. Funcfic-n~l electron transport systems are available for the prodllction of ATP using oxygen as a t~rmin~l electron acceptor.
Previously ul~~ d ~luc~lions l~~d~ thog~onicity and virulence can be addressed by r~ ;n;~g certain classes of genes such as adhesions and the lipooligo~ h~ri~e biogenesis genes. Moxon and co-wc,lkrl~ (Weiser et al., Cell 59:657 (1989)) have obtained evidence that a number of these virulence-related genes contain tandem lPI ,. . . ~~r repeats which undergo frequent addition and del~*c n of one or more repeat units during replie~ti(ln such that the reading frame of the gene is changed and its r~lession thereby altered. It is now Fo~.~ihl~., using the complete genome sequence, to locate allsuch tandem repeat tracts (Figure 5) and to begin to determine their roles in phase v~ri~til n of such pole"li~l virulence genes.
H. in.fluenzae Rd pqss~-s a highly effit~ient natural DNA
r..i ...i~l;on system (Kahn and Smith, J. Membrane Biol. 138:155 (1984).
A unique DNA uptake sequence site, 5' AAGTGCGGT, present in mllltiple copies in the genome, has been shown to be nP~ ~.y for effiçient DNA

SUBSTTTUTE S~}EET tRULE Z6~

W 096/33276 PCTnUS96/05320 uptake. It is now possible to locate all of these sites and completely describe their distribution with respect to genic and u~ ,ellic regions. Fifteen genes involved in tran~ro~ ation have already been described and sequenced 1fiPl~l, R., J. Bacteriol. 173:5612 (1991); Ch~ntllpr~ M., Proc. Natl. Acad.
S Sci. U.S.A 89:1616 (1992); Barouki and Smith, J. Bacteriol. 163(2J:629 (1985); Tomb et al., Gene 104:1 (1991); Tomb, J, Proc. Natl. Acad. Sci.
U.S.A 89:10252 (1992)). Six of the genes, cornA to comF, comprise an operon which is under positive control by a 22-bp palindromic co-ll~nce regulatory el~mpnt (CRE) about one helix turn U~ tiealll of the promoter. The rec-2 Lldllsr ,. ,.. ~linn gene is also controlled by this pl-omPnt It is now possible to locate additional copies of CRE in the genome and discover potential tran~r~,llll~Lion genes under CRE control. In addition, it may now be possible to discover other global regulatory çlemPntc with an ease not previously possible.
One well-described gene regulatory system in b~etPn~ is the "two-colllponent" system composed of a sensor m~1e~ll1P that detects some sort of environmPnt~l signal and a regulator molcculP that is phosphorylated by the activated form of the sensor. The regulator protein is generally a tr~nccriI)tion factor which, when activated by the sensor, turns on or off e~les~ion of a specific set of genes (for review, see .Alhright et al., Ann. Rev. Genet. 23:311(1989); Parkinson and Kofoid, Ann. Rev. Genet. 26:71 (1992)). It has been ~-~ili...;.l~l that E. coli harbors 40 sensor-regulator pairs (Albright et al., Ann.
Rev. Genet. 23:311 (1989); Parkinson and Kofoid, Ann. Rev. Genet. 26:71 (199V). TheH. influena2e ~enomP was searched with r~>lçsç~.l;.li~e proteins from each family of sensor and regulator proteins using tblastn and tfasta.
Four sensor and five regulator proteins were idPntifie~l with cimil~rity to proteins from other species (Table 6). There ~ to be a corresponding sensor for each regulator protein except Cp~R. Searches with the CpxA
protein from E. coli idPntifiP~ three of the four sensors listed in Table 6, butno ~ 1itinn~1 ci~nifie~nt m:~t~.hP.s were found. It is possible that the level of sequence .cimil~rity is low enough to be llnrlçt~P~t~hle with tfasta. No SUBS ~ ~ T UTE S~EET tRULE 2~i) W 096/33276 PCTrUS96/05320 representatives of the NtrC-class of regulators were found. This class of proteins intpr~ct~ dir~;lly with the sigma-54 subunit of RNA polymPr~P
which is not present in H. iny1uenaze. ALl of the re~ t~r proteins fall into theOmpR subclass (.Alhri~ht et al., Ann. Rev. Genet. 23:311 (1989); p~rkin~on and Kofoid, Ann. Rev. Genet. 26:71 (1992)). The phoBR and basRS genes of H. influenaze are ~dj~ nt to one another and ~rG~.. ~hly form an operon.
The nar and arc genes are not located ~ rPnt to one another.
Some of the most ihllGlei,Li"g questions that can be answered by a oo rl gen~mP sequence relate to what genes or pd~lW~y~ are absent. The non-~~ gr.~ H. iny?uenaze Rd strain varies ~i~ifi~ntly from the pathogenic serotype b strains. Many of the dirr~.e-~ces bG~een these two strains appear in factors affecting infectivity. For PY~mpkP, the eight genes which make up the fimbrial gene cluster (vanHam et al., Mol. Microbiol. 13:673 (1994)) involved in ~lh~inn of b~r~ i~ to host cells are now shown to be absent in the Rd strain. The pepN and purE genes which flank the fimbrial cluster in H.
i~1uena~ type b strains are ~ rPnt to one another in the Rd strain (Fig. 7), .gge j~;.-g that the entire fimhri~l duster was eY~i~l On a broader level, we d which E. coli ~ s are not in H. inJquenzae by taking advantage of a non-re~--n-l~nt set of protein coding genes from E. coli, namely the University of W;~ fiPn~mP. Project contigs in (3Pn~nk 1,216 predicted protein sequences from fienR~nk ~c~ ns D10483, L10328, U00006, U00039, U14003, and U18997 (Yura et al., Nucleic Acids Research 20:3305 (1992); Rllrl~nd etal., Genomics 16:551 (1993)). The ...;n;...~... threshold form~tçhes was set so that even weak m~tehPs would be scored as positive, thereby giving a minim~l e~ e- of the E. coli genes not present in H.
iry~uenaze. tblastn was used to search each of the E. coli proteins against the complete genome. A~l blast scores > 100 were considered m~tl~hes.
Altogether 627 E. coli proteins m~tf.ll~ at least one region of the H.
iry~luenaze genome and 589 proteins did not. The 589 non~ .;..g proteins were ~ ;.. ;.~ and found to contain a ~ lionate number of hypothetical proteins from E. coli. Sixty-eight percent of the itlentifiecl E. coli proteins SUB5TI~UTE S~tEET tRULE 2~i) W 096/33276 PCTrUS96/05320 were m~t~hP~1 by an H. influenaze sequence whereas only 38% of the hypothetical proteins were m~tchf?ll. Proteins are annotated as hypothetical based on a lack of ~ S with any other known protein (Yura et al., Nucleic Acids Research 2~.3305 (1992); Rllrl~n-l et al., Genomics 16:551 (1993)). At least two ~ùlcllLial PYpl~n~tions can be offered for the over l~,l;se~ on of hypothetical ~lulci~ls among those without .~ hPS some of the hypothetical proteins are not, in fact, tr~n~l~tP~ (at least in the annotated frame), or these are E. coli-specific proteins that are unlikely to be found in any species except those most closely relatcd to E. coli, for PY~mrle Salmonella typhimurium.
A total of 384 predicted coding regions did not display .cignific~nt cimil~rity with a six-frame tr~n~l~tion of GPnR~nk release 87. These nni~lPntifiP~ coding regions were colll~d to one another with fasta. Several novel gene f~miliPs were idP-ntified. For PY~mple, two predicted coding regions without ~t~h~ce m~tfhP.s (HI0591, HI0852) share 75% identity over almost their entire lengths (139 and 143 amino acid residues rc~ rely).
Their .cimil~rity to each other but failure to match any protein available in the current d~t~h~ees suggest that they could lc~lcselll a novel cellular function.
Other types of analyses can be applied to the ~mi~l~ntifiPfl coding regions, int~ inE~ hydru~llly analysis, which in~ tPs the p~ttPrnc of potential membrane-cp~nning domains that are often conserved bclweel~
members of lcce~lol and L-a,ls~llcl gene f~miliPs, even in the absence of significant amino acid identity. Five ~Y~mpl~s of uni~lentifi~i predicted coding regions that display polcll~ial tr~ncmpmbrane domains with a periodic pattern that is ch~r~tPrictic of membrane-bound ch~nnPl proteins are shown in Figure 8. Such in~llllaLion can be used to focus on spe~ific aspects of cellular function that are ~rr~l~d by targeted dPl~tion or mutation of these genes.
Interest in the mPAic~lly illl~ll~ aspects of H. infl~uenaze biology has ~ focused particularly on those genes which ~letPrminP virulence ch~r~tPrictics of the C,l~ lll. Recently, the catalase gene was c-h~r~ teri7Pd and sequenced - as a possible virulence-related gene (Bishai et al., J. Bacteriol. 176:2914 SU8STTTUTE S~EET tRULE 26) W 096133276 PCTrUS96/05320 (1994)). A number of the genes responsible for the capsular poly~rçh~ricle have been mapped and sequenced (Kroll et al., Mol. Microbiol. 5(6):1549 (1991)). Several outer membrane protein genes have been i~l~ntifi~1 and sequenced (Langford et al., J. Gen. Microbiol. 138:155 (1992)). The lipooligosaccharide co---ponent of the outer membrane and the genes of its synthetic ~Lhw~y are under intensive study (Weiser et al., J. Bacteriol.
l 73:3304 (1990)). While a vaccine is available, the study of outer membrane components is motivated to some extent by the need for improved vaccines.

Data A~ fy The H. influenaze genome seq~l~n-~ has been deposited in the Genome Sequence D~t~R~ (GSDB) with the ~rc~ic n number L42023. The nucleotide sequence and peptide tr~n~1~tinn of each predicted coding region with i~l~ntifi~ start and stop codons have also been ~e~ioned by GSDB.

Production of an Antibody to a Haeml r ~. 7~s influen~ Protein Subst~nti~lly pure protein or polypeptide is isolated from the L~l or Lld--srol..~d cells using any one of the ,,,~1.o~iC known in the art.
The protein can also be produced in a recombinant prokaryotic eA~res~ion system, such as E. coli, or can by ch~mic~lly synth~i7Pd ConcPntr~tic)n of protein in the final ~ n is adjusted, for example, by con~ntr~tinn on an Amicon filter device, to the level of a few miclu~ la,l-s/ml. Monoclonal or polyclonal antibody to the protein can then be pr~cd as follows:

Monoclonal Antibody Production by Hybndoma Fusion Mnno~ n~l antibody to cpilopes of any of the peptides identifiç~l and isolated as d~-~ihed can be pl~C d from murine hybridomas according to the cl~ic~l method of Kohler, G. and Mil~tein, C., Na~ure 256:495 (1975) or SUBSTITUTE S~tEET tRULE 2~;) W 096/33276 PCTnUS96/05320 modifit ~tions of the methods thereof. Briefly, a mouse is le~LiLi~ely inoculated with a few micrograms of the sPl~t~1 protein over a period of a few weeks. The mouse is then ~-rifi-ed, and the antibody producing cells of the spleen i~l~t~d The spleen cells are fused by means of polyethylene glycol with mouse myeloma cells, and the excess unfused cells de~Lluyc~d by growth of the system on selective media comrri.~ing aminopterin (HAT media). The ~"~f ~i~r"lly fused cells are diluted and aliquots of the dillltion placed in wells of a microtiter plate where growth of the culture is continued. Antibody-producing clones are idPntifi~l by det~tion of antibody in the Su~-~ t fluid of the wells by i-i----l---~e~y procedures, such as ELISA, as origin~lly described by Engvall, E., Meth. Enymol. 70:419 (1980), and modified methods thereof. Sele~ted positive clones can be exp~n-1e~1 and their monoclonal antibody product harvested for use. Detailed procedures for monoclonal antibody prod~lctinn are described in Davis, L. et al. Basic Methods in Mol~-ll~r Biology Elsevier, New York. Section 21-2 (1989).

Polyclonal An~ibody Pro~ tion by Imm~ ~'iolz Polyclonal ~~ ulll c ~ g antibodies to heterogenous ~iL~pes of a single protein can be prt~ed by i-------~ g suitable ~nim~l~ with the s~d protein described above, which can be unmodified or modified to e~h~n~ e ;.. i~g~ ity. Effective polyclonal antibody production is affected by many factors related both to the antigen and the host species. For example, small mc l~lll~-s tend to be less immllnogenic than other and may require the use of carriers and adjuvant. Also, host ~nim~l~ vary in response to site of inocul~tion~ and dose, with both inadequate or excessive doses of antigen resulting in low titer ~nti~ Small doses (ng level) of antigen ~imini~et~red at multiple intr~-lermal sites a~ to be most reliable. An effective ~ i.. -.. ~;,i1l;on protocol for rabbits can be found in V~itllk~iti.C, J. et al., J.
Clin. Endocrinol. Metab. 33:988-991 (1971).

SUE~S 111 UTE S~tE~T (RULE ~6) W O 96/33276 PCTrU~96/05320 Booster injections can be given at regular intervals, and antiserum harvested when antibody titer thereof, as dcLellllined semi~ ely~ for e7 by double immlln-Yliffusion in agar against known con~ntr~tion~ of the antigen, begins to fall. See, for PY~mple, Oucht~rlony, O. et al., Chap.
19 in: Handbook of Experimental Immunology, Wier, D., ed, Blackwell (1973). Plateau c~ n of antibody is usually in the range of 0.1 to 0.2 mg/ml of serum (about 12 ~cM). Affinity of the ~nti~r~ for the antigen is determined by prcl~ing colll~cLiLi~le binding curves, as described, for e-~mpl~, by Fisher, D., Chap. 42 in: Manual of Clinical Immunology, second edition, RoseandI~ n, eds., Amer. Soc. ForMicrobiology, W~hington, D.C. (1980).
Antibody ~le~.,~;( n~ prepared accol~ g to either protocol are useful in 4~ e immunoassays which determine con~-ntr~tions of antigen-bearing ~lb~ P-s in biologi~l s~ --F'--; they are also used semi-~ nf;li.li~ely l~i or qualitatively to identify the p~e3ellce of antigen in a biological sample.

Preparation of PCR Primers and Amplification of DNA

Various f~gm~nts of the Haemophilus influenzae Rd genome, such as those disclosed in Tables l(a) and 2 can be used, in accordance with the present invention, to ~rc~alc PCR plilllcl~ for a variety of uses. The PCR
primers are ~lcÇ~dbly at least 15 bases, and more preferably at least 18 bases in length. When sP~ ting a primer sequence, it is ~lcrcllcd that the primer pairs have app~ ly the same G/C ratio, so that m~lting telll~ldlules are approxim~te-ly the same. The PCR primers and ~mplifi~l DNA of this FY:Imr)le find Use in the FY~mples that follow.

Gene ~ on from DNA Seq~le~es Conesponding to ORFs A fr~gmPnt of the Haemophilus infl!uen~:ae Rd genome provided in Tables l(a) or 2 is introduccd into an c~,lc:ision vector using convention~

SUB5 111 UTE ~HEE~ ~RULE 2~) W 096/33276 PCTrUS96/OS320 te~hnolngy. (Techniques to transfer cloned sequences into GA~re~sion vectors that direct protein tr~n~l~tion in ~ ,.."~ n, yeast, insect or b~ctPri~l ~A~1~7~10n systems are well known in the art.) Co~ nGl- ially available vectors and eAyre~:,ion systems are available from a variety of suppliers inrl~lrling S str~t~E~Pn~ (La Jolla, California), Plu~ega (Madison, Wisconsin), and Invitrogen (San Diego, California). If desired, to enh~nre ~A~ ssion and f~ilit~t~ proper protein folding, the codon conteAt and codon pairing-of the sequence may be o~Li..-i ~ed for the particular GA~les~ion org~ni.~m, as ~Yrl~in~d by ~tfiF-l~l et al., U.S. Patent No. 5,082,767, incol~uldlGd herein by this reference.
The following is provided as one eyenlrl~ry method to generate polypeptide(s) from cloned ORFs of the Haemophilus genome fr~gm~nt Since the ORF lacks a poly A sequence because of the b~rt'--ri~l origin of the ORF, this se~lue lce can be added to the construct by, for example, splicing outthe poly A sequence from pSGS (Str~t~genP) using Bg~I and SalI restriction endonurle~ enzymes and inccl~ld~ing it into the m~mm~ n ~A~lc;ssion vector pXTl (str~t~genp) for use in eukaryotic t;Apl~ion systems. pXTl contains the LTRs and a portion of the gag gene from Moloney Murine Leukemia Virus. The position of the LTRs in the construct allow effici~nt stable ll~.~r~;lion. The vector inr~ es the Herpes ~impleY thymidine kinase promoter and the sPlPrt~hle neomycin gene. The Haemophilus DNA is obtained by PCR from the b~Ctpri~l vector using oligonucleotide prim.ors complemPnt~ry to the Haemophilus DNA and co~ g restriction endonuclease se~luel~ces for PstI incol~la~d into the S' primer and Bgm at the 5' end of the corresponding Haemophilus DNA 3' primer, taking care to ensure that the Haemophilus DNA is po j;l ionP~ such that its followed with the poly A sequence. The purified fr~gm~nt obtained from the r~s~llting PCR
reaction is ~I;gr.~l~ with PstI, blunt ended with an e~rom~cl~ -, digested with Bgm, purified and ligated to pXTl, now colll;.i.-;..~ a poly A sequence and digested Bgm.

SU8STTTUTE SHEET tRULE 26) W 096/33276 PCTrUS96/05320 The ligated product is transfected into mouse NIH 3T3 cells using Lipofectin (Life Te~hnolngies, Inc., Grand Island, New York) under conditions outlined in the product specific~tion. Positive tran~r~;l~ are s~-lected after growing the tr~n~f~tPA cells in 600 ug/ml G418 (Sigma, St.
Louis, Missouri). The protein is preferably released into the ~ t However if the protein has membrane binding domains, the protein may ~ddition~lly be retained within the cell or e~res~ion may be rçstficte l to the cell sllrf~re Since it may be n~ry to purifv and locate the tf~n~fect~i product, svntnetic 15-mer peptides synth~i7P~l from the predicted Haemophilus DNA
sequence are injected into mice to generate antibody to the polypeptide encoded by the Ha~mophilus DNA.
If antibody p~ lc~ is not possible, the Ha~mophilus DNA sequence is ~rlrlitinn~lly incul~oldt~d into eukaryotic c;A~ ion vectors and t;A~ sed as a chimPric with, for eY~mrl~-, B-globin. AnLil~ody to B-globin is used to purify the çhim~fic. Co,lt:~nding protease cleavage sites ~ngin~fed b~Lw~l- the B-globin gene and the Haemophilus DNA are then used to s~~
the two polypeptide ff~gmPnt~ from one another after tf~n~l~tion. One useful ~A~l~on vector for pe~ B-globin chim-ofir~ is pSG5 (Str~t~genP). This vector encodes rabbit B-globin. Intron II of the rabbit B-globin gene f~rilit~t~s splicing of the t;Apr~i,sed tf~n~r-fipt, and the polyadenylation signal inc~l~uldl~d into the consL.u~;~ increases the level of ~Al~ression. These techniques as ri~ ~ ;1~1 are well known to those skilled in the art of molecularbiology. Standafd mf~.th~l~ are published in methods texts such as Davis et al.
and many of the methods are available from the terhnir~ iSt:3nr~
e~le,~ es from Stf~t~g~ne, Life Te~hnol~ gies, Inc., or Promega.
P~ly~lide may ~ ition~lly be produced from either construct using in vitro tr~n~l~tion systems such as In vitro Express~M Tr~n~l~ticm Kit (str~t~g~on~-).
While the present invention has been described in some detail for ~ oses of clarity and un~ g~ one skilled in the art will appreciate that various SU8S i l l UTE 5}~EET tRULE 26) W 096/33276 PCTrUS96/05320 ~~.h~nges in form and detail can be made without departing from the true scope of the invention.
All p~tf~.nt~, patent applications and public~ticn.c referred to above are hereby inc~ dl~d by reference.

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8 00 ~D ~ ~ ~ ~ ~ C cn ~ c ~ ~ ~ _ ~ (D O -~- '~ o r- -- _ o o 1' o 8 g '- ~ g ~r _ ~ g 0 I T T I I I ~ I I T I I I I I I I I I I

76.11 SUB5TTTUTE ~iHE~ tRULE

W 096/33276 PCTrUS96/05320 o C'~ 1~ 0 C~l C) O~ t~ 1~ ~ Cl~ O N C'~ 0 0 0 1~ r--- 0u) t~ t~ o 1~ ~ D 0~ O 0i _ 0 ~ t~

~0 0 u~ o o a~ ~ c~ ~ c~ co tD ~ r' ~ ~ ~ ~ c~ 0 0 N0 C'~ 0 0 1~ 0 ~ 0 CD O ~ 0 0 0 -- -- ~ ~ C~

~~ C -C O ~ O

S o O o S S S

c = = s s E _ ~ c s ~ ~~ ~ ~

~- ~ ~ C~ -C ~- ~ ~ E _ ~ O _ E E IL

c m ~ ~~ ' _ o ~ E 2 2 2 ~ E ~~ ' - Q a~ -- Q ~ Q C c c ~ C C a~ ~ o at ~ E
~ ~ ~ ' ~ ~ ~ ~ ' E 2 ~ 2 2 ~n c~ ~ , c E 4 = E -- E 7' ' ~ ~ ~ o ~ ~ E

D -- = = ~ ~ -- ~o o o ._ S S S S = o E c ~ ~ =

--Q _ N O 0 ~J 0 0 _ O> ~D _ ~ a~ 0 O ID O C'~ ' 0 O N tS~
ID 0 ~-- ID _ ') O ID ~ ~ O ~ ID O N ~ D 0 ~r N
Q ~r N 0 tD D Cl) 0 (~ ~ O ~ D N ID 1~ 0 ID N _ N ~ 0 _ ID 0 a~ 0 _ 1~ N 0C'~ 0 _ _ O N O a~ _ O N 1~ 0 ~ 0 0 0 0 O CD 0 0 C'~ N_ O ~ C'~ ~ ~r 0 0 0 0 0 ~r O O
_ r-- N ~ er1~ C~.l N 0 N N N 0 _ N N ID
~- -- - - --- - -_ _ ID ~ O '' O0 N t~ 0 ID t~ ~ N C~) O O ID ~ t.D N 0 C ~DD C'~ N 0 0~ -- -- 0 N ~00 ID ~ ~ ~ ~ 0 ~ t~ 0 _ ~~D ~ 0 0 0 _ ~ ~t O N _ O N 0 _ ~ ID O 0 -- C~
S _ _ ~ _ O ~ N N _ C~ _ NO NO ID

_ 0 ~0 0 _ N 0 0 0 ~:~ _ 1~ 0 -- -- 1~ C0 O 0 N 0 0 t~ ~ c,~ a~ c0, ~ 2 o _ _ 2 2 2 2 C ' ~ C'' c ~ ~ 0 ~ c ~ 0 __oo _ooo_ ooooo___o_ __ I I I I I I I I I I I I I I I I I I I I I I I

76.12 SUBSTITUTE SHF~ tRULE 2~) _ ID _ 0 tD O ~ O O O ~ -- O
cq _ o o oa> c~J _ ~ _ ~I c~l o o~
-- _ N O

N ~ ~ ~ _ ~ ~D O tD

s, ~ a ~ , ~ ~ ~O ~" C ~ O ~

5~ oQ,CL C ~ ~DS C~ ~ o c o ~

O O O O ~ _o s E c ~ E ~s, E--0 ~D ._ ~ ~ ~ 00 c o o ;-s ~
0 ~c ~ ~ t~ ~0 ~ S. a~
~ a) ~ ~ ~ o cq a 0 ~ D
,~O tD C~ ~D D ~_ ~ S ~ O ~ O cv ~ _ O
,~~ 0 a~ e~ c . ~ ~ ) o ~ o ~ ~
-- E ~ 0 ~D u~o _ 0 ~ ~ et ~ '' ~ o 8 ~~ -- D -- ~ a~ ~ o .- ~D ~ ~r ~ ~ ~ ~r o ~ 10 2 a~ _ ~ ~D a~ ~~ a) a~ ~ s o r~ Ir ~ a~
~~O O D 1~ E -- ~ c~ .C o a~ J ~ u~ rD t~ lD ~D
S lD Q U') Q a) a) a) _ ,~D ~ ~ o crl ~ _ 0 EO ~ ~ a~ ~ o _ ~ ~ ~ ~ c-~ et ~ ~ ~
a~s ~ -- D ~ ~ ~ ~ o -- ~D o ~ ~ ~ ~ ~ o ~ 11'~
.c Q O~ Q Q -- -- -- -- -- ~ -- --CJ ~r 1~ 0 D a) O) ~D tD ~ ~D D If~ 2 D C'~

~D ~__ --__OO _____ __ I T I I I I ~ ~ I I I I I I I

76.t3 SVBS 11 i UTE S~E~T tRULE 26 W 096/33276 PCTrUS96/05320 0 C~ O ~ C~ O O N tD _ ~ 0 ~ C~ C~ ~ 0 Cl) O 1~ lO ~ 0 C~l O O t' O 0 t~ 0 _ O CO O N U~
0 ~ ~ c~J ~ c~ o> ~ ~~ 0 0 u~

c~J ~ e~ C'J 0 ~ r- c~ ~ C'~ -- ~ -- ~ -- -- C~ 0 ~

.~
c '' o c ", U~
.L) _ ,~ ~ m o ~
~
._ ~ c s~ C t~ E ~c u~ ~ O O O ._ ~ .- ~ ~~ - 3 . ._ o Q Q Q 8 c ~ s ~~ O ~ ~ c ~ v ~
E ~5 s o o o -- u ~ o C .~ D D D = = ~ S c c C ~ ~ D D ~ C ~ .C ~ I I I m -~ ~ m ~
C a3 ~ a~ ~ Y ~) 8 ~ .-- ~ ~ c~ Y C 0 ~ ._ m~ ~ ~ 3~
O E ~ ~ ~ ~ ~ g I ~ D~ ~ ~ ~ m ~ ~ _ ~n o C ca ~ Q o _ o ~ o ~ =
m c _ m ~ = ~ n n ~ ~ n n ~ = E 1 c O ~ ~ er 0 ~ ~ ~ CU O r~ ~
~D _ ~ O C'~ ~ tO ~ 0 ~ ~ O ~ ~ a~ ~ _ 0 o _ r~ _ ~ ~ C'~ ~ ~ _ U~ O ~ ~ ~ ~ CO C~ lD 0 _ ~ CD ~D 0 0 0 ~ er _ C~ _ O cn ~ C ~ a~
r ~ o _ ~ o ~ D E u~ _ o c~J
n ~ c~
~ 0 cn ~ t~ ~ 0 ~ ~ 0 ~ -- 0 ~ E ~ 0 _ o o 0 tD C~ c~ 0 C~l __ C~J r~ (D ~l c C'J 11~ 0 _ ~17 ~ ~ U~ ~ _ ~ C~l O O ~ O ~ 0 ~ C~
c ~ _ ~ O ~ D W ~D n ._ u~ _ o E ~ _ -- _ c~J o _ r~ E u~
O -- -- E
-- _ C~l 0 r~ D ~ 0 _ O CO 1~ C~ I~ o ~~ ~ ~ ~ o u~ _ cn co ~ ~ ~ ~r o c~ 0 ~ 0 -- _ O N 0 __O__OOOOOOOO C OOOO
_ I I I I I I I I I I I I I I I I ~I I I I

76.14 SU8STTTUTE SHEET tRULE 2b~

W 096/33276 PCTrUS96/0~320 O U~ _ tD t~ O ~ ~ O ~ I~ O _ ~

1~ a:~ ~ .- _ o~ c~ ~ _ _ _ ~ r- o ~ ~ ~ u~ tD O O ~ l' O

~ u .c - - o . - ~ - -~ _ 8 8 s~ ~ _8 8 I ~.- _ E o E c Q, s:~ s~, ~s, s ~ ~ ~ - a -- " 'n '~ s ~ ~ ~ v _ _ _ ~ ~ _ J E Z ~c x x~ _ ~ ~ _ ~ ~ ~ Q Q C
t~t~ ~o o~ _ o o et~ 0 c~ l 1~ o) C'J ~D O C~l C'7 N C' t~ 10 ~J C! N ~ C'J tD O 0~ ~ ~ ~D 1~ 1~ . _ r~
a~ D O C~ o _ _ ~o _ _ ~ o a~ ~ CD 10 0 ~ ~--a~ a~ Q _ O C~ _ O 1~ O) 0 O a~ CD a~ o _ ~ cJ o~
o _ o o c~ ~ _ a~ o ~ o _ ~ o C~l ~0 a~ r~ a~
9~ ~ o a~ ~ a o~ ~ a~ a~
n _ ~ Cv u~ o o7 c I o ~ a~ _ ~ a~ --oo a~ o 1~ a~ c~ o a~ o ~ a~ D o a~ _ ~D o _ _ ~ _ -- ~ ~ o o~ D ~ a~
a~ _ _ _ _ _ _ ~ _ _ _ ~ ~ _ _ _ _ c~l ~ _ cJ _ t o _ _ r a~ ~ ~ a~ o c~ a~
trl o _ ~ a~ o a~ _ ~D o _ _ ~n _ _ ~ o~ o~ o ~ r~ u~ co o o_oo_ooo__oo__ oooo_ooo_o I T I I I I I I I I I I I I I I I I I I I I I I I

76.15 SUBSTT~UTE SHEET tRULE 2~i3 W 096/33276 PCTrUS96/05320 O ~ o c~ ~o a) 0 e~
0 ~ 0 ~ N ~D O 0~ 0 CD O
In N ~ 0 ~ ~ ~r N ~ ~t FJ 0 N C'~ ~ ~
~D O ~ N ~ N -- t~
c~J a) _ ~ o 0 lD _ _ ~ ~ I~ _ O --~ 0 0 U~ ~ 0 ~
0 ~ ~ D O a) ~ 0 _ tD 0 In IO ~ 1-- o N
_ 0 0 0 N N C~ ~ -- t~ ~) C'~ ~ ~ ~D

a~
.~ .~0 ~ Q
~Q o ~ ~

sO --O E 'C' C ~ C s s c ~, _ D-- C llJ
IIJ _ c .~ c ~ -- ~ c ~ c~8 -- ~ D ~
C [~ 'C 'C I~ ~C ~--C D m ~ ~,~ Q ~ ' tD
~ 8 c ~D _ _ D ~ C~ ~E -- 0 a~ --_ _ ~S c~ ~ a~ C ~ c ~ ~
"~ "' ~~ ~~ '' ~ -- ~ E UJ ~ u,, c c C ~ c~ C ~ 'a ~ .c ~ E

8 = 0~ s E E ~ ~ O

s s ~ ~ ~ C ~ _ O ~ ~ E E E = ~
c LO fD Ln fn f~ O r~ 0 ~ ~D fn 0 L ' ~r Q 0 t~:) a~ cn ~ ~ ~D fn f~ Q Ln ~ ~0 _ f'~ fn ~ I 0 0 1-) o~ ~ N fn N fD 0 ~D ~r O n 0 0 ~D L I W
Ln fn f~ fo ~ m D ~ Ln ~D fn f.'' N tlS N D
O o cn O N N N N N ~I fn ~ D S l'_ ~
~ f'~ f.~l N f'~ r N f'~ f.~: N Q Ln n c -- _ . _ _ _ _ _ _ 0 O
Lt7 fD fD 0 fl) 0 ~ cn fD N ~ U' I~ _ I~ f~ Q cn fn o t~ _ ~, ~ n r- ~ Ln n c~l O c~ 0 -- a~ Ln _ _ f~ fn ~ ~ ~ _ o f~ ~ a cn ~ ~ Ln ~ -~ f~ tO _ Ln _ ~ Ln ~D ~D ~ ~ Ln 1~ N -- O ~r 2 O O O O ~ f'~ N N N N N fJ~ D --C 1~--~ f~ N f~J f~ t~ r_ ~ ~ N f.~ N f.~J ~D Ln n L~ ~ er ~D 0 Ln N f.~ '* ~ f~ f.~ 0 o fn LO O
f'~ f~ f.'~ f'~ ~D N NN C~J a7 0 _ ~ O fn Ln ~D
_ o-- _ '~ _ 8 8 g o ~ ~ N -- -- -- Ln Ln I I I I I I I I I T I I I T I

76.16 SVBST~TVTE SHEET tRULE 26 O O ~ U~ O U~ o ~t a~ o ~ c~ ~ o a) ~D 1~ 0 ~

c~ o _ o ~ ~ c~ O
-- t' ~ N _ 1-- -- O ~ 1~ C~ 0 0 .~
C
_ _ ~
CD E ~ 8 ~ ~- -- ~ -- --s 2~ C _ ~ 0 ~ _ s .~ ~ O

8 . - 8 8 . c ~ ~ ~--a ~ ~ ~~v ~ ~ o u~ 2 ~' 2 ~ E ~
~ ~ s ~ O O O a, O ~ Z O O a~ a~
, ~ ~ 0 ~ 0 0 Q ~ - ~ ~ ~ ~

o o o s C ~ ~ E E E ~ c - 7 7 7 7 c ~ o , -- -- -- ~ 8 8 8 O 1~ O ' ~
V o o ~ ~ ~ I ~ ~ ~ ' - Q ~ ~ ~ ~ ~ ~ ~
V V ~ ) ~ o C UCI c -- E E c C ~ F
N N d d ~n z ~ ca tO O ~ ~ 2 ~, 2 2 2 2 ~ 2 CD ~O .0 ~ O C~l 0 r~ 0 0 C~l ~ 0 ~D 0 ~ D N
tD ~ t~ 0 1~ 0 ~ 0 u ) a) o a7 c~l o C~J O~ C~l _ I~ U~ 0 0 C'~ _ O) 0 0 0 .D CD O ~ a~ 1~ ~ 0 0 C~
0 0 ~ ~ -- ~ CO O _ O 0 0 1'~
~ 'O ~ C~l ~ 0 _ _ -- ~D ~ _ _ .~
O ~ _ _ 0 C~ 0 C ~1 O ~ 0 ~ 1~ 0 0 ~ N U~
0 0 o ~ C ~ ~0 0 8 ~ 0 C ~ t~ t~ O C~) ~D cr~ I~
O Cl) U~ 0 ~ ~ 0 0 0 0 _ ~
0 O 0 o 8 t~ In C~ N O a~ 0 ~ ~ ~ O) 0 F
0 C ~ ~ o ~" _ ~ o 0 1~ t O ca~ D 0 c _ _ _ ~

0 1~ CD O 07 ~ 0 r~ _ O
N ~ ~ In CD O ~ ~ ~ ~ ~r L~7 0 0 0 0 0 r--O Q O ~ I~ O O O ~ O O O O O O O
O O _ -- O O _ _ _ O O O O O O O _ I I I I I I I I I I I I I I I I I I I

76.17 SUBS l l l UTE ~}~EEr (RULE 26 W 096/33276 PCTnUS96/0~320 0 o, c~ 0 _ ~ ~ ~D x ~ 0 o ~ o~
~ _ o ~ o ~ c~ ~ o CD _ 0 ~1~ 0 0 ~O CD 0 ~ t~ 0 ~ 0 ~-- ~ 0 0 0 0 U7 - ~ 0a> c~i 0 c~ 0 ~ o o ~ o ._ .-- ._ 8 8 ~ ~

.~ ~ 2 ~ S ~ ~ O
Q - .~ D ~ ~ 0 0 0 _ - - m E ~ ~ ~
a~ 0 ,~ ~Q D~ a~0 c a) ~ ~ 0 _ Q

~ ~ ~ s 2 ~ s s ~' E o E .~ ~ - - E ~ = D D~ ~
~ c c S ,C C C 0 ~D D D ~~ C .~

~ c 0 0 ~ 0 ~ ~ ~ ~ ~ ~ ~ 0 0 ~ ~ ~ 2 2 x = s = s E = E E 2 2 2 E 0 E 0 E E E E ~ ~ ~ ~ ~ 2 Q C o O ~ ~ g - ~ ~

C~ In C ~ q ~ a~ o _ ~ ~ n o ~ C~ o ~ _ Ir) r C~J l~ 0 r ~ N C') C'7 ~ ~) ~ ID C~ C~l ~D 0 C~
O ~ l _ 0 N O _ 1~ ~D ~ ~ O 0 1) 0 0 ~r e~ 1~ a ~ C~J 0 0 0 0 C'J 1~ ~J C'J ~J 0 Q C'~ ~ ~) ~ ~' -- -- 0 0 0 0 ~ 1~ ~ 0 a~ _ ~ ~ ~ cu ~ ~ r~
-- C O
c~l 0 ~ ~ a) ~ u~ er 0 07 a) 1' ~ ~ 0 0 c~l ~ 0 c~
O C~l ~ ~1 0 U~ 0 0 c~l 0 0 c _ _ ~ ~-- CD ~ I~ C~J ~ ---- ~ O ~~ O C') 0 _ _ U~ _ O o 0 C~ ~ 0 U~ C~ 0 ~J C
~ ~ 0 ~ 0 0 ~ ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ ~ O ~ ~ ~ E
0 a~ 0 0 1~ tO ~
~ 0 ~ ~ r~ ~D _ O ~ tD 1~ m ~ 0 ~ ~5 N U) tD --~D ~ C') C'~ C" C" 0 C~J 0 0 0 a~ 0 ~ 1~ c~J ~ a~ tD ~D 0 -- -- O O O O O O O O O _ O _ _ ~O O O _ _ _ I I I I I I I I I T I I I I I I I I I

.

SUBS 111 UTE SHFET tRULE 2fi) W 096/33Z76 PCTnUS96105320 0 c~ o 0 ~ c~l o o 0 _ u7 ~ _ e~ ~ O O
_ U~ ~ ~ O C~ U) 0 ~ C'~_ ~D 0 ~ ~ ~ O
~D ~ ~ ~ ~ 0 ~ ~ 1' 0 0 ~
C~J ~ ~ _ ~D _ 0 0 ~ ~~ c~ ~ ~ ~ O ~ 0 ,c~
., ~
E ~ _ c o ~ ~ o -- E

s s = s O _ --O ~ u s 3 ~ ~ ~ o ~ _ .o _ ~ s s s I C ~ ~ ~ ~ .~ ~ ~ .c ~ m ~ _ ~ ~ _ _ E s ~ _ ~ ~ O xO ~ ~ ~ ~ c c ~ ~ O
s s ~ c s ~ ~ ~ EE
c ~ ~ O S ~ c ~C~ u~ ~7 ~ ~ ~ a) ID ~
~ E C~ 2 ~ ~ O 0Q ,~ ~ ~ ~ ~ ~ ~ ~ ~ ~
q) ~D 3 ~ 0 ~ O _ E ~ ~ Q
D C 0 C O O c ~D c c ~
C ~a c ~ a) o _ _ _ ' _ _ _ _ _ ~ Q ~~ ~~ a~ O O~ ~U C a~ ~ ~ C C C C ~' ~ C C
s ~ o -- -- 2 Q ~ nl ~ Q ~ 0 0 0 0 0 0 0 0 0 o ~ ~ ~ 2 ~ ~~ ~ ~ ~ ~ ~
_ o _ ~-- ~o c~ I~ o Q --u~ _ c~ u~ a~ ~ 1-- 1.0 0 ~ ~ O 0 a~ o c~
U~ ~ ID ~ O _ O ~ O ~ ~ ~ r ~ 0 ~ o~ -- O
_ ~ 0 0 o 0 ~ _ ._ _ u~ -- o o o o a~ o a~ o u~
_ _ _C _ C
tO ~ 1~ a~ tD ~ 1' 10 ~) 0 ~ O ~r ~ G ~
~D ~0 _N 0 C'~ C~ N ~~~ _ C3~ o C~l ~ N 0 CD ~ ~ C3~ O

~ ~ O Ln _ 0 ~ ~D c 0 0 - ~ ~ L~ ~ O ~ ~ 0 Ln ~r tD O C'~ ~ ~ 0 ~~ _ 0 -- ~" O CO 0 0 0 _ ~ O Ir~ Q O ~ C O O ~ O~ O
Ln Q N C'~ ~D _ _ Ln ~ r- C~ I_ Lo ~ L ~ LO Ln Ln ~ Ln C~
. _ _ _~ _ ~ _ ~ _ O Ln _ _ ~D 1~ L~ _ ~ O N r_ o r~ ~~ o ~ ~~L~ _ t~ t~ a~ ~ ~~ ~ 0 a~ ~--Ln r~ -- C'~ ~D _ _ ~ ~D ~~ ~ ~ ~ ~r er ~ ~ ~r N
OO O __OO_ _O OOOOOOOO_ I I I I I I I I I I I I I I I I I I I

76.19 SUBSTITUTE S}~EET tRULE 26) W 096/33276 PCTrUS9610~320 ~r _ _ 0 u~ t~ c~ 0 a~ o u~ r 0 ~D ~ O ~
~~ ~ . ~ 0 o ~ u~ ~ tD _ I~ O ~ r o C~ 0 00 U~ ~ 0 0 Cl~ ~ a~ C~i _ ~ _ c~i ~ ~ C'~ 0 ~D U') O C'~
0(O 0 0 0 O~ 1~ 0 1'- 0 a) o~ 0 0 ID ~ CD 0 - 0 1~ 0 ~ 10 C~ i N 10 . _ O O) _ 1.0 C~i N 0 t-- 10 CD
-O ~1 e ~ ~ I 2 ~ o = ~ -~. a~ a E E ' E -" ~ 2 0 ~ .' 'a E ~ ~
3 c ~ ~ ~ Q O _ ~ x ~ ~ o ~ C ~ ~ 2 _C _ -~ 2 ~ ~) ~" o ~ " C C ~ , ~ ~ 2 n. Q
_ ~ ~ ~ I ~ - ' ' ~ CO ~ ' ~ ~ ~ E .~ ~ ~ ~ Q

~ 0 r~ 1~ 0 c~ D 0 q~ _ a~ ~ ~ ~ ~ ~ ~ o o ~ o ~ ~ ~ 0 a ~ ~ ~ _ o o c ~ ~ ~ O ~ C~J ~ O ~ ~ _ C~J ~ t~ O C~
r ~ ~ _ o ~ ~ _ _ u~ ~ 0 0 C~l .Q
O o _ a~ 0 u~ 0 0 _ -- ---C ~ 0 c~ U~ 0 CD ~ ~ 0 o ~ U~ 0 ~ ~ C~
0Q C~l 0 ~ In cq 11~ _ 1~ 0 r~ _ 0 0 ~ 0 ~~1 O ~ 0 tD _ ~ o ~ Ir) ~ ~ 0 ~ ~ ~ n o~ L 1~
S ~ ~ ' 0 0 r~ ~ l O ~ 0 ~ O c~ r~
Q ~ ~ -- _ ~ _ ~ _ O O ~ _ 0 ~ 1'' O~
-- -- -- -- -- _ _ O In ~ 0 IS~ 1~ ~ C~J C~ O In ~ ~ 0 c~ In _ N
~ ~ ~ o _ ~ _ o ~ _ 0 0 ~ c~ o _ ~ ~ 0 1~ c~l _ -- O O_ OOOO_OOO_ OOO __OOOOO
~ I I I I I I I I I I I I I I I I I I I I I I

76.20 SUBSTlTUTE S}~EET tRULE 2~) W 096/33276 PCTrUS96/OS320 O _ u~ r~ o 0 ~ O

~ E
~-- o _ _ ~

C ~ j E c = c - ~ ~

_ o ~ ~ ~ ~ ~ s ~ ~ ~ ~
--s ~--~c c ~ ~ m c ~ ~ E --_ E
E ", D q~ C = ~D S -- a~ ~ C --~ E ~~ g e ~ c ~ ~ ~
.' .E ~ ~ = o E ~ ~ ~ _ s ~ ~ ~ ~ ~ s s s c c s 0 0 c _ c_ _ ~ ~ _ ~ ~ O s s E s = s ~ ~ ~ C 0 Q -- Q ~ ~ ~ ~ a~ ,- _ _ ~ 0 ~ ~ O O ta 0 0 o o s s ~ ~ O _ o ~ r, C ,~, ~, ~, _ _ ~ ._ ~ s , I Q _ s sQ ~, o a)u~ u~ O oq- ~ 1~ 0 o o 0 ~ a~
-- _ ~ ~~D o _ tO oo~ ~ o) c~l ~ O _ ~ ~ ~ ~ r~
O _ ~ 0~ O CD ~ )O ' C~l ~ ~ _ 0 ~
aO ~ CD 0 U~ l ~) ~ C~ CU O ~ ~ CD
tq --IU 0 _ C~ 0 ~ t n et ~I ~ O) -- ~ ~ ~~ ~ ~ 0 ~ rs~ ~ 0 ~ ~ ~ a ~ rD o~
cc _ -- _ _ _ _ ~-' ~ ~~' ~ n~ o ~ ~ a. ~ ~ u- _ r~ ~7 ~ ~ ~ ~
~ - C ~C C~l ~ C ~ ~ C ~ ~7 ~ cr ~7 _ ~ ~ 1~ IS.7 ~
_ ~ ~,7 ~ O) ~ r~ a~ ~ ~ ~ ~ ~ ~ ~ 0 ~ ~ ~ ~ ~ r-7 It.7 ~D ~ ~~ L7 c~ ~~ a ts. a.. ~ ~ C~J ~r.7 o aJ 0 0 c~ a. a.. ~ ~
Ec 0 -- ~.7 ~ e c~J -- a ~7 _ r~ 7 - ~ ~ ~~3 ¢~ ~ a ~~ 0 ~ ~A~ ~ 07 C.7 W a. ~ ~.
~7 -- ~ _ 0-C~ ~ 0.7 _ _ a O ~ ~ Ct) ~J a7 0 _ 0.7 C~
~ ~ o c ~ ~ ~ ~ ~ ~ _ LA, a. ~ ~ ~ ~ ~ 0 ~ _ - ~ ~ C ~ ~ ~ ~ ~ ~ ~ ~ ~. ~ ~ a~ 0 ~ a.
O O o ~~C _ _ _ _ o _ _ o _ o _ _ _ _ O _ _ _ c~ I I I I I I I I I I I I I I I I I I

76.21 SUE~STrrUTE S~E~ tRULE

W 096/33276 PCTrUS96/05320 .~ o a~ " 8 , a ~S - o .c S "~

s O E o C s E 5 ~ ~", o UJ s E
~ C -C o ~ ~-Cn ~C T~ . Q a~
O ~ c < ~ ~ ~ s c~ ~ E
~ ~ 0 P~ '~ S ~ ~, 0 SQ -- ~

O ~ ~ C ~ Q E c $ ~ c ~ 5 0 c ,ta .c Q E c .~ c .~ ~ 0 c a~ o . s c 2 Q ~r~ S 2 ~ ~--~5~ ~ ~ o N o-- --~
Q ~ 0 1~ ~ C~ ID o~ Xo a~ m o O E
~ ~- ~ - ~ LL~ E c ~ ~ Q ~- ~~C __ ~
'O -~ (~ ~ Q-- Q ~ C ~~ S ~
o ~ ~ o o> ~r lo c~ CO N
~ CO ~D Q ~ _ ~-- UD es 0 ~D er r~ r- D~ cn ~i C~ -- C~cn un o o c~ N ~t ~t _ cn ~0 0 C~
~D UD e~rn cn ~ C~ r~ C~ et r~ ~D ~D ~O 0 cn c a~ O C~ " 0 e~ _ O C~l CU N 1'~al o C~
O er ~ C~~ er ~ _ O ~D r~ r~ CU r~O ~D N
~QC '~ Co ~
~ ~ cn ~ 0 0 ~D et ~D r~ er 0 _ L~ etO ~r ~r ._ ~ cn ~ un ~c~ UD 0 0 _ 0 r~ _tD cn 1 r~ ~~U O X cn ~D r~ C~ 0 co cn 0~n ~ r~
E ' UD r~~ o ~ cn ~D C~ er ~D r~ ~ CD~ UD cn ~~ ~) O ~ ~ 0 ~ 1~ ~ _ O C~ ~ ~ ~ O O
~ eS 0 r~ ~U es ~ _ O ~D r~ ~ r~ cn ~ tD C~
~D er 0 r~ _ UD 0 oD 0 ~D UD _ r~ UD 0 O r~ c~ C~ ~D r~ 0 UD 0 ~D ~D tD 0 0 C~
e~ CU CU C~ eS O ~-- cn UD ~D ~D _ cn un C~
O _ _ O O O O _ _ _ . O O _ I I I I I I I I I I I I T I

76.22 SUBS i 11 UTE S~EET (RULE 26) W 096133276 PCTrUS96/OS320 _ ~ ~ ~ ~ ~ m o N ~ ~ ~ ~ ~ ~ m ~
- O ~ ~ O ~ ~ ~ ~ m ~ ~ m ~ ~~ ~ o o o c~ ~ ~ O ~ o ~i m ~ ~ ~ o m ~ ~~ ~ m o ~ ~ ~ ~ ~ o _ O o ~ _ . o _ ~~ ~ m o ~ ~ ~ m ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 o m ~ Q ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ m O ~ ~ o O

s o ~ ~ ~' s ~ = c ~ E' - ~ o s I _ = ~
S -- ~D C ~ X C ~ ~ ~
~C ~ 1 ~ ~0~ 8 ~ ~0D ~ ~ 5 0 I c = s ~ ~ ~ o C C o c ~ n ~ O C ~ m = ~-- ~ ~ ~ D so ~ C s s E ," '' ' m 2 0 sO s Q ~ Q Q -- -- 0 ~. 0 .-- 0 0 Q_ ~ ~ ~' ~ ~0 ~ ~ E 0C ~0 s s ~ ~ ~ C ~Q ~ ~C

~ E 3 ' 7 ~ ~ y ~ ~
Q _ -- ~ x~ _ Q c U~ ~ 0 ~ Q
D C~l lD 0~ ~ _ 0 o~ _ _ m ID tr~ O
~D c~ D O _ D ~ ~ ~ _ a) c~ O
~D ~D _ ~ D O ~ m {~ C ~ O ~ D ~ _ tD ~D
-- t~ O~ O O _ ~D ~ ~ (D o _ r- cl) ~ m ~ ~D
c~ a~ _ ~ ID ~ _ _ ~ ~ ~ ~ In ~ ~D ~ ID C i~
_ _ . _ -- o O O a~ D a ~-- O a~ D ~D r~ O a~
C~J O) ~ ~ ~ t~ ~ ~ lo ~ o ~ _ ~ a) ~ D ~ ~ ~ 1~ O
_ ~ ~n tD 1~ _ O o 10u) -- ,C ~ ~ ~ D ~ ~t O ~ a~ o _ ~D m _ O c~ tD tD ~ ~0 cr7 ~ _ ~ m c~ ~D D _ D
-- -- -- _ -- a~ -- z --l O _ _ C~J lD ~ O 1~ c~l N ~ C~) ~ N 0 ~ 10 C~J ~ CJ ~ ~ ~D 1' 0 m o ~~ ~ o r~

O _ _ _ O O _ O O O _ O _ $ O g O _ _ O
I I I I I I I I I I I I I I I I I I I I

76.23 SUBSTITUTE St~EET tRULE 2~i~

C" I' ~ ~ al ~t a~ _ ~ I~ ~ ~ ~ o~ ~ 1-~ o o N N
D O ~ ~0 ~ Cl ~ ~_ C~l N C'~ N N C) ~ C'~
~ N 1~ C'~ _ ~ ~ r_ ~ _ N C~ _ _ ~ N N C~
0 0 ~ r' N 1~ N r-- O C'~ O N CD I
O ~-- O 1~ ~ O t'~ _ CD O 0~ i N 0 O) U~

O N 1~ 1~ _ C'~ U~ C~ _ ~ N O C~ O U) cr~
'' O r~ 0 ~ N N ~D r~ O C'~ _ N 0~ O>
O t_ q- N ~ C'~ D N O (.0 ~ C'~ D 1~ C) C'~

-O

N N c~ ~ c c E ~ ~sO ~ ~ s c ~sl ~ 2 ~ E ~ __ _ c _ 2 2 = O v=~ o I E 0 ~ ~ ,~ c _ o ~ a ~ ~ --~

= O c c ~ ~ 2 ~ 2 -- O ~ c o 2 2 s c 2 s 2 E E--~ ~ ~ ~ = 2 ~ o 0 0 E E

_ ~ ' C~ Q O C ~ ~ N CO _ ~ O ~) 1~ U~ ~ ~D In LO ~ N C'~ ~ tD ~t t~ C~ 7 C~
~D O) N _ N C~ O N N U7 10 ~ ~n 1~ C~
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20~ -- _ _ _ _ _ _ ~ O C~ N U~ _ C~ _ O 11') 0 O~ m CD C'~ N U~
~' o o o _ _ o o 8 _ aO' ~o o _ o ~ ~ _ ~ o ~--¢ I I I I I I I I I I I I I I I I I I I I

76.24 SUBSTTTUTE SHEET tRULE 26 PCTrUS96/05320 C~J 0 0 C~ N 0 0 _ C~ 0 C~l C) 0 U~ 0~ ~ ~ O a) ~ 10 C~l ~ ~ r_ O ~ O U'~ ~ 0 a~ 0 Il~ O _ t~ c~
~t ~ _ o o o) _ ~ ~ ~ O ~ ~ o~ O ~ 0 ~O

U~ ID ~ O) I~ _ _ a~ ~D C~ _ ~ 0 0 0 C'~ _ CD ~ ~ 0 0 a~
-- 0 ~ 1~ 0 ~r o ~ o ~~ o ~D O) i~ 0 -- C~J

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s ~ . Cs, ~e__~c~S9~9 3~_a 9-o-o ~ 99 E ~ ~ a ~ ~ 9 a ~ Q g 'E ~

~ ~ a ~ 9 9 9 9 - 9 9 1 ~ ~ ~ e 1~ U~ ~ 0 0 0 C~J o C9~ 0 0 0 C~ D N O O r_ _ ~
0 ~ ' O 0 Q If ~ n O _ 1~ ~ _ C~l ~0 _ ~ C') 0 1~
O C'~ O ~ 0 ~O ~O _ 0 ~ ~ C'~ O _ ' ~ C'J C'~ C~J O ~ O
c~ o ~ o o r~ C~J o N 1~ ~ ~ O ~ 0 _ r~ o C~
L I~ ~O _ c~ 0 er C~ O _ el ~ o ~-- o N
O C~l 0 ~n ~O ~ C~l tO 0 ~n 10 ~ ~ N ~r r-- O CO 1~ CO 0 ~r ~ ~ C~l 0 -- ~0 -- ~ o t~ 0 a~ o ~ ~ w ~ r~
0 ~ 0 ~ O C~ CO ID 1~ ~ ~r 0 U~ t~ r C~ J ~ O _ ID
1~ ~O ~ 1~ ~ O ~O _ _ _ ~ 0 C~ _ _ N N 0 O ~ O 0 O O
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~O O C~l 0 U) ~O q N 10 0 U~ U~ ~ U7 N e~ D N ~-- 0 0 ~ ~
_ r~ ~ 0 ~ t~ _ m C~ 10 D 0 0 _ C~J _ 0 0 0 ~-- _ N
O ~ _ O O O O~ ~O N ~O r~ ~ ~ N r~ ON ~r ~~ C" ~O N C-~ ~ 0 0 I I I I I I I I I I I I I I I I I I I I I I I I I -76.25 SUBS 111 UTE SHFET tRul E 26) o~_ ~0 o~ O_000_Oa~
~ ~ O O C~J ~D C~ ~ CD ~ _ C'~ ~D ~ C'~ ~ ~ O _ u) ~ u~ _ _ _ o ~ o ~ u~ o a~ o 0 ~o r~ c~i u~
~D ~' ~~ I~ U~ ~ 0 ~ U~ ~~ 0 ~D ~ t' U~ a) w ~ ~
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m c~ cv) 8 ~C a~ ~C 0 0 ~ la tl~ ~ ' n~ 0 2 2 ~ ~ E ~ E ~ 2 ~ 2 0 ~ = = --0 LD ~ ~ D c~ ~ ~ ~ ~ r~ ~ O ~ -- ~ ~ C'~ ~ ID 1~ 0 D ~ 0 tl tD C~l O C~l tD r~ ~ 2 ~ LD ~D c~l D ~ ' D -- ~_ _ r~ _ 1~ 0 0 ~
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~ -- O lo oD Do o LD ID 1~ ~r ~r ~ 8 o ~ o o o _ I I I I I I I I I I I I I I I I I I I I I ~

76.26 SUBS 111 UTE St~:ET tRULE 26) W 096/33276 PCTrUS96/05320 _ ~ o ~ ~ ~ 0 0 ~ 0 ~ o C'~ o C') ~ o U~ ~ 0 C~ o o u) 0 u~ ~ ~ _ ~ u~ ~ 0 o ~ ~ ~-- o r~o ~ In CD

o u~ ~ O C~ l ~ 0 0 ~ U~
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o ~ _ C _ ~ ~ O

S U,~ ~~ ~ .C C~ ~ 0 ~ S
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_ -- a ~ I ~ --o o D _ T T T T 3 ~ e ~ ~

C CL ~~ o ~ D D D -- Q 2 2~u a~ ~ G) a~ ~" a) c~ c 0 a~
~ E E --,c C ~C ~C ~ ~ E E E E E E E E E E E

o o O Q ~ ~ S z z z z D O C~l ~'3 1~ r-- CD O O C~ _ N ~:r ' _ L~ 0 C'~ t~ O
~ o o ~t o ~ o ~ o ~ ~ - ~ 0 ~o ~--_ t!~ ~ _ ~ _ _ 0 _ 0 C~l _ U') _ C'J ~-- 1~ 0 ~ ~, N ~ ~ O LO
~O ~ LO ~ et _ 't ~ O ~ ~ _ C~l ~ L~ o _ ~ L~ L~ O ~~
O 0 q- _ C~ J Lt~ I~ O LO ~-- ~ L~ ~ _ L ~ ~ o 0 a~ o c~ C3~ o C~ C~ ~ 0 o ~ 0 _ r_ ~ L~ ~t t~
C" ~t LO O 1~ ~'~ .0 ~ C~.l 0 O' L.~ C~J 0 ~ -- O 0 0 0 C~l ~ I' ~ I~ ~
O 1~ -- C~l C3~ r~ D ~ o ~~ _ n ~ D O C~l O tD ~t r~ ~o ~ ~ ~ ~ 0 ~ L~ ID 0 ~ ~ ~ ~D O rD ~D ~ O _ Ln _ ~ ~D ~ Lr~ ~ ~ LO ~ ~ ~ 0 ~ ~ D O c~l a) ~ ~ ~ ~ r~ 0 ¢~
c~ Lo 0 ~ _ ~ ~ D Ln D ~ ~ ~ D O ~ ~ 0 0 -- ~ N ~ 0 0 ~ o c~ o ~ o c~ ~ 0 o ~ ~ n c~ ~D ~O
_ _ _ _ , -- LO 0 tD LO O r-- 0 _ c~ LO 0 ~ LO ~ _ c~ D O a) U~
D 0 C~l _ LO _ tD U~ 0 o O O ~D LO 0 LO C~l ~ ~ o _ ~ ~ l~ Ln LO
~000~O00~0_O__OOOOOOOOO_oO_OOO
I I I I I I I I I I I I I I I I I I I I ~ I T T

76.27 SU8STlTUTE S~ T (RULE 2~i~

W 096t33276 PCTrUS96/OS320 o~ o c~ o 1~ 0 o~ o r~ o ~ ~ c~ o ~D ~D ~ O
0 _ ~r ~D C'.l O 0 11~ O O O C'7 0~ O') C) U~ q' ~ O N ~ O C~l 0 ~ C~ O
~t) t'') 0 r~ o o> ~ ~ o ~ o c~ D 0 0 c~ l _ 0 U~ O ~) 0 C~J 0 a) ~o a) o ~ c~ _ _ o 0 c~i _ In o _ u~ tD O a~
~7 ~ a~ ~D _ O ~ ~ ~ ~ 0 a) o 0 u~ 0 _ ~ O ~D O ~
t _ 0 O~ ~ 0 0 0 C'~ ~ O ~ ~D ~0 0 C~ ~ C~ t~ ~ O O~
~D 0 1~ Ln 1~ tD 0 a) o~ a~ Ln 0 Ln ~D Ln ~ Ln In C~ ~ Ln Ln Ln c~ Ln tD _ a~ _ ~ ~ E ~ Q ~ ~ ~ ~ 0 ~ ~ ~ 0 Q ~ ~ o ~ 0 0 ~ Q Q ~ -~
I I I I ~ ~ ,~ .c ,c E ' E E E E ~ Q Q ~ ~ _ 0~ C) ~ (D 0 0 ~J D c~ c~ ~ C~ 0 0 _ O' ~ ~ 0 C~l 0 0 C~ D c~
~D m 0 0 _ o ~ D tD 1' ~ 0 0 0 0 o C~l C'' _ 0 ~ et C~ C~ r' o~ _ o o~ Ln c~ ~ n c~ D Ln 01~ C~ 0 10 0 0 C'7 _ C~ 0 Ln _ ~ L I ~J O~D ~ ~ O _ ~ C'l 0 C~ ~qLn C ~ a~ I~ Ln 0 ~ O~ O C~J
~1 O) 01 ~ ~-- O C~ c~ O C~ ~ O ~D ~D O Ln Lr~
~ Ln O ~D Ln O Ln --~ ~ 0 0 l~ 0 c~ _ L~ J Ln 0 ~ O C' ~D
1~ 0 CJ 0 Ln ~ 0 O~ '~I Ln C'~ l O ~ _ _ 0 c~
Ln ~0 ~ O _ o 0 0 ' 0 ~D lD O O ' tD _ ~ _ 0~ O ~ O ~t ~ Ln t~
~ 0 ~ ~ ~ 0 ~ ~ _ 1 o ~ o _ ~ n ~ 0 0 ~ o ~ n ~ ~ L~
o) ~ r' Ln C~ 1 Ln ~ a~ _ _ ~ ~'~ ~ ~l C') ~,~ 0 ~ ~D q c~
~- 0 ~ o o o c~ '-'.1 o~ ~ ~ ~ _ a~ o) ~J _ o c~l lD C' ~D D O
~ ~n o ~D Ln O Ln ~ ~ ~ ~ ~ ~ N ~ ~ - Ln ~ ~ n ~ ~ o o 0 c~l 0 ~ 0 c~J ~r 1~ 0 Ln ~ 0 ~D ~ ~ -- c-~ Ln C~ 0 -- O C'~
o ~ L0n ~ a) Ln ~ C~ ~ 0 ~ ~ ~ 0~ ~ _ o O o o o o o o o~ o I I I I I I I I I I I I I I I I I I I I I I I I I I I I

76.28 SUBST~TUTE SHEET (RULE

W 096/33276 PCTrUS96/OS320 ~ C~ D N 10 _ tD ~ O O ~D O C~

. _ O o o _ ,_ ~ O
a _ c ~ ~c sO sO

~ sO ~ s_ _ s= s s s s E

O "~-- o I ~ .~ .~ E Q Q Q 2 c ~
-- ~~ C 0 ~5 Ul ,~ ~C ~----O ~C C LL ~ C

~ E ~ ~ ~ ~ ~ C ~ -- s ~ ~ _ o _ ~ ~ O

s _ ~ X --~ ~ ~ -C C _---- -- ~~ o o o o ~ s 2 2 - ~ ~ - - ~ 2 ~ ~ ~ ~ ,2 ~~ - ~o ~~ ~ -2 ~ .~ ~ ~ ~ o c 0 ~ E E Eo E .Q ~ 2 0 ~ ~ Z ~
Q ~S ~D ~ aJ o ~17 ~ al Q ,0 0 0 0 ~ -- -- -- -- = .--CC -- s o ~ ~ G7 ~0 o o o o c ~ ~ o~ m o ~ Q Q Q 0 al 3 c Q Q Q Q Q ~8 Q Q Q --Q Q ~ Q
~D 2 2 2 2 2 a~ 0 n ~0 _ O O O _ ~. ~ :~ _ ~ ~ x 0 a7 _ o C!~ ~ N ~ ~7 0 0 _ _ _ 0 1~ C!) C' U7 C'~ _ _ U~7 - ~O ~ O _ ~ U~7 ~ _ C'l 0 C~ 7 N a- o ~r ~
D 0 U7 U7 ~ O C ~O 0 U~ O O ' C~ Ul N r-- a7 q O N ~ N ~r N _ ~I CD N t~7 _ a) U~ ~ ~1 1~ C'J _ 0 N
~7 N C~ n ~r o ~t -- ~ ~ u~ ~7 o c~ ~ ~ a7 ~- N _ el-IC7 ~7 ~ 0 _ N U~7 r~ 7 ~ ~ tD U7 C~ N N C~ 0 _ 0 0 ~ N 0 0 N Cq C'~ O t'~ U~ ~D _ D U~ ~ _ a7 ~7 _ t~ _ ~ U7 -- 0 _ N ~D 0 _ N cq ~ ~ ~ 0 0 ~r U~ a7 0 U~
_ ~_ 0 N 0 0 ~ ~ 0 _ C~ tC7 ~ U~ 0 N U7 ~ O O O
a7 o ~t a7 ~ _ N -- a~ 0 C~
tD N 0 rl ~ o ~ -- 0 ~ u~ ~D al J7 0 ~ 0 ~7 ~ N _ ~r D _ N U~ N a~ ~ ~ U~ U~ 0 N N 0 n _ 0 A

U~ _ _ N O C~ U~ 0 _ 0 a:l ~0 U~ ~ _ 1~ ~.0 0 0 C~ 0 _ o u~ r 1~ ~ u~ D _ _ a~ 0 u~ _ _ ~t ~D CP N U~ O _ ~ C~J 10 C'~ ~ 10 10 N C~J N N N O O t~
OOO_____O__O___O O -- __OO
I T I I I I I I I I I I I I I I I I I I I I

76.29 SUBSTITUTE SHEET (RULE 2~i~

W 096/33276 PCTnUS96/05320 _ o 0 a~ ~ ~ o r~ 0 c~ ~ ~ O C~ ~
~ 0 C~ O O _ a~ ~o 0 0 1~ 0 0 N N C'~ 0~ C'~ ~ ~) ID O 0 1 _ _ ~ o ~ a~ _ 0 ~ ~ 1"c~) o a~ ~ _ o _ c~
0 0 0 ~~ t' Ir) ~D tO a~ 1~ ~ 1~ ~ t-- 0 0 0 ~ N 0 0 U'l _ _ 0 0 C~ O 0 t'~ 0 0 ~-- N O~

_ o Q o o C o o o s ~a s ~ ~ ~ c~
- ~_ oS ~ S~ 0 Q m~ s ~~ ,s, D CD ~ s s s sS ,~,~, s ~ C ~C ~ m s m s s s fi 0 0 0 ~ ~ ~ s s ~ m î~, ~ LJ~ J s ~0 0 s F 3 Q D ~D C -- Q - 'Q ~a c ' ~ ' ~ m (~ C~ D tD c Q--S ~C o ~ ~ m L mO 2 2 ~ ~ ~ ~ c L ~ ~ L _ L -O O ~ ~ ~ E

_ m C~ x ~ ¢ Z ~c~ a ~
~a a) ~ ~ 8 D Q D ~ a~ c L c ~ _ L O ~ O ~ E ~
C ~c ~ ~ ~ a) ql ~ ~ ~ ~ ~ ~ ~ ~ -y ~ ~ ~~ ~ :- Q ~
O o o o o o ~ o ~ ~ C~ 'S ~ ~ ~ 0 ~ C~ ~ _ a) a) O ~D O a) ~D ~D ~ ~ '0 C~ Z Q Q Q ¢ ~0 C~ 0 ~ ~-- ~ O ~ C~ l 0 0 C ~'1 L. ~D ~D O r~ t~7 0 _ N a~ ~ Lo 1~ Q _ ~ 0 C~ l Q
z ~ CD a~ o o ~o c~J ~ o C~ lo o ~ 0 ~ m ~ ~D
C~ 0 -- -- r~ 0 C~ 0 C~ E ~ D 0 -~ ~ 0 Lo Q _ LO 0 N lo r~ 0 0 0 ~ -- tD _ L ~ Q 10 Lo ~ ~
--O r~o ~ ~ c~0 L~ ~ c~l 0 LOLO c~ rO LO
c a~ -- _ _ ~_ 0 0 ~D 0 LO ~ J LOS e~ _ 0 LO C~ D LO ~J ~ ~ L~
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0 r~ O Z ~ LO LO r~ ~ LO
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_ o _ 8 _ _ o _ o o _ ~ o o o o o o _ o o o _ _ I I I I I I I I I ~ T 1-- I I I I I I I I I I I I

76.30 SUBS I ITUTE S~EET tRULE 26) W 096/33276 PCTnUS96/05320 o In ~ O ~ l W ~ ~ o ~ c~ t O
0 ~ U~ i o ~ o o ~ 0 ~ C'~
a:~ ~ 0 0 c~ 0 a~ 0 ~ 0 0 0 0 0 c-7 _ o r-- ~ o _ o ~ ~ u~ LO ID O ~D 0 ~ ~ i 0 0 ~ _ o ~ E
o -- ' s s .E -- E ___ ~- ~ ~ Q s _ _ _ I _ - ~ E
c m c ~ ~-" ~o ~O o IlJ ~o ~ ~_ s a, E s s s ~, ~~ ---- 'C ~ S ~ S S ~ , J ~ S J ~ ~ _ c c z uJ ~ _ s ~C --~ _ _ F ~~ _ s~ s O -- ~ J ~ ~ J- J J --~ ~ ~ ~ ~ ~ ~ ~ I I - ~ ~ _ ~ ~ ~ ~ 2 ~ 2 ~ 2 2 oc co co oc c a~ E E E ~ ~ Q ~ Q. Q a o ~ C E
c 0 ~ D ~ ~ ~ ~ C ~ ~ 0 S o o o 00 ~/0) 0 0 0 0 C X Dc D D D D D Z CZ; C D 8 D D D D 8 D 8 OO00 r~ 00(O~C'J~_ 'I~U~
O ~ 0 ~ L~ D C
Ir~ o o 0 Z ~ a~ l C ~ _ o~ o ~ t~ c~l n rD 0 ~D ~ G ~ o _ ~ U~ C~l _ O ~
O _ -- Q
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E u~ CD 0 ~ ~ ~ 0 0 ~ ~ ~ 0 U~ ~ o u7 c~) 0 e- r~ ~ 0 ~ U~
0 Q a~ la er O _ C~ D ~ -- ~ 0 . 0 L~ o ~ I~
~ ~ ~ _ _ ~ o ~ ~ c 8 lo ~D U) O 10 a~
0 -- ~ ~ 0 0 c~ ~ 0 - ~r Lo - a~ ~ ~ c~ 0 o r~ o 0 ~D In _ ~ ¢~ 0 _ ~~ 0 _ ~ ~,D -- r-- ~ ~J V~ ~ -- Q ~r 0 0 ~ O
~ _ o o c~l o c~ c u~ 0 ~ ~ ~

76.31 SUBST~TUTE S~EET tRULE 2~i~

W 096133276 PCTrUS96/OS320 ,"~ ~
_ _ ~ _ o _ a~ 0 0 0 ~ o ~ O 1~ 1' C'~ O
-- -- c~l _ _ -- _ c~J c~l . . _ _ In _ 0 ~ ~ ~~ 0 -- C'~ ~ ~ ~ ~ ~ ~ -- ~ 0. ~~ I~ ~
-- 0 C'~ ' O ~ I~ C~ ~D ~ CD O ~ O C'~ ~D O ~ u~ 0 a~
~ O~ O) ~ 0 0CD 0 ~ 0 o~ 0 0 c~ 0 a~ a~

a~ 0 0 a~ t~ ~ ~ ~ ~ c~ a: 1~ 0 r~ ~ 0 0 ~ 0 o~ ~ 0 - - - . - . - - - . - . - ~ - - - o o o o o ~ - o ~a C~ 8 .~ .'a .~ .~ .~ .ta .~ .~ .W 8 .~ .~ a 8 8 ~ , 8 ~
ss~sssssssss~ssssss~ as ' ' s ' ' ~ ' ~ ~ ~ ~ ~ s ~ ~ ~ ~ -- ~ C s s s s ' S a~ X X X X X X X Sx SX SX SX S S c ~
~ ~ ~n ~ ~ ~ ~ ~ ~ ~ ~ ~ X ~ ~ ~ ~ ~ ~ ~D X X ~: X U~ --â~ 0 _ ô _ C~ ~ -- ô _ C~ J llJ Q 11~ _ ô
N J ~ J J J J J C~J N ~ c~
Q Q J Q Q Q Q Q ~ Q Q ~ J Q Q Q ~ Q Q J J J N J C~ Q
_ _ ~:L _ _ _ _ _ _ _ _ -- Q -- -- -- -- -- -- Q Q Q -- {~ Q --Q a) . O _ C~J t" ~ Il~ I~ ~~ ~ -- O _ C~ C~'7 ~ U~ -- -- -- -- -- -- O
J J C~J N J N N J C~ J N C~l 0 ~ ~ C~ t~ C~ J ~ 1~) ~ 1~ J ~
C C C C ~ ~ C C C C ~ ~ ~ ~ ~ C C C ~ ~ ~ ~ C C C C

Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q 1 ~
EEEEEEEEEEEEEEEEEEcEEEEE~E
o o o o o o o o o o o o o o o o o o o o o o o o o o S~ DC ~ ~ ~ ~ S~ ~ ~ .n Q ~ ~ ~ ~ 8 ~ ~ ~' ~J ~c ~c ~~
tD ~ ~ ~O 0 0 _ ~ C'~ 0 CD ~ 0 0 _ ~ r~ tD 1~ e'J ~' C~ ~ ~ ~ W
C~J ~ 0 ~ 1~ ~0 0 0 ~ ~ l 0 _ 0~ ~ N O C~ f~ . CO C~J _ N
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o o o . o o o o _ o o o o o o o o . _ o o o o o _ o - I I I I I I I I I I I I I I I I I I I I I I I I I I

76.32 SUBSmUTE S~E~ (RULE 2~) W 096t33276 PCTrUS96/0532 _ CJ C~ r O 1~ ~ N C'~ N ~ ~ C~J O C~ 0 _ O t~ O.

o o o u~ o c~ O ~ _ O a~

- o - c o ~7 a) o s ~,3 s s c a~
C
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8 ~ ~ I ~ -0 ~ ~Co -o ~D ID 0>' '8C ~a ~ ~ 2 2 2 ~ 2 2 2 2 2 2 2 2 ~ ~ 2 2 2 2 c ~ 0 ~ ~ ~ ~ C
Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q ~ '~ CC " Z ~ ~ 0 a ~ ~n ~ as ~ tn a~ ~O ~ ~ ~ ~a ~ ~ ~n ~ ~n n5 a~ Z~ cr .--C . ~
E E E --c c . E E E E E E E E E E E E E E 0 0, ~ Z
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~ O 11~ _ ~ D ~r ~D 1.S~-- ~n ~ ID O ' ~ C~J _ 0 -- tD 10 ¢1 ~t C~ ~n _ D ~ D _ C~ ~ ~) (D ~ ) D ~O ~ C'~ C') ¢~ N
t O 0 ~1 ~ ID a~ J 1~ 0 ~ o tD ~ 0~ 8 ~ 0 0 c~ ID L'' O ~ O ~ 0 a~o 0 0 ~ c~J c~ D ~ 0 r~
o o ~ u~ 1 1~ o ;' c~ _ o 1~ ct~ ~r 0 u~ ~ _ O c ID ID ~t O In _ ~ ~D ~ ~ ~ ~t In el ID 0 0 ~ _ O ~_ ID ~t tD ~ ID
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O O O _ _ o o o o o O ~0-- 0 0 0 In O 1~ ~t O ~ ~ Q ~~ C" r-- ~
I I I I T I I I I I I I I I I T I I I I I I I T I I I

76.33 SUB5TITUTE SHE~ tRULE 2~i~

W 096/33276 PCTnUS96/05320 _ ~ t~ O ~ ~ o o ~D O O C~l ~ ~ C~ O

0~ 0 ID 0~ _ 1/7 N C') U~ In O _ ~ r~ 1~ ~ U~ . U) O ~ ~r U~ ~ ~ ~ O~ 0 C~J eJ 0 1~ C'~ O C~J O U~ C~i I.t7 0 ID ~D _ C" O ~--0 0 a~ 0 ~_ ~ 0 0 1~ ~ 0 0 0 0 a~ ~ 0 0 c~ 0 0 o> a~ 0 0 0 C'~ O O C~l O C'~ 0 C~ D 0 U7 C' O 0~ .0 N O N 11) Cl) ~ U~ 1~ ~ ~7 N ~

._ _ ~ S

S S ~ a~ Ul C ~ o s s _ C ~ ~ X
o -- _ . _ s O ~ ~ ._ ~ o _ s, s 0 ~
~5~ 0 _ o ~0 S 5~ ~ SQ C~ ~ ~ S S O ~a Ul ~ LIJ c s O O ~ O ~ s ,c ~ -- s s e e s ~ ~ c Y ~

~ ~ s s 2 Q' ~ ., 2 ~, Z Z C _ ~D 0 ~ C~J ~r o ~ O 0~ D ~ D ~ ~ a~ o ~ 0 ~ a) ~D ~ _ O ~ In ~ tr~ ~D ~ u~ ~ cn 0 ~ O ~ C~.l o O C~l 0 Ln --~0 ~ O C'l N _ ~ t 0 C~J ~D ~D O (D 0 ID er U~ 0 0 0 C3 ~) tD ~ _ ~ 0 a~ D ~D ~ _ ~n 0 _ ~ 0 e~ ~D 0 m _ ~D ~ C~l o 0 0 ~ _ ~ ~ 0 ~ ~ _ 0 ~ m o ~ _ _ ~ ~ _ ~ ~
~) a~ 0~ C' O a~ C~J 0 C~ t' N C~.l _ ~ C~J C'J 0 . _ _ _ _ _ _ 0 C~J ~ m D C~t 1~ ~ _ C') _ a~ O C3~ O U) 0~ C3~ ~ ~D ~ ~ _ o~
a) 0 ~ tD ~ ~ ~ ~ r-- -- O ~ -- 1~ 0 0 0 ~ r~ In ~D O _ O O O O ID ~ C~J ~D F) ~ ID ~ a~ ~D ID c~ 0 _ u~ C3 _ a~ ~ ~ ~ _ ~D 0 ID C~ D ~-- 0 _ 07 t~ m 1~ C3 o 0 0 ~ ~ ~ ~ m ~ ~ _ 0 0 m o ~ _ _ a) cn rr) o a~ ~ 0 ~D t3~ q C3~ C3~ 1~ t~ C~l C~l _ ~ C~l C~J 0 ~ -- _ _ _ ~ _ _ r~ lD Ol ~D _ ~ 0 ~ m u~ D ~ 10 _ O tD _ O O In C3~ 0 0 ID r-- c~J N 1' ~D N _ ~ C~l i~ C~ IO ~ O _ 1~ ~ O u~ ~D
~ ~ ~ ~ ~ ~ ~ ~ m ~D ~ ~ ~ ~ ~ ~D ~ ~ _ ~ ~ N m o --__oooo_oo_o__o_ooo_oo oo ' I I I I I I I I I I I I I I I I I I I I I I I I

76.34 SU B STlTUTE ~ ET tRU LE 2 W O 96133276 PCTrUS96/05320 ~ C~ ~ 0 ~ O U~ CD O ~ ~ ~ ~ ~ ~ e~ l O C~
O ~ 0 U~ O ~ o ~ ~ ~ a~ o ~ _ ~ ~ ~ m (o r~ ~D

~ o c~ 0 0 ~ i ~ O O ~ t'~ _ u7 ~ ~ u~ r~~ er ~ ~--o ~ ~ 0 0 a~ 0 r~

~ C C s _ ~' c~ 'o ~ s s ul s c ~ ~ c _ _ c _ c ~ ~ ~ s ~ a~
D ~ 8 ~ o c ' ~ ~ O u.~ _ ~ ~ c ~ ~E

s~ ~-- Z ~ ~c ~ ~ ~ ~ ~ c c c = n E = O O o = = c ~, ~ CS OC OC
G ~ ~ ~ ~ ~ ~ ~ c ~ ~ ~ ~ ~ ~ ~ ~ C C C cE c o ~c~ , ~r r- c.l LO _ CO o ~r N er t~ ~--_ _ 0 0 OD o ~ r~ 0~t CO L l O c In CO CJ O ~ UO In o In o~ o _ C~ o CO
U~ CO 7 ~ C~In o~ ~ _ .- r~ o o 0 C~ _ o ~r 0 _ u~ C~ 0 _ In C~ 0 ~ n r~o CO ~ CO ~ _ 0 In CU r~ In In ~S D N O C~ _ CO
U~ ~ ~ COo U~ ~l In ~ 0 ~t o~ 0 r~ 0 In r~ 0 ~D oD C~ 0 UD
U~ C~ ~ D ~t0 N In ~ I ~t c ID O 0 In u~ In rq c~ u~ c~ c~ r~
g o ~ a~ 02 0 _ cr~ _ ~ In o r~ 0 r~ o -- 0 -- 0 ~ o ~
C~ 0 In ~ InCL ~r u~ UD - 0 C~ O r~ CO u~ ~r - UD In T- C~ In c~ ~ CO
~r o 0 ~f~ C~o _--_ In C o C~ _ o _ C~ o~ ~r In o o CO r~ In OD
_ o a~ ~ o~ o ~ 1~ t') q~ t~ t~ ~ 0 u~ ~ 0 0 c~ ~ 0 0 r~ r~ ~ c7~ o OJ In UD - 0 ~t o~ 0 r~ 0 In r~ 0 oD o~ - 0 In r~
a~ C~ ~~ C~J L~ t 2 ~~ o 0 In ~D In ~ ~ In t') c~l r- ~ C~J
-- -- Z-- -- oL -- -- -- -- _ C~l C ~ 0 UD ~D r~ OD cq C~l CO ~-- OD O 't -- O 0 -- O r~ un co o un oo Cr UqD aD cq C7 0 cq co cn cn u~~ CD~ U~~ Cq o C~ U~ C~ un c~ cq _ T - I I I I - - - ~ ~ ~ ~ - - ~ ~ - ~ - - - ~ -76.35 SVBSTrTUTE S~EET ~RULE 2~) W 096/33276 PCTrUS96/05320 C~l CD ~O ,~D~ ~D 0 U~ o c~ 0 _ U~ O C~ O O) _ t~ o 0 cn~ ~ c~> ~ ~ ~~ r~ u~ c~ 0 c~ 0 r~ 0 _ o~
o~ 0 c~ ~--0 r~ t~ t~ 0 0 0 CD _ C~i m0 o 0 a~ ~ 00 1~ o ~ _ o ~ _ 0 0 a) u7 ~
0 r~ ~ ~D~D ~n ~D r~ ~ ~~ ~ tD ~ 1~ 1~ t~ ~ ~ C~l O) ~t C~J
S O
_ _ ~
E ~ ~ ~

o sO = = ~ ~ -o Q o ~ w c ~ . ~ ~ , ~ C = ._ g 9 e o E = ~ ~ ~ ~ ~ ~ w - g - - i 3 ' _ 0 ~C E ~ o ~ ~ z Q ~ O o~

= 2 ~ ~ ~ Q ~ C ~ C ~ = = w = c - - ' ~ ~ 8 ~ ~ ~ ~a ~a ~a ~8 I ~ C~ ~n o (D D ~ r-- ~D O 0 0 0 C~ .C _ a~ Q 3~ ~~ ~ _ 0 0 _ 0 _ ~ ~ _ _ ~ _ c~l ~ O a~ o ~ 0 ~ ) 0 ~ a _ o _ o ~o o 0 ~ ~ c~ o c~ 0 ~ _ ~ 0 J O c~J r~ c~J ~ 0 ~ O Q 0 ~ t 0 C~
o u~ 0 C~ D O ~ ~ o U~ ~D 0 ~ r' ~ 1~ N o a~ D 0 ~-- 1~ o~ l O C~J
~D O t~ _ ~ 0 c~J O 0 1~ ~ O t~ ~) O 1~ ID ~ I~
~D ~r ~ o :~ _ 0 ~ t~ 0 ~ ~ 0 _ u~ ~r o c~ o~ ~ _ ~D IS7 ~ D 0 ~ a~ ~a ~ ~ ~ o ~ 0 ~
--0 C~~ o ~ 1~ 0 ~ u~ ~O o ~ ~ ~ ~ o 0 ~O ~D 0 u~ l ~ 0 1~ a~ 0 ~ r~ o C~l ~
-- -- -- -- C~ -- -- _ _ _ o) r_ ~ O u~ _ o 0 tD ~ _ _ -- 0 C~
,~ o u~ ~D 0 G ,_ r~ .~ N 0 1'-- .D 0 1-- ~ 0 er _ ~ O) C~.l C'~
--O_O OOO_O_ O__OO OOOOOOO_ I I I I I I I I I I I I I I I I I I I I I I I

76.36 SUBST~UTE SHEET tRULE 2~i) W 096/33276 PCTrUS96/0~320 0 _ 0 ~D~O O U~ O O~ ~ . ~ _ C~l ~ -- ~' o ~ a~o> o a~ _ cn 0 r~o ~ r~
~r N O _ ~N O ~ ~ C~ ' O

0 0~ ~ 0 0 1~ tD 1~ 0 C'~ 0 ~ 1~ 0 0 a~
N U~ 10 0 0 C~ 0 U~ D 0 0 as ~ ~ ~ ~ ~ ~ e s ~ e~_--~

E ~ 0 n~ ~ ~ ~ ~ ~ o o E s ~s ~ D c--8 _ _ s -- ~ s o~ _ ~, .~ ~ ._ E _ ~ a~
s ~ 8 ~ c a~ ~ ~ .~ o ~ ~ ca c~ Eo Q 2 ~a sO sc s o c~ 0 s E s ~ ~ E E ~ ~ ~ ~ E

~ ~ s o o u ~ ~ ~ 0o u E E ~ o ~ ~ u o o Q ~L Q Q ~ Q Q Q Q Q Q ~0 ~J ~J ~ ~ D D D ~ 1 _ In r~ D C~ _ ~ ~ Cr) a~ 0 C~ O C'' ~O ~ 0 0 0 C~J C~
~O ~ -- 0 0 Q 0 0 ~ a~ O
O _ 0 0 0 C~ 0 ~ ~D O _ ~ ~D ~ C~! r~ c~ u~ _ _ _ I' 0 ~ Ir ~ 0 _ _ ~J ~ ~ 0--Q ~D ~ Il C ~ C~ O ~ 0 0 0 -- O C~ C ~D ~ ~ ~ CD ~ O C~ ~ 0 ~-- Q C~ 00 C~
__ _ _ _ o ___ ~___ ~ O ~ <~ ~ t~ 0 0 0 ~ _ ~r Q ~~ ~ O ~ O tD r-- C'~ CD
O r-- ~ ~ tD FJ ~0 0 C~
O tO U~ 0 C~l C ) C~l 0 C~l ~ 1~ In _ _ U:l o~ ~ 0 r ~D ~~ 0 -- 0 1~ -- 0 ~ O ~ ~ u~ ~ ~ -- LO _ O ~
D E c~ N C~J c~ 0 ~
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o ~ o --~ ~ ~ ~ ~ ~ ~ ~ 0~ ~ 0 ~ ~ ~ Q ~ ~ ~
O o o _ . _ o o _ o _ o ~o o _ o _ _ _ I I I I I I I I I I I I ~I I I I I I I T I I

76.37 SUBST~UTE S~t EET ~RULE

W 096/33276 PCTrUS96/05320 ~ ~ _ ~ ~ o ~ ~ ~ o , ~ Q ~ o ~ ~ ~ ~ ~ _ C~ 0 O) ~ l 1~ N C'J ' C~.l O O C'~ ) C~
0 C~l N ~ ~ ~ U~ 0C~l 0 C~l C'~O O N C'~l 'S 10 0 0 O) ~ tD O C~ 0 ~r ~D 0 0 E
--o o ~o .E _ E --o i s O ~ E ~ " E

c Q c~ LL C Cr) 0 _oQ Q
_ ~ o o I ~ - ~ ~ ~ ~ Q ~ ~ ~ ~ _ m ~ _ 0 ~D .~ 0 .~ ~ ~ _ _ Q Q ~ ~ V) ~D Q ~
E E ~ ~E Q ~C al o o ~ 'D Q Q Q ~D E Q ~ Q ~
E E c~ aE, ~0E SQ oE E ~ ~ ~ ~ 0 E ~ Ec Q ~ SQ 'CD UJ
0 a O ~.0 0 Q ~0 ~-- Q Q c c c Q = ~ E c Q 2 E ~ ~ s, ~o O _ ~ ~ ~ ~ _ ~ _ = E

o7 ~ E a~ --O --O~--O Q-~ --~ Q Q Q Q ~- C
_ O r~ 0 07 a7 ~7 r~ O c7 a7 ~ c~ ~J _ ~t N cn a7 a7 a7 C~ a7 a7 a7 ~ a7 _ a7 a7 a7 ~ a7 _ c~ a7 _ O
o _ _ r7 0 N ~7 a7 r- r~ r~ r~ ~n co a7 o o7 u~ a7 c~
, u~ 2 ~ ~ N U7 C~l 0 0 0 0 ~ ~ ~ ~ U7 C~ _ C'7 _ c~ a7 ~ cu c~ r~ r~ r~ r~ c~ cu a7 a7 a7 a7 a7 cu cn a7 CD a7 a7 _ a7 UD Lr~ a7 r- cu co O o a7 cu _ cu o u7 a7 ~ ~ a7 u7 a7 cn u~ cn O u7 a7 r~ cu ~r O O C7 _ CD O o U a7 r- ~ a7 r~ 0 0 0 a7 c~ cn u7 a7 cu _ u7 a7 a7 u~ c~ a7 a7 ~u u~ u~ ~t u7 _ - ~r cu cu U7 - r~ cn CD CD a7 ~ O O O ~t C~ _ CU
_ _ _ _ _ ~t CU ~ r~ r~ ~ U a7 a7 O CO U7 _ CU O ~~ ~t ~~ ~t C~7 U7 ~ 1~ U7 U7 CU ~_ CU _ cn 0 c~7 CD CD _ CU _ CU CU CU N ~t ~ ~t ~ CD U7 cn cn _ _ U7 0 0 ~ CU U _ _ _ _ U7 UD U7 UD _ _ U7 CU
I I I I I I I I I I I I I I I I I I I I

SUBS i I l UTE SHELT (RULE 2~1 W 096133276 PCTrUS96/05320 ~ U~ ~ o~ O~O _ er ~ 0 0 0 C~l ~r o Ln 1~ r~ ~ o r~0 o o u~
J ~ 0 C~ 0 a~ o 0 ~ o C'~ Cq 0u~ i 0 u) 0 _ ~ 0 oi c~7 ID ~
u~ _0 _ ~ t ~ ~ 0 o s ~ ,c ~, o ~C
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0 0 _ 0 _ 0 _ 0 _ C - - o .C c 2 C C
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~ U~ 0 _ U~ ~ O ~ ~ C~ ~ 0 ~ 0 CO ~~
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t~ C~l -- er ~ O ~ _ O q ~_ lo 0 ~) O
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0 0 CO O ~ 000 U~U~ ~ _00 LD ~t ~ O ~'0 r~ 0 0 ~

o _ooo o_ _ ___o_ T I I I I I I I I I I I I I I I

76.39 SUB5 111 UTE ~i~EET (RULE 2~i) W 096/33276 PCTrUS96/05320 0 _ ~ o _ C~ 0 _ 0 c~ 0 _ 0 ~ c~
-- 0 0 0 lD ~ 0 0 0 U~ 0 0 C~J 0 t~ U~ l O C~l r~ CD ~ tr) 0 C'~ N 1~ C~ O ~0 0 O U ) O r_ ~ _ 0 ~ tD C~.l 0 ~ C~ ~ 0 N
0 0 Ir) ~ 0 0 c~ 0 ~ 0 ~ c~ 0 c~J
0 0 1~ er ~D ~ r~ 0 ~ 0 0 ~ 0 0 0 1~ w r--c. ~ ~ O C'~ 0 ~ 0 0 O~ 0 C~l 0 0 ~ U~ O C~
0 0 U~ 0 C~ o ~ 0 O~ O C~ D O C'~ _ I~

.a~
a ~

a ~ O O ~ _ oO ~C ,= O C c = .~

~ ~ ~ o ~ ~ cCa ~--O Cl Q L~ cnQ 111 ~ C 'C
o _ E E E ~ ~, ~-- c c s ~ E ~ m --~1~ 2 ~

C Q ~ Q ~ ,,2 LL~ 0, ~ ~ ~" cL ~ ~ ~ c 2 c 2 E _ E E c ~ m ~ ~ ~ ~ e S~ o ~ e Q S E ~

o - ~ C c ~ m ~ ~a c c Q ~n a) ~U

E o E = = D = .~ .~ S ~ S ~ -- O o -- ~ ~ E ~ o ~-- c ~ o y e e S~ = ~ ~ ~ ~ E o ~ = = ~ m ~ ~ O = ~ ~ ~ E ~
U') 0 0 D 0 0 _ I' O 1' r~ ID 0 D 1'-- C~J --c _ O ID 0 0 1~ U~) O
tD 1~ 0 C~ 0 _ 0 U~ 0 _ tD t~ ~ ~ _ (D ca ID ~ _ ~-- O ID 0 1~
C~l ID ID 0 -- C~l ID U~ 0 _ C~J 1~ ~1 11~ 0 n) ID 0 u~) o 0 0 r~J ID
O ~ ~ ~ 1~ ~ C~ O O ID 0 ID ~ 0 C~l ID o O 0 ~ ID 0 C~
O O _ _ c~J 0 15) Ir~ ~ o ~5~ ID C~ I 0 ID N 1~ 1~ 1' ~ 0 ' U:) _ _ _ _ 0 Ir) N el _ _ 00 0 e~ C~l ID ~,~ 0 _ _ ' _ ~t _ _ _ _ _ _ a~ -- -- ---- 0 0 _ ~ O ~ 0 ~ ~ ~ ~ ~ l ~~ ~ ~ ~ er 0 _ C'l 0 0 ID 0 0 0 ~ 0 0 D C~J C~ ~ ~I C~ ~ ') 0 C~ J _ 0 C~ 1~ 0 ID ~ 0 0 ~ 0 0 ' ~ 0 ~ r'- 0 S O~ O ~ O 0 ~-- I
cn ~ ~ ~ ~ ~~ al _ ~ ~ ~ ~c n ~ ~ Q t~ ID~ ~
u~ o _ _ ~ 0 0 ~ 1~ 0 ~ID C'. ~~1 0 ID JC ~ 1~ r~ -- 0 0 r-- ~
o _ _ _ ~ U~ C'J ~ _ _ ~n 0 0 ~t ~J ID la 0 -- -- ~ -- ~ e~
-- -- O . _ _ 1~ r~ -- C'.J ~ _ ID 0 0 0 0~ 0 N 11~ C~l 1~ 0 ~ 0 ~ 0 C~l 0 0~ 0 ~ 10 0 0 N C~l _ 0 1~ _ 0 m U~ C~,l C~ J _ _ _ 0 U~
O O O o C~ r _ o ~ 0 c~ D O ~~ _ _ r' _ _ O _ _ O _ O O _ O _ O O _ O O O O _ -- -- O O O
I I I I I I I I I ~ I I I I I I I I I I I I T I

76.40 SU8STITUTE S~ EET tRULE 26) 0 C'~ N O tD ~D ~ ~ t~ ~ O
0 U) O ~ ~D ~ 0 0 ~ _ ~ O C'~ r o O 1~ 7 o ~ o ~ c~o a~ o ~r c~i ~ _ _ ~D ~ 0 0 c~ ~ -- ~ 0 m o -- c~J 0 0 _ C~

Q

rl e e o - ~ ~ u o ,ta T = ~
c s ~ ~o s s _ a) E ~
C S -- CO ~ ~ _ s ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ O~ ~ ~ __ E o ~

~ ~ ~ e . ~

E = o s ~ 0 ~ ~ ~ C =, ~ o E o .= ~ ~ = E

~ W W ~ W W s s s ~ ~ ~ E E ~D s ~ a. f~ ~ 8 U~~ a~ Q 8C 3 _ e~ et 1~ 0 ~ ~ D C'~ ' 1.0 ID C'~ 0 o2~ ~ ID
D 0 tD ~ _ ~ ~ ID U~ 0 n t~J D C~J O ~ O 1~ 0 ~ O U~
~ ~-_ 0 ~ 0 ~ ~ 0 0 a ~ 1 ~ _ ~0 ~ a O o t~ ~ 0 C~J O a) O 1' 0 ~1 _ 1'~ D _ ID D 0 ID 0 O 0 C _ ~n --C~ 0 ~ 0 0 _ C~J -- ~ 0 0 ~ ~C~J 0 ' a~ O r~ D ~C ID 0 ~O1~ 0 0 ~-- ~ IDID 10 ~D ~1 0 DD ID 1~ D _ 0 _ 1~ r' Cl. -- C~
___ __ _ ___ _ ~ ~ 0 ~ ~ ~ 0 ~ a~ cn 0 r_ cn ~D ~r -- O O ~D cn ~ ID a) c ~_ _ O ~ ~ ~D ID ~) 0 r~ C~ O ~ m C:10 q ID O ~ ~ ~-- -- --~ tD ID ~ ~J ~ 0 ~t) ~ _ ID ID O ID 0 ~ ~ _ 0 ID ~ ~) C 0 0 r~ 0 0 0 ~ 0 1--- 0 1~ C~ ~D C~J ~ ID O 1~ D O C') ~ t0 0 ~L _ tD
0 ~D ~ t~ C~l _ _ _ ~ 0 0 ~ r~ C~l 1~ 1~ \~ 0 1~ D 0 ~ ID 0 O O ~ 1~ ID ID ID tD C~l 0 ID 0 U' ~ 0 _ 0 _ ~ ~ 3 _ C'~
_ _ _ _ _ _ _ _Z _ ~ C~J 0 1~ 1~ 0 ~ 1~ Cq N _ ID lo ~D ~D 0 0 ~ 0 c'.l ~D 0 Cl O
_o~___0ooo_C~ o_ c~ 0 c~
~D tD O O 1~ ~D 0 In ID ~D C~l 1~ 0 ID U~ ~ 0 _ ~ ~ O C~l OO___OOOOO__OOO_ OOO__O

I I I I T I I I I I I I I I I I I I I I I I

76.41 SU8STITUTE ~EET (RULE 2~i) .

.W 096/33276 PCTnUS9610S320 O t!~ ~ N ~r ~D O a~ 0 _ a~ O C'~ ~-- ~ In a~ C~l ID ~ U'7 0 ~ C~ 0 LO ~ 0 O C~ J N
~ ~ t~ ~ O O Ir~ 0 ~D 0 a~ 0 ~
ID ~ ~ i~ r~ ~D 0 t~ 1-~ 0 0 ~D 0 0 0 c~ D 0 t~ 0 0 ~ a~ o c~ tD ~ ~ O O C~ 0 _ ~ U~ 0 C~
o ~ ~ Q ~ ~ ~ ~ o ~ o 0 _ .~ ~ 0 C~

O ~ D o --o c ~ cl e~

O S= .-- o ~ ~ ~ S D E o ' ' ~-- e ~-- D e ~ - ~ ~~ ~ ~ ~ ~ I ~ ~ E ~ ~ c .0 z z --~ m s ~ -- E
~ To C ~D C ~ Q Q ~ E t ~ o ~ 2 ~
s--. y~ Z ~ - E

s E ~ ~ ~ E E ~ i y E ~ ~

V) ~ ~ ~D Q-Q-Q-Q O ~ ~ --0 E E E E -~ ~ ~ c c c _ _ ~ D 'C ~ ~ ~C C C ~C
o ~ m ~ 0 N _ ~ ~ _ ~ 0 o ~ a~ m ~ ~ 0 ~ ~~ o ~ ~ ~ ~ O c~) ~ ~ 0 O _ ~D O ~ ~ o) ~ o c~l tD O ~~
~D ~O ~ r~ a~ ~ I~ I~ r~ ~ tD CD ~~ O 0 1.0 0 1~ 0 - - - ~ - - - - - - - - - -_ O U~ O ~ ~ ~ ~ e~ O C~ ~ ~ ~ ~ o ~ ~J
l 0 U~ ~ O ~ ~ t~ ~ L, ~O ~ O ~ _ ~O ~ 0 ~ ~ ~O
O ~ ~o n ~ 0O ~ ~ ~ 0 O, ~D 0 1 O O t'~ 0 ~ N ~ O r~ ~ ~D
O ~ 0 a~ 0 Q a~ _ 0 -- ~ D O ~ ~D ~ N ~ C~ D 0 ~-- 0 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ O _ O O O O O
- I I I I I I ~ I I I I I I I I I I I I I I I I

76.42 SUBST~UTE ~tEET tRULE ;~6) W 096/33276 PCTnUS96/OS320 ~ 0 _ 0 ~~ 0 ~ ~D O ~ a~ 0 O O) ~-- N N tD C~ l _ 0 ~ l ~ O O C'~
0 1~ o u~ ~ o 100 o~ o C~ c'J 0 c~
~D ~ 0 O) _ ~ c~ ' ~ c~J0 N 0 0 U~ ' 0 0 0 0 00 0 0 1~ 1~7 r 0 0 a~
~r 0) ~7 0 ~ ~ o 0 0 ~ N u~ _ O) 0 C~l 0 ~-- CD ~ 0 0 a~ 0 _ _ a~ o ~ 0 u~ a) 0 ~ cr~ _ ~ O C~i _ .~
C C O
c c E
c E ~ .0 ~ ._ 0 0 ~ .c O o o ~ o z z 0 E ~ s c ~ ~ "
~ c 8Q ~ ~ 0 0 C ~ ~ E 0 .~ ~ ~ O 0 0 0 0 o ~
e _ ~ ~ ~ .c --s ~ ~ 0 ~ s s s c a c c c O O m ~ _ ~ ~ 0 ~ ~ ~ I I
Q Q Q Q Q c 2 C ~ ~) ~ y ~ --2.2.c .c .c ~ ~ 2 2 2 2 s ~ ~ c ~ 2 ~ 2 2 2 ~
Q ~ D ~ ~ ~ ~ c ~ y ~-- --O --O oC o O O ,_ ._ ._ ._ ._ ~~ ~C ~ -- ~C t~ ~ C O o o Q -- 0 a~ 0 0 0 0 0 0 0 2 ~ Q O ~ 0 0 S0 ~ o ~ ~ ~ ~ ~5 '~
0 0 V~ 0 0 0 0 Q --.-- ~
D ~ ~ 8 0Q ~D ~1 = Q) ~D 11) ~ ~ ~D
_ _ _ ~ _ _ _ ~ S S S S S ~ <~
LO c~J ~ 0 cn O ~ Cq 0 0 1~ Cr) Cr~ 0 cn ~ ~D _ ~ ~D
~ ~ ~ cn ~cn O ~ c cn 1~ 0 0 ~ LO LO ~ C~ C~l C
cn ~ cn O Cq _ ~ cn ~ D ~ 0 C~ ~ -- Cq O c~ O
~ cn O ~ ~ 0 ~O L' I tD _ cn ~ O _ ~ _ C~ ~ O ~ O L~
0 LO Cq Cq ~ O C~l 0 ~ _ o cn _ cr~ cn _ o C~J O O ~ ~ C~ L I LO ~ _ ~ C~ 0 C~J C~ ~ LO ~ _ C~J C~J
- - . - - - - - - - - - - - -LO cn ~ Ln ~ C ~ o ~ cq cn .- o Ln 0 1~ ~o o _ n l~
c~ o l~ o Ln c~J cn 0 ~ cq L~ cn ~ cl~ 0 o ~ Ln _ _ cn o ~ ~D
LO ~ D 0 0 - O ~ ~ LO er LO ~ c~ CU o o LO ~ cn ~c~ -- cn c~ D 2 Q LO L~ O _ a~ 0 ~ _ LO O O cn cn ~
0 lD c~ o C.~ n ~ 0 _ _ cn o -- c~ r o cn o o C~l O O ~D ~ I~ C~l L) ~ LO L ~ _ C~ C~J C~J ~ Lr~ l C~
-- -- -- -- ----Q ~ ) -- -- C.) _ _ _ _ _ _ _ _ O 1~ LO _ ~- LO O -- ~ LO _ ~ LO O _ _ LO 0 0 r~ ~ er O
C.~ cn ~ o ~ _ c~l cn cn Lo ~ -- --3 Lo Lo c~ -- cr) N o C~ _ C~ ~ C
I I ~ I I I ~ ~I I I I I II I I I I I I I I

76.43 SU85mUTE 5}~EET tRULE 263 W 096/33276 PCTnUS96/05320 0 o U~ ~0 0 ~ ~D 0 ~ U~ ~D O et _ O _ e~ 0 _ 1~ O 0 _ _ ~ t'~ 0 C~ O O 11~ 0 t~ O C'~ 0 ~ 0 C'~ O ~
_ C'~ I~ ~D 0 0 0 _ a~ _ o c~ _ O _ U~ O 0 0 ~D
0 0 ~ 0 ~D 0 ~-- 0 U~ tO 0 1~ 1' 0 0 0 ~D 0 0 - o c~l ~r o 1~ ~ 0 (~ 0 c~ tD O 0 C~l O t'~ 0 ~ C~
~ N 1~ 0 _ 0 0 ~ 0 0 0 ~D 0 ~D 0 ~ 1~ 0 ._ ~ .~ ~
a~ ~
_ ~, C o o ~ Il~ Q
C ~ ~ 'C C C s o ~~ o ~ s, ~ m c ~ O LlJ O O
o o ~ 0 ~ _ E

sO ~E ~ ~ c y ~ .c 2 ~ ~ j _ ~ ~ E o ~ ~ c c E E E ~ ~
O o o ~_ ~~ Q ~ C ~ C ~ C - xQ x x x - Q
_ , c c ~ ~~ _ ~ ~ ~ ~ ~ ~ 2 ~ 2 - Q
; X ~ ~C C ~ ~o ~Q Q 2 2 ~ 2 ~ ~ ~ ~ ~ .~ ~ o ~ .~ _ c Q ._ ~ --0 _ o In ~ . ~ 2 ~ _ ~ ~ C~J o r~ n 0 r ~- 0 ~ D
~_ 0 ~ ~ ~ c~ ~ 0 0 n ~ lD 0 o ~ ~ r~ 0 c~
_ <D ~ ~ -- C~ O ~ ~ 0 r~ 0 0 _ ~ 0 ~ ~D ~ ~ '-_ ~ 0 _ ~ ~ aJ ~n ID ~ _ ~ ~ 0 ~ _ ~ ~ ~ ~ n o a~ C~ D _ _ ~ In O ~ 0 N C'J ~ 0 0 _ 1~ r~
_ _ _ _ _ Q _ _ _ - 0 ~r C~ ~O _ ' Q 0 In In r~ 0 ~r ~ O In ~ ~ ~ o In o ~ _ ~ ~ _ 0 ~ c~ ~ o 10 ~ ~
CC~l 0 0 0 ~ ~ t~ D 0 0 _ ~r O O ~ ~D
o~ _ In 0 _ 0 r~ ~ _ o ~D ~ 0 0 ~ ~D _ _ m e~ _ o 0 c~ ~t ~ 0 _ ~ o ~ r~ 0 c~ r 0 0 _ ~
-- _ _ c~ _ _ _ O tD 1--- ~D N 1~ 0 0 0 O -- O 1~ In -- m ~D In 0 0 n 1~ ~ _ ~ o ~r _ o ~ ~ ~ ~s _ _ o _ 0 a ~ O _ O ~ O ID 1~ 0 C~ 0 o _ ~ c~
o - - - o - - o - - - o o o o o o o o o o o o ~I I I I I I I I I I I I I I I I I I I I I I I

76.44 SUBS 111 VTE SHE}~T tRULE 26) W 096/33276 PCTrUS96105320 ~ 0 _ N ~ C'J O C~ C~ 0 C~
O O ~
CD O _ O O ~ O U~ O O O
~ o o o~ o o~ O O O
N O CD ~h ~n O O) C~l O t~ 10 0 1~ 0 0 0 ~ t O CD a~ o a~ o o o 0 CO ~ O ~ 0 o ~o o o o E ? E E E
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76.46 SU~15 1 1 1 UTE St/l E~T tRULE 2fi') W 096/33276 PCTrUS96/05320 o m ~ ~ _.o ~ ~ ~ ~ ~ _ ~ ~ ~ o ~ ~ ~ 0 01 C~i O cq _ ~ In C~ N ~ ~ I~ tD a) O 0~

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76.47 SUBSTIl UTE S~}EET ~RULE 2~i~

W 096133276 PCTrUS96/05320 o c~.i _ c~J o ~ o ~ (D tD C~.i C~i _ O ~.0 _ O O

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76.48 SUB5T~TUTE 5~EET tRULE 2~) W 096/33276 PCTrUS96105320 u~ 0 c~o ~ _ o ~ o ~ c~
o o a7 ~ o c~ o c~

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76.49 SUBS 111 UTE S~E~ ~RULE 26) W 096/33276 PCTrUS96/05320 0 ~ O O) ~ O ~ ~ ~D ~r c~) ~D ~ ~ a~
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76.50 SUBSTlTUTE S~EET tRULE 2 W 096/33276 PCTrUS96/05320 ~ o E E E E E E E

Q O _ _ _ _ _ _ _ O O O O O O $ O
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o o o o o o o o o c' o - - - - o - o - - o o 76.51 SUBS 111 UTE ~HE~T ~RULE 26) W 096/33276 PCTrUS96/0~320 O I_ _ '" a, c _ â:

-- c~ E ' cr: ô ~ Q F

Q ~ ~ ~~ ~ ~ ~ _ o 'n m a~ C a) O o t_ s ~ tn ~ c, ~ ~ ~ ~ s E ~ e ~_ t" ~ Q _ ~ ~ ~ ~ ~ Q Y c~ tn o Cl I I

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I I I I I I I I I I I I I I I I I I I I I I I I

76.52 SU85mUTE S~tEET tRULE 26 CA 022i8741 1997-10-21 W 096133276 PCT~US96/05320 ~ Q ~
_ Q c~ _ _ _ _ _ _ O Q ~ ~ 0 ~ .Q--~ m m m m m m m m C C _ _ _ ~ ~ ~
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76.53 SU8STITUTE SHEET tRULE 2 -W 096/33276 PCTrUS96/05320 N ~ C~ l 0 ~ . C~J O O U) C ~r C~ ~ ~ ~ O U'~ O tO ~ _ tD O _ 15~ tD
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-76.54 SU85mUTE SHEFr tRULE 26) W 096133276 PCTrUS96/05320 ~ 0 ~ 0 ~ c~ 0 o u~ o ~ o ~ ~_ 1~ o ~ a~ c~ o c~
Lt~ O lD O _ . C~l O O C~ 0 0 0 0 d- C~ C~ tD O lD _~ ~0 1~ ~ 0 _ O N In ~'.
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O _ O O _________ O__ O O __ O ____ O O ___ O _ IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

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76.55 SUBSTITUTE SHEET tRULE 2fi~

PCTrUS96/05320 _ ~ ~ 0 ~ ~ o o ~ ~ ~ _ o ~ 0 0 ~ ~ ~ o ~ LO 0 ~ Q 0 Ln~ Ln ~ ~ 0 ~ Ln 0 a) ~ ~ t~ Ln _ ~_ 0 Ln c~ D ~ 0 0 ~ ~ C'~ ~ ~ _ LO
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76.56 SUBST~TUTE S~ EET tRULE 26) W 096133276 PCTrUS96/05320 0 ~D d~ a~ 0 3 ~D d~ O _ ~ ~D O _ N C'J O ~ ~D ~D C~ 0 _ 0 0 ~ ~D _ _ 0 1~ ~~ _ O "t ~ a~ O O U~ D ~D _ ~ _ c~ tD el~ 0 0 It) C~J O O C~ In o _ c~l ~ o _ c~ u~ ~ Q O C~ 0 _ ~D _ ~ U~ 0 C~ O
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76.57 SUBSTITUTE S~EET ~RULE 2fi) - - -W O 96/33276 PCTrUS96/05320 cn O O tD tq ~D _ In Ir~ t,q t~ ~ In t~J _ ~ In ~ t') O '~J ~ ~) ~D O _ 0 0 ~_ o e~ o t,~ o ~ ~ t~ t,~) ~ t~l t'~ t~J 1,0 ~ I tD O 15~ ~t tD _ tD ~ ~ ~ 'D ~-- _ ID _ t'~ N _ tD tD
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0 0 0 0 0 0 0 rln 0 0 0 0 0 0 0 0 0 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 OOOoOOOOOOOOOOOOOO___----------------------IIIIIIITIIIIIIIIIIIIIIIIIIIIIIII

..

76.58 SUBSmUTE ~EET (RULE 26) W 096/33276PCTrUS9610S320 r~ 1~ t~ ~1 0 N ~ 0 ~ ~t C~ ~ O C) 1~ C~J O tD ~ ~ ~ l 1~ 0 O) O U~
U~ u~ ~D 07 O~ ~ ~ It~ O It~ ~ o~ c~ c~ O~ ~ ~ ID tD 11~ 0 tD O O _ C~l et O ~ t~ O
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__________________,_____________ IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

0 ~ 0 Ln a~ ~ o ~ o r~ D Ln Ln et N00-.0 ~-- O et Ln ~ ~ 0 0 ~0 et 0 C~l o a~ a~ -- 0 et C~ -- 0 Ln 0 ~ c~ o NN0 ~DN000tD--0 et NLn C~l et N Ln Ln C~ 0 et et O a~ 0 et ~ 0 C'~ ~ ~ et U~ ~ CD 0 0 ~D 0 NLn0 et 1~ 0 ~ C~lONNC~e~ Ln r~ 0 o o ~ ~ r- 0 et Q a~ 0 C~ et Ln r--r~ 0 t:D 0 a7 o 00000000000000__._C~NNN0 C~ C~ 0 et e~ et et 0 _ O O O O O O O ---- -- ---- -- ------ ---- -- -- --_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Lnt5~_0__r~ 00~ N~0 et ~ 0 0 0 CD et 0 et C~ et ~ C~ O Ln 0 et La ~D 0 0 r~ et _ c7 Ln r~ ~ ~ C~ et C7 0 0 C~ _ et C~ Ln et C~ _ 0 Cq O e~ 0 C~ C~
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_ _ C~ et Ln U~ ~D 0 0 _ ~ 0 0 C~ r~ 0 _ C~ C~ r- 0 Ln Ln r~ r~ 0 0 0 0 0--00000000000 c~00___NNNC~lNC'~ C'> 0 L') C'~ et et et Ln 0 O O O O O O O O----~ _--_----_ _ _ _--_ _ _ _ _ _ _ _ _ _ _ 0 0 0 _ r~ C~ et UD 0 0 0 _ L~ UD O ~ aD r- 0 o Ln UD r~ r~ et n UD et Ln CD r- 0 C~ C~ C~ C~ ~ C~ C~ C~ C~ t et et et Ln ~ Ln Ln Ln UD UD UD ~ ~ r ~ r- 0 0 0 0 0 o o o o o o o o o o o o o o o ~ o o o o o o ~ ~ o ~ o o o o o o - - - - - - - - - - - - - - - - - - - - - - - - - - - - -76.59 SUB5TITUTE Sff EET tRULE 2~) W 096/33276 PCTrUS96/05320 co a) c~ o) 0 a~ o cn ~ C~ 1~ cn ~ N--O--1~ 0 o u~ ~ 0 In 0 ~ ~ ~ cr) cn 0 ~ ~ 0 o cn r~ 0 cr~ _ o a~ ~ ~ c~ 0 c~ cn o cn c~ ~ ~ o c~ ~ ~ 0 o ~ ~ _ ~ u~ ~ 0 0 c~ N C17 ~
c~ n ~ ~ o 0 ID cn cn n n o o _ , ~ 0 ~ ~--O ~t ~ O ~ C~ D C00 "~ ~--cn r' C~l o _ c~
u~ q ~t cn ~ ~ ~ ~o o ~ _ co o o _ I~ c~l ~ co ~I ~ Ln ~D co r~ ~ ~ 0 _ et o ~o C~ ~ ~ ~ ~ 0 0 U~ ~ O O C~ O ~ J C~ ~ 0 cn c~
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____~_____ IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

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o o o o o o o o o o o _ _ _ _ ~ C~ c~ c~ r7 r7 r7 r7 r7 r7 ~r ~ u~ u~ (D LDL U7 U7 U7 U7 U7 U7 U7 Ln Lr7 U7 U~ U~ U7 U~ I u u~ u7 u7 u7 u7 L~7 U7 U7 U7 U7 u7 u7 .-~ U7 u7 ~t O _ O r~ r- cu O cu 0 0 r.7 ~t a7 0 0 ~ cn c~ C~ c~ r7 0 _ U7 _ ~ c~ _ _ 0 0 cn 0 r~ co UD 0 0 r7 L~7 ~t u~ O CD ~- 0 U7 'J O U~ ~~ r~ r7 u7 ~J _ o cn c~ ~ r~ ~ u O cu ~t CO O cn ~7 0 ~7 ~D CU ~t C~ r- cn r~ ~J L~ ~ r~ _ ~D _ u7 r7 _ r7 ~ c~ O r7 ~-~ L~7 U7 ~D ~ ~' 0 0 0 cn o o _ r~7 ~ _ ~ L (S,7 r~ 07 (D ~-- 0 0 _ ~-- ~ ~ O O :~JO O O O O O O O O O----------CU ~ C~, cU r r7 r7 r7 r7 ~t ~ ~t u7 u7 (D ~D D
L~7 U7 L~7 L~7 L~7 U7 U7 L~7 L~7 L~7 U7 L~7 U7 U7 U7 L~7 ~7 U U7 U'~ U7 U7 L~7 U7 U7 U7 L~7 U7 U7 U7 L~7 ~7 ___~--____________________________ ~ U7 ~ CO CD _ C~ r7 ~ u7 (D r~ 0 _ C~ 0 0 _ r7 o ~ u7 (D 0 0 c~ CO ~ ~-- _ CU ~t - - - _ _ C~ C~ C~ C~ C~ CU C~ CU r7 r7 r7 ~ r u7 u7 u7 u7 u7 (D (D D r- r- CO CO 0 _______~_______________.________ -76.60 SUB5TITUTE 5~EET (RULE 26) =

W 096/33276 PCTrUS96/OS320 o D
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m ~ ~ O ') 0 ID O O C~ D cn 0 ~ ~ ~ In N e~J ~D _ ~ ~ ID ~ ~D O 0 C'~ C~l O
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76.66 SUBST~TIJTE 5HEET tRULE 2h) W 096~3276 PCTrUS96/05320 (1) ~.~N~T. INFORMATION:
(i) APPLICANTS: Human Genome Sciences, Inc.;
Johns Hopkins University (ii) TITLE OF lNV~NllON: The Nucleotide Sequence o~
the Haemophilus in~luenzae Rd Genome, Fragments Thereo~, and Uses Thereo~ ~
(iii) NUMBER OF S~U~:N~S:
(iv) CORRESPO~N~ ADDRESS:
(A) ~n~T~T.q~q~T. Sterne, Kessler, Goldstein ~ Fox, P.L.L.C.
(B) STREET: 1100 New York Avenue, N.W.
(C) CITY: ~h;ngton (D) STATE: DC
(E) C~U~1~Y: USA
(F) ZIP: 20005-3934 (v) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: 3 1/2 inch diskette (B) COMPUTER: Dell Pentium (C) OPERATING SYSTEM: MS DOS v6.22 (D) SOFTWARE: ASCII Text (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: (Not Yet Assigned) (B) FILING DATE: (Herewith) (C) CLASSIFICATION:

(vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/476,102 (B) FILING DATE: 07-JUN-1995 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/487,429 (B) FILING DATE:07-JUN-1995 -77.1-SUBSTITUTE ~i~tE~ tRULE 2~

CA 022l874l l997-l0-2l W 096l33276 PCTrUS96/OS320 (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER: US 08/426,787 (B) FILING DATE: 21-APR-1995 (2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 1830121 base pairs (B) TYPE: nucleic acid (C) STRAN~N~SS: double (D) TOPOLOGY: linear (xi) S~YU~N'-'~: DESCRIPTION: SEQ ID NO:l:

AAAGTATTAC CTGCATTA~A CGGTAAATTA ACTGGTATGG CTTTCCGTGT TCCAACGCCA 120 AACGTATCTG TtGTTGATTT AACAGTTAAT CTTGAAAAAC CAG~ll~llA TGATGCAATC 180 AAACAAGCAA TCAAAGATGC AGCGGAAGGT AAAACGTTCA ATGGCGAATT A~AAGGCGTA 240 T~A~GT~ACA .T~A~GAT~ T~l"L~1"l"r~l~ ACTGACTTCA ACGGTTGTGC TTTAACTTCT 300 TACGATAACG A~ACGGGTTA CTCAAACA~A GTATTAGACT TAGTAGCTCA TATCTACAAC 420 TAGAATTTAA TTTACGCTCT A~AAATGAAC AAGGGATCAC TA~AAATAAT TTAAAACAAT 540 ATGAAAATCA AAAATAGGGT TAATATGAAT CTCGATCTCC AllL~ L~A TCGTATTCAA 660 CAACAAGCCA AAACTCGTAC AAATATGACC GCACTTCGCT ATA~AGAACA CGGCTTGTGG 720 CGAGATATCT CTTGGAAAAA CTTTCAAGAG CAACTCAATC AA~ull~lCG AGCATTGCTT 780 GCTCACAATA TTGACGTACA AGATA~AATC GCCATTTTTG CCCATAATAT GGAACGTTGG 840 ACAATCGTTG ACATTGCGAC CTTACA~ATT CGAGCAATCA CAGTGCCTAT TTACGCAACC 900 AATACAGCCC AGCAAGCAGA ATTTATCCTA AATCACGCCG ATGTA~AAAT ~ C'~lC 960 GGCGATCAAG AGCAATACGA TCAAACATTG GA~ATTGCTC ATCATTGTCC AAAATTACAA 1020 AaAATTGTAG CAATGAAATC CACCATTCAA TTACAACAAG ATCCTCTTTC TTGCACTTGG 1080 -77.2-SUBSTITUTE S~tE~T tRULE 2~) -CA 022l874l 1997-10-21 GA~AGTTTTA TTAAAACAGG TTCAAACGCC CAACAAGATG AACTAACCCA ACGCTTAAAC 1140 AAAGGTGTCA TGTTAGATTA CGCTAATCTC GCTCACCAAT TAGAAACACA TGA'l'~'l"LL~'A 1260 CTTAATGTGA CAGATCAGGA TATTTCACTT 'l'~'l''L'L'L'L'l'AC CA'L'L~'L~'L~A TA'L'L'l"l"L~AA 1320 TTTTACGAAA AAATTTATGC TGCCGTATTG GATA~AGTTC AAAAAGCCCC AAAACTTCGC 1500 CAAATTATGT TTCATTGGGC AATTTCCGTG GGACA~AAAT ATTTTGATCT ACGTGCGAAT 15 60 AACAAAGCTA TTCCGTTCTT ATTGAAGA~A CAATTTGCTT TAGCAGATAA ATTAGTGCTC 1620 TCAAAACTTC GTCAATTATT GGGGGGACGA ATA~AAATGA TGCCTTGCGG AGGAGCAAAA 1680 GGTATGACAG AAACAACTGC AACC~11L~L TGCTGGCATG ATTTCCAATT TAACCCAAAT 1800 TCAATCGGCA CACTGATGCC AAAAGCGGAA GTGA~AATTG GGGAAAATAA TGAAATCCTT 1860 GTGCGTGGCG GAATGGTGAT GA~AGGCTAT TACAAGAAGC CAGAAGAAAC GGCTCAAGCC 1920 TTCACCGAAG ATGGTTTCTT A~AAACTGGC GATGCAGGAG AATTTGACGA ACAAGGCAAT 19 80 TTATTTATTA CCGATCGTAT CA~AGAATTA ATGA~AACCT CA~ACGGCAA ATATATCGCA 2040 CCACAATATA TCGAAAGCAA AATCGGTA~A GATA~ATTTA TCGAACA~AT TGCGATCATC 2100 GCTGATGCGr A~AAATATGT ATCCGCGCTT ATTGTGCCTT GCTTTGATAG TTTGGAAGAA 2160 ATTCTGAAAA L~LL1~AGCA TCGTATTAAT GCGGTGCAAA AAGAATTGGC TCATTTCGAG 2280 CAAGTAAAAA AATTCACGTT A~LL1~L~AA GCATTCAGCA TTAAATTAGG CGA~ATTACA 2340 ATGTATCATT CACAAGAAGC ATAGCTA~AA GGCTCTCAAT TGAGAGCCTT 'L~'L'l''L'L~'LAA 2460 CACATGTTCT AGCATATCCA GATCATTA~A ATTATCGCCA AATGCAATCA CTTCATTAGT 2640 TTGTACGCCA A~ATAATCTT CCAAAA~CG CACCGCACTT CCTTTGGTTG CA~L~l L~LG 2700 CATTACCTCT A~AAAATTAG CGTGGGAACG ACAAATACTT A~ATGTGGAA ATTTTTCCTT 2760 -77.3-SUBS i 1 1 UTE SHEE~ ~RULE 26) W 096/33276 PCTrUS96/05320 CGAACGTGTC GCTACTTCAT CAAAAGGATG AATCTCAATT TTGGTCACGC TGCGTTCATA ~880 AATCACCCAT TTA'llll~lA CATCGCGCGC ATGGCAATCA TTATTTGTAT AATAATTCAC 2940 GCCAAGCAAA GGATGTTCCG CCAAAACAGT ATTAATCTCT A~AATATCTT TTGGCTCAAT 3000 AAGTACATTA l"l~llL-AA G~1~111C~A ATAAGGCAAA ATACCTAAAG GAGAACGCGC 3120 CGA~ATTGGC ACAAAAGGAA TGCCATTCGC CGTTAAACGC TTAATTACCA CAACAGTTCG 3180 TCCTTGCATA ATTTGGGTTT CTAAACTTTC CAlll~llCC GCTTCATCGT CTTCAATATG 3360 lG~lll~l~l TGTTCTGAGG CTTCTCGCTC CACGACTTGA CGACAAATAA CGAGATCCCC 3480 TAACAATGGC AACTCCACCT CATCGGGGCA TTCAAATGGA AATGA~AGCA CGTTAGTCGG 3540 GCGAl~llll CCACGATAAG TTAAATTTAA TTCATGGCTT TCGGCTTCAT CCACAATACG 3600 CTG~l~ll~l~ GTTGGCAAAC CCTCTATATT ll~l~lGGCA ATTTGCAAAT CAACCAATAC 3720 ACTTCCCATT CTA~ll~lC~l AAAl~l~llll CAATTTCTAA CCGCACTTTT GCACTTATTG 3780 AATACATATA ACAAACGGTG GGCTTATGAC CA~llll~lA TGTGTAAAAA TGAGGGGAAT 3840 ATAlllC~ll TTC~ll~CC~l AGCAAAACCA ATTAAAGTCA AATTATGTTT TTCTGCCATT 4080 ~ll~llllGCA CCATTTCATA ACTCGCTCGA CTGGAGGCTA AAATAAAACC TCTAGGTTTA 4200 TAaATAGCTA ACATACTTCC ATATAAATCG AAAAATGCAC AAGCATGGGT AGCACCAGTT 4320 TCAAATTGAA AAGTACAGTC TAATTTCGGA AAAGTTTTAT ATACTTGATT CAAll~ll~l 4440 SUBSTmJTE ~;~EFr tRULE 2f;) CA 022l874l l997-l0-2l PCTrUS96/05320 GTACCACA~A TACCACAACC AGTACGCCCC GTAAGATTAC GACGATGCTC TTTTAATGCC 4500 ATA~ATTTAC GGCTGGA~AG TTCAATTTGC ACTTCAATAC CATTGCA~AC TTCTACAACA 4560 TCAATACCAT AAATATCTTC TGGTTTATTG ATAATTCCCT CTGTTAGAGA AAAGCCTA~A 4620 GsAAAATCCT CTAAATTGTT TGGGGAACAC ATCATAACTG CGTGAGAAAT GCCGTTATAT 4680 ACCAAAGAAA CTGGTATCTC AACAGCCAGT ATGTCCTCTT ll-l~llGCAA AAGTGCGGTC 4740 AATTTTnCTG TAllllll~L ~lll-~lAAAA AAGTTGATAG lll~lCGAAT CCAGCACTGC 4800 ATTTATTACC AGTCCATTAG TTAAATGTAA A~A~L~l~Ll A~ATTATTTT TATATTTATG 4860 ATCGTTACTC TAGCCATCCA ATAAATCAAC ~lllLlACGA TGATTTATAT ACTAGAGAGT 4980 ATCTCAACAA ~ll~ll~llG AAAGGAGTGA TTATGCAGGT CTCAAGAAGA AAALl~ll~A 5100 GTACATATTG CGCTGTAAGT TGCGGTATGT TGTTATATAG CACAGGCA~A CCTTACAATT 5280 CATTAAGCAG CCATACTGGC ACAAATACTC GTTCA~AACT CTTTCATATT GAGGGTGATC 5340 CAGATCATCC AGTCAGTCGT GGTGCGCTTT GCCCGA~AGG TGCTGGCTCA CTCGATTATG 5400 TCAATAGTGA AAGCCGTTCT TTATATCCTC AATATCGTGC GCCAGGTTCT GATA~ATGGG 5460 AACGAATTTC TTGGA~AGAT GCCATTAAAC GTATTGCTCG TTTAATGA~A GATGACCGAG 5520 ATGCCAACTT TGTTGA~AAA GATTCA~ATG GA~AAACGGT TAATCGTTGG GCAACGACAG 5580 CAAGTCTTGC TCCATCATTT GGTCGCGGTG CCATGACA~A TAACTGGGTT GATATTA~AA 5760 GTTGGGCAAT TGAAGCGAAG AAAAACGGTG CGA~AATCAT CGTTATTGAT CCGC~llll~ 5880 ACCGTACAGC AlCC~ll~CT GATCTTCATG CGCCAATTCG TTCTGGTTCT GATATTACGT 5940 TTGTAGGGTA TAACGAAGAA A~ACGTAACT ACGATAAATC TA~ATGGAAC TACCAATTTG 6120 -77.5-SUBS i 11 UTE S~E~ tRULE 2~i~

W 096/33276 PCTrUS96/05320 TCTTAAAAGA GCAC~LL-l~L CGTTATACCC CAGAAATGGT TGAACGTATT ACAGGCGTAA 6240 AACAAAAACT CTTCTTACAA A~L~l~l~AAG AAATTGGTAA AACCTCTGTG CCAAATAAAA 6300 ACGCAATTAC ACCAAAAGAT ALC~LlC~AA ACCAAGTGAA CTATTATCGT CATACTTCAA 6600 AAll~lll~l TAGCATGATG AAAACTTTCT ACGGAGATAA TGCCACTAAG GAAAATGGCT 6660 GGGGATTCGA lll~llACCA AAAGCAGATC GCCTATATGA wCCAATTACT CACGTTAAAT 6720 TACCAAATAA AAATAAAACG TTA'l~lG~lA TGAGTAAACT GAAATACTTA ~lC~ll~ATGG 6840 ATCCTGCAGA AATTCAAACA GAAGTTTTCC GTTTACCAAC TA~ll~LLlC GCAGAAGAAG 6960 TTTATAAAAA AGAGGGTGGA CAAGGAATTG AAL~llll~A AGCGATGACT TGGAATTATG 7140 AAGATCTTTA TGAtCCAAAC GGTAACTTGA TGTACAAGAA AGGTCAATTA CTCAATGGAT 7260 GTTCAAATAA AGAGTATCCA TTTGTAGCA~ CAACTTATCG TTTAACCGAG CATTTCCACA 7800 -77.6-SU8ST~TtJTE ~;HEET (RULE 26) CA 022l874l l997-l0-2l ATGGCTGGAA CTGCTCAAGG CGTTCA~ACG CAAGACGTTA TTAAAATCTC CGCAACATCT 8220 CGCTCTGATA TCAATGCACA Al~l~llGGG GTTTATGACA ATCCAGTTGA TCTTGATGCA 8400 G~l-l~l~ll ATTGTATTGC AGGCTGTCCA TTCAATATTC CACGAATGAA TCCTGAAgAC 8640 AA~lC~l~-lAT ACAAATGTAC T~-1-11~-L~-1A GA~lC~l~-lll CTGTGGGACA AGAGCCCGCT 8700 TGCGTGAAAA CCTGTCCAAC AGGTGCTATT C~l-llCGGCT CTAAAGAAGA AATGAAAATT 8760 TACGCAGAAC AACGCGTGGC AGATTTAAAA lCCC~lG~ll ATGAAAACGC AGGACTTTAC 8820 GATCCTCCAG GTGTAGGCGG TACACACGTA ATGTATGTkT TGCATCACGC AGATAAACCT 8880 TTTTATGACG ATGTTCACTG GTGTTGCATT L-ll~-L-lCCCT GACTTTGCTT GGCTCACAGA 9240 TAATGGCAAA TATAACCTTG GTCAAAAAAT G~-l~-llllGG ACATTAAACT TGGCAATGGT 9480 -77.7-SUBS i 11 UTE S~tEET (RULE 2~i3 AACGTTATTA GTCACTGGCA TCATTATGTG GCGTCAATAT TTTTCACATT A~ll~l~AAT 9540 TATCTTAGTG CATATATATA TGGCATTTTG GGTTAAAGGA TCAATTCGCG GTAll~ll~A 9660 AGGTTGGGTA ACC~11C~L1 GGGCGA~AAA ACACCACCCA AGATGGTATC GTGAAGAAGT 9720 TTTATCAAAA CTTGAGGAAG ATTTACTCAA CGAGCAATCT GGCAAAGTAG GTA~AACCAA 9780 AAATTGACCG CACtTTTTAT TATAAAAGTG AGAGAATATG AGTATCAAAA TCTTATCTGA 9900 ATCAGAAATT AAACAAGTAG nAAATTCATA TCAAGCCCCA GCGGTTTTAT TTGCCAATCC 9960 TaAAAATCTT TACCAACGCA GAGCGAAACG TTTAAGAGAC TTAGCACA~A ATCATCCTCT 10020 ATCTGATTAT TTATTATTTG CTGCAGACAT AGTTGAAAGC CAA~lllC~A CGTTAGAAAA 10080 A~ATCCTTTA CCGCCACAAC AGCTTGAACA GTTAAATACT ATCGAGCCAC TA~ATGCCAA 10140 AACCTTTAAn AGA~ACAGTA TCTGGCGTGA ATACTTAACA GAAATTCTTG ATGAAATAAA 10200 GCCCAAAGCT AACGAGCA~A TTGCTGCAAC AATTGAATTT CTTGA~AAAG C~L~llCCGC 10260 TGAATTAGAA GAAATGGCAA ATAArCkCTT AGCACAAGAA TTTAACTTAG TCAGCAGTGA 10320 TCCTCATAAT AGCCAAGTTG AAAACGCTGA A~ATTTACAT CACTGCCCTG TTTGTGGTTC 10440 TGACAAACTC GAAATGTGGT CACTAAATGA AGAACTTGCG ~ll~lLC~lG CCGAAACCTG 10620 TGGTAGTTGT GAAAGTTACT TGAAAATGAT GTTCCAAGAA A~AGATCCTT ACGTAGAACC 10680 TGTAGCCGAT GATTTGGCTT CTAllll~ll AGATATTGAA ATGGAAGAAA AAGGTTTCGC 10740 AATATCTAGG CTAATTATTT AAATCTATAG ATAACACGCC ATTACCACTG CAllll~lCG 10860 TCCACCACTG GGTTTCGGAT AATAATTTTT CCGAATATCC ACTTCATTAA AACCAATTTT lOQ20 lllllC~lll AATTGAAAGA TTAATTTTCC TAACAATAAT TTGCCAAATC CACAACCTTG 11040 AGCAAAACCG ATAATCTGAT TATTCTCTAT TAATTTTA~A TTGAGATAAC GCTCCCCTTG 11160 -77.8-SUBSTrTUTE S~E~ (RUI E 26) ATTA~111111 AACGTACCAA ATGACCAAGG CACCAGATGG GCTTGCTGTT CGATTTCATA 11220 CAATCGCTCG A~ATCACAGG CTTCAATTTG AGAAATAATA GACATAATTA AGGCTGCTGA 11280 A~111~11GCC ACAACGCTCG TTTGGCTTGA TGATTAGATT GA~ATTGCTG CCAACTTGGC 11340 GAGCGATA~A CCTGCTCAGC CTGCTTGCAA AATGGCA~AG TGCGGTCAAT TTGGTCGCTA 11400 1111~LGATA GTAACCAATA ACGAATAGGC TGTTTACATT CCATATGCTG GATTTGATCG 11460 TAATTCAAAC ATAAACAATT 'l"l'~'l"l"l"L'l"l'A AGATTAAGGC TTAACAGCAC ATCAGCCAAC 11520 CTAATTCCTA CTGAACCTTG CAGTACCTCG GGGCGATATA ATTCCCACTG GGA~ATGCCC 11640 A111~11~1A A~AGAAGATC GC~1~L~LLC ATAAGTGAAT TTTTAAAAAC GTTGCTTGAA 11700 A~ATAGTGTT AA'L11~LLLL ATTAATCTTT GCTA~AATGG TGCGTAATTT TAACCAATAA 11760 CCCACAGGAT TCAAAGCGTG A1LL~L~LAG AAAGCCAAGT TTTAGAACGC CATATTTCAT 11820 1L11LGATGG TA~ATCGGTA TTATTTGCTG GCGGTATTTC TGATAGTTTT CCTCA~ACAT 11880 TAGCCTCAAA ATGCTCATCA ATCCA~ATTT GGAGTTGCTA TTTTGACTAT GCAAGAACAC 11940 AAAGTGCGGT CAA'LL1L1CC GTTGAATTTC AAGGTCAAGC GGATTTAATC GTTTATTATT 12000 TTGGTCAAGA AATATTAATT A~1LG~L~AAA ACCGTTGTGG CGTGCGTTCA GTAGaAAAAA 12120 CATTATCACC CTATGGAGAA ATAGCAAAAA TTGACTCTGC ~LC~LC~11GC GGTTTATATC 12180 ALL111~ACT CCA~AATAAA CCGCACTTTG AACTTA~AAA 1L1~LG~AGA ACCTACCAAC 12240 TTGATCTTGG CTGTGGGGCG GGGGTAATTG GCTCTATGAT A~AAAAACGC ACGCCTAACG 12420 CACA~ATTAC AATGACAGAT ATTCACGCAA TGGCATTAGA ATCAGCGCGT A~AACACTTT 12480 CTGAAAATCA ATTACAAGGC GAGGTTTACG CCAGTGATGT ~LLLL~L~AT ATAGAAGGAA 12540 AATTTGATTT GWTCATTTCT AATCCTCCAT TCCACGATGG CATTGATACC GCCTATCGAG lZ600 CAGTGACAGA ACTCATCACT CAAGCGA~AT GGCATCTCAA TCAAGGTGGA GAATTACGCA 12660 AA~1L~L1GC TCAAACAGGA AAATTTA~AG TGTATTCAGT GAAAAATTAG A~ACA~AAAA 127&0 -77.9-SUBSTmJTE S~EET (RULE 2~i~

CA 022l874l l997-l0-2l W 096/33276 PCT~US96105320 TCCATATATC CTAAACTACG CAGCGCACGT TCATCATCAG CCCAACCAGA TTTCACTTTT 1~900 ACCCAAAGTT CAAGATGGAC Lll~llATCA AATAAACGTT CCATATCGGC TCTAGCTTCC 12960 ATACCAATAG TTTTAATTTT TTGACCGCCC GCACCAATGA CCAll-l-lll"l' CTGACCTTCA 13020 TCGATTTCAA CAGTAACAGA ATAAGGCAAT TCTTCACCGG TAAAACGCAT TAALll-ll~A 13140 ATAAACGGCA ACAAATCATC TTTATTCTTG ATGTTATCTA ~Ll"l~ll~AT AGCAAGCACA 13380 A~Lll~l-l~AT ACGCACCTTC AGTTTTAATC CCAACAATGC GGTGACGGGT A~-Lll~lGCT 13620 TTACGCGATG TAATTGAAAT 'l"L'l"l"l'~'l'C~l AAAATTTTAT TTAAGAGCGT TGATTTACCC 13680 ACATTTGGGC GACCTACGAT AGCAATA~AG CCGCAATAGG LLL-L~LC~AA Ll~lLCGGTC 13740 ATTTGATGTC CA~LL~LLLl AAAATTTGTT CTGCTGCCGC LL~lL~AGCT TTACGACGGC 13800 TAGATCCTTT TGCCACAAAA GTGCGGTCAA LLLL~LCCGC A~LlLL-ACT TTGCATTTAA 13860 GCAAATGTTT GCCTTGTAAA TA~LL~-L-L~LA AACGCGTTTT CGCATCTTTT TGATTATCGC 13980 ~L~LLLAAT TTCTGCCAAT AA~L~Ll~AT ACCAATTTCG TATCACTTGG GTCGTCACAG 14040 ATTCAAATTG GCGCGCTAAA ATCGCTAAAG TGGGTTCGCG TACCA~AGTA GCACGCATAC 14220 GGCTCAGTTC LC~Ll-~ATTA CAACGTGGAA ACTGATGATA AAGTGCTTCA GCGATAGTGA 14280 CAAGTCGATC TAAATGATTC ATCTTATTTT ATTGCTGTAA AGAAACGCTC AAAACGGA~A 14460 CCTGTTGGCC ATTCATTCGC LL~'L'l--l"l"l'~'l- AAGCTCATCC A~ATATAAGT GGCTTTACCC 14520 -77.10-SUBSTITUTE SHEET tRULE 26 CA 022l874l l997-l0-2l W 096133276 PCTrUS96/05320 ACAATATTTT TTTCAGGTAC A~AGCCCCAG A~ACGACTGT CATCGCTGTG ATCGCGATGA 14580 TGTGGGA~AA ATTCAAGGTC TGAATAACGA CGATACTCAC TAATTAACAC GTTATGTGTT 14700 ACCACTTTTA GC~1L1111G TTCCACATCA AAAATGACGC GATCTCCGCC CTTTCCAACA 14880 ATACGCTTAA TATAATCCAC ACCAGACATA TTATCTTTTG AACTTAACGC TA~ATTTTCT 14940 GCA~AAGCCG CTC~l~llGC CCCAAGACCA GTACGAATTA ACG~ll~llG TGGTGCTTTA 15000 AACACAATCA CATCGCCACG TTGTGGTTTT TCGCCTGCAA TAAlG~l~ll TTGGA~AATC 15060 GGAl~lll~A CACCATAAGC ATATTTATTC ACAACTAAAA AATCGCCAAC GCGTAAAGTG 15120 GACTCCATTG AGCCAGAGGG AATTTGAAAC GGTTCA~ACA AAAAAGAACG AACCAAAAAT 15180 ATTTTGGCTT lll~lLC~lC ACTTAAGGTT TTACCAGAAC ~ll~ll~lGC ACGTGCCACT 15300 TGACGATGAC GTTTTGGCAG CACCACAAAA CGATGATAAC ACCATAATAC GCCAGA~AGT 15360 GCGGTCAAAA TTAGTAACAA AATACTA~AA GTATTTGGTA ACTGAAAATA ATCTA~AACT 15420 TTCCACACAC CAAAGCCGAC AGCCAATA~A ATCACAAAAA ATAAATTTGA CATAATTTTC 15480 TACCTA~AGA CTTCATACGT TTTTTCCCTT ~'l L l ~'LGCTT CTGTAAGAGT TTTTTCTTAC 15600 GGCTCACGTC ACCACCATAA CATTTTGCTA ATAC~lllll ACGTAATTGT TTCACCGTAG 15660 GAATTAACTC ACGCATTTTT TCAACCAATT CACGACCACG ATATTGTGAA TTATCTTTAT 157&0 TATCTGCCGC TTGGA~ACGT TTAAAACCGT AATCTAACGA AGCATAACCA CGCGATGTTG 15900 ATTTTA~ACG ATCAAAGAAA TCTAAAACCA CTTCGCCCAT TGGAATTTCA TAAGTCAGCG 15960 -77.11-SU~5TI~UTE 5~tE~T ~RULE ~3 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96105320 AAACAACCCA ACCCACTTCG CCGCATTCTA AAACGGTAGT AT~ll~ll~L TTTGGCGTGA 16560 AAATCCCTAA ACGATCTACG TTATAAGTTT GCC~l~-lGGA CATCACTTTA ATTTTATCGC 16620 TTTTTGCCAC GATTTCTTCT AATACATCTT CGATACCTAC ACCC~1L11A GCTGAGCATC 16800 GAAAGTACGA GTGATCACGT CGC~ll~llG TTCTGGCGTT AAAGAGTTGA AACGTACTGC 17520 GTAACCAGAA ACACGGATAG TTAATTGTGG ATATTTATCT GGA~ A CCGCATCTTC 17580 AACTTGGTCT TCAGCGAATT CGCCTTTTGC ACATAAGCAA CGTGCTTCAT llllllCGCT 17760 -77.12-SUBSTITUTE S~EET ~RULE 26) CA 022l874l l997-l0-2l W 096133276 PCT~US96/05320 CA~ATCATTT TAATATTTCA AATTATTTTA TATTTATTTG ATA~AGAGCA GGTTATTTTT 17940 TTAATTAATT TTTATAAATT TGATCTA~AT TAAAATTCAT TAATTTTTAA ATA~AATTTA 18000 TATCAATAAT TTAACATTAA TTTAACTTTT TATTGAATGA A1~11111~1 TTATAATGAA 18060 TAAAAACTTA TTAATAGGAT A~AATAATGA A~AACTGGAC AGACGTTATC GGAACAGrAA 18120 AAACGATTTA TCCCCCACAA GAAGATGTAT TTAACGCATT CAAATATACT G~L111~AGG 18240 ATGTA~AAGT GGTAATTTTA GGTCAGGATC CTTATCATGG ACCAAACCAA GCGCACGGCT 18300 TGG~1111LC AGTAAAACCT GAAGTAGCCA TTCCCCCTTC CCTATTA~AT ATATATAAAG 18360 AACTCACACA AGATATTTCG GGATTTCA~A TGCCATCA~A TGGTTATTTA GTCA~ATGGG 13420 CACACGCCAA TTTAGGTTGG GA~AGGTTTA CAGATA~AGT TATTGCAGTA CTCAATGAAC 18540 ATCGTGAAAA ACTGGTGTTT TTACTTTGGG GCAGTCACGC ACAAAAAAAA GGGCA~ATGA 18600 GA~'1"1"1'~'1"1' TG~'1"1'~'1'C~j'L CA'L'L'L'1"1'C~A A~ACA~ATTC ATATTTGGAA AGCCACGGAA 18720 TAAAACCGAT AGATTGGCAA ATCTA~ACCA TATATCTCTA A~AAATAACC GCACTTTAAT 18780 CTCTCAaAGT GCGGTTAAAT ATTTCAGTAT TTTAATTAGC CGTGATAACG CCCTACGCCT 18840 AATTCATCTT CTTTACGTGT GCGATTCATC A~'L'1'~'L'1'~'LG GAGATTGCGC AATACGTAAT 18900 ATTTTCACAT CCACA~ACTT ACCGATCATT TCTGGAGAAC CTTGGA~ATT AACAATACGA 19020 '1LC~LL1~AG TACGTCCCGT CAATTCCATA ATAL~L1L~1 TCGATGGGCC TTCAACTAAC 19080 ACGCGCTGCT CTGTGCCAAG CATACGACGG CTA~ATTGTG CCG~LL~L1G ATTAATACGC 19140 TCTTGTAGCA CATA~AGACG ~'L~'L'L'L~'L'L'1' TCATCTTCCG TGACATCATC TGGCATATCT 19200 GCTGCTGGCG TACCTGGTCG GGCTGAGTAC ACA~AACTGA AGCTCATATC A~AGTTTACT 19260 TGTGCAATCA AATTCATAGT TTGCTCAAAA TCTTCCGCCG TTTCACCAGG GA~ACCAACA 19320 -77.13-SUB5 i 1~ UTE S~EE~ ~RULE 263 W 096/33276 PCTrUS96/05320 GGC~ll~lGC GCGAGGTTCT GGTAAGCGGT CAAATTTCTC AATTTCAGGG A~ACTTACGT 19860 CTACGACGGA A~lllllCCA CCACGAATTT GATTAATCAT TTCAGGCAAG CGATGCAAAG 19920 TTAATAATAA TACGTCTGCT TCTTCAGGTG ~llCC~lGAG TTCTAATCCG TGGGTGCTTA 20160 GCGCAAGCAT ATATTTATAA TCAACTACTT TGTCTACTAC ACCGTCA~AA TAGCAGTTAA 20640 GCGC~l~llA CATGTCCGAC TGTTGCAAAT ACGGGTACCA TTGCAGCTAC ATATGCACCG 20540 CATGCGCCTT TG~lllllAG GATATCGTCC CAGGTGACGA TACTTAATAC AATACAAAGC 21180 -77. 1 4-SUBSTITUTE SHEET (RULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 CCGAATAATG CAATTACGAA TAACACGCTG AGTGCTTTTT CACGA~AAGA CATTGGACCT 21300 AA~ L~lA AGC~llllLl CGCAATGGCT TTATTATCCA ~lLllll~AA TTCTGGTGGA 21360 GCTAAGAACC ATTTGATCCA AGTGGTTTCA A~ACCAAGAA TTGGTGCCAT TAATGA~AGA 21480 GCTAAGGCAT TAGGAGCCAT TGCGGTTAAG A~AATATAAG AGGTAGTTTT AACCACCATA 21540 TATACGTTCA TCATCA~ATA ACGCCCTGCT LlLllCGGGC llllll~lGG ATCTGAACCA 21600 GAGGGCGTTG CTGGCGAGAG TA~AAGATCT AAGAACATGG TAACATAGCC TAAGCGTAGG 21720 ACA~ATGCTG AACTCA~AGT GAATGCGGTA AAAATAAGCC Al~ll~lGCC AGATTTATAA 21840 CCATCCAACA TATTGCCGAC TTTAACCAAT l~LllCGCCC CTTCAGTATT ACCGATGATA 21900 ACGCCAGA~A CCGCAATTGC AGCCAATAAG ATAACGGGCT CGCCATAAGG TTTAAGCACA 21960 AGCCCAACGA TAGTGGCGAT ATA~ACACCA AGTAATCGCC AAGCAATCAA AGA~AGCCCA 22020 TCAGGAGCAG GTAGTAAGAA AGTGATCAAT GGGATAGCCA TTA~AATCAC CA~llll~lA 22080 TTTTTGGATA ATGCCATATT AATTACCTCT A~ATGATA~A AAGAAAATTG TTAGTGCTAA 22140 TAAATCAGCA CTACCGCCCG AACTTA~ATT ACGTTCAATG CAGGCGGTAT CA~ATTTCAT 22200 TG~l~LllGC TGTATGA~AT ACAATCCCGC TAAACCACCT CGATGAACCA CGTTAGTGTC 22320 GGAGTTAATT GCCATTA~AT TCAACAACAA AATCAGTA~A CGATGTTCCC ATTCTAACTG 22380 ~l~ll~AGGA TAA'LlllL~A GTTCATCCGT TA~ACCTTGA GTA~ATTGTG CAACAAGTGA 22560 GCAGATTAAT TTAACATCAA AATCTACCGC ACTTTGAACC A~A~lllLll GTGCCAATAA 22620 TCGTCCAATT GCCGTACACA CTAAACCA~A AGAAAAAATA G~1C~L11~1 GG~l~lLlAC 22680 GCCATCAGTA ACTTTA~ACA TTG~LllllC TGCTAATA~A CCTA~AGGAC GAATTTCAGA 22740 GAGAATTTGA TTTTCAGACA AATGCGCGGT CATCATGCCT TTGAGAACAA ACTGCGTA~A 22800 A~AAGGTTTT A~ACTAATCG CACTTTGCTC AAAAGTATGT AGGTTCATAT ~lLl~lGCGA 22860 ACCGTTATTG ATGGCATCCA CTA~ACCAGG TTTTGGCGAT AAGCGAGCCT CTTGTATTAA 22920 -77.15-SUE~5 1 1 1 UTE ~ EET tRULE 26) CA 022l874l l997-l0-2l W O 96/33276 PCT~US96/05320 TGCCAGATAA ACTTGTTCAC CAATATGTTC TGCGA~ATCA TGAl~l~l~lG CGAGAGATTG 22980 TTCTCCGCAC ACTAAACAAG TTCTTGGAGA AAGATCA~AA TCTGTACGAC TCAGTAGATT 23100 GCCTTTAGCA TTAAACACAT CTA~ATCCCA CA~ACGAGCA AGAGGAATAC TTTCTTCCAA 23160 TTCAATCATC AGAACTTTTA GCGTACGAGC ATCTATCGGT AATACA~AAT AGGCTTCATG 23220 CCCC~'1"1"1'~'L AGCGGACGGA TTAlll~lll TACTGCTGTG ATGTTTAACT GAGTAAAAAG 23280 TGCGGTCAGA ~ AGAG ~''l''l''l''l'~'l'AAA AACATAATCC AACAAAGCAT 'l"l''L'l''l''l"l''l'AC 23340 TCCACCCACA GCAGTTA~AG TGATGCAAAG TAAGGTTTGT CCATATTGTG TTATAAGCTG 23400 ll~ll~lAAA ATTGCACGTT CCTCTCGAGC ATTAAGCAAT GCTTCAAGTG A~AllllL~A 23460 ACC~'1'~'1'~'1'A GAGAATGTCG TAAAAAAATG CTGCA~AATT TGACCGCTCT TTTGTATAAA 23520 AATA~ATTTT CTTAACTCTT TCCATTTATA TGGTGCTGGC GAAAGCTGAA AGAGCTAATT 23580 GAGTCCCTTT CAA~l'~lllG GGCTCCTTTC CTGATAATCA TGGGAAGACA AGAGTTAATT 23640 ll~llllGGT TTACCAGTAA TGCTGTAAGC ACGTTCACAA A~ll~ll~AA TAGTA~ACAA 23820 CAATACATTC ACGTTAAATT TAGTGTCGAT TTCTA~AGCA GA~AGAATCA CCATATCTAA 24120 TAAllllllA ATAAGACCAG CCTCATGTAA TGCCACCATA CTTGCAGTAA TTCCGCCAAG 24300 TGCGAAATCT GCAGTGATAT TTTCACGACG CAllllll~l TCTAGAAAGC GTGTAACAGC 24360 TAATGCTGCC CCCCCAGAAC CA~lll~lAA TGAGAAGCCA TCTTTA~AAT AACCACTGGC 24420 A~AAATTACT TCTGCACATT TACGCGCAAT GAGTAATTCG CGTGGATTGG TAGTCATTCG 24480 GGTTGCACCA CCACCAATTT TTTTCGGGTC ACCGACTGCT TCAACTTGCA CGATTA~ATC 24540 TACTTGATCT TGAGCTATGC TGATTGGGTG GTGCGGGTAT TCAACAAATT C~'l'~'l'~'l'~AG 24600 77.16-SUBS i 11 UTE ~HEET (RULE 2~) CA 022l874l l997-l0-2l W 096133276 PCTrUS96/05320 A~lllllCCA GTAAATCCAT TGGCATTACC GAAL~l~l~A CAGCAAGGCA CGCCTAAAAA 24720 ACCAGAAGAA TAGATTTTGG TGACCACGCC ALllll~ATA TGTTCGACAA TCGGGAAGTG 24900 CATACCATCT TTTAAGCCAG AGCGTTTAAT CG~Ll~ll~l AGAGAGGTAC AAAGTTTGCG 25080 AGCGTGATAT TTTTCAATAC ~ll~ll~l~l ~L~lL~L~ATC TTTTTATCTC CCTTTACTCT 25200 TCAATCATTT TACCGTTTAA CGAAACAACA CCAGCCCCTT ~LC~LL~AGC TTCTACTGCC 25320 GCTTCAATAA TGC~LLLLGC CTGCTCCACG ~L~LLLLL~LG TCGGTGCAAA TAA~Ll~L~l 25380 AACAATTCAA TTTGGCGTGG GTTGATTAAG GATTTACCGT CAAAACCAAG ~L~LLLAATT 25440 AACGCAGCCT CTTTTAAGAA GCCTTCTTCA LL~LlCGCGT TAGAATATAC GGTATCAAAA 25500 TCCCCTCTGG TGAACGCTCG ~LLLLlAAGT TACGTACGTA ATCCTCTGCA CCCAATGCGA 25620 ATTCGATTGC GGCTAGCATT TTAGTCGAAC CTG~LL~LCG ACCGCAAGCT TTCTCAATCT 25740 CGACTAATAA ACGAGCAGAA L~lllllCTT TGAGAGCAAC CGCATCTTCT AAGTCAAACA 25980 TGCACGCATT GCAGCAGCTT TTACTCGAGC TTGTAACACG CAATCTAACG CCC~LL1~1~ 26160 -77.17-SUBS l 11 UTE S~{EET tRULE 2~i~

W 096/33276 PCTAUS9610~320 llllll~AGC CAAATGCTTT CGTACTGTAG AAGCAGAAAT AATGTGGTTG CTTGCTGTTT 26520 _ TTCTAGGTAT CTCGATAACA TTTATTTTTG GTGCATTCAT TTCGGCATCC ATTAACCAAT 26580 GA~l~l~llAT TCCCAAAGCT TGAGCAATAT GTAAACGGAA TAACTTCAGA TCAATCTCAA 26700 GAATCATTTC AAAlC~lL~ GTGTAAGAAA ATTGCGATGC ~l~ll~ACCG ACAATAAATA 26880 ATGGATTCGC GTTCATTACA ATCGAGCCAA TTCGATTACC ATCCACACGC Al~ ~lCCC 27000 ATAATGAGCA 1l~lllll~l A~ACGCGTAG CACTATTTTC TAATAATACT ACATAAGGAT 27060 TGCCTGCTAA ACCGCCACAG ACAACGATTT ~llC~llATC ATTATAGCCA ACAACAAAAT 27300 ACTCGATTTG TTCATCTAAT TTAAGCGCAT TTTGATGTAA AAAl~l~l~A ATGAGAGAAA 27360 G TTCAGTAGAA ATTCGCTCA~ ATTGCATCGA CTCTCCAAAA AAGAAGA~AA 27420 TACATTGAAT AATTTATAGG CAATATTGGC GGTTATTCTG AGTTGTA~AA ATAAaCCGCA 27600 GC AAGCA~AAAG TGCGGTTTAA TTTAGCGGAA TTTTAAATTA TTTCACTAAT 27660 c TGTTCA~AGC CCATTTCATT GGCTTTATCA CGGAATTCAT CAAATTCAGT TGGCGGCACA 27780 -77.18-SUBSTtTtJTE SH E~ tRULE 2fi) CA 022l874l l997-l0-2l W 096/33276 PCT~US96/05320 AATAATTTAA GTGACCATTC GTAATCCGCA CCTGGACGAA lLl~lllATA TAAGCGCGGT 28020 AC~llll~lA AATTATGGTT A~AGACATCT GGCGGATTAT CTTTTAATTT CTCTA~AGCC 28080 TGTGTAATGC GACCACGA~A ATCAGGCACT A~AATTTCAA TCTTAATGTT AGGATTAAGC 28140 llll~LGGCT CTTCAGGATC TGGCGGTAAT GGTTTACCGT GAGCCACATC ACAGAATGGG 28320 CAACGGCGCG TACAAATTGC ACCTA~AATC ATA~AAGTGG CTGTGCCATG ATTA~AACAT 28380 lC~l~lAAAT TTGGACAAGA TG~lLC~lCA CAAACAGAAT GTAATCCGTG ACGGCGCATT 28440 G~llllllLA ATAAATCTTG ATTAGGATCG ATATTTTTtA CGGGAATAAT TGAGGTTTTT 28560 GCCGCATCGC GATATTTTAC ACCGCGTTCC ATTTTGA~AG GCGTAGACAT AGTATTTTCC 28620 TA~ATA~AAA TGCCCAAATT GGGCATTTAG TTTTTATA~A ATGTTATA~A ~ll~llATAT 28680 TATAGCCTAA AAGATTGGCG AA~l~lllAA TTAATTTTGC TGA~ACATTA TCGCAATCAG 28740 CTTTATCTTG ATTAACA~AA TCCGCTAACT GACACATTTC AAGCCCTGCA TAACCACAAG 28800 GATTAATATA ATGGA~AGGA TTAAGATCCA TATTAATATT CAATGCCAAC CCGTGAAAAG 28860 AGCAACCACG ACGAATACGT AATCCAAGAG aACAAATCTT TTTTCCATCC ACATA~ACAC 28920 CTGGCGCATC AGGCTTTGGA TAGCTTTCAA TGCCATATTC AGCCA~AGTT TTAACCACCG 28980 ~ ll~AAG TGCGGTAACT AATTGACGTA CATTTA~ATT TTTATGGCGT TTAATGTCAA 29040 GTGTA~AAAC AGGATAATGT TGTACTAACC A~AlllC~lC TTGC~lll~A GCATTTCGAG 29220 TATCAGtA~A ATCCTGCATT TTGTGCCA~A lll~ll~ATA ATCTTGCAAT CCTAACTGAC 29280 GAACGATAAG GGAATTGnTC ATACTAAATA ACCATTTTCA CGCCTTCAAC TTTAGCCAGT 29340 TCTTTATAGA ~l~-L-ll~lAC CTGATCAAAG TTTTCAGCAA TAATATCAAT TGA~ACTGAA 29400 TTATAAGTGC CTTTACTACT GCG~llLl~l TTTGGAATAT AATCGCCTTT AATATATTTT 29460 TGCACCACTT GTATAAGATC TTGTGCTAAC C~l~ C~AT TAATTCCCGC AACTTTA~AA 29520 GTCATTTTTG CTGGA~ATTC CATTAATTCC TTGAGTTTTG CATAATCGTT TTCTATTGTC 29580 Allll~lllC CTA~AAATAA AATA~ATCAA A~AGTGCGGT CAATTTTCAA A'1'1~'1-1'1'11'A 29640 -77.19-SUBS 11 I UTE S~EET ~RULE 2~i) W 096/33276 PCTrUS96/OS320 TGAGAATAAC C~'l"l"l'~'ACAG TCAATACTAA CCAATCCCAT AGTTTACCAA AAATACCCGC 29700 ll~lllACCA GCCTCTAAAG TTTTAAATGT TTCGAAATTA GCAAAACCCC ATTGTAAAAG 30000 L~ ACTT TCTACTTCAC GAC~lll~lA AGTTGGCACA CCCATTACTA CAGA~ATTAA 30060 CC~'1'~'L~'-1--1'C ATTCCATCAA CATTGATAGT TTTATCCCAT AATAGTCCAT TACGGTTAGC 30180 ~l-'l'~'l"l'-l~ATT TTATTAAATG TAAAGTTTTT TTCGGAGTAA ATTTTATATT CTtCAGGTAA 30240 AlC~l~-lAAA CCATGGGGCG TGGTGAAATT TGTATTTTTC AAACCAAATT GTTGAACATA 30360 TTTATTCATT ~l-*l~-lACAA AGTTCGGTAC ATTGCCAGAA ATATGTTCAG CTAATGCAAC 30420 TGTATTTAAA TCTAAAAACA ~llll-lGATGA ATCAGGGAAA TTACGCCCCC ACGCACTTTC 30540 TGGAGTTACG CCAAACTGCA TATCCTCTGC AGATACCGAA AAAGCACTAA GTGCCACA~A 30780 ACTTGATAAA AATGCGATTT l'-l ~-l--l'~'l -l ~''L TTTCAACATA ~l~-l~l-lCCT ACAATTAATT 308gO
TTTATACGTA TAAACAATTA ATGGCTTATT ATTTGCCATT ~ll''l''l~'l-AATT TA~ll~l~AC 30900 TTGTGCCATT ll-'l~'l-l-l'l-~l CATCAAAAGG CCCAATATAA ATTTCATATT TATTTCCTGA 30960 GCTACGAGAG GTTAATTCAA GCATTTTCAA ACAGTA~AAT TCGGTTCCTT TTAGAGCATT 31080 TATTGACTTA GAl~l~ll-AT CAAAAAGTGT GTTAGATTTT AATACTAAAC GATCGGCAGC 31140 'l-l'C~l~AGTT TTTGCTTGTT TAGCCAGTGT ll-L-l~lGGCT GCGCCTGATA AATTCCCATT 31200 TTTAGCAACG TGCAACGCCT CAATTCTTAC CTGCCCTATG CCGCGGGA~A TTAAGCCAAT 31260 ~l"l~llllGCC GCAGCGTGTG A~AGATCAAT TAAACGTTTA TCACTAAAAG GCCCACGATC 31320 -77.20-SUBST~TUTE SHEET tRULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 ATTAATACGT ACGATAACTT TACGATTGTT ATGTAAATTT GTCACTA~AG CATAAGAATT 31380 TATTGGCAAT GTTTTATGTG CTGCAGTAAA L-l~-l-lll~AG TTATA~ACAT CGCCACTTGC 31440 l~lL-llGCGC CCATCAAATT TAAGATGATA ATAACTTGCT AAACCTTCTT TAATATAAGA 31500 TTTGGCTTCA TTCCCACTTT TAGTGGTATA AGTTTGCCCT TTTACTGAAT AA~lC~l-lGG 31560 TGCAGGCATT TGAGTTGCGA TAGA~AGATT ATCCCCTCGA ATACCATACA lLlLl-lGCGT 31620 ATCAGCCTGT GCAGGA~AAG CTACGCTTAT CATA~ATAGC A~AAGTGCGG TCAAATTTAA 31680 CCCAGTTTTT AATTTCATAA AATATTAACG ~-l-lll~ATTT All~lll~-ll TAAGA~AGAA 31740 AAAATGA~AT TAGCTCCTTT TCATA~ATTG ACTTTTATGC GTATGAATAG ACATCAGTAA 31800 ACCAA~ACTT GCCATAATCG CAACATAAGA GGTACCACCA TAACTA~ATA AAGGTAATGG 31860 CACACCCACA ACAGGCAAAA TTCCGCTTAC CATTCCAATA TTCACA~ATA CATAAACA~A 31920 GA~AATTAAT ~ll~-LlGCAC CAGCAAGAAT ACGCCCA~AA GAAGTTTGAG CATTTACGGC 31980 AATCATTA~A CCTCGCACAA TAATA~ACAA GTA~ATCGCC ATTAAAATCA AAAAACCAAT 32040 CATTCCGTGC TCTTCACCCA TTACCGCA~A AATAAAATCT GTATGAGGTT CGGGCAAAAA 32100 TTCTA~TTGT GATTGAGTCC CCTGCATCCA GCCTTTTCCG CTTAATCCAC CAGAACCAAT 32160 CGCAATCTTT GATTGTA~AA TATGATAGCC AGCACCGAGA GGa~l~lllll CTGGGTCCAA 32220 A~ATCCAGCT AAGCCAATCA CTGCCGCTAA AATAAGCCAC CAGCTCATTC CTGCTAAAAA 32340 CACGACA~AT AAACCTGACG CACTGACCAA AATTGATGTG CCTA~ATCAG GCTGAATCGC 32400 CACAAGCAAT GTTGGCAGTA GAATCATTGC AATCGCTATA AAl~lll~AC TTAATTTAGG 32460 TTCAGAGGGT TGA~AACGAA TAAATCCAAG ATCAAGCCAA CGCTGTGCAC CTTTACTTGT 32580 CGTACCAATA ACATCTACCA AGATCAATAA CACAAAACCA ATTA~ATA~A GATAAGGTGC 32640 TAAGACCTGA ATAATTCGGC TATTA~ACAT C~lllCGCTG GCACCTGATG CACTATATAA 32760 CACCAGCATA CCATAAGCAG TTATTGCAAG AAGTCCGATA AACAGCCA~A AATCAATATG 32820 CA~ACGTTGC CA~ACACGCA ACCAAAAAGG GATTTTATCT TCCATTTATT TGTTCGCTCT 32880 CTTGTGACAA A'1-~1111L11 TGCTGAATAG GTACATTATA l-l-l-ll~AACT TGTGGTAAAC 32940 -77.2 1 -SUBSmUTE S~ET tRU-E 2~i~

CA 022l874l l997-l0-2l W 096133276 PCTrUS96/0~320 CGGTA~ACCA AGCGTGATCA TGCAATTCTT TTTTTAAGCC TGCCGTATTA TAlllll~AT 33120 ~lllC~lllAA ACTA~ACACT TGTGCAGTGC CAGATTTCCC TGCAACACGA TAATTTGCAT 33180 CTGCA~AGGC TTTTCGCCCA GTTCCATTTG CAGCATTAAC AACATTGTAC ATACCGCGTT 33240 TCGCTGCCTC CCAAGCTGCC ACTTTAGGTG TATTAATATC AGGATA~AGT AACGGATCTT 33300 CTTGACCAAT CCCAACCGAA ATCGTATCGC CTTGCACCCA AGGGCGTTTA TAAC~LLlll 33480 C~ATTC TCGAGTTGGT ATATTGGCAG CC~L11~11C TTGAATTTCA ATCCCCGTTG 33540 GCATACCA~A ACCA~AATCC TTCATCCAAT TAGA~AGGCG ATCAATACCC ATATTATAAG 33600 CCACTTGATA A~AATAAGTA TCAGAGGATT CAGTAATCGC TTTATTCAAA TCCGTATCCC 33660 CGTGGCCTGT llllllCCAA TCACGAAAAC ~llLl~lGGA ATTAGGTAAT ACCCAATATC 33720 CCGGATCAAA AAlC~Ll~lG TTTGGTGTAA TCACATTTTC A~LlL~lGCG GCTACTGCAA 33780 TA~AAGGTTT GA~l~lCGAA GCGGGCGGAT ACGCACCTTG TGTCGCACGA CTATA~AGTG 33840 GACGAGCAAG ATCATTTAAT A~ACGTTTAT AATCTTCGGA GGA~ATACCA TCAACAAATA 33900 GCACAACTAC AGCACCTTTT AGTCCCGATA A~AGTTCAGT AATATAACGC TGTAATGCCA 34020 AATCAATGGT TAAATGAATA ~lllllCCCG CCACAGCAGG TCGGCTACGC A~AGTGCGGA 34080 TTACTTTGCC GCGATTATTA ATTTCTACTT CTTCA~AACC CGTGGTACCT TGCAGTATAT 34140 ATTTATCCTC lC~lll~A~A CGTTCTACAT CTTTATCATT CATTTTACCT ACATAGCCCA 34260 AAATATGCGC CAll~lllCG CCATATA~AT AATGGCGTTT GA~ATAAGGA CGTACCTCTA 34320 AGCTCGGGTA TTGGTAGCCA TTTACCGCAA AGCGTGAAAT 'l''l'~'L'l'~'L'L~'L GTTA~ATTCG 34380 GCTTTAATAA AATCGGTGTA TAACGCGTTC CGCGGCGACG TTC~LLLLlA AAATTTTCAA 34440 TATCGTTATC CGTCAATCCC ACAATATAGC GTAATTCATC TAAAGTGCGG TCTA~ATTTT 34500 CA~lLlLlLC TGGCACAATG TATA~ACCAA AAAAAGTAAG ATTTTCGGCT AATAATTTGC 34560 CATTAGAACG CGTTTGGTAA GTATCGA~AT TAACAATCTG TAGCTGATAA ATATTGGTGA 34680 -77.22-SU8STITUTE ~}tEET tRULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/OS320 GGTTACGCTC CG~llllllA TCGCGGAACG ~llC~l~CGT TGGTGTATTG AAGAATTTTT 34800 TTA~ATTCAT CTGACTAAAA TAAGGATGTA TTATTCTCGA TGATAAGGAT GATTAGTGGT 34860 TTTTCCACAG GCCGCTAACA TCGCTTTACC ll~ll~ll~l AAAATGCGTT TAATATCAGC 35160 A111111C~A CGCTTGCCTG CTGGGATTTC AATTAGTTCA AAAGGCATAT CTTTTGGGAA 35220 TTTACTAAAA TTTACGCCCA AA~lll~l~l AATTGATACA TTTCACGGGC GTCACGTTGC 35400 TTTCCACGTA CATCAAAATG TACAATATCT GTtCCCTTTA ACCCATCTAA GGTTTCCATC 35640 TGAATACCCT CTTGCGCAAA ATCCACGCAA A~AATAAGCG CGAAATTAAC CGCGCTTTTT 35760 ATGTCTA~AT TGAAATTATT TTTACTATGC TGCCCATAAT AACACTGCCA ATAACTGTGG 35820 ACCGTTATCT TCTTTAATTT CATTCGCAAA TGCTA~AGCG GGAGGwTCCG TCATTGAACC 35940 TGCAAGTAAA CCGCATATTG TGAGGTAATT AA~llllC~A TATAAGCGTG CTATAGTCCC 36000 AACAATAATC AACGGCACAA AAGTGATA~A AATACCGTAT CCCATCCATT CAAGTCCCGA 36060 ACCATTCACT AAAGTATCAA AGAAACTTCC ACCTGATTTT AAACCAACAA CCGCCAAGA~ 36120 TTTACCAATC GTGCCAATTC TCGCTA~AAT CAACGCAACC ACCAATGGCC CGCCAGCAAG 36240 CCCTAATTTT AACGCAACAG GGA~ACCTGG AATATAGAAT GGAATCGAAC CAACGAGTAC 36300 CCCTAAACCA ATACCGATAA ACACTGGTAA CATTTGCACT TGAAGTAATT l~l~ll~lGC 36360 -77.23-SUB5 1 1 1 UTE 5~ET ~RULE 26 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 ACGTGAAATT ACAACCCCAT ATTTTTGATG AATGCCTaAC GCACGGAtCT TTTTGCCTAA 36540 TAn~ ~A nTCGTTACCA CCACACGCTC GGAACGAATT TCGCCACTAT AGGCAACGGT 36600 TGGTGCATCA A~llC~l~lC CGATAATTAA ACGCAnTTTA GCAAGCGAAT TATCATCACC 36660 ATCATCGCGT TTTAAACGTG AACATACGAC ll~ll-ATCG CTA~ATCCCG GAATTTGAAT 36780 CTGCCCTGCC CCCAACGCAG GCGTATTAGT AACAGCACCA GAATA~ATAC CTAAGGCAAT 37080 AATCAAAATG GCAAAGGCAT TTAGCTTTAA ACCAGATTTT CGTAAAGA~G AAAAAAAGCC 37200 AGGTCCAACC TGAATACCAA TAGTATAAAC AAATAAAATC AAACCA~ATT CTTGCACAAA 37260 ATTGACCCCT TAAAAATGAA ATTTAACTCC TTCGGATTAT ATCCAAGTTG LlllllGAAA 37500 ACCTTAACCA AACTCAAAAA ATGATACGTT CGTCACATTT lll~llGCGA AATTGAGCAT 37560 AGCCTCTACA ATACCGA~AA lllll~ACCC TTTTACAAAA AGTGCGGTTA llllL~ACCG 37620 CACTTTTAtC TCGGATGGAA TATTTATGGA TTACAGCCAA GAAGCTATTA ~ll~l~llAT 37680 TTGGATTTTA CAAACGCTAG CCATCACCTC AGTC~~ l AGTTTTGGCA 'l"l"l"l"l'~''L'l"l"l' 37740 GGTGCGTTTT ACCCAATGGG GAAAACAATT TTGGATGTTT GCAGGCGGTT AL~111~ACC 37800 TAAACGTAGC ATTAAACCTA TCTTATTCTT TCTGCTTATT GTTGCAATGA CATTACTTAG 37&60 -77.24-SUB5T~TUTE SHEET tRULE 26) W 096/33276 PCTnUS96/05320 ATGGCTTAAC GAGCAGCTTG TTAATA~ATG GATGGCACAT CGCGCCTATT ACA~AACACA 38100 GTATTTATCA GA~AATCTTG ATAACCCCGA TCAACGTATT CAACAAGATG TGCAATCTTA 38160 TGTAAAAACC ACG~1-11~-1-1 TAAGCACTGG CGTCATTGAT GCGGTCACCT CGATGATCTC 38220 TTAL-1~1-1-1A ATTCGCATTA AAGAATATGC TGA~AGCATT G~1--111-1ATG CAGGCGAAAA 38460 TATATTTAGA ACACTAAAAT TTTCAGGATT TAACCTAGTC GTAAGCCAAA 111~1~11~1 38580 11-1-LC~ATTG TTAATTCAAG TTGGACGTTA CTTTGAAAAG CAAATA~AAC TAGGCGATCT 38640 AATGCAaACC TTGCAAGTAT TTGGTCAGTT ACACGCAAAT CTTTCATTCT TCCGCAGTAC 38700 TTATGATAAT TTTGCAAGCT ATAAAGCAAC GCTAGATCGT TTAACTGGGT l~-l~l-lATGC 38760 CATTGAAAAA GCAAATAATA AATCACA~AC ACAGATCCAC AATCATCCAA CAGATGTGAT 38820 TTTCAAAAAT TTAAGTATTC A~AATCCATT AGGTCATACA CTAATTAAAC ATCTAAACAT 38880 GCTTTTACGC ACCATTGCGG GGCTTTGGAG CTATGCCGAG GGGGA~ATAA ATTGCCCTAC 39000 GCACAATCAG ~1-1-11~-1-1~1 CACAAAAGCC GTATGTGCCA CAAGGAAATT TAATGTCAGC 39060 TAAAGTACAA CTAGGACATT TGGCTGAACA ATTAGA~AAA GAACAAGACT GGACGCGTAT 39180 ~1~-1-11-~1~11 GGCGAACAAC AGCGTTTGGC GTTTGCACGA TTAATTCTAC ACA~ACCAGC 39240 TCAATTGTTA CAACAAGAAC TACCACA~AC GACAATCATC AGTGTGGGAC ACCGTTCAAC 39360 CCTTAAAACC TTACATCAAC AACAGTTAAT TCTGCAAGAC A~AGGGCAAT GGCAAGTGCT 39420 ~1--111~-1ATGT TTGACAAAGT CA'1-1-11-~1AC 1111-1~-1~AA ACA~AACTAA CTTTCATTTT 39540 AAACGGTATA ATTATGTTAT TTAAAAAAAT TCGTGGGTTG TTTTCAAACG AL~-1--11~-1AT 39600 ACC~1~-1~11 GTTGCGATTC GTCAAGATCG CGTAGGCACA TTAAAAAGCA TTGCAGCTGT 39720 -77.25-SVBST7TUTE S~{E~T (RULE

-CA 022l874l l997-l0-2l W 096/33276 PCTAUS96/0~320 GGGTA~AGAA GCTA~ATTAA TGTTAGGTCG TACTCCCAAA AGTATTGTAG CAATTCGTCC 39780 GATGAAAGAT GGCGTTATTG CAGACTTTTT TGTGACAGAA A~AATGTTGC AATACTTTAT 39840 CA~ACAAGTT CATAGCGGTA ATTTTATGCG TCCAAGCCCA CGTGTATTAG TATGTGTGCC 39900 AA~ ~-ll-A AATGGTATCG TATATTCTTC TTCCGTGCGT ATCGGTGGTG ACC~l-ll-C~A 40140 CGAGGCGATT Al-l-l~ll-ATG TTCGCCGCAC TTTTGGCTCG GTTATCGGAG AACCTACCGC 40200 CGAACGCATC AAACAAGA~A TTGGTTCTGC TTATATTCAA GAAGGTGACG AAATTAAAGA 40260 AACTGGTGGC GGTGCTTTAT TACGTAATAT TGATATTTTA ~-l'-l'-l-~'l'AAAG AATCTGGTGT 40500 CCCTGTTATC ATCGCAGAAG ATCCATTAAC ~l~-l~-L-lGCT ~lG~lG~lG GCGAAGCATT 40560 AGAAATGATC GATATGCACG GCGGCGATAT TTTTAGTGAT GA~ATTTAAT CAGAATATGA 40620 ACAAAAAGTG CGGTTAAAAA TAACCGCACT TTTCCTTTCA ~lLll-ll~AT TCAACAAGAG 40680 A~AGTTTAAT GA~ACCCATT TTCGGCA~AG CCCCTCCCCT AGGTATTCGT CTGCTTATCG 40740 CTATCTTTGC ATCTATTGCC TTAATTTTAG CTGATGGACG TAATAGCTCA ATAACGA~AG 40800 CACGTAGnnn AATGGAAACG GCAATAGGCG GTTTATATTA TCTTGCA~AT AGCCCTAGA~ 40860 AAGTCGAAAA TCAGCGATTA C~l~llllAT TA~ATTCTCC GTTAAGAACC GATGAATACA 41040 GGCATACCGA TGAACTAAGC CTCGATAACG TGCCTCGTTC CGTTGATATA GA~AAAGGCG 41340 Al~ll~lCGT AACCTCTGGG CTTGGTGGAC ~'l"l''l"l'~"l"l'~A AGGCTATCCC GTAGCTGTTG 41400 -77.26-SUBSTITUTE SHEET ~RULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/OS320 TACA~AGCGT TTCACGTGAT AGCTCTAATT ACTTTGCAAT AGTTAAAGCT A~ACCTTTAG 41460 AAGCTAATGA AGCAAATTAT AGAGTGAAAA A~ACACCCTT AACAGAAAAA GA~Lll~lAG 41640 A~AATGAAGA AAAAACCATT ATTGAACCAG ATATTCCAAC AGALLLL~L1 CAAAATGAAG 41700 AAGATCTTCC CATAGAACAG CAAGAAGA~A GGATAGAAGA CTAATGCAAA CACGATTTAT 41760 TTGGCCAGTT GGTTTCCA~A TGCTAAAGCC TGCGTGGCTT GTACTTGTAT TACTTTATTG 41880 GGTATTAGCT ATTCCCAATA AAGTAAGTAT AGG~1G~L~A TTTTTACTCG GATTAACTTG 41940 GGATTTAATA TTAGGCTCTA CATTAGGCGT TCACGCTCTT GTA~11L~1A CGAGCATGTA 42000 CATCATTGCC AAAAACTATT TAATTCTGCG A~ATTTATCA CTTTGGTTCC A~AGTTTATT 42060 GGTTGTACTT 'LLC~L~11~A TTATAAGATT ACTTATTTTC TTAGTTGAAT TTTCACTCCA 42120 TACTGCCTTT TTTCATTGGC AAGCCATCTT GGGCGCATTC G~1L~1G~LL TACTATGGCC 42180 GTGGGTATTT TTATTAATGC GCAAAATACG CAGA~AAGTT A~ATTACATT A~AAAAGAGA g2240 GATAACTCTC T~LLLLLLAT GATTTATGAA 1~L1L~A~AC ACCTAATTCA ATGGCTTATT 42300 GCTATCCAGT AAAGAATCAC ATTCCCAACC GATATACTCT CCCGA~AATT GTTCAGCCAA 42360 L1LLL~AAAA C~1L~1ACTT GTTCA~AAAT TTCGCTATTT TCTAATGAAA 'L'LL~LlGCTC 42420 TTGTAATGTC GTGAAAGAAT AATCCCCTAA ACTAAGCTCA TCCATA~AAG GGAACATTTT 42540 CTG~L~LL~A TCAAAATGAA AACTATGCTC TACTAAATAG GTATCACTTA AATTACGACC 42600 TTTACTTTTT AATA~ATCAA GCAATTCTTC CGTTGCATTT AACTTAATCT CCAATGGAGA 42660 AGCGAGCAAA AAGTCA~AAT AAGTATCCCA AATTA~ATCC TTTTGCACAT TAATATCTTT 42720 AACAAAATCA A'LL1~LL~1A AAGTTTCTAC AATAAGATTT TCATGCTTAC AATAAAAATG 42780 TATTTTTATT TGAGAATTAC AAATA~AATG CCCCGCAAAA AATACATTTG GAAGTGCGGT 42840 TA~L1~L~1C AAAATTTTAA ATACACGGTT AATTAACTTA TCGTATTCAA CTTCTGAGGG 42900 TA~ACCCGTT TCATCATCAG CCTGATAATC AATAGTA~AC TGCACTATTT TATCGAGACC 42960 TTTACCGTGA TA'LL111~AA CATCTTCAAT ATTTGCGGTA AACACGGCAG GCATACCATT 43020 CACAGTAGAA CGATAATTCT GCCAATTTGC CATATCCATT TCGCTTTCCT ATTTA~ATTC 43080 -77.27-SUBS 111 UTE S~{EET ~RULE 26) CA 022l874l l997-l0-2l CACATCGACA CAlC~ll~AG CTAATTTTTG GCTTACCAAA ATATGATCAA TTCGTAAACC 43200 TGGGTTCAGC TTACGAAAAC 'l'~L~'l"l~l'AA TCCGTAATCA TACAAACGTT GATACCACGC 43320 C~ll~llCC GGTAAGAAAG AACATTTCCC TGTGCGTAAC CAACGTTTAC GATTTTCATC 43380 ATTCGATTTG 'LC~'l'~'l''l'~'l"l' TTTCTA~ATA ~l~ll~AAGA TCTGCATAAA ATTTCTCTTT 43500 AGCTGGAAAT TTA~l~lC~l GCGCACGGCT TTCCCCCTGT GGGAAATAGC CATTAATGAC 43560 ATTGTCAGTT GGA~AACCAC GACGAATCAC TTTAGGTTCT TGTTTAGTCA ATAATGCCAC 43680 GCCATAATGA C~lll~l~AC CGTGATGAAA TACGTGATAA CCTAAGTTTT CTGTAATTTC 43740 ATAGGGAAAA GC~lC~l~AG CAACTTTAAT llC~l~lAAG CCAATCACAT CTGGCTGATA 43800 'l''l''l"l"l'~'AATA ATGGCTTCAA GTTGATGTGG GCGAGCACGT AACCCATTTA TATTGAAAGA 43860 AATAAATTTC Alllll~llC CTATTAAAGA GTGAAATTGG CTTTATTATA CAGAGATTTC 43920 AATTCCAATT GAGTAGCGTG CAAATAAGTG CGGTCAATTT ~ TTTACCATA~ 44100 AGCCCATCGC CTAAAATCGG GCTACCTAAA ~llLl~ATCG CAACACGTAA TTGATGCGTT 44160 AAACGCGTAA TTGCGGGATT ~'l'~'l"l''L'l'~'l"l' TGGCAAAGTT TCCATGCGCC TTCTCGAGCT 44280 ~ l~ATAT CCCCGATAAT CAAACCTTGT 'l"l'~'l''l"l''l''l'AG GCTTTTGGTT ACTTAATGCC 44340 GCATTTAACG CCAGAnTTAA CA~ACCCGAA GTTACTTTAT CTAAGCGATG AACCAACCAT 44460 ACTTTAGGCA CATTCAGTTG TTTTGCAACA A~ll~l~llA AG~ll~llC TTCTTGATCT 44520 TTATGAACGC TA~TACCCTC AGA~ll~llG ATAATAATAA AATCGCTATG TTGATAAACA 41580 CTTTTACCGA ACTAAGTAAT TC~l~ll~AA TATGTGACAG TTTTGGTTTT TCGTTTAATT 44700 -77.28-SUB5 111 UTE ~EET tRULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 CCATTCTTAA CAATCTAATA CGTGnAAAAT ACCCTAATTC AATCCCATAA ATTTCAGCAA 44940 TCTTATTCAT TAATCGAAGA TTGCGCCACG CAATnAAAAA CATATCCACT ACAGCAAGTG 45000 AAGATTTTGC AATATCTAAG CAAAGAATTT TA~-Ll-l-lllC TGCGTTATGA ACGGAAAAAA 45240 CATCACCATT TTTTACCGCA ~L-l"l~lAACC AAATCTGCTG A~L11~11~1 TGCCATTGCT 45300 CAC~-L-l-L-l-L-l TA~ACGAACT AAACGTCGCC ACTCACAAAT AAL~l~-L-l-lA ATACCCAATA 45360 ATTTTAATAA A~'1-11-1-1'~'1'A AAACTGGATT TTGGTTTCAA TG~ll~-ll~A AGTTGAGCAT 45540 CAAGTAACTC TCCGTCCAAC GCTTCATCTA GCTTTGCTTC CATATTATGG AAnTCTTGCT 45600 TGGGCTGATA ~'L~'ll'~-L-LCC TCTACATTAA CTGAATGTTC A~AAATTTGT TTTTCCATTG 45660 TTCATCACTT GnAAAGATAG AAAGTAATCT TAATAAACTC AAGAATA~AT TGTAGATTGA 45780 AACATAGATG TTCACGGTTG CGCGAATGTA A'L-L-L~L'L'L~'L CCACCGTGAA TAATATTACT 45840 GGTTTCATAC A~AATGGTCA TTGTTGAGAA CACTACA~AT AATGCACTAA TTGCGACCGA 45900 TGCGAACATT GCGCTTGATA AGAATGACAT A'L~'L-L'L-LL-LC GTAGTCAATA CATAAGCGGA 46020 ACGTGCCACA TACATATTTA AAATTGGCCC GALG~-L~LAT CCCATA~ATC CAGTGAAAGC 46140 AAAGGCCGCC AAAATACCAG CAGGGCGATC AGCTAATTTA TTGGTTAAGA A~AGTAAGCC 46200 AAAAGCTCCT TGTAAAATAA ATAAAAAGTC LL~-l~-LAAAG TAAGGGCTAG GGATAAAAAA 46440 -77.29-SUBS 111 UTE SHE}~T (RULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GTCAATGGTA TTAATGGAAT TAATTTCATC A~AATGAATA AATTATCATC ATCTAAAGTT 46500 GTCTGAATAT CGCTATCAGA CAATTTTCCT TCTTTCACAA ATTTTACTTT TCCC~llllG 46800 TTATCATCTA ACACAACTTG GCTATGTGGA TTTTCCTGTT TGC~llllll CGCACCATTT 46920 TTTACAAACA TACCTGTACC AACAATCGCA TCATCCGCAT TAATAATAGT G~ll~lll~G 46980 TATTTTACAG GATTAAAATG GGATGCTTTT ATCACATCAA TCATCGACTG ATTTTnCTCT 47040 ACTTTGACCG ATGGTAAAGA ll~ll~lAAT TGCAAATTGT GTGCCCAAGT TGAACTACTA 47220 AATATCACGC CACAAACTAA GGCAAGAATT l~llLlllCA TACATTTTCC TCAAAAATTT 47280 ATCAAAAACT TTeACGCTTT G~CGAAA~AC A~l~lllllGC TATACTCGTG CGCCTATTAT 47340 ATGTAATCAA GAAGGAAAAC CCAATGGATC AAATGCCTAA TTGCCCAAAA TGTCA~AGTG 47400 TGCTTGCAGA AGGCGACAAT GTACTTTTGA TTA~AGATTT AAAATTAAAA GGTTCATCAG 47580 TCGATTGCGG CAAAATCATG TTGAAATCTG A~lllll~AA A~AGGCTTAA TCGAAAAAAC 47700 GCG~l~lAAA TAGACCGCAC TTTGCACTTT AAAGAAATAA ATTTATTTAA TAATATCAAT 47760 CA~ll~l'~lG ACTAATCGTC CAATTTCATC CCAATTATTG GATTGAATCA A111L11~1C 47820 TTTAATCATT TTCACTCCGC CTGAAGCCTC TGCAGGGAAA AATTTTACCG CCGA~ATTCC 48000 -77.30-SUBSTI i UTE ~E~T (RULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TCCGCTACTT TTAGCTA~AA CTA~11~11C CGCAGTTA~A ACTGTGCCCG CAGCAATTAA 48180 A~AGTCAGGT CTATTTGCAC GCAACA~ACG GATCGCATCT GCCGCTGCTT CAGAGCGA~A 48240 AGTAATCTCT GCCACAGATA AACCATTTTT AGCCAACGTA TCTGCTAGCG GCA~AATATC 48300 11~11~AGTT GTGTATGACA 11LL1LLAAT TTGCTCCTAT TAGACTCCAC TATACGCAGA 48420 AAAACCGCCA TCAACAGGTA A~ACCACGCC ATTGACA~AA GCAGAATAAT TTTCATCTAT 48480 TAAGAAAAGT AATGCACCGA GCAATTCTTC TGACTCACCA A~ACGTCCCA TTG~L~l~ll 48540 AGTGAGGATT TTATTTGCTC TA1~1~L1GG TTTTCCTTCA GTATCA~ATA ATA~AGCGAG 48600 ~111L~ATTA CTAACTAAAA ATCCTGGTGC GATAGCATTA CAACGAATAC CAA~ L L LC~A 48660 GA~ATATACA GCAAGCCATT GAGTA~AATT ACTGATTGCA GCTTTTGCAC CAGAGTAAGC 48720 AGGAATCTTT GTGAGTGGCG TA~AGGCATT CATACTGGAA ATATTAATAA TATTTGCCCC 48780 'LL~LL1ACCA AGCATATCTT TTGCAAAAAC TTGGGTTGGT AATAATGAAC CTAAGTAATT 48840 GAGATTAAAT ACAAATTCTA TACCAGATTT ATCTA~ATCA AAGAATGTTC TTGTCGTTTC 48900 ATTTAAATCA AATTGATGGA ACTCATTATC 1~LL~LCGCT TTTGGATTAT TCCCACCAGC 48960 ACCATTAATT AAAATATCAC AAGTGCCAAA ATCGGTTTCA ATTTGATTTC TCA~LL~Ll L 49020 AATATTTTCA AGTTCTAACA CATTAGTTTT ATAGGCTTTT G~LL11C~LC CTGATTGGTT 49080 AA11LC~11L GCTACTTTGT CTGCAGCCTC GAAATTCA~A TCTAACAAGG CAATATTAGC 49140 TTTAGTATAC GCTAATTGCT TAGCGAGA~A TGAACATAAC ACTCCGCCAG CCCCCGTGAT 49200 TATAATTAGT TTA'1LL1~LA AGTTATGGTT TGCTGCAATA TTCATAGTAA ACTCCATTAA 49260 TTA~ATTCAG ATTGAAGATG AGA~ATTGCG ACTTTATCTA TAATCGCACC TTTATGTTGA 49320 A~ATAACCGT TCAGA~ATCC AGCATTAAAA GAATCACCAG CCGAGGTTGT ATCCACTACA 43440 GCACCATTCT TACCGCACTT CACAATCACT 11L~1ATAC CAATTTTATG TAATCGCTCT 49560 AAAGTATCCC TAGATGTTTT ATCTTTCCAT AATGCTTGTT CATCATCA~A AGTCACCAAC 49620 GCTATATTGA CACTAGGCAA AAGCTGCA~A TAACAATCTT GTG~11~1LC TAATGAATCC 49680 CA~AGTTTTG GGCGATAATT ACTATCAAAA ACAATTTCTG TGC~L1LLL1 AGCTA~AGAA 49740 -77.31-SU~SmUTE ~E~ tRULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/0~320 CTTAAATA~A TCACATCAAC TTGCTGAAGT TCTGCAATAA CCTTAGCA~A ATCCGGATGT 49860 TGAACCATAT AACGTGCTGC AGATTGATTA CGCCAATA~A GGAACGTGCG TTCGCCTTGA 49920 AGTTCAATCA TACACTCGCC GATAAATGCT All~lllll~A TGATGTAACT TCCTAATAAA 50220 TCAAGATAAC CAATTCATTG GAACAATTAC AATTTCAGGA A~AAATACGA TCAACATCAT 50280 AATAATTGCG TACACA~ATA AGAATGGAGC AATTCCTTTG GATAATGCTC CTATCCCTAA 50340 AGATA~ATTA ATCACCATCA TGATTCCA~A ATACGCAATA TCAATATTAT ATGCTCTTAA 50460 AACAAGTAAT AAAAATAGCA TTATAATA~A CATTAAAATT GTCGGACTAT CAGTTAATCC 50580 TTTAATCGTT TGGACTAATT ~l~llGGAAT TTGAGCAACT GTAATCGCAA AAGCAGATAT 50640 ~ATT~e~A~ GCAGCAACAA ACATTACCAT TGAl~l;l;~ll~ TTGATGGTAC CAATGAAGAC 50700 ~l~llllAAT TTAGA~AATG TTAAGCCTTT ATAAGCAATA CTTACTATGC CAGCATA~AT 50760 AATGATAGGT AATAATAAAG GCCAAAATGC llllllAAAA GCAACCCATC lll~lllGCC 50880 A~lll~llll ~lll~lAGAC TTGTATCATT ATTTCTATAC A~AATTTTCC AAGTAACCCA 50940 AATACCTGCA GCACA~ATTA AlC'~l~lGGA ACGAGCACCA TCATATTTTT TAGAAATCAT 51120 CATACTTGTT GCAAAATTAA TGATTCGCTC AGA~ATTCCA CCATGCTTCA TTATTTCTCC 51300 AGTAAGCATA AAGAAAGGAA TAGCCATCAA AGGnAAATTA ll~llCCCA TCACAAAGTT 51360 'll~l~lAATT AATTGCGTAT CAAACATATC AAGATGATAT AGCATAATAC TCGCACTCAA 51420 CAGCATTGAT AGTGCTACAG GTACACCAAG A~ATAACAAT AAGAATAAAC TACACAAAAT 51480 -77.32-SUBS 111 UTE S}~E~ tRULE 76 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GnAGATATAC CTGTAGCTGG CAlll~llGA GTATAGGTCA AAGACATCAG TTGTAATGCA 51660 TTGGCnACAA GTATAATCCC A~AGnAAATC ATATATACAA AACA~ATCCT AGAAAACTCT 51840 TCAGAAAATG CAATTCCAGA ATCAAAGAAG TACCTCAAGA CAGAATTA~A AAACACGAGA 51900 GAAATCATAA TAACTAATGC CAAGATAGAA AGATATTCTA ATG~LlL~lC TA~ATACTTT 51960 GCTATTTTCA TAAAACAAGC TC~''L'L~'L'1"LA TCCCCCATGA GCAATTTATA AAATTGAACA 52020 TAGGGGATCT TATTAATTAT TTAGCTTCGT TAAlLLLL~LG GACTACATCC TTAGCCCAAT 52080 CATATTTTTT ATA~AAACTA TCATA~AGCA CCTTAGATGC ATTCACCATG TCATTTTTAA 52140 A'L'L~'L~'L'L'1"L AATTGCTAAT TCCCACTCTT L~L~LL~ATA CAATTTAGCT G~LLLLL~AA 52260 A~ATAATTTG A'L~'L'L~'L'L'L'L GGAATTTTAT TCCAAGTTTT TAAGCTAATT TGTAATAATC 52320 CTTTAATTAA CATATACGGA ~L~L~L~L~L~AC CATCAATTAC ~'L'L'L'L~'l''L~'L AATGCAGTAA 52440 A~ACTTCACT GAGCGGCATG ~lLL~LGGAT TTATATTCAT TGCTTTAGCC CAATCAACAA 52500 A~AGTGAATT CAGCGGAACT CTTAAACGTA AACCTTTA~A ATCGTCA~AT lL~L~LAATT 52560 TTTTATTAGA TGA~ATAACA CGA~ATCCAT TCATACCATA GGCAAGTAAT TTAATTCCAT 52620 ACTTCTCCAT LLlLl~ACCA ATTTTATTTG CGATTGGAGA TTCCAATACT TTTTTAGCCT 52680 CTTGATTATC CTTA~ATA~A TAAGGCCATT CCCA~ACTCC AAAAATAGGA TCTACATTTT 52740 GATCTTCACC GCCAAGTTGA TTATTAGGAT A~AGTCTAAT CTCATATTTA TGA~LLl~Lll 52860 CATTTTCAAT 'L~'L'L'L'L~'L'LA AAATATTCCT GTAATGCAAT ATGTGATGGA TGAATATCAG 52920 TTA~L~LLLlL TAGAAAACTG CATTAATTTT TAAATAATTT TCTGGATGAT CAGATAAATC 53100 AGA~ATAAAA CTAGGAATTT CTTCA~ATTT GATACACTTA GTAATGATAT GAGATGCATT 53160 -77.33 -SUB5TITUTE S~E~ (RULE 26) CA 022l874l l997-l0-2l W O 96/33276 PCTrUS96/OS320 AATTTTATTA GTAGCAAGCA TATCCAATGC CTCCTCAAAT TCCCCCTTGC ~ll~ll~LAGA 53220 ACCATAAATA TTCAATTCTT TA~AGGTAAT TA~ATTTGTT GGTAATGGAG 'L'l"l'~'l'~'l"l''l''L 53280 TGGCCATCCT GTTAAAGCAA TTCTTCCTGC A~AGGAGGCA TAATGCAGAG TATTTTtGAT 53340 AGA~ATATTA GCACCAGATG CCTCCATAAC AACTTCAGCC ATACGACCAC TTGTAATTTC 53400 AACCGCTGCT AATGCAGCCA TTAATCCAAT TGCACCAGCT CCAATAATTA CTA~ l~llC 53580 CCCTGATTTT AAA~ll~lLC TATGTA~AGC GTGTAAAGCT ATTGTTAAAG GTTCAGCTAA 53640 AGGTAATTGA TGAATCGGTA GGTTATCTGG GACTTTAGTT A~AAGATGAG CGGGATGTCT 53700 ~ CGGGA TAAGGCACTT CTTTAACAAC TACATTGTTT G~11111~1A AACATATTGC 54060 TTATGTTTAA CTATGATATG ATTATGAAAC ATAAAAACTC TTTTTGGAAT ACCA~ATATC 54180 TA'lllll~lG AGCCATATCA CAAA~ATAAA AAATTGGAAT ACCAATTTAA GGAAAAATAT 54240 AAGTAGTATT GCTGAATTCG CAGCGTTACA AGCGACTAAA AAAGATATTT TAAATTTA~A 54600 CAAAGATTTT CATTTGGCAC TTGCAGA~AT TACACA~AAT GATGTGTTAG TCAAATTACA 54720 TTTACA~AAT GATTATCATC ATTTATGGAT AGAAGATCAT CAAACAATTT TATCTGCTAT 54840 -77.34-SUBS~T~UTE S}~E~ ~RULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TCAAAAGA~A AATGCTAATG AAGCTAGA~A AGCTATGTGG CAACACTTAG A~AATGTAAA 54900 AGTA~AATTA TTTGAATTAT CTGATGTAGA AGATCCACAT TTTGATGGAT ACCTATTCAA 54960 TACAAATCCA ~~ ~lAG GTATCTA~AT ACTTGTAATA ACATAGGAGT TA~AAATGGA 55020 ACAAGCATGG CGTTGGTATG GACCA~AAGA TC~1~1L1~1 TTATCTGATA TTCGTCAAGC 55080 AGGCGCAACT GGTATAGTCA CTGCACTTCA CCATATTCCT AACGGTGA~A TATGGgGTAT 55140 TGAAGAAATT AaAAAACGCA AAACTGAAAT AGAAAATGCT GGTTTAAGCT GGTCAGTAGT 55200 GGA~AGTGTA CCAGTTCATG AAGAGATTAA AACTCAGACT GGAAATTATC AAAAATGGAT 55260 TAATAACTAC AAACAAACTC TTCGCAATCT TGCTCAATGT GGAATTGACA ~l~lllGCTA 55320 CAATTTTATG CCAGTTTTAG ACTGGACTCG AACCGATCTT GCTTATGAnT TACCAGATGG 55380 AC~lC~l~AT GCAGA~AAAA CCTATAATCA AGAAGAACAA GTTGCAGCAA GAACCTATTA 55500 TATTTCATCC GA~AAATTCC GTACGCATTT GGCTTATTTT TTA~ATGAGA TCGTACCTGT 55680 AGGCTTACCA CGCATAGTTT CAACTATTGA AGATATGCAA TG~lll~lAG A~ACTCAACC 55800 ATTACCAGCA AATGGTTTTA CAATGTGTAC GGGTTCTTAT GGCGTACGTt CCGATAATGA 55860 l~lC~lAAAA ATGACTGAAC AATTCGCTGA TCGTATTTAC TTCGCTCATT TAC~ll~LAC 55920 TATGTTTAAT GTAGTA~AAG CTTTATTA~A TGAAGAATAT CGTCGATTAA ATCAAGGAGA 56040 A~AAACCAAC CCTGGCTACT CTGCTATTGG TCGGTTAAAA GGTCTAGCTG AATTTCGCGG 56160 TTTAGAGATG GCATTAAAAA AAGTGTATTT CAATAAGTAA AAGA~AAAGT GCGGTCATAA 56220 A~AACATTAT TTTTATCGAC CGCACTTCTA ATTTATTTCA TCAATCTTCT CATTCGAATA 56280 TTGATCATCT CGACCACAAC AGAGAATCCC ATTGCA~AAT AGATGTAACC TTTCGGGATG 56340 TGAATATCCA AA~lll~lGC AATTAAACTA ATTCCGACTA A~ACCAAGAA AGCTAAAGCT 56400 ATCACCCCCA CGGCAATCAT A~TCGCCA~A ATCATCACAG GAAGGTGGCT TGCCATACCC 56520 -77.35-SUBSTJTUTE S~E~T tRULE 2f~i3 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96105320 ACCGCTGTAA TGACAGAATC TA~AGaA~AT ACAATATCTA GCACAGCAAT TTGAATTAAT 56580 ACGCCAAGAT AACTCACTTT ~LllLlGCTT TCAGATTCAT G~L~ll~llG ATGATTTATC 5~640 GC~L-lllAA TTTCGCCAGA A~LllllATA ATCAGGAATA AACCACCGAT TAATAAAATC 56700 AAATCACGCC CAGAAATTTC TTGATTA~AC ACAGTAAATA ACGGTGCAGT AAGTTTCATT 56760 ATCCACGCTA GtGaCATTAA AAGTAAAATT ~ll~llAGCA TTGCCA~AGC AAGCCCAAGA 56820 ATACGACCAG ACTGGCGTTG GCGTTCAGGT AAACGTCCAA CTaGGATGTT AATAAAAwTA 56880 ATATTGTCGA TTCCTA~AAC GATCTCTAAA GCCGCAAGTG TCACAAGTGA TATCCACGCT 56940 TCAGGATCTG CAATCCATTC A~ACATAATT TTTCCTATAA TTGAGTTAAA TA~ATCCGAA 57000 TGATTAGTCG TTTTTAAGCG TTTCAAAAAT CCTTTCAGCA AGTTTAGGGG A~ATGCCCGG 57120 CAGTAAAGCC TGACGACGTT TAGCTCCCAC ACCTTCAATG ~LL~L~LA~AC CA~lll~l~l 57240 AAAGGCTTTT TGAC~Lllll TACGGTGTCC GCTTATTGCG TGATTATGGC TTTCATCACG 57300 GAL~l~ll~A ATCAAATGCA ATGCCA~ACT ATCATCAGGC AAATGAATTT CGCGGTCTTG 57360 ATTTAATTGC C~L1~1 1~AC CATCAATAAA AATAATATCG GGAATTTTAT ~Ll~ll~lAA 57540 ATCACGCTCA TAAC~Lll~l GCAACACTTG TTCCATCGCA GCATAATCAT CCCCGCCAGT 57600 AGALl~lllA AGTTGTACAT TTAAAGCCGC TTTAGCATTA ACTTGTGCGA GCTGTAAGTA 57840 TTTACTTTTA TCGC~LLL~A CG~LLl~LlG AATCGTCACT TTTCTGCCCG CTTGCTCGCT 57900 GATACTTCGT CCTTGATGAC CTTGTAAATA A~ATTGCCCC ACAAAAGTTT CGGTAAGTTC 58020 CGATAAATCC GTATTGGCGG GGACTTTTGG GA~ATAACTG CGATTGCCTA GCACTTTTCC 58080 TTGACGAATA AACATCACCT GTACACAGGC TAACCC~L~L TGGTAAGCGA TAGACATAAT 58140 ATCCATATCA TCTAAACGTT CATTGGATAC AAALl~llll TCTATAACCG AACGCACAGC 58200 -77.36-SUBS i 11 UTE SHEET ~RULE 2h~

W 096/33276 PCTrUS96/05320 CATTTTACCG ATTAAATAAT CTAACACCTG TtGATCTTTG CCTTGTAAAA ATAAGCGAGC 58320 TAATTCAACT TGCTGATTAT ATTCTTCATC GGA~ACATAT CCCTGTACAC AAGGTGCAGA 58380 ACAACGCCCA ATTTGATACT GCA~ACAAGG ACGAGAGCGG TTGGAATAAA CGGAATTTTC 58440 ACATTGGCGA ACAGGGAAAA ~Ll-LlLGCAA AAGCGATAAC GTTTCACGCA CGGCTCCCGC 58500 GTGAGGATAA GGCCCAAAAT ATTCACCTGC AAALlllllA GAACCACGAT AAGAAGTAAT 58560 TCTTTGGTGG C~Ll~lLLGG TTAATAAAAT A~ATGGATAG GATTTATCAT CACGCAATAA 58620 TACGTTATAA CGAGGCTGAT AAAGCTTGAT AAAATTATGC TCTAGCAGTA AAG~LlCC~l 58680 TTCAGATGAA GTTAGCGTGG TGTCAATATG ATGAATTGAC GCCACCAACG C~ L~ 1 ~ L 111 58740 TTTACTGCTC AGATTTTTAC GAAAATAGCT TGA~AGACGT Ll~lllAAAT CCTTTGCTTT 58800 CCCAACATAA ATAACCTGAT CTTTATCGTC ATACATAcGA TAAACACCAG GTTCGTGAGA 58860 GACATCAGTG AGGAATTTTT TAGCATCA~A CATTTTAATT CGCCGCTAAA ATTGCCCGCA 58920 ~LllllCCAA ATCTTCGGCG GTATCCACCC CCACTGCAGG CA~Ll~lLLC GCAAGTTCTA 58980 CGTGAATACG TTCGCCGTTA TATAACACAC GAAGCTGCTC AA~LLLLL~L AGATTTTCAA 59040 CAATATGACG TAAGTAAGCG TCAGAAAGCT GTA~LLL~LG AACATCCTGC AAATTCATAA 59160 CAAGGCTTGC CATATTGACA TTAAATTTTG CTA~ATTATC TGCCACTTGT CGCACGATAA 59340 TACAGACTTC AGCACCA~AA CTTTTGGCAA CATCAGCCAC ATTTTCATTA TCGGTGGCAA 59520 TAATCACTCG GCTCGCCCCA GACTGCAGTG CTTTCTCA~A TACATGTTGA ATCATTGGCT 59580 TACCTTTAAT ATCAGCAAGA GGTTTTCCTG GCA~ACGACT TGATGCAAAA CGAGCGGGGA 59640 TAATCACGGT AAATGACATA ATTTATTCCT TALLCLLlAA TATTTCAGCT TTATCGGCAA 59700 TCTATTTTGG CCCAAAAGTG CGGTAAATTT TCAC~LL~LL TTTCAGCCTC AATAATCTCC 59820 -77.37-SUBSTITUTE ~FET tRULE ~

CA 022l874l l997-l0-2l W 096t33276 PCTnUS96/05320 GCGTCCATTA CGACAATTTC TA~ATCACGT TGTAATTGAT AATGCTGCAA ACCATCATCA 60300 CCACGAGAAA TCACACCTAC ACGCAGACCT C~lllllll~ ATTCTTCCAT AAGCCAAACA 60540 GGTGCGCGAT AAGAAGACTT CAGCCCCA~A GAGAATAAGG CGCGACGAAG TTGGCTAATC 60660 CCAllll~l~l CAAGCAATGT TTTATGGTTG CCACGCTCAC GAATTTCTCC GTGATCAATC 60900 CGAL~lll~l TTAATTCCTC TAATGCAGAT TGGATTGCTC GTTCTGATTC CGTATCTAGT 61020 GCAGATGTAG CTTCATCTAA AATTAATACT GGCGAATTAC GCAATAAAGC ACGAGCAAtC 61080 AaAACTTGCG GTAATTTTTC GATAAACTCT AAAGCATAAG CCGCTTTTGC TGCAGCGATA 61200 ATTTCTTCGC GAGAATACTT Al~Ll~lGCT GCATAAGCAA TATTATTCGC AATAGTATCG 61260 TTAAATAAAT GGA~ll~LlG AGA~ACCACA GCGCAGTTTT CACGTAAATT AGATA~ACGA 61320 TAATCTTGGA TATTTACGCC ATCCAGTA~A ATTTCGCCTT GCTCAATATC GTA~AAACGT 61380 TTTCCAGCTG GAACGCTAAA AGA~ATATTA TTTAATGCAA GTTCATCTTT TCCTTGATAT 61500 -77.3 8-SUBS 111 UTE 5HEET (RULE 2~) CA 022l874l l997-l0-2l W 096133276 PCTAUS96/0~320 TCAl~-lLlll CTGGCTCTAA ATCTA~AATG GCA~ATAGCG TTTGACATGC TGCCATTCCA 61620 CTTTGA~ATT GTGCATTCAC CGCAGTTAAT GATTTTAACG GACGCATCAT AGCTAACATT 61680 GAAGA~AATA CCACTGTA~A TGAGCCTGCA CTCA~ATTAT CTTCTGCAAT CAATGGAGTG 61740 GTAGCTA~AT AGAGCACCGT AGCTAATGCG AGAGATGCAA TAACTTGCAC CACAGGATCA 61800 GA~ATGGAAT TTGCTGTCAC CATTTTCATG ~-lllllC~AC GCATATCATT ACTAACATGA 61860 TTA~AATGCA ~ll~llCCAC ATGTTGCCCT CCGA~AGAAA GCACAACTTT ATGACCTTTT 61920 CTACGAAAAA ~llllL~ATAC CA~ACGAATT A~AACAGCAA TGATTGGACC TATAATA~AA 62040 G~lC~ll~lC GCACAATTGT AATCA~AGAT CCTGAAGAAG AACTTGCAAT CATTTGGGAA 62160 TCATAAGTAA TCCGAGA~AG TA~ACGCCCT GTTGAATTTT GATCA~AGAA ACTCACTGGC 62220 CACGCCAAGC AATAATTAGA AATA~AGTTG GTAATGCCGC GTA~AATAAT CATCCCAACG 62340 ACGACA~AAG CCATCATTTT CAAAAATGAA lG~lllGCCT TACCA~AACC A~lC~lC~AAC 62400 AACGGTTTTA ACAAATA~aT CAAGCCTGAG TCAGCTAATG CATTAAAAAC TAACGCGACG 62460 CCAGA~ACAA TAAGCCCCGC TTTA~AAGGT TTAATCATTG GCCACA~ACG CTTAhACGTT 62520 TGTAAGGTTG A~AAATCATT ll~l-l~lAAT TTTTGCTCTT GCATAATCGC TATCTAATAG 62580 TA~AAATTGC ACGCATTGTA C~llllATTC CTTTGATAAT CC~ATTACAC GCGCATACCA 62640 AGGGGAAAAT TTTGTGCGAG CTTGCTGGAT TTCTAATCGG TCTTGA~AAA AATTTACCCG 62700 cACTTGCCCC GA~ACAGCGG TAllLl~lAC CGCACTTTTA TAGCGATGAA GCCTTTCCAT 62760 AACCGAATAA TGAGGGAATT TCCACGGATT CCAACGCCCA CTAGA~ATAA TCGCTACATC 62P20 TGGTCTAACc TGAGAAAGCA AGTATTCACT TGTCGATGTT TTACTCCCAT GATGCCCCAC 62880 TTGCAACACA TCGATTTTGC CTA~AGTGCG GGCA~AAATT TGCTCATTTT TTGCTTCAGC 62940 ATCGCCAGTT AGCAAAACGC TAll~lllCC ATCATCGACT A~AATCACAC AAGAATGGGA 63000 ATTATCAGCT CGTGTCACAA C~ll~l~AGG AGA~AGTATT TGA~AATGCA ACCCTTGCCA 63060 ATGCCAATCA CGCCCAGCAG TACA~AAAGT GCGGTAATTT TCCCCATAGT TTTTCCGTGA 63120 AGGGGTAATC AATTCCACAT TGGGATACGC CTTTA~AATT GTCGAAGCAC CACCTGCGTG 63180 ATCGTTATCG TCGTGGCTTA A~ATCAATTT TTCCA~AACA ATC~ll~lC TTTGTA~ATA 63240 -77. 3 9-SUBS 111 UTE S~EET (RULE 2~) W 096/33276 PCT~US96/05320 TACCTGCCAA GTTGGCTTGC TCAATTGTTT A~ACAACA~A ATCGTAAAAC ACAGTAAGAT 63420 TGCTAAATTA AATGAAACCG TGAGCCAATT CCCTTGAAAA ACAGA~ATTA ACCCAGTAAT 63660 LC~llCGGCT AG~Ll~lllG CTAGTTGCCA AGAAAACATT GTGCCGTTAG TAAAAACGGC 63720 AAATAAAATT AATGGCACAA GCA~AAAACT ATAAATTGGA ACCGCCATAA AATTGGCTAA 63780 AAATCCACTC AACGATAAGC CATTAAATAG AAAAAGTTGC A~AGGTGTAA AAAAGAGCAA 63840 TAACCCA~AT TGCAAATGAA ATA~ACTAAA AATCCACCGC ACTTTTGGAG A~AAAGGGCG 63900 CGCTCCACAA GAAAGCCA~A AACTGACCGA AAGCGGCATT AATGGATCGC AGAAAAGCAA 64020 AAATAAAACG A~AACAAGTG CTGAAATGGC ACGAAAAGTT GGCACACTAA AACCAGCCAA 64140 ATACGCATAA ATTA~AGCAA ATAAAACACC AAAAACTAAA GGAAAATAAG GATGAATAAA 64200 ACGCGTAGGA AAGAACACTT GCACAACACG CGCCAAGcAA AATCCAATTC CCATAGCCAA 64260 CCCAATATGT AAGCCAGAAA TAGCAATAAG ATGTGCGGTA LlG~LLL~Ll GGTA~ATTGA 64320 TAGAGATAAT CCTTCCGTTT G~LL~111AC TTGTTGCAAT LlLl~lGCAC GCAATGATGA 64440 AACATCCGCA ATTTTCACCG CA~LLLLL~C CGTTCCAACA GCCGTAATTC CTTTTGAAAA 64500 AATTTCAGCT TGCCA~ATTT CCGATAATTG AGGCACCTCT TTCGCTTTCC AATTTAAGAA 64620 AAll~lL~l TCTTGCAAAT TATTCTCCAA TGTTGCTGTG GCGATAAGCG TTTGATAATC 61680 CTGTTGGTGC AAAATTTCTT GAATCTTA~A AGTTACCACT TG~LllLGAG CGGTAATATT 64740 TTGAGCTTGT TGTGATAAAC TCAAAGCCGA ATAATGA~AA TAGCCAAGAG AGGCAACA~A 64800 AAAAGCAAGG CTAACTAAGA AATTTCTACG CAAGAAAATA AAAAGA~AAA TCA~AACAAG 64860 -77.40-SUBS 111 UTE S~EET ~RULE 26) , CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/OS320 TA~ATCCGCG ACAATTAACA AGACAACTAA AGTTATTAAG TTTAATTTCA TTTTTATAAA 64980 AGATTAATTC CAGC~L~l~l AAGCCTAGGC TAGTTTTATT TAAATATGCA AACGGTTGCT 65040 TCAAATTTTG CGATCCATAT CGTAAAAATA AALll-LL~AG GAAAATTTAC TTGCTAAAAC 65100 AAACAACTTC TGATATTTAT ACCGCCCGCA A~AATTGGGT TCCTA~AATA GCAGTCAGGA 65160 ACA~ACTAAA ATAACAAGAC AGGAAGTCGT GAAATCCACG CTTAATTCTG TATGTATTAG 65220 CAAATGAAAA AAGATGAAGA ATATATGAnT GAnGAGCA~A lL~LL~ATTT CAGA~AAATT 65340 AAATTAACCG CA~LLLl"llG CATTTAAAAA TGCAGGA~AA TCCACTTGCC 'L'l"l"l"l'~'L'l''LA 65760 CAAGAAAAGA GCCAAGTCAT TTATTTCCAA CAACA~AACG GAGTAAATTA TTCTTACTTA 65820 TATCAAAAAT LL~LlLGGCA AGAAGACAAA A~AATCAAAA GAGGTTGCCA AAACAAGTGC 65880 TCATTCTAAA CGAGTTGAGC GTTCTAATAG CCAAATGCCA AAAGCGCGAG CA~AAAAATC 65940 AGAACAAACA CGTCGCTATG ATAAAAATGT GATTAAAGCG GCTCAATTTG ATALLl~lCC 66000 GCGTGATTTT AGCCGTAATG CTCTCAATGT AGTGGAAAAA CTGCAACGTC AAG~lLLL~A 66060 GGCTTATATC GTCGGTGGAT GTATCCGCGA TTTATTGCTC GGTAAAAAAC CA~AAGATTT 66120 CGAGGGCATT AAAGATCTCA AAGCAGGCAA GCTACGCTTA ATTGGCGAtC CTGTTACACG 66480 ~lLC~lL~AA AAACCGAGCG AACAACCAAT TCGTGrACTT GCGCCTTTAT TA~AAAATAT 66600 -77.4 1 -SU8ST~TUTE S~EET tRULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TCCGCCAGCT CGCTTATTTG ACGA~AGCTT AAAATTATTG CAGGCGGGAC AAGGGGTAAA 66660 ACGGATGAAC GTGTTGCGGA TA~ACTTCGT ATTAATCCTG CATTCTTATT TGCAGCATTT 66840 GCACCACGTC GTCATACTGC GGTCATTCGT GACATTTGGt TCTTACAACT GCAATTATTA 67020 GATTTATTGG CTATGCGAGC AGA~ATTGAA GGTGGCGA~A CCATTGAATT AGCCAAATGG 67140 CGCTTACATC CTAAACCA~A GAAAAAATAC TACCGTCCAC GCC~lC~lAA AACAACGTGC 67260 TGGTAACAAC GAG~l~llll TATAAAAGCA AACCGCTCGG CCCACAAGAT CAACCCGATT 67440 TAGATTTAGA TATTTTGCTC TACGGCAATG A~ATTATTCA A~ACGAACGC TTAACAATTC 67620 CCCATTATGA TATGCATAAC CGTGAGTTTG TCATTGTGCC ~ll~lLl~AA ATCGCATCGG 67680 AAATGATAAA ATTAAATCCC TAGA~ATTTC ACCGCACTTT TATGAACCTC AAAAGTGCGG 67800 TAGAATCAGC CCACATTTTT CTTCATTCAT GACCCGTTAT GGA~AGTTTG ACTCAATATA 67860 TCCCTGATGA Allll~lATG CTCCGCTTCG GCAAAAAATT TGCCGAAATT CTTTTAAAAT 67920 TGCATACAGA AAAAGCAATT ATGGTTTATC TTAACGGTGA TCTTGGGGCA GGA~AAACAA 67980 TAGTGAATAT TGATTATTAC GATGATGCAC GAAATATTGA ATTAATCGCA CA~ACAAATT 68280 -77.42-SU8ST~TtJTE SHEET (RULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS9610S320 TGGGTAAAAA TATTATAAGC GCA~ ~lA ATTAACTTAT TTATGAAAAC TAAAATTTTA 68340 'lllllC~lll llll~l~AAC GTTTAGTTTC TCTATTTTTG CAGCACCTAT TACGATTGCG 68400 GAAA~AAATG TTACCCTTTC AATTGCA~AA GAATTAAAAG CCTTATTAGA TAAAGATCCA 68520 CATTTTCGCG GTGTATTAAC GCGTA~AAGT GATTATTATA TTTCCGTGCC AGAACGTTCA 68580 TCACCTGATC GTCGCGGGGC ll~l~LllGG GTATTGTCAA ACCGTCGAGC CAATGATGAA 68700 ATGGGTCAAT GGTTAGAAGA CGATGAAAAA CGCTCGGAAT TACTTGGTGG AGCGGGA~AG 68760 CATAGCCAAC GTACAGGCTA l~l~llAGGC GAACATATTT TGCACCATTT TGCTAAAGTA 68880 ACAACATTAA GTCGCAGTAC GCCACAACAT GCAAGTCTGG ~l~Ll~lACG TTCGCCAGAT 68940 AllC~ll~lG TGTTGGTAGA AACTGGATTT CTTTCCAATT CAGAAGAAGA AAAAAAACTT 69000 CATAGCGGTA AAACCAACAC TTTAGTTAAA GACAATTTAG TGCAAAACAT CA~ACAAAAC 69120 GATATAAAAA AATCAGGGAA A~ATAACCGC ACTTCAGAAC A~AATATA~A TGAAGATAAT 69180 ATTAAAGACA GTGGCATTCG CCATATTGTA A~AAAAGGAG AAAGTTTAGG TAGCTTATCA 69240 AATAAATATC ACGTA~AAGT CTCTGATATT ATTA~ATTAA ATCAATTAAA GAGAAAAACA 69300 CTTTGGCTAA ATGAAAGTAT TAAAATCCCT GATAATGTCG AGATAAAAAA TA~ATCATTA 69360 ACAATTAAAG AAAATGATTT TCATAAAAAA CA~AATAGCT TAGTA~ATAA TACCAATA~A 69420 GATTTAAAAA AAGAGAAAAA TACACAAACT AATAATCA~A AAAATATAAT TCCGCTCTAT 69480 CATA~AGTAA CAAAAAACCA AACACTTTAT GCTATTTCGA GGGAATATAA CATTCCAGTA 63540 ATAAAATTAA GAGA~AAATA AATGCCTATT A~AATTCTTT CCCCACAACT TGCTAACCAA 69660 ATTGCTGCTG GAGAAGTGGT AGAACGCCCT GCATCAGTGG TA~AAGAATT AGTGGAAAAT 69720 AGCCTTGATG CAGGTGCAAA TAAAATCCAA ATTGATATCG AAAATGGTGG GGCA~ATTTA 69780 CGACATGCCA CGAGTA~AAT AGCCGATCTT GATGATCTCG AAGCGATTTT AAGTTTAGGT 69900 lllC~lGGCG AGGCATTAGC TAGTATCAGT TCCGTATCAC GCCTAACCCT TACTTCTCGT 69960 -77.43-SUBS i I I UTE S}{E~ tRULE 2~

CA 022l874l l997-l0-2l W 096/33276 PCT~US96/05320 ACCGAAGAAC A~ACTGAAGC GTGGCAAGTT TATGCGCAAG ~1C~1~ATAT GGAAACCACA 7002D
ATCA~ACCCG CATCACATCC TGTCGGCACA ACAGTTGAAG TCGCCAATCT llllLl~AAc 70080 ACACCAGCCC GCCGAAAATT TTTGCGCACA GATA~AACAG AATTTTCCCA TATTGATGAA 70140 GTCATTCGTC GTATTGCTTT AACGA~ATTC AACACAGCAT TTACATTAAC GCATAATGGA 70200 AAAATTATCC GTCAATACCG TCCTGCCGAA GCAATCAATC AACAACTA~A AC~1~1CGCC 70260 GCTATTTGTG GGGATGATTT TGTCA~AAAT GCCTTACGAA TTGAGTGGAA ACACGATGAT 70320 TTACATTTAT CAGGTTGGGT GGCGACACCA AATTTTAGCC GAACTCA~AA TGATTTAAGT 70380 GCCTATGCAC AATATTTACC AACCGATGCT TATCCTGCGT '11~1~11~11 TATTGATTTA 70500 AACCCGCACG ATGTAGATGT CAATGTTCAT CCAACCA~AC ATGAAGTACG CTTTCATCAA 70560 CAGATTAATT GGCATACAGA CCA~AGTGCG GTAGA~AATC ACGAAGA~AA TACGGTGCGT 70680 GCGCCACAAT ATCATGA~AA ACCACAGCAA AATCAACCGC A~L111~1AA CACACCAATG 70800 GA~1~1L~AT CACATCTACG AGCCCTTTCA CTTATTGA~A ATCGTGCGTT GTTATTACAA 71040 CAGAACCAAG A111~11111 GCTTTCATTG GAAAAATTAC AACGCTTGCA ATGGCAACTA 71100 ACCGAATCAC AATTTCAAGC ATGGCAACAA TATTCAGATG ACTTCA~AAA AATTGGCTTT 71220 CGCACACA~A ATCTACAAAA ATGCGTGATG GCAATGCTGA CTAGAGATGA A~ATTCATCA 71340 TCATTTTTAA CCGCACTTTG CGCACAATTA GAATGCA~AA CCTTTAACGC TTTAGCGGAT 71400 GCACTCAATT TATTGAGCGA GACGGAACGT TTACTCACGC A~ACAAATCG CACAGCATTC 71460 ACCCAATTAC TCA~ACCTGT TAATTGGCAG CCTTTATTAG ACGA~ATTTA AA'11~11~AT 71520 GA~ACCAACC GCAATTTTTT TAATGGGCCC AACAGCCTCA GGTAAAACAG ATTTAGCCAT 71580 -77.44-SUBS i i I UTE SHEET (RULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTtUS96tO5320 GGGAATGGAT ATTGGCACAG CGA~ACCATC A~AAGAAGAA CTTGCCCTTG CGCCTCACCG 71700 TTTAATTGAT ATTTTAGATC CATCAGA~AG CTATTCCGCA ATGAATTTCC GCGATGATGC 71760 GCTACGCGAA ATGGCGGATA TTACCGCACA AGGCA~AATT CCGTTACTAG TGGGCGGCAC 71820 GA~1~11~1AT TACA~AGCCT TAATCGAAGG GCTTTCGCCC TTGCCTTCTG CTGATGA~AA 71880 TATTCGCGCC GAGCTTGAAC A~AAAGCAGC TCAACAAGGT TGGGCAGCAT TGCATACAGA 71940 CAATCGCGCT TTAGAAGTTT TTTACATCAC AGGA~AATCA CTCACAGAGC TGACTGAAGA 72060 1~111-LGCAT GAACGCATCG AACAACGCTT TCATA~AATG ATTGAACTAG GCTTTCAAGC 72180 AGAAGTGGAA A~ACTTTATG CGCGTGGCGA TTTAAATATT AATCTGCCGT CAATTCGCTG 72240 TGTAGGCTAT CGTCA~ATGT GGGAATATTT GCAAGGTGAT TACGCTTACG AGGA~ATGAT 72300 LllCC~lG~l ATTTGCGCTA CGCGCCAACT TGCAAAACGC CAGCTTACTT GGCTGCGTGG 72360 TTGGA~AACA CCAATACAAT GGCTAGATAG TTTACAACCT CAACAAGCGA AAGA~ACTGT 72420 ATTACGTCAC TTAGATTCTT ATCA~AAAGG TTAGA~AAAA TGACCGCACT TTCTGCCCTC 72480 ATCGAACA~A AATTACAATC TCTTGGCACA A~1C~1~LGCC AA1~1111CC AGAACTTTCC 72540 CCAGAAAAAA TTCACGAAGC CATTCAACAA AATTCA~ATC ATCCAGAACT GC~L~lllAT 72600 CAATTAGGCT ATGCCATAGC AATGTCTGAC TTTGTGGA~A AAGTCTTGCA A~AATACCCG 72660 CACTTAGTGA AACAATGGTG GGA~AAATCC CC~1~L1--L-LG CAGATTGCAC TGCCTATATT 72720 GAACGTTTGA ATAAAGAGTT AGCCAATGTA CATGACGA~A CTG~-L~-L~1A TCA~ACATTA 72780 CGCCAATTCC GTAACATTGA AATGGCA~AA TTAAGTTTTT GTCA~AGTTT GAATCTTGCG 72840 ACAGTTGAGG A~A'1--L-L-L1~1 TCAGCTTTCA CAACTTGCAG AGAGTTTAAT TATCGCTGCC 72gOO

AATCCGCAGC AGCTTTATAT TCTAGGAATG GGGA~ATTAG GCGGCTTTGA ACTA~ATTTT 73020 TCCTCAGATA TTGATTTAAT TTTCACTTAT CCATCACAAG GGGA~ACGTC CGTTGAGAAT 73080 ACGAATGCTC GAC~L-L~1~1 GGATAATGGA AAALLLLL-1A CACGTTTAGG GCAACGCCTT 73140 ATTTCTGCCT TAGATGAATT TACCTCTGAT G~LLLL~LAT ATCGAACCGA TATGCGCTTG 7~200 -77.45-SUE~5TITUTE 5~E~T (RULE 2~i~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 CAAACAAAGG ATCCCAACGT TTCAAAATTG A~AAAAATGT TACGCCCTTT TGTCTATCGC 73380 CGTTACATTG ACTTTAGTGT GATTCAATCT TTACGTGA~A TGA~AGGCAA AATTGAGCGA 73440 GAAGTACGCC GTC~lG~lll GA~AGATAAT ATTAAACTAG GTGCTGGTGG TAllC~l~AA 73500 CAACATTCAC TCTTAAAGAT CTTGCCTGAA ATTACCA~AC TAAGATTAAT TACCGAACAA 73620 GCCATTAACG ATCAACAAAC GCA~ACACTA CCAACCGATG AAATAGATCA AAllC~lllA 73740 GTCGAGGCAT GTAAAACTTT CAC~l~LllA AATGA~AATA ATCAAACCAT TGAAAAACAT 73800 TATCCAATAG A~AATTGGGA CGATTTTTAC CGCACTTTAC AACAAAAACA AGAAAAAGTG 73860 CGGGCAGTAT TTACTCAATT AATCGGTGAT GAACAAGATG A~l~llCACA AACTGATAGC 73920 CAATGGCAAG AlLlLllAGA AGCAGATTTT GAGGATATTG AACA~ACATT ATTAGAGAGT 73980 GTACTTGCAC TCATTTTTGA ACAAGA~AAT TACCGCACTT TGCTTCCGCG GATTCTGAAC 74160 ATTATTGA~A A~ATTTCGAG TCGCACGACT TATTTAGAAT TATTATTGGA A~ATCCTCGC 74220 GCACTTCAGC AAGTTATTGA A~lll~LGCG CAGTCTCAAC TTATTTCAGA ACAATTGGCG 74280 GAACAGCTTA TCGATGCTTT ACGTCAATTT AAACAAGCAA CCCTATTA~A AGTGGCAGCG 74460 GCAGATATTT TAGGTGCATT GCCAGTAATG A~AGTAAGCG ATCATTTAAC CTATCTTGCT 74520 GAAGCCATTA TTGAAGTGGT TGTGAATCTA GCTTGGA~AC AA~lllC~lC TAGATTTGGT 74580 GTACCTGAAC ATTTACAAAA TAACGA~AAA GGATTTTTAG TTAllG~llA TGGAAAACTA 74640 GGTGGTATTG AACTCGGTTA TAAATCCGAT TTAGACCTCG TA~ l~lA CGATGCCGTA 74700 GAAAGTCA~A CAACAGGTGG CAAAAAAGTG ATTGATAGCA ATCAATTTTA CCTACGCTTG 74760 -77.46-SUBST~TUTE ~t~EET tRULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TCTGCATCAC GAGATATTGA ACAATTA~AA CAAGATGTTG TTGAGATGCG GA~AAAAATG 75060 TTTGCCCATT TATCTCACTC A~AACACAGT GAATTTAACC TTA~AACAGA TCGCGGTGGC 75120 CAACTAACAA AATGGTCAGA CAATGTACGT AllLlC~ATG ATATGGCAGA GGCTA~AATT 75240 ATTAGCCA~A CAGACTGCGA CACATTA~AA CAATGTTATG TCGATTTACG CAATACCATT 75300 CATCATTTAA ALll~llGGG TA~ATCTTCC GTTGTGGAAG ACAGTGAATT TGTTA~AGAG 75360 CGGTCATTTA TTCAAGCATT TTGGGATAGG TTATTTGTAT CCTA~AATAT GGCTTGTGGA 75420 C~Lll~AAAA ATAGCCTTCA TCACA~ATCT TCTTGA~ACC TCCCA~AAAC TA~ATATTCA 75480 AATTTCACTT CCGCCCAAGA GTCTTGCCAA CGCAGGTACA CGTTCAGCTT GTGA~AGTGC 75600 GGTCATTTTT GTTTCAGTTT TATTATCAAC AGTA~ATTTT TCCACATTAA ACTGATGATG 75660 TTGACGTA~A AGTTTTCCGA CAACACTTGC L~lllllCCG CTAATGCCCA CGTCCACTTC 75780 ATCGA~AATT AAGGTTGGAA TAGCCGATTG ATCAGAAGTT A~AACTTGAA TGGCTA~AGA 75840 ATTACTACGC A~AGTGA~AA TCACATTATC CGCACCATTT GCACTCACTT TATCTA~ATC 75960 CGTATTCAAC TCTACATA~A ATTCAGCGTT TTCCATTGCA A~Ll~LlllA TCGACTGTGT 76020 TGCTTGCATT TGTTCA~ATG ~'LC~'l"l"L'l"l'C TTGCTCAATC AACATCTCTT CACTTTCAGA 76140 AAAATCTA~A AGTGCGGTTA ATTCTGCTTT TAA'LLllllG TG~L~ll~lA CAAGATCTTC 76200 AGGTTTAACT TGATGTTTAC GAGCAAGTTG TA~AGTCTGA CTAATTCTTT GTTCGATTTC 76260 CTGTA~AAGC TGAGGATCTT GCTCGATATT ACTTGATA~A TTTTGCACTT CACTGGTTGC 76320 AAGTTCAGCT AATTCATCAA TATATTGTGT CGCACGATAA AGCA~ACTAT CGATATTTAC 76440 GGTGTCATTT TCACTTA~AA TTTGTAGGGC TGATTGGGAA AGTTGAGTTA G~L~llCGCT 76500 GCTAGATA~A CGACGTTGTT CAl~l"l~lAA TTCCA~ATAT TCATTTGGTC GAAGGTTA~A 76560 TTCATCTAAC TCATCCACTT GATACTGTAA AA~Ll~lllA CGTGCTTCAT TTTCCGCCAC 76620 'l"l"l"L'L~'L'L~A AAGGTTTTAA CTTGATTTTG AAGATTTTTC CA'L~L~'L~AT AATCTTCACG 76680 -77.47-SUBSTITUTE ~t E~T tRULE 2 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 CATTTTCACA AGTAATTCAG GATGAGCGGC A~AATTATCA ACTAACTGAA GCTGATAGTC 76740 AllllllAAC AATAATTGAG AAGC~l~llG CCCATTAATA TGAACGAGAT ATTGAGCAAT 76800 ~ llAAT TGAGAAGCGG ATACTGGTGT ACTATTAATA AAAGCCTTAG AACGTCCGTC 76860 CTCACTCAAC CAGTGATAAG CAGGATTTTG CGATTCTAGT TGGA~AGTTG CACAAATTTC 76980 CGCACGCTCT TGCCCTTCAC GCACCATTGA G~lll~lACT ~lll~lCCGA AACATA~ACC 77040 TA~AGCATCA ATGGCGATAG AllllC~AGC ACCAGTTTCC CCTGTTATAA CAGACATTCC 77100 A~AGGATTTT TTACAGTATT TTGTCAAATC TATTTCAATC GAAAATTTTT ACCATAATCA 77280 A~ATGATTTT AACCAACCTA ATTTGCTACT TAACACATTG TAATAATTAT AATTTTCAGA 77340 GGTAAGGTAA TTTGACTATC ACAGCCCACT TCTAATTGAG AGGTATTATG TTCAGCA~AA 77460 AACATTGGCA CTAATGCAAT GGCATTAAGG TTTGGTGTCA A~ATAGGTCC ACCAGCGGAA 77580 AGAGAATAAG CCGTAGAACC TGTTGGAGTA GA~ACAATTA ATCCATCAGA ACGTTGAGAA 77640 AATGCAAACT TATCATTGAT ATATACGTGA A~ATCAATCA TATGTGCAAT TTTGGCGGGA 77700 AGCTGGGAAT AGGCATTTTT CGGGTCAATA TCCGTTAAAA ATCCCA~ATT ACCACGATTA 77880 TCTCCACCAA TCACAATGGC TAATTGGGCT CGGTGGCCTA ~lLl~ll~LAA CGTAGCAAGA 78000 TGTTCAAAAG GTAACTCAAG TGTTATGGCG A~11~111L1 CCACCAACAC TTGATAACCA 78060 CGTTCCATTA ACCAATGAAA TAA~LllllG TGCATTTGTA AGTTAATATC ATTGCGAGGC 78120 TTACCTACAA GAGCAATGGT TTTA~AGGAA CGATATA~AT GATTCATA~A ATGACCGCAC 78180 TTGAATTTAA CAllllC~lC ATTATATCGT TTTTTGCTAC ACTATGCCCA ATTACGATTA 78240 ATCAATTTTG TTTTACGGAG AAAAAAATGT CAGAACAAGA ACA~AAAGTT GA~ATCCCAG 78300 AAGTAGAAAA GCAAGAAGAA ~lC~ll~lGG AAGA~ACACA ACAAGCAGAG CATTCTCAAG 78360 -77.48-SUBST~UTE S}tEET tRULE 2 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 AATTTGATCC TTTAGAAGAA GCAATTGCTC GCGTGCAAGA GCTTGAAGAG CAGCTA~AAA 78420 CTCAAATAGA AGAAGCGGCA AACA~AGAAC AGGATATTTT ACTTCGCTCT CGTGCTGA~A 78480 TTGA~AATCT TCGTCGTCGT ACTGAACAAG ACGTAGAAAA AGCACATA~A TTCGCCTTGG 78540 CAGCAAATAA AGAAGATGAA AGCGTA~AAG CCTTATTTGA CGGTGTAGAA CTAACCTTAA 78660 AAGAATTAGT TTCAACCGTT GGGC~-L-1--1-1'G GCGTGGAAGC TGTGGGAGTT GTCGGTGAAG 78720 ATCAAATTAG C~1C~LATTG CAAAAAGGCT ACACCTTA~A TGGTCGAGTC ATTCGCCCAG 78840 CGATGGTAAT GGTGGCAGCT TAATTTACAT ~L~1-L~-L~1A~A GAGCGGTCGG ~L-L-L'l' L ~GACC 78900 ~-1-1-L-L'L'L~-1--1' TTTCCTGAAT AACTACATAA ACTTTACGGA TAATTTCCCT AAAATCTTCG 78960 ~'LC~'L'L~'1'AG CCCAATCTAG AAGATCAACG CGCCACGGTA AATCTGATTC AGA~AAAGCT 79020 TCCTTTAATC TGTCACGAGC TAAAAAATCT A~AGGTTCCT CAGAGATAAT CGCAAGGTCA 79080 AGATCGGAAT A~LL1L1-LLGC TTTTCCCTTT ACACGAGAAC CGA~AGCCCA CACGGTATAA 79140 TCAGGTACTA AL1~1-L~LAA AATAGTTTTC ACAATCGCCA A~LL~LL~AGA TTTTATATCA 79200 AGCTGTGCAA AACTAGTCAT ATTGATTTCT CTGACGTAAT TGTTCCAATA GGA~ACTACT 79260 TTCTATTA~A AAATCATCAA TTTGTGCATA AACAGCCATG G~1-1-1-L-LC~-L GATCATAAGT 79320 ACCAAATCTC AATGCTTCTC GCAAAATATC CTTA~ATCCA TAAGCCCCAA TGTCATCGGT 79440 ATTAATTGCA 'L~LL~L1~AA GTTGGCGTTT CATCATTTTT A~ACTTAACT CATA~ACA~A 79500 TTCA~ATTTC TGAATTGCAC CTGCAATTAA GGTATCTTGT ACAATAGAGG GTTGCATATC 79560 A~ACCAATTT ~L~L~1~A~A TTTGTACTAC GGTTTGCTCT AACGAATA~A ATGCAGCATC 79620 TAATACATTT A~ATTTAGCT TATCAGTCAT CATTTTTACC 'L~1~LLA~AT ACTCATCTAT 79680 TTTACCATAG ACTATTTTTT CTCAAAACCT ATAACCCCAA AAGTA~ACAT TGTGATATTG 79740 ATCACAAAAT CA~AAATATT TGAGA~AAGC TCTCAACAAC TTAATTTGAT A'L'1"1''1'-L~'1'AA 79800 TAAAATCAAT CTTTAACA~A ATTATCTTAC GACA~AAAGG TCTAAAACAC TACATATTGT 79860 ~L~-LL~ATTA 'L~1LL1LAGA TCTATATATA GTGCAATCCG CATTTCAAAA ACACTATATA 73920 TTGGAGCTAT ATCATGAGTA ACTTTGGGGT CATCAAGCGC GA1G~1-L~-1C GTGCGGAGTT 79980 TGAGATTCAA CGTATCATTA ATGCCATTAA AAAAGCCGCA AGTnCGGTCA ATATTTCCGA 80040 -77.49-SUE~S 1 i i UTE S~EET (RULE 26~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TGAATTTTAT TGCCACCAAA TTGGGCAAGA AGTAGGGAAT GA~ATTTTCA CCCGTCATCA 80100 AGGCGAGATT GATATTAATC AGATTCAAAA AATCGTTGAA GATA~ATTGA TGGCAAGTCG 80160 AAAACGTAGC CAGCTAACAA AAGA~ATTGA AGGTTTGATT GAACA~AGCA ACGTAGAATT 80280 TAACTGTATG TTAGTTGATT TAGAAGGGAT GCTTTCTCGT GGTTTCA~AA TGGGCAATGC 80520 GGAAATCGAA CCCCCTA~AT CTATCGGCAC CGCAACGGCA GTGACAGCAC A~ATTATCGC 80580 CCCTTATGTG CA~ATCAGTT ACGA~AAACA CCTCA~ACAT GCCCAAGAAT GGAACGTGCC 80700 CTTAGAATAT GAAGTTAATA CACTACATAC TTCA~ATGGG CAAACACCAT TTGTGACCTT 80820 LG~ G~l- TTAGGTACAA GCTGGCAATC CCGCTTAATT CAGCAAGCTA TTTTA~AAAA 80880 TCGGATTCGT GGACTTGGAA AAAATCATAA AACACCAGTA TTTCCA~AAC 'Ll'~l-l"ll'~AC 80940 ATTAGAATGC GCATCAAAAC GTATGTATCC AGATATTCTC AATTACGATC AG~Ll~L~AA 81060 AGTCACGGGC L~-ll-llAAAG CCCCAATGGG ATGCCGTAGC TTTTTAGGTG CATACGAAGA 81120 A~AAGGCCAC GA~ATTCACG ATGGGCGTAA TAATCTTGGC GTGGTGAGTT TGAATTTACC 81180 CGTCGCTCCT ATTCTTTATA TGGAAGGTGC TTGCGGAGTG CGGTTAAAAG CGGATGA~AA 81360 TGTGGCACAA ATTTTCA~AA ATGGACGTGC CTCTATTTCA CTTGGCTATA TCGGTATTCA 81420 CGAAACCATT AATGCACTAT ATAACA~AGG ACATATTTTT GATGATGAAC AATTACGCGA 81480 AGGTTATGCC TTCAGCCTTT ACTCCACGCC AAGCGA~AAC TTATGCGACC GCTTCTGCCG 81600 TCTAGATACC A~AAAATTTG GCGTAATTGA AGGCGTCACG GATA~AGGCT ACTACACGAA 81660 CAGTTACCAC TTAGATGTAG AAAAGAAAGT GAATCCTTAC GATA~ACTAG ATTTCGA~AT 81720 -77.50-SUB5 1 i I UTE S}~EET tRULE 2~) W 096/33276 PCTrUS96/05320 CGGCACA~AC ACACCGATTG ACGAATGTTA TGAATGTGGT TTCACCGGCG AATTTGAATG 81900 TACCAGCA~A G~L1-11~1~L GCCCGA~ATG TGGCAATCAC GACAGCACAA AA~L~l~l~l 81960 CACTCGCCGC GTCTGTGGCT ATCTAGGCAG TCCTGATGCC CGCCCATTTA ATGCGGGA~A 82020 ACAGGAAGAA GTGAAGAGAA GAGTTA~ACA CCTTTGATTA ACACGATAGC A~AAGCACGC 82080 AL-l-l-lllAAT GCGTGCTTTT TGTTTCCAAC TTTGGCATTC CTA~AAATCT CCGCTAAAAT 82140 AACCGCACTT L-L-l~-l-lATCT TCTAGGA~AG CAATATGTCA GATATTCTCA ATAACCTTAT 82200 TCAL~-Ll~ll A~ACTTGAAA A~ATTGATGA TTTAATCTTT CGTGGAGA~A GCCAAGATTT 82260 AG~LlllC~l CAAGTATTTG GTGGGCAAGT TGTGGCTCAA GCATTATCAG CGGCAATGCA 82320 GGTGGCGCCA GAAGATCGTA TTTTACATTC TTGTCATGCC TAllll~llG CTCCGGGAGA 82380 TAGCCAATAT CCGATTATTT ACGATGTAGA AACCTTGCGT GAAGGGCGTA A~LllL~lGC 82440 ATTATGCGTA A~AGCCATTC AACATA~AAA TACCATTTGT CATGTAACCG ~LL~LLLCCA 82500 AGTGCCTGAA A~AGGTTTTG AACATCA~AA TACAATGCCA AAL~LLG~lG CGCCTGAAGA 82560 CTTTACGGAT GAAAATGTGA TGCTACA~AA AGTAGCTCAA ACCTTGCCAG AACCACTCAA 82620 TGA~AAATTT GCAGCAGAGC GTCCATTTGA GGTGAGAACA A~ATATTTGA ATAACCCATT 82680 TAACGGGACA AAATTGCCAG CCGAGCAATA TTCTTGGTTT A~AACCAATG GTGA~ACGCC 82740 GCTTGATATA A~AATTCAGC AATGTTTATT AGCTTATTTT TCCGATTTTC ACTGTATTTT 82800 GACCGCACTT CATCCGCACG A~AAAGGCTT TTTACAAAAA GGAATGAAAG TGGCAACCAT 82860 TGA~AGCAAT AATGCCTTTG GAGGTCGTGG TTTGGCCCAA GGGCAGATTT TCTCGCAAGA 82980 TGGTCAATTA ATCGCAACAA CACAACAAGA AGGCTTGATC C~LLLlAGCG AATAAGAGAG 83040 A~AAAATGAC CGCACTTATT ACACAATTTT GGCAACAAGT TGA~ACTGCG CTGA~AACAG 83100 CA~ATCCACA AGAAAAATGT CGTTTAGTCA ATGATCTCTA CGATAATCTT CTGCcAcA~A 83160 TTCAGTTGAT TA~ATTAGAA GATTTTCCCG AAATCGTGCC GCAAGATAAT ATTGCCGCTT 83220 TTCCTGA~AA ACCGCTCTTA GTTGCACCGA AAGATGTGCC A~AACGTTCT TTTGCCACAG 83280 -77.5 1 -SUBSTITUTE S} IEET ~RULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/05320 TAG~L-ll-l~l GAAAGATTGG CTGCGTGTCG CTCGTGAAGA AAGCACGCAT TTTTCCTTAG 83460 GTGTATTAGA AGCAAGAGGC CTCGATGCAA CAC~L~ll~-l GCAAGAGAAA ATCGCACAAC 83640 AA~L~l-L-L-LAC AGAGCTGTTA CACAAATATC GTATTGTAAT TTTTAAAGGT GTCATTAATA 83820 AACAAACATT AAAATCCTAT ATTAAGAAAT GATGA~AAAA TAAAGAGACT AAGTTCGATT 83940 CAAGTTGTCC CATTCGGCCC AL~L-l-~LAAT ACGATGCCCA TAGCTGTCAA TTCATTACGT 84060 TTCTCAACAT ~-L 1'~''1'~'1'1-'1"1' TAACTTATTA ATTTCACGTG CCATTTCGAA TAAAACAGAA 84300 AACGCACCTT GTgCTAAATT CAA~Llll~''l' TCGCTATAAT TGAGCTGGCT ACGATAATGT 84480 GTGAAGAAAT TGCCGAGGGA TTTCGACATT LLL-L~-L-LLAT CCACCATAAT CATGCCAGAA 84600 GAAGCCCAAC TTG~L-LC~-ll LL~lllCGAC ALlL-LC~A~A GCACGAAATC CATTGGATTT 84840 -77.52-SUB5 imJTE SHEET tRULE 2 -CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 ALllC~lGCA CCATGCGATC CACTAACTGA TCGCAGGTTT ~Lll~llllC TAACGCACGT 85140 TTAATAATTT TGTCATCTAC GTCCGTTATA TTACGCACAT AAGTTA~ATC GTAACCCAAA 85200 GAACGTA~AT AACGGGCAAT CACATCA~AA CACACA~AAG TGCGTCCATG GCCGATATGG 85260 CACA~ATCAT A~ACAGTGAC GCCGCA~ACA TACATTCCCA CTTTATTTTC GTGGATAGGT 85320 TTA~AGATTT ~'l''l"l''L'l'~'l'~'l' CGTTAAGGTA TTGA~AATTT TTAGCATTTT TAAGCTCGTA 85380 AAATGA~ATA A~AACA~ACC GCACTTTTAT AGCACTTTTA CCTCGATTGT GGAATAATAC 85440 AACCCTTAAT TTTTTAGAGG GA~AACA~AA TGGTTACATT ACACACA~AC TTTGGcGACA 85500 TTA~AATTAA ATTGGATTTT GATA~AGCTC CAGTTACAGC AGAAAACTTC TTA~ATTACT 85560 GCA~AGACGG TTTTTATAAT AACACAATTT TTCATCGTGT TATTGATGGC TTTATGATTC 85620 AAGGTGGCGG TATGGA~AGC GGTATGCGCG A~AAAGCAAC TAAAGCCCCA ATCCAAAATG 85680 AAGCGAACAA TCGTTTAAGT AACA~ACGTG GAACCATTGC AATGGCTCGC ACTTCAGATC 85740 CACATTCAGC GACAGCACAA LLlLl~ATTA ACGTGGCAGA CAATGATTTC TTA~ATTATC 85800 GTTCA~AAGA AATGTTTGGT CGCGAAGTCG TTCAAGAATG GGGCTATGCA GTATTTGGCG 85860 AA~LG~ll~A AGGTATGGAT GTTGTGGATA A~ATCA~AAA AGTGA~AACA GGCAACA~AG 85Q20 GCTTTCATCA AGAL~llC~A ACTGAAGATG TAGTGATTAC ATCGGTTTCT ATTGAGTAAC 85980 A~ATGAGCAT AAAACAACAT CGCCCTA~AG TTGGAGA~AT TCTAGAATGT GATTATGGTC 86040 AATTTTCGCA TACCTGTCAC GTTGATGGAC ATATTCCACC TGA~ATGGTT A~AAAACGTT 86100 TG~LL~Ll~l TTTGAATGCT AAACTGAATG GGCTTATTTT AGTTGCACCA ATTTCATCTA 86160 A~ATTAATTT AGATGGTATA A~AAATGGCT ATCATATTGA AATAGATTCA GAATTAATAA 86220 TAA~LC~L~-l CC~l~-l~-lAT CATATTTATG ATA~AGGAAC TA~AATTACT CAATATTTGC 86340 CAAGGGATGT TGTAACA~AA GTTCA~AGAG CTATCATAAA AGCAATCAAT GCAAGCTCAT 86400 TCATCGA~AG ATGAGTTTTT A~ACGCCATT GAGCGATGAA TCCCCTGATT AGCGATAATT 86520 AGGGGATTTT TTATAGAATT TAGATA~AGA TATTTATGCA ~LL~L-LC~AC ACTCACACGC 86580 AGCAAGCCGA TGTGCAAAAA ATACTGGTTG TGGCGGTGAA AGAAGCTGAT TTTA~AACAA 86700 TCCA~AATAT GACCGCACTT TTTCCTGATA ATTTGTGCTA TGGGCTTGGG CTCCATCCTC 86760 -77.s3-SUBSTITUTE S}~EET tRULE ~6) CA 022l874l l997-l0-2l W O 96/33276 PCTnUS96/05320 TTTATATTCA AGAACACGCC GAAAATGATT TGAL-L~l~Ll AGAACAAGCC TTAAAAAATC 86820 TCACCGATGA ACTTTGGGCA AAACAATGTC ALl-L-l-l-llGA AAGCCAACTT TATTTGGCAA 86940 AACAATTTAA TTTACCCGTC AATATTCACA GTCGA~AAAC CCATGATCAA ATTTTTACTT 87000 TTTTAAAACG TATTCCATTA TCTAAACTTG GCGTGGTACA TG~LL-L-L-L~A GGAAGTTACG 87060 ATCAAGCAAA ACG~-Lll~Ll GATTTAGGCT ATAAAATCGG AGTTGGCGGC ACTATCACTT 87120 TGGAAACAGA CAGCCCAGAT ATGCCTGTAT TTG~Llll-A AGGCCAACCT AATCGACCAG 87240 TTAAAAAACT TACATGGGAA AATGCTTGCC AGALLLLLlC TTGATCCACG TCACATTACT 87360 GA~AGTTTTT CTCAACACAC AATAAGGATA TATTATGTCG CAAATCTATA CTCAGGTGAG 87480 ATGGGATTAA CCCTAAAAGA ACACGCTGAA ~L~L~LATGG CATTAGCTGA AAGTTCAGCC 87660 TCTGCTGGTC TCTGTTATAT GATGAGTAAC GTTGCAGTGA AL-l-~LL-lAAA TCTATTCGGC 87720 AGCTATCAAC TCAAACAAAA AA~L~-ll--LL~L GACATTGTTC A~AATAAAAC CTTTGCCGCA 87780 CTCGCCTATA GTGAATTAGG CACGGGTACT CACTTCTATT CGA~Ll--L-LlA CATCAACATG 87840 GTGATCATGT AGGCGGTGAA TTAAATTCAG CCAATGCATT CACCGAAACC Ll~l-l~AAAA 87960 TGGATTACAA CAATCCAGAA CATAAAGAAA TGATGGATTT GGAAGGATTA A~ACGTTGGA 88020 AAAAATTGCC CCATTAAGGG GCAATCTTAT CAAL~-ll~lA AAGTTACTTA TAGCTTTAAA 88140 CAACGATTAA ATATGTTGGT TAATGAAGTT AGCCAATTGA ~-L-L-L-l--lG~lA ATGCACCAAC 88200 -77 . s4-SUBSTITUTE S}~EET (RULE 26) W 096/33276 PCTrUS96/OS320 TGCGTCATTA ATGTGTAATA CTTCGCTCAT 1"1--1~L111~C TTA1-1-1-1~-1G AATGGAATCC 88500 CTATATAAGG G~1-1-L1-1-11A AACTTACAAG TGCGGTGCAG AATAACACCG TTTTA~AAAA 88560 TGTA~ACTAA ~1C~-1111AAT TGCCGA~AAC TAAGACGGCA A~ACAATATT TTCACACACT 88620 TTACCCGATT TCAATTTATA AA1~111~AT A~AGTCACGT CTGCAATATT GGTTAGTGCT 88680 TCTTCGGTTA A~AACGCTTG GTGACCTGTT AGCAATACAT TATGGCAAGA AGATAAACGG 88740 CGGA~AATAT CATCTTGAAT CA~-1-1C~1~L~A GACTTATCTT CA~AGAATAA ATCACGCTCA 88800 11~1C~1AAA CATCCATACC TAACGCACCG ATTTTACGCT GTTTTAACGC ATCAATCGCA 88860 GCTTGAGTAT CAATCA~AGA ACCGCGACTC GTATTAACGA TCATCACGCC AL~lll~ATT 88920 TTTGCAAAAG CCTCGCAATT TAATA~ATGA TA~1111~1G GCGTTGCTGG GCAATGAAGC 88980 GTAATCACAT GAGATTTAGC ATA~AGTTCA TCTAATTCAA CATATTGTCC CCCCAGTTCT 89040 TCTACTACTG GA1111-L~AA AGGATCGTAC GCCAAGATAT TCATGCCA~A ACCTTTCA~A 89100 ATATTGA~AC CAATTAACCC CTCAAGAGAG A~ATTCGCTT CTCGGGTACG CTGATAAGCA 89220 CGATGAATTC GACG~-11~AG AGTCATCATC A~ACCGATGG TA1~11CCGC CACCGCTTCA 89280 TCTAATACTT TTCGGCTACC ATTATCATTC ACGA~AATGC ATACTACTTC GCAATGTTCT 89460 GCCA~ACGCA CAGTGCTCTC GTTCAACATA A~ATCA~AAA ATTCTA~ATC GA~ATTATAT 89520 TTCGCGTTAA TGAGCTCAAT ATA1-L-1--L~-1-~ TCATAACTTT TAGTGCTATA GATTGCAATT 89580 ~L~-L-L~-1-ACAT CTTCAATACC GACTGA~AAA CGCAACAAGG TATTAGTAAT CCCACGAGCT 89700 ACACGCTCGG ATTCTGGAAT ATCCATATGA GTTTGAGTGG CAGGATAAGT AATA~AACTT 89760 TCTGTGCCGC CTAGACTTTC TGCA~AAGTA ATCAATTTGA TGGATTTTAA A~ATGTATTA 89820 ACCCAAGCTT CATCTTGCAA ACGGA~AGAC AACATCCCAC CTTTATTCGG ATAAAGCACC 89880 GATTCCACTT GTGGTTGAGC TTTTA~AAAT TCCGCAATAG CTTGTGCATT TTCTTGATGG 89940 C~-LL-L~ATAC GCAAAGAAAG G~-L~1L~ATA CCACGAATAG TCAGCCaAGA ATCA~AAGGA 90000 GA~AGCACCG CCCCTGCACC ATTTTGAATA TAAGCAATGC GATCACAAAG TTCTTGCCCT 90060 -77.55-SUBS 1 1 1 UTE S~E~T tRULE 2~i3 CA 022l874l l997-l0-2l W 096/33276 ' PCTrUS9610S320 TGAATTACCA CATCCGCACC TA~ATCTAAT GGACGAGAAA GCACAGGCGT TAAAAACGTA 90180 CAll~llC~A TTAAAGGATT CGATGGGGTT TCAATA~AAA TCG~lllC~l ATTTGGGTTA 90300 ATGGCAGCCT CAATTGCTGA AGCAGATGCT GTATTAACAT A~ACAGGTTT TACACTATTG 90360 GAAAACGCAA AACCACGATC TCCATTCTCT AATTTAGCTA TC~lll~llC TAATACTGTG 90540 GGA~AAAGTG ATAAAAGTAG AAATTAGA~A ATTACATA~A ATTTCATTTT TCCATCATTT 90840 ~l~l~l~ATTT ATTTGAACAA AATGAACTTT TTTTAAACGG TTAGACAATT TTTTTAAATC 90900 CCCGCTCCAA TTCGTGGCGT GTTAGCA~AG CGGTTATGCA CTGGATTGCA AATCCATGTA 91080 GCTCGGTTCG ACTCCGGGAC ACGCCTCCAT AATACGCA~A TGTTAGTTGT CTATATGCCC 91140 TTTTTATTGC CTAAATCTGA TACTACTTTT TA~ATTACTT GCTTATTGAA A~ATAGCTAT 91440 ACTTCAATAA GTAAGCCCGT AGTTGTGCAA AATCATTATC CATTTCATCT GA~AGCAATG 91620 GTAGCTGATT ATGTTTATCC A~l~lll-AG GTAATGGAAG CTGAATACCA AGAATACGTT 91680 CTTTAAGTTG A~l~lll~AAC ACCTGATAAG CTATCGCACC GTGAGGTTCA CATAAATAAC 91800 -77.s6-SUBSTTTUTE SHEET tRULE 26) CA 022l874l l997-l0-2l W 096133276 PCTrUS96/05320 CTTTCGACTG CATCGCTTTT AAGGTATCTT ~''1'~1''1"1'CGCT ATCACTTAGC ATCCCCGAAC 91860 CTAAATCAGT TAAATCCCAA CCA'1"1"1'C~'1"1' TAAACAATTC CTCCACTCTT GGCCAATTAT 91920 TTGGGCGACT TACATCCATT GCATTAGA~A GGGTTGCAAC TGTCGTTTTA GGATCCCAAT 91980 TACCCGATTT CAAATAACGT GGCACAGTAT CATTTGCGTT TGTTGAGGCG ACA~AGCGTT 92040 TTGGCACAGA AACCACGACA TTATCACGTT '111~1-11LGG CAATTGTGCG ACAGCTTCAA 92160 AGTAATAACA AACTTGAGCT AATA~ACGGC TGATATTAAT AGAATTTGCA GAGTTAAGCC 92220 CGA~ATCAGC GTTAATCGCA ACAGTACGAA TATTCCCACC TAAAGTACAG AACAGCTTTT 9 2340 CTTGCAATGG GCTGATTTTG CCTTTTGGAT A~AGGATAAC TACATTAATA '1"1"1"1'~'1'AATC 92400 CATAAAACGC ATGTGCTACA GCGGCTCCAG TATCGCCAGA CGTAGCCGTT A~AATAGTAA 92460 TTTTGCCATC GCCACGTACC GCAGCAAGTG CCTGTGCCAT A~AACGCCCA CCA~AATCTT 92520 TAAATGCTAG CGTTGGACCG TGA~ATAATT CAAGTGCATA AATATTTTCT TCCACTTTTT 9 2580 GTAATTCATT AATGTTATTA AGTTGAGGAA TAACTTCTGG A~AGAATAGA CCTTGATCCC 92760 GCCCAAGACC TTGACGAACA GCCTGAGA~A AAGTGACTTG L L~l L~LGGG 'L~LLL~ATAT 92820 TGTATAAATT CATATTTAAT CC~'L'L'1"L'LAA TCTGATTTCA TCTATTTAAA TTAACTTATT 92880 TAA'1''1''L~'1'~"1' TGTGCCTTCG TTATCAACTT TACATACATG CACA~AACCT TCATTATTTT 92940 GTA~ATAATG G~'L'L'1'~'1'AAA TAACTTGA~A GTTTAATTGC A~'1"1''1'~'1'AAA TCAGGGGCAA 93000 TAGAGA~AAT AGTTGGCCCT GAGCCTGA~A TAC~L~LGGC AAGTGCGCCT AA~L~lC~AG 93060 TAG~'L'L~'1''L'L TACTTCAGCA AAATTAGGTA ACAGAGATTC ACGATAAGGC TCGGCAATGA 93120 CA'1'~'L'L'L~AT CATAATCGCG GCAAGATTTT CCTGATGGGT ATGGCAAGCA TGCACAAAGC 93180 CACCTAAATG ACGACCATGG GCAATCACGT '1LL~LCGAGT ATAGCTTTTC GGTA~AATTG 9 3240 CA~AAAATGG CAATTTTTGA CAAATATTGC CGAGCGATTG CACCATA~AT TGCACACCGC 9 3360 CTCCCATCAT TTCAAGCAAT TCCATTTTCG A~AAAGGTTC ATTATGA~AC TGATTTAATG 93480 -77.57-SU8STITUTE 5t{~:ET tRULE 2~3 CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/05320 llllll~GAG CGTTAAACGT AAAGGTTTAA CATTTGCTCC GCGTAATTTT AATTGCTCGC 93600 TAAATAGCAC ATAAGCTTGG TAAACAATAT llllllGCGG ~ll~l~llCGGT AATTTACGAA 93660 GTAATGTTCT TA~AATATCT GCAAAGATAC CTGCCGCAGT AACTGCATTA CCTGCGCCAT 93900 ATTTTCCTTC ACTAATTTTT CCAACATAAC GCAATACTTT GC~ll~lGCT TTAGCTGTGG 94080 GATCATCTCG AGGATCTGGC TCAGTAAAGC ~~ CACG CGCAAGTGCG GTTACTTCTG 94320 GGCGTAACTC ATTGTAATAA ACTAATTCTC GTGTATTCGC llllll~lll GGCGTAACCA 94560 CATGGAAACC ~Ll~llllAAC GCACGAGCAT AAAGCCCTGC TACAGATTCG GCTGAAGTAC 94620 AATCTGATGG CTGAGTCGCA llLl~lAAAT C~lllllCCA ATCCTCTAAA TTTAATCCAT 94740 TCTTTGCTAG ATACTCCTTT TGACGCTTTA CCTGCTCAAT TAAll~lCCG CCTACTCCAC 94860 TAATCACTTC AATTGGTTCT AATTGATGTT CATTTAATTC ATTAGCAAAC TCC~111~1A 95160 -77.s8-SUBST~UTE SHEET tRULE ~) -W 096/33276 PCTrUS96/05320 GTACGGTTTT CGCTACTTCT GCAGATTTCA CAGGCACACA GA~ACTAATA CTATATTCAG 95220 ACGAAGACTG AGTAATTAaA ATAACTGA~A TGCCTGCGCC TGACATGGCT GAAAATACGC 95280 GAGATGCCAT GCCTACCATA CCTTGCATAC CAGGGCCTGA CACATTAAAC ATCGCCAaAT 95340 TGTCTAAGTT AGTGATACCT TTAACTTGCA AA~111~1~A TTTCACATTG CCATCAATAA 95400 TCGAACCTGG TGCAGAAGGA TTTCCTGTAT TTTTAATGAC ACAAGGAATA 1111~1GGCA 95460 ACAATGGCCC AATCGTACGA GGATGAATCA CTTTCGCACC GA~ATAAGAG AGTTCCATCG 95520 CTTCACGATA AGAAAGCGTT GGTAATA~AC GTGCATCAGG CACTA~ACGC GGATCGCAAG 9 5580 TATA~ACGCC GTCCACATCG GTCCAAATTT CGCATACACT TGCGCCTA~A CAAGCGGCTA 9~ 640 AACAGGCGGC AGAATAGTCT GAGCCATTAC GACCGAGCAA TACCAACTCG C~ L 1 1 1 L ~AT 9 5700 CAC~1-L-1L~1- TGA1-L~LL~A ATTTCAACAG AAGATTCAAG ATAACCGCCT TTTGCCAATA 95820 A11~L-1L~AC AGGATCCACA ATATGTACGC TATAGCCACG CGCTTCA~AC CAAGCTTTCA 9 5880 TCATTGCAAT AGAAAGTTTT TCCCCACGGC AATCAATGGT CGCTTTAACT GCAL~ll~lA 95940 CTTTTCCTGC CTGACGGATT L~L1~1AATA ATCCTTTAAT TTGAACA~AT TCAGCATCAA 9 6000 TGTTATAGAA AATTTCGATT G~-L-1C~-11~A AATGCGTATC GGTTGATTGA TTTAATGCTG 96120 ~LL-L-1L~'AGA AAGGGCGACG AGATGGTTGG TTATTTTGGC TGGTGCAGAT A~AACACCTG 9 6180 CAGCCTGCTC TTCTAAATGA GCTTGCTCGA TCAATTTCGC CGCTTGGGAA A~ACGTTCCG 96240 GATTTGCAAG CGAAGTGCCG CCAAATTTAA GTACGCGCAT AA11G~L-L~-L CCTAGATATT 96300 ~1~1-1111-AA ATTTATA~AA AAACCCGCTA TTCAGTTGAA TCGCGGGTTT TCTGTATCTT 96360 ~11-1L-LQCTG CACTAACCCG CACCATTAAT CATAATAATG GTCATCATAA TGGCGGTAAT 96420 CGTGCTAATG ATTACGGATA AAGTGCGGTT A1LL1L~ATT ~L~-LLL1ATC TTGAAAAATG 96480 AATGCGTAAA GAAATACCGA AATTTCCCGA G~L-L~-L~A~A CAGA~AGTGA CAAATTTTTC 96540 AGAAATTTTC TTAGTCAATA AATTTCGTGT A~ACTAACCG CA~LLLLLLA TA~AGGAAAA 96600 CCTATGAATA TCCAGCATAA TCTCAACCTA ATTCAGCAAA A~ATTGA~AC GGCTTGTA~A 9 6660 GAAGAAAATC GCAATCAAAA TACCGTA~AA TTACTTGCCG TATCTAAGAC CA~ACCTATT 96720 TCTGCTATTC TTTCGGCTTA TCAAGCGGGA CA~ACGGCTT TTGGGGA~AA TTACGTGCAA 96780 -77.59-SUBSTITUTE ~HEET (RULE 2~;) W 096/33276 PCT~uS96/05320 ATCGGCCCAT TACAATCGAA TAAAACCCGT ~LC~llGCAG AACATTTTGA TTGGATGCAA 96900 ACGCTTGATC GAGCA~AAAT TGCAGATCGT TTA~ATGAAC AACGACCGAC CAACAAGGCT 96960 CCATTGAATG TATTGATTCA GATTAATATC AGCGATGAAG A~AGTA~ATC AGGTATTCAA 97020 AAGATGTTGG AG~l~lllGA ACAACTTA~A CAAGTCTTAC CCAATCAACA AATTGATACA 97200 ~lll~lATGG GAATGACGGA TGATATGCCG AGCGCAATAA AATGCGGTTC TACAATGGTA 97260 TGGAATAAGG CCCGAATTTA AAACAAGCCT TA~ ~llAA TGA~ATTTAA ATGCCAGTAC 97380 TCTCGCCACA TTTTGAGCGG TAGA~ATTAA A~LLLL~llCG C~lL~lLlGA GAATATCCGA 97440 ATCATAATCT TCACGCAAAC ACCCTGCGAT GGCGATCACT GGCTTATTGA A~L~llllGC 97560 ACCCGTAATC ACTACATCAG CAL~llllAC ATAGTCAATT A~ATGTAACC GGTCTAACAC 97680 ACCAGCAGCA CCTGCGCCAG CCTGATCACG AAlLL~lllA CCGCAATCGC GTTCGGCAAT 97800 TTCAGCAAAA TGCGA~AGTG CAGCATCAAG Ll~Lll~ACC ATTTCAGGCG TTGCGCCTTT 97860 AAGAATGA~A ~L~l~lACGC CTAAATCTAA TGCCAGTTTA ATCAACTCCC CTGTGCCGTA 98160 TGCCATTTCG ATAATCGCGG TTTTTCCATC TCCCGATA~A CCGAAGAAAC TTTTCACTTT 98280 GTCACCCA~A GGCGCGGTGA CTTCACATTC AATGAGCTTG CCTTGCGTGG CATCCACAAG 98340 TTTAAAAGAA TCAGGTGCAA TCACA~ATTT CATAACAACT CCTAGAATTT AAATACGCCA 98520 -77.60-SU8ST~TUTE S~i~ET tRULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 A~AATTAAGG TAGA~ACGAT GGTCATCATC AaACCGACCG CACTTTCATA AGGAATAAGT 9 8580 TTTA~ACGTT CTTTGATATC CATATTCACA CTACCGCCTG TGGCATGGAA GA~AGAACCA 9 8640 TGTGGCATAT GATCA~ATAC GGTCGCCCCT GCATGAATCA TTGCTGCACC AGCAAGACTG 9 8700 GTGGTAGAAG CTGTCGCTAA AGACATCAAC ACCCCTGA~A TTGGTGCAAG AATGTATGAT 9 8820 GGCA~ACCTG AATGTTCCAA ACCTTGAATC AATACTTCTT TTA~ACCAGA ATTAGCAATG 9 8880 ATGCCAGCAA GCGCGCCTGT ACCAAGTAAC ATAATTGCCA CGG~'1~'L~AT TTTACTCAAT 98940 CCATTGATAG CATAACTATT TATATTGCGA AGTTTGCCCA TACA~AACGC ACCAATCA~A 99000 AATAGCAAAA TTGCCACTAA AGGTGCGACA AGTGCGGTCA GA~ATGAAGG TA~ATTTTGC 99120 GTTTCAAGCA CGATTACCTC 'LL-L~-L~AGTC ACTTTAGAAC ~L-L-1~-L-L~AT TAAGCGTTTT 99180GCTAAGAAGT AGGTGAGAAT CA~ACCA~AT AGCGCGGGAA TTATACCAGC CATCATCACG 99240 GAAGTGAGTG GCA~ATGA~A AGTATCTGCT GCCGCAATGG CATTTGGGTT TGGCGACATA 99 300 ATATTACCAG CTTTACCACC GCCAATCATG GCGAGCA~AA TTGCAGCTTT CGATA~ATCG 99360 CTGCGACGCG ATAACGCTAA AGCAATTGGT GA~ACAGTAA TCACTGCCAC ATCCACGAAC 99420 ACACCCACCG CAGTTA~AAT CATCGTCGCT AGTGCCAAGG CGAGTA~AGC TCGAGTTTCA 99480 CCGATCATTA GGCTCACTGT TTGCGATA~A TCCGCACCAC CAATTAAGCC TCCAACCA~A 99660 GCTCCCACTA ACATACCATA AGCTGGTGAG A~'L'1-1"1-'L-L~A A~ATGAGGAA GATAGCAACG 99 720 ATTAACGCCA CCAACGCACC TATTGCTGAG A~-1~'L-L~-L~'A 'L-LL-1-L-L~-1~'L CCTATAAAAA 99780 TTA~AACCAA GGAGATTATT ~1~1-~-1--1-11'AT AGGGGA~ATG CTTTATTAGA GCAAACA~AA 99 840 AGTGCGGTTA A~AATCATCA AA~-L-1'L~'LAA AGTTATACAA CCTCAATGTT CTAACAACGT 99900 TCCGAGATAG AGCGTTAATT TATCATCTAT CTTATTGA~A AATAAGCCAG TTATTTGCTC 99960 TA1--L'L-1~-1--LC AATCGATAAC GCA~AGTATT CGGGTGAACA AATAATTTTT CCGCAGTGAG 1000 20 ATA~AGATCA CAATTTGATA A~AAATATTG TTGAAGGGTT TTATAAAGTA TCGCATTTYC 1000 80 TTCTGAGA~A nGGGGAGA~A GGGGTTTTAT CAATTCGTTC CCTTGCCAAG AATGGGATAA 100140 TCCAGCAAGT AACACAGGCA ATCGATGCTC ATCAAACACA TA~ATACCTT TGCGTGGATG 100 200 -77.61-SUBSTITUTE ~i~tEE~ (RULE 2~;) - =
CA 02218741 l997-l0-2l W 096/33276 PCTrUS96/05320 A~l~Ll-l-lAAT CCATAAGAAA GCGTGCTTTG CGCACTTTGA AAAGACAAGG GAAGCTGCTC 100260 AAAAAGCGGT AGATTTAGAC AAGCGCCTAC AGCAATTTTA TAAL~-Ll~l--l TTGAATAATC 100320 TGCAGGTAAA AGC~-LlllCA TTTGAGCAGA AAGTACGGTG GAGTTTTGCC A.~GTCTTTAA 100380 GACCACAACC TGATCAAGGG ACA~AATTGC CACATCCTGT GCA~ATTCAG ACTGTTCCAA 100440 ATAATTGATC AGA~LL~l~-lA AATTATCCAG GGCTGGATTA AGTAACTTAA TCAATACAAC 100500 CACACGAGAT TTATTTAAAT CAAAAGAAAA AAATTTCGCC TG~-L~ll-C-'A L~-l~l-llCCA 100560 ATTCAAATTG CAATGTAATA ATTGTAAAAT AAALl~ll~l TTGTAACGAC GATGCCAGCT 100620 'Ll~ll~-llCG AGTAAAGCCT ~Ll~ll~CCAC AATAAGTTCT GCCGTCATTT TCACTAGTTC 100680 CGCTTGATCA ATCTCTACCA CACGATTTTC CCGCAACGCC AACACCGCTC ~L~-l~l-GCCG 100860 AGTCAAATAT L~ll-l-lATCT GCAAGAAAAG ACGGGAGACT ATTCTCCCGC ACTGCGTTTT 101100 TATCGCTATA AL~ll-l-lATT CTGAACTTGA ACATATCCCA TAATTAATGC CAAAATACCT 101160 TGCCCATTCT TC~-L 1111~1 TACCTAGAAA TTTGATAAAG CTGAACGCCA ~Lllll-l~AGC 101340 AACTGGGCAG ATTGAAGTTT CACCATGTAA AG~ll~lC'~A ATAATGCTAC TTACAAAGGA 101400 AGAAGTCGCT TTATTTGGTT TTCCTGGACG GATACA~ATT GTGGGCAGGC GAAGACAGAG 101460 ACCATCAACA AAAC~-L-l-lLC TTGTATAGTC ATTAATAAGT AATTCACTCA TTG~Lll-l--lG 101520 ACCACCAAAT ACAGCAAGTG AACTAGA~AA ATAAAACGAA TTTTAGTATC AGATTCATCA 101640 AAATATGGGA AAGTGGCGAC ATTCCATATT TGTCCACTAA CA~ATTTTGA TCACATAATT 101700 TGCGACAAAA AL~-l-l-~-L-LGA ATCTGCACAG AATGGCATTA GAGAATTA~A TATTAATTTA 101760 ACTATCGTAT AAATAAATTA ATATA~ATGA TCTGCACCCC AAAACTA~AC AAATAAGCTT 101820 r ACTCATTAAG GTGCAAATCA AAGTGCGGTT CATTTTTATA TTATTTTTGG CTACATACAG 101880 -77~62-SUBS i 11 UTE S~ET tRULE 2~) CA 022l874l l997-l0-2l CAATAAAATG TAATTTATGT TCAGGATCAT TA~AGGTTTT GAACATTCTT TTA~ATTGCT 101940 CACGATTTTC CGCTTTCATC GCATTACGGA TGATTTTTAA CGTACCGaAA ATTCCTTCAT 102000 CATA~ATCAT TC~llllGGG GA~AGTAATG TCATCTCACC AGAGA~AGTA TCAACATTTC 102060 TA~AACCACT TTCTTGGAAT ATGCCTTTCC ATCCATCTTT CGTTAATGGC GTGACAGTCA 102120 CGTTAATCGC TTTGCGCATA lllL~lAGAA TAGTTTGATG ATCATTCCCC ACCAGCATAA 102180 CATCGTGAGT AAGCAATAAA CCATTGGGTT TTAACACTCG A~AATATTCT GCAATGGCTT 102240 l-l-l-L~-l-lCGC TTCCACGGGT AACATTGTGA GCATCGCTTC ATTGATGACA ATATCAAAAC 102300 TTTCATCCTC GA~AGGCAAC TTCATCGCAT TCGCACGCTG TACATGAATT TTTTCCTGCA 102360 CTTCAATATG ACAACCA~AT l~lllCGCCA ATCCAATTGC AGTCGTCCCC ATATTACAGG 102480 CAACCTCCAA CA~LlllllA TCTTGGCTAA AACCGCCATT AGCAATTAAC CAATCTGTCG 102540 ~ l-l-l"l'ACC GCCTGGACGC A~ACGCGTTT TACCCA~ACG TGCAAGA~AA TTATGCCCTA 102600 CTTCATCTTT TGCCATTTTT Al~lC~lAGT AATTAACTTG ~llLllATAT TATAGATA~A 102660 AATGATAACT ATTAAAATGT CAGATCA~AT A~ATAnGGCG GAATAATTGT TCCGCCTTTT 102720 CCTATTATTT CTTCAATGCT lllll~AATT CAAGTAATTC ACGACGTAAC TGTTTCAATT 102780 CGCTTTCCAT TTCAGCTTGT TTATACAGTT L~ CG~l TTCTGCTTGT TGAGAGCGCA 102840 TCATCACTAC ~ ~AC AATTGCA~AA CTTCCGCAGA ATTGACCGCA ~-L-l'-l~-l~'l-LG 1 0 2900 AAACTTAATC TCTCAAGCGG TTTATTATCC ~-~T~r~AA Lll~llGGTG TGGATTTAGC 102960 GGATAGTCAA ATTACCCAAG GTAATGA~AT TATTCAATCA ATGGGCTTAA CA~ACGTTCG 103020 TTTGCTTGAA TATTTTATTT ATCAAGTTGG tTCATTTACT ATTCAATCTT TAACACAGCA 103080 TATTGAGGAA AATA~AGAAT TTGCCAATAT TACTGAAAAT GAACTGTATT CTGCGGTGCT 103140 TGAAGATAAC A~AACTTACA TACCGAAAAG CTTTACTCAA TATGTAAAAA CATTGGTAGA 103260 AGGCGCAAAT CAGTATATTG GTGCTGGA~A TATGTATAAC GGCGACGTAG AAGATTTGAA 103320 TA~ACTGCAT CTTTATATAA l~l~l~A~AT GGA~AAACCG ACAACTA~AG CTGAATTGAA 103380 ATCAGCATTA CAAGGCTATT TAATTCA~AA TGAATATCAA GATATGAATA ACAATGATAA 103440 ATTGATTGAT GAAACTTATG ATTGCACTGA ~-l-l~ll-lAAT GCG~llLll~ ATGTATTAAC 103500 AAGATTAGGT ATATCCAGCC TGTA~ACCTA TAA~l~l~l~l ATG~llC~Ll TAATGTACCG 103560 -77 .63 -SUBSTTTUTE S~EET tRULE 2~i~

Llll~lllll CATCTAAATA TCAATTTAAA TTGAGAACTA TTTGCATTTA AATAAAATTA 103620 TTCAATGCAA TTTAAACATT TCA~ACTTGC TACCCTTGCG GCaCACTTGC lllLL~LGCT 103740 GAACAAACAG CGACTTTTGC CGAL~LLL~L GAAGCAGGGC TTTTAGCACC AATTTCAGAA 103980 GCATTAAGTG GCC~Ll~lCG AGTAGTGGTT TACGATCACA CTAAATTATC TGAAAAAGAT 104100 TCAACTTCTG GTGC~Ll~lL AGAGCAAGTT GTTGCGTTAA GCAAAATGAA AGGGGACAAA 104220 GTGGCATTAC AAGCG~LL~A AAATGGCGAA GTACCTgCTG CGTTAATCAA TAACTATTAT 104340 TGGTATAACC TAGCAAAAGA AAAAGGCGTG GAAAACCTAA AAAGCCGTCT TTALlll~ll 104400 AAAAATCAAG CTGAAGCACA AAAATTCGTT GALLL~llAG CGAGTA~AAA AGGTCAAGAA 104520 CTTGAACCTT ATGAAAAATT AGAAGCACCA ~LG~l~lCCG CAACAACAGC TCAAGATAAA 104640 GTATTTGAAA AAATTCACGC ACGCGTTTAC AALl~L~l~A CAAAATTAAC CGCTTGCGTG 104760 TCACTTGGCA C~LLlL~lGC TTTTTtACTT GAACGTTATC GCTTTTyCGG TAAAGCTTTT 105060 TTTGAAGTGG CAATGACGTT ACCCCTTTGT ATTCCCGCCT TTGTAAGTgG TTTTACTTGG 105120 nTCAGCCTCA CATTCCGCGT TGAGGTTTTT TGGGGAACAA TTGGTATTAT GACATTAAGT 105180 TCATTTCCTT TGGCTTATTT GCCCGTTTCC GCCATACTAA AAAGACTTGA TC~L1~1~11 105240 -77.64-SUBS i 11 UTE ~HEET ~RULE ~) CA 022l874l l997-l0-2l GAAGAAGTAA GC~1~ CGCt TGGTAAAAGC C~1~1~LATA CCTTTTGGTA TGCTATTTCC 105300 CCGCAACTTA AACCCGCCAT TGGTAGTAGT ATCTTACTGA TTGCTTTACA TAL~LlG~lC 105360 TGTATACTTA '11~L1111GG GGAAATTTTC TTTCGTGGAA AACAAACCCT TTACCACAGT 105540 GGAAAAGGCG TTA~LC~LCC TTATCTCGTA AAAACACTTT CCTTTGGAAA ACAATGTTTA 10 5600 ACCTTCGGAT 111L~L~1AG CATATTCATT TTAAGCATTG GCGTGCCTGT GATTATGTTA 105660 GCCTTGCCAT TA~LL1GGGC AG~L~11C~1 TACCGTAGTT ATTTAACGAT TTGGATCGAC 105840 TTTATGCTCT ATTTGCCAAT GGCACAAACT ACATTAAGAG C~L~LLLAGA GCAACTTTCC 1060 20 GATCAAATTG AAAAAGTCGG ACAAAGTCTT GGGCGAAACC ~111~1ATAT TTTTCGCACC 10 6080 TTGACGCTAC CAGCCATATT ACCAGGTGTG GCAGCCGCAT TTG~''L'L LG~ l 'L'L L l L'L~AAT 106140 ATGCTCGTtC '1LL1LLCGGG TATTCCTGTA TTTTTATTGA AAAAATATGC GTTTAAATAA 106320 AATGATA~AT AATCCGTTAT TAACCGTTAA A~ATCTCAAT AAAL1LLL1A ATGAACAACA 10 6380 AGTTCTGCAC GATATTTCAT TCAGCTTACA ACGCGGAGAA ATC~1~11L1 TACTTGGTTC 106440 TTCAGGATGT GGCAAAACTA CATTATTACG TGCCATTGCA G~LLL1~AAC AACCCTCTAA 106500 TCGCAACATT GCTTACGGAT TAGGCAACGG CA~AGGAAAA AATAGCGAAG AAAAAACGCG 10 6680 CCAAGAGATG CTCCAAGCAC TTCGCCA~AG CGGTGCTTCC GCAATTTTCG TTACTCACGA 106920 t -77.65-SVF3STrTUTE S}{EET (RULE 2~') W 096/33276 PCT~US96/05320 ATTAGGCAAT ATTCCTATAA AAAATAAATC AATCTCACAA AATCAAGGTA GGATTTTGCT 107].60 ACAAATAAAA CAAATTGAAT TTAAAGGnAA AATTACCTCC ATTCAAATTG AAATTAATGG 107280 TGTTTATTTA CATAGAAAAG GG~~ llA CTCCTAAGAA TAAAGCCTTA TCTTCACGAT 107400 AGAAATTCAC TCAATTCAAA GAAGTAGCCG C~'l''l"l''l"l'~'AT ATTCCCAAGG CTCCAGTTGT 107700 AAAGATTGAC ~l~lGGCAA AAGATCAGGA TCAAAAATAT CCACTTCCGT TCCCCAATGA 107760 AATTAAAGCC A~llllllGCC GCA~lll~ll GCAAAGCTTG AAATGCTTGC ACAGCTTGCG 108000 TTGTGGTAAA TTTCACCGCA CTTGCCAAGG l~lL~lACAC TGACACATTC ATTGACTTTA 108180 AAATTCCATT CAATACGATA TTTCAAATTG 'l'~'l"l"l"l''l'~''l'A GCATTTCAGC CA~lllllGC 108420 TTAATGATTT CATCCGTGAC ll~L~lGCAA TAACGCAAAT TGAACTGAAT ATATAACTCA 108480 r GGCGGGAAAA ATTCATTGCC TTTATCCCAT TGGTAAGTCG TTAATTCTTG CAAAAATAGC 108600 SUBS i 11 UTE S~ET tRULE ;~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GCTGCTTTAT GGATTGGGTT TTCAGCTA~A TGCGGATAGG CTACGTGTCC TTGAATACCT 10 8660 TGAATATAGA GA111C~1~L AATTGAGCCG CGGCGACCAT TTTTGACAAC AL~lC~lAAG 108720 TTTTTAGCAC TCGATGGCTC GCCAACCATA CAATAAGTAA '11111L~ATC ACGCGCCATT 10 8780 AAC~1~1~AA CCACGTGTAT AGTTCCATCT TTTGCGGTAG C~L~ll~ATC AGAGGTAATC 108840 ATCATTGCTG CAAGGGAGCC TTTCATATCC GCCGCACCAC GCCCATA~AG CATGCCATCA 10 8960 TCCGTATGAC CTGCA~AAGC AATAACTGGC TCG~1C~L1C C~'1'~'L'L'L'1'GC CCACA~ATTC 1090 80 AAC~L~LLAT TA~AAGGCAT CCATTCAATT TGA~AACCTA A'L'L'L'L'1'~'1'AA ACGTTCGGCA 109140 ATAATTTGCT GACAGCCTTC GTCATTTGGG CTAATAGACG GGCGACGAAT TA~ATCTTGT 109200 GCCAACGA~A CCA~LLLLLC TTTCATA~AA ACTCCTAAGA A~ATAACCGC ACTTTAAGCA 109260 A~AGCAGCCT GATATTCCTT TTCATTA~AT CCAATTAATG C~LLLC~ATC TTGTA~AATA 109320 ATTGGGCGTT TAATTA~AGT TGGATTCTCA GCCAACACGG A~AGTGCGGT GGTTTTATCA 109 380 ACATCCCAGC CA~ATTGAGT TTCCGCTTGG GTTA~AAAAT TTA~ATCTAA CCCATCAACA 109500 CGGTAGTCGT GAA~LLL~LG TTCGATATTG TGATCCGCCA GCCATTTCAA CG~'LLL~L'L'l 109560 ACTGTATCGC AATTTTTAAT GCCGTA~ACT GTAATCATAT TTCACCTA~A A~AGA~AAAT 109 620 CCTAACAACT TATTGATACG TTTAATA~AC GCAGCTGGAT TTTCCA~AGA TCCGCGCTCT 109740 GCTAACATAG ~L1~LL~AAG TAATAATTCC ACCCAATCAG CAAATTCAGT TTCATCTGCA 109 800 ATATCAGCCA ~'L'L'L'1''1''L~AC TA~ATGGTGT TCTGGATTCA GTTCA~ATGT GTATTTTACT 109 860 TTATCCGTAG A~ACCACCGC TGGTGTATCC GTTA~ATTGT GAGTTA~ACG CACC~'L'1"L'LC 1099 80 ACACGTTCGC CAAGCAAGTT TTTCACACGC TCAATA~AAC TACCA~AGGC TTCATCTTGT 110040 'L~'L'L'L'L'L~'1G TTTCAGATTC TTTATCCGCT A~ATCGCCTA AATCCA~ATC TG~'1"L'L'L~'1'A 110100 ATA~LLL~LA A~LL~LLLACC ATCGAATTCA GTTA~ATAGC TTAACATCCA TTCATCAATG 110160 CGATCGGA~A GCAACA~AAC CTCAATGCCT TTTTTATTGA ATAATTCCAA GTGCGGGCTA 110220 ~LLLLLC~CTG CAACATAACT ATCCGCTGTA ATGTAATAGA TAG~LLLLlG CCC~L~11LC 110280 -77.67-SUBSTITUTE SHEET (RULE 2~i) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GCAAAACGCA ATAACTTCGC GACAGTTTCT TTGTTAGCAA AA1~1-1~1GC AGGGCCTTCT 110400 TTTAAGACTA AACCAAACTC TTTCCAGAAT TGAAGATATT TTTCTGCATC A'L~1111GCT 110460 AA11111~1A GCATTTGTAA TGAACGCTTA GTTAATGCTT TGCGTAGTGC AGCCGTAATT 110520 CGTTGAACAT AAAGTTTTAA GCCATGTTTA L~11~1C~AT TAAATAAATC CCAAGGTGCT 110700 CAAGTCACAG GATCAACAAA ATCATGGCTT AA~1~111~1 AAAACGCTTT GTATTCCTCA 110820 TTTTCGCCGC A~1~111GCC TTCATCATCG TA'11~111'CG TCAGCATTTC CACTGGCAAG 110940 GCCACAGAAT ATTCGCCTTC ACCCGCAGAT TCCCAAAGTA CGGCTTTATC CGC~l~ll~A 111120 CCAGCTGCTC TG~11111AC AGTCACTTTA TCTGCCACAA TAAAAGCAGA ATAAAAACCC 111180 AA11~1111G 11C~1GATTT TGCAATCGTA CCCAAATGAT CGATGACTTG CTCACGGGTC 111300 TTATCTGCCG CATCAGAAGC ATTAGAAATC AATTCACGTA AGAAAATTTC llL~lLAGAG 111480 TACAAAGAAT GAATCATTAA TTGGAGTAGT l~lll~ACTT CAGATTGGAA TCCGCGAGTT 111540 TCTTGATTTT GTGACATAAT 11111C~L1C ATAAAGATAA AAATTGAACG TCACAGATAT 111600 AATTTATGTA TATAATGAAT T~1~1111AG ATACTAGATA GTAATTTAAT AGTAATGAAA 111780 CTTGGCTAGT GCATTCCCCC A~1C~L11CG CACTAGCCAT 111111GGGA A'1'11"1~1'ACC 111840 TTAATCAAAA A~111~11~1 GATAAAATCA ATGACTATGC GCCCAACGGC TTACAAGTCG 111960 -77.68-SUBSTrTUTE SHEET tRULE 2 W 096/33276 PCTrUS96/05320 CACAATTAGC CAAACTGCTC GATATTGA~A ATTTACAACC ATTAGAA~AA GGCTCTGTGA 112260 TAGAA~AAGT GTTAAATCGA AAACCGTTAA TTTGCATTGA AAACGGACCG CACTTAATCC 112380 GCTGCGACGC ATTTATTACA GGGGAAGTGT CAGAACAAAC GATTCATTCT GCCC~l~AGC 112500 AAGGATTGTA 11-1-~-11~-1~-1 GCAGGTCATC ACGCAACAGA ACGCTATGGC ATCAAGGCAT 112560 TAGGCGAATG GTTGGCGAAA GAATATGGCT TTGACGTAGA ATTTA~AGAT ATAGATAATC 112620 CAGCATAAAA TACAAAAGTG CGGTAAAAAT A1-L-1-~-11111 TAACCGCACT TTTATCTTCT 112680 CTAATGCAAT ACGACGACGG CGAGAtCCTT TGATAATATC TGGGTTGGCA C~L1-~1-L-L-LA 112920 GGGTCATGGA GTTAATGATC GCTTCCATTT TGACA~ACAT l--L-l~l~ATCT ACTTGATTTT 112980 CCAlll--l-lll CATTTCGATC AG~l~llCGC GGA~ATCATC TA~AGTAAAA TCATCGCCTT 113100 ATGGCTCAAG CGC~L~l~Ll TTCTCGCCCA CACCCAAGAA TTTGATTGGT TTACCTGTGA 113280 CCC~-L~-lAAG AGGCAATGCT TCATTAAAGG CTTTTGCTGT ATTTGCCGCA TCTTGACCAG 113400 lLlC~LCCAT CALLl~-l~LA TCAACGTGTA GGCGACCTGC CGTATCCACA ATCAACACAT 113520 CGTAGAATTT CAGTTTTGCA TCAGCAAGCG CCGATTTAGC AATATCAACG GG~L-L-LL~ll 113580 TAACATCCGA TGGAA~AAAA TCCACGCCAA CGGATTGAGC CAAGGTTTCA AGTTGCTTAA 113640 -77.69-SUB5 111 UTE S}~E T tRULE 26 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TCGCAGCAGG GCGATATACG TCAGCAGACA CCACTAACAC 'l"l"L~'l"l'-l"l"l'A TGGCGTTCAC 113700 TTAAGATAAC TGCTGGTGGT TGGGTTGCGA GATTTA~ACT CTCATTCGCT TCGCCCATGG 113820 TGA~ll~LlC CCCAAGCGCG ~'l"l''l'~'l"l''l''l'A CTTTTGCGAT A~ATTCACGC ACCACAGGCA 113940 AATTCTCAAA CATGGCTAAC AAlC~l~lll TTCTTA~AAA ATTGTGCTGA TTATACCGAA 114120 GCGGTGAAAA ATGACCGCAC lllll~llGA TTAACGAACA AAAGGATTTT CCCTTGGATA 114360 TTtCTGGTTC TGAAACTGGA TTA~l~lCCC TCAATAAATA lC~l~lLC~l TTTCTATCTG 114480 AACAAGGCAA TAAAGGCGCG AAAAAAGCGG AAAAACTGCT AGA~AAGCCA GATACCTTGT 114540 TCGTAATGCT CGTATTTTCT GAAATATTCC CCA~AACTGT GGCTGCAATG CACGCAGAAA 114720 TGCAAAAACA AGTAATTAGT AGTGAAGAAC TGCGTAGTAT TGTATCAGAa GCGGGCGAAG 114900 CAACACCAAA TGAACAACAT CCACAAATGT TGCTGTCTAT TTTGGATATG GA~ACCGTCA 114960 CAGCCTTGAT GAACAAGTGC TTGGCATTTT GCGCGTGCGT GA~GCATTCC GCTTGCTCCT 115140 TGAAA~AAAT GAATTTACCA AAGAAACCTT AATTCGTGCC GCAGATGAAG TGTATTTCAT 115200 -77.70-SUBSTJTUTE 5HEET ~RULE 2~) W 096/33276 PCTnUS96/05320 GGAAGA~ATT GTTGGGGATT TTACCACTTC CACCGCCCCA AGCATTGACA AAGAAGTAAT 115380 AATGTTTAAC TGGGAATTAG ATACAGAAGA TGCTCGTACT TTTAATGGTT TAATCTTAGA llS500 TALl~ll~AA GTGGGCGATA ATATGATA~A ACAGGCGA~A ~LC~l~AaAC TTTAATCATA 115620 AAAAACTCCA CCAAATTGAA CCGCACTTTT GACTTGGATC ATAAGTGCGG 'L'l'~'l"l''l''L'l"l"l' 115680 GCGCATTTTT TAGAAAAGAT TTTTATAATT ~lll~lAGGT ATATTTTGAT AGA~AAGA~A 115740 GATATGGAAC ACGAATATCA ACGGGCGGTG ACTCGCGTGT GCGTACA~AC GGCACTGCTC 115800 TTGTTACAAC ATGGGGCAGA AAGTACCGTG GTGGTACA~A TGGCACAGCG TTTAGGCGTA 115860 TTATCAGATA ATCATTGCAT TACTACCGCA CGA~AAAATA CAGATA~AGG CATTAATATG 115980 CA~ATGGTTA CTGATGTTCA ACGCATTGTG ATTGCCGTTG AGCATCATTT GTATGAGTTA 116040 GAGATCGCAC AAAGA~AACT GGATCAATTA A~ACCGCTTA AATATAACCG ATGGTTAGTT 116100 ATTTGCGGCA TCACAATATT TATGTTGA~A TTACTCTATG ATATGCTATT TGCTGCGATT 116220 CCAGCGGTGG GCTTTGCTTT AGTATTTAAT GTACCGCCCA AAGCCTTA~A ATATTGTGCA 116280 GTATTTGCTA CAll~lllGC CaCTTGCGTG ATTGGATTTT TAGGCGTGCA TCTTTCCCAT 116400 GTTCATGCTT ATAAAGCAAT GATTTCAATG GTACA~ATTC ATCATTTTGG ~Llll~l~AT 116520 GTATTTGGAT TGGCTTTACC AGGCTTATTG TTTTATCGAC A~AAACCTGT GGTGTAACAC 116640 TA~AAACAGT GCAACA~AAA AGCCGACATT TGTCGGTTTC TACTATTCTT GTGATTTTTT 116700 CTTGAGGTAT TCATA~AGCT CATCTTTAAT CCGTAATTTT C~'1''1"L'L'L'L~A AATAACGATT 116760 TGTATTCCAC A~AAAGTTGA TCCACTTCTT CACGATCA~A AGAGGATAGA ATTAATTGAT 116880 TAAGATTATT TTCTTGAGAA AACTTA~AAT GTGAGGCAAT TTGCTGAACA GTTTCATTTT 116940 CAACTTTAGC TCTCGCTTTC ACA~AATCAG ATTGATTTAA A~AAGCCATT AATTGAGCGG 117000 -77.71 -SUBSmUTE S~EFr (RULE 2~i) ATGAAGTAAG AAlllll~lA AATTCATGAT ACGCAGAATC TGTCGCCTTA CGCTCAATTT 117060 AGTGCGGTCA ATTTTnCTTT ATTTTTATAC GTTGGCTTTT AAA~lG~lll ATTTGAAGAA 117180 AAGCGCGTGG TGAAGATATC GCACCATTAT TGGCAGA~AT GGATGATATG GGCAATCAAT 117480 CATGTTTCCG TTCTGAAGCA G~ll~llACG ~'l'C~'l'~ATAC TCGTGGTTTA ATTCGTATGC 118080 ACCAATTTGA TAAAGTAGAA ATGGTACAAA TCGTTGATCC AGATA~ATCA ATGGAAGCAC 118140 AAGTTTTACT TTGCACAGGC GATATGGGCT TTG~ll~llG CAAAACTTAC GATTTAGAAG 118260 TTTGGGTGCC TGCACAAAAT ACTTATCGAG AAATLl~llC TTGCTCAAAT ATGTGGGATT 118320 TCCAAGCTCG CCGTATGCAA GCAC~ll~lA AAGCA~AAGG CGATAAGAAA ACTCGCTTAG 118380 TGCACkCATT AAATGGTTCA GGCTTAGCGG TTGGTCGTAC TTTAGTGGCT GTACTTGAAA 118440 -77.72-SUBSmUTE ~{EET (RULE 26 CA 022l874l l997-l0-2l AATTGACATC AATATCCAGA ACATTACTCT A~AAAACATA TCAAAGTATC TAAATTGTTA 118740 TCCACGTATA AAACAGTATA ATTCCATCA~ TAGCTCATAA ACCAACAGGA GTATTTTATG 118860 A~ATTATATG GTTTAATTGG TGC~1~1L~A 111~11CCAC ATGTGGCATT AGAGTGGGTA 118920 AAAATACGTG AAAATGCTGA TTATGAATTT GAAC~1~L~A CTCGTGAGTT AATTA~ATCA 118980 ~-L-L~LLLCGC AGAACCAAGC GATTTTGCAC TATTTAGATG AACTTTATCC TAATTCAAAA 119100 TTATTTGGTA GCAAAACCGT ACGTGATA~A GCCAAAGCAG CTCGCTGGTT AGCATTTTTT 119160 AATTCCGATG TGCATAAATC ATTTGTGCCT CTGTTCCGTT TGCCAAACTA TGCA~AAGAT 119220 GCAGTCGCAA ATGAGCATTT AGA~AGTCAC ATTTATTTTG GAGAAAATAT TTCCGTTGCA 119340 GATGCCTATC TTTACATTAT GCTAAACTGG TGCAAAGCAG TCA~AATTGA TTTCAGCCAC 119400 AGAAAAAGTG AAGAACTAAA AGTATAAACA GGAAGTTTCT ACAAAAATTG CCC~1"L'L-L-1-A 119520 ACC~-L-L-L~-1A TCACGTTAAG TTTAAATTTA AGTGAGTAAT TTCGCGTCTT ACCCAACACA 119580 GCTAACCCAT TGATTCTACT ATGATTAAAC TGGTTAATCC AATGTCGCAA TGtTCTACTG 119640 ATGACTTGTT GTTTGAAAAG A~L~1-L~-1AT TTGGCTATAA AAAATCTGCn TCTTACAATT 119760 AATTATCATT AAGATTTAAG GGTATATATG AATATTTTAA TTAATAAACG TA~l-~-l LLLLA 119880 TTAGTTACCC TTGTAGGTAT TCAACTAAAT GTAACCGCAA AACnAAATTC TTCTAATTCT 119940 G~LC~LL~AG TATTAAAACA GAAAAATATC GAACAACnAC AAGCGGATAA TGCAGCAAAT 120060 TTAATTAATA TCTTGCCAGG TGTGAATATG GCTGGCGGGT TTCGCCCTGG TGGGCA~ACA 120120 GTAACAGTAG ACA~AGGAAA TTATTCTCCT CAATATGGTA ATGGTGGTTT TGCTGGAACA 120300 GTA~AATTTG AAACTAAGGA TGCTAGGGAT TTCTTGCAAG A~AACCAGAA AATAGGTGGT 120360 -77.73-SUBSmUTE SHEET ~RULE 2~i3 CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/05320 TTTTTAAAGT ATGGA~ATAA TAGCAATAAT AACCAAAAAA CTTATAGTAC TGCACTAGTT 120420 TTACA~AATG AACAAAAAAA TATTGATTTA TTACTATTTG ~Ll~l~lAAG AAATGCTGGC 120480 GATTATA~AA GACCCGATAA TAGCAAAATT ~LllllL~AA A~AATAATCA AAAAACCGGA 120540 TTAATAAAAT TAAATTGGCA AATTTCACCC GAGCATTTAC TCACATTATC GA~L~lLlAT 120600 GGTATTCATA AAGGCTGGGA GC~lLlCGCA GCGAAAAGAG ATATCCTACC TAAACCAAGT 120660 TTGAGTGATA TAATGCGTTA TGGTACTGAT ATAGCGTGGA AACGTA~ACT GGTTTATCGA 120720 GATCAAAAAG ATGAAAATTA CACATTAAAA TACAACTATC TACCTGA~AA TAACCCATGG 120780 ATTAACTTAT CTACTCAGTT CAGCTACAGT AAAACCACAC A~AATGATAT GCGTCCCAAA 120840 GAAGCATCTT CAGGATTAGT GGGTAGCTTA GGTAATCA~A GCTGGATAAC TTATTCAGAT 120900 CTTACTTTTG ATATAAATAA CACAAGTACT TTTAATATCA A~ACTACTGT TCATGAACTA 120960 TTATTTGGTT TGCAATGGTT AAAAAACACA AGA~ATACTT TAATGTATGA TAAAAGTA~A 121020 GTGAGA~AAG CGGATTATAA TTATGGCTAT TTCCAACCCT ATTATATGCC ATCTGGACGT 121080 CAATATACAC AGGC~LlllA TTTACAAGAT CA~ATA~AAT GGAAGAATAT AATTTTTAGC 121140 ACAGGAGTGC GTTATGACCA TATCAATAAT ATAGGGCAGA A~AATTTAGC ACTAAAATAT 121200 AATGATATCT CTGCAGGACA TGATTATAGC CAGA~AAATT ATAATGGTTG GTCTTATTAT 121260 TTAGGTTTAA ATTATGATGT A~ACCATTAT TTAAGTTTAT TTACGAATTT TAGTAAAACT 121320 TGGCGAGCAC CTGTTATTGA TGAnCAGTAT GAGACGCAAT TTAAGCAATC lL~l~lGCCT 121380 GCAACCTCTT TAAATTTAGA A~AAGA~ATG ATTAATCA~A CGAGAGTGGG TGGAATTATT 121440 AATCGCGGCA AGAATGAAAT ATTTAAAACC AGAGGAGTTA ALl~l~LAGG CAATGCTGCA 121560 GATACCAATA ATAAGGTTTG TCCTA~AATC ATTGAAAATT ATCGTAATTT GCCAGGTTAT 121620 ACATATTCTT ATGTA~AAGG AAAACGTGAC ACCTCACCAA GA~ACCCATG GGGTAAAACC 121740 TCAACATGGA TTGCTGA~AT TCCCCCTAGA AAAGCAACTA CTGCTTTAGG TTTCAATGTT 121800 CCA~AATATT ATCTCACAGT AGGTTGGCGT GCTGAGTTTG TAAGAAGACA AGATCGATCG 121860 -77.74-SUBST~TUTE S~tEET (RULE 2~) .

W 096/33276 . PCTAUS96/05320 ACAGGTAGGA ATATCAAATT TAGCCTATCT CAGA~ATTTT AGAATA~ATA GCCCGATTGA 122100 ATCTAATCGG GCTTTATCAT AACTATAATT AGATCATA~A A~AATGTAGA GATAATA~AT 122160 ATAATTnCCT ATACTAATTT TAGTATTCTT TA~AGAGCAA ATTTA~ATAA TA~ATCCA~A 122220 TAAGTACGAC ATCTTAAATT ATAGATAAAT ATCA~AATTA '1~1111ATCT TTACCCTATT 122280 ACTTTCCATA ATAGAAACTA AACTTACCTA A~AATTTAAA TATAATTTAG CATCTnGCTT 122340 AACAACAAAG TCAATACACA l'-L l ~''1"1~ lAG TTTTCCTTTC TTTCCGATTA ATATACCCCA 122400 AACTATATAG C~L~11~11C TCACTAACTT TCCTACTATA GGAATATCAT TAGCATAAGC 122460 TATGAAGAAG AAAGTTA~AA CAGAGGCATT ATGTAATATA AGTTATTTAT ATAATTTAAC 122520 ATAACTTTCC ATATAACAAC AACGCATCTT TATAACATAA TTGCAATGTA '1"1'~'1'~'1"L'1''1'A 122580 AATTTATAGC AATTACCTAA ATAGTA~AGA GTACGAATAA AGTACATATA GGCTATTAAT 122640 TACTTTAAAA AAAATTA~AA TATATTTGTA GATTTATGGA CAATTACATT TATCCTTTA~ 122700 AAGGTAGTTA ATCTAGAGAA A'1"1''1''1''1"1'ATA GCAATACAAC AAGTTTACAA GGAATTCA~A 122760 TATTTTTAAT TTTTAGAAAA AAACA~AAAC CCTAGCTTTT CAACTAGGGT '1'~'1'~'1''1"L'L'1'A 122820 TGTGATTTAG ATTTGTATCT GATAACCTGG CGGTGCCCTA CTCTCACATG GGGA~ACCCC 122880 ACACTACCAT CGGCATTACA GC~'L'L'L~'ACT TCTGAGTTCG GTATGGTCTC AGGTGGGTCC 122940 ACCGCACTAT CGCCGCCAGG ATAATTCTTT GATAACTCGT ~'1''1"L'L~'L~''L'L TTATCTCTCG 123000 'L~L~LLL1AT ~L~LC~L1AC TCA~L~LLLC CTCTTACCTT TCA~LC~LLC TTATTGGTCA 123060 CAAGCTGAAT CCGATTTTCT TTCTATTAAG L~LL~LATAT TTA~LLl l~'L 'L'L~L'l"l'AGTC 123120 TTTTACTTCT CTTTCGCTCT GCTTTTATTT GCTTCGCTTT TCA'1'~'L~'1"1'A CTTCACTTAG 123180 CACTTATCTC TTCCGCATTT AGCTACCCGG CAATGCGTCT GGCGACACA~ CCGGAACACC 123420 AGTGATGCGT CCACTCCGGT C~'L~'LC~'1'AC TAGGAGCAGC CCCAATCAAT CATCCTACGC 123480 CCACGGCAGA TAGGGACCGA ACTGTCTCAC GAC~'1''1'~'1'AA ACCCAGCTCG CGTACCACTT 123540 -77.75-SUBS i I I UTE SHEET ~RULE Z~i3 W 096133276 PCT/U~ 320 ACCTACTTTC GTACCTGCTC GA~-Ll~l~lG TCTCGCAGTT AAGCTTGCTT ATACCATTGC 123780 ~LlC~llAGA ACATCAAACG TTAAAGGGTG GTATTTCAAG GTCGCCTCCA CAATGACTGG 123960 ,.

GCTATAGTAA AGGTTCACGG G~L~111CC~ TCTAGCCGCG GGTACACCGC ATCTTCACGG 124080 CCGTTTACTG GGGCTTCGAT CAGGTGCTTC L~lLlCGATG ACACCATCAA TTAACCTTCC 124260 AGCACCGGGC AGGCATCACA CCCTATACGT CCA~LllC~l GTTTGCAGAG TG~L~l~lll 124320 CACCCGAGTT CTCTCAAGCG CCTGAGTATT CTCTACCTGA CCAC~l~*~l CG~Llll~AG 124500 TACG~lllAG TAAAGCCTTT CGCTTAGTGG CTTTTCCTGG AAGTGTGGTA TCAGTTACTT 124560 CAGCTCCGTA GAGCCTCGTC ATCATCTCTC l~l~llAAGG AAGTCCGGAT TTGCCTAAAC 124620 GTGATACGTC CAGCCCACCT CTCGATGAAC ~Ll~llCCGC TTACACAACG CTCCCCTACC 124520 CGCGCAGGCC GACTCGACTA GTGAGCTATT ACG~LLL~ll TAAATGATGG CTGCTTCTAA 125040 GCCAACATCC TAG~L~l~lA AGCCTTCCCA ~LlC~lLlCC CACTTAATAT AGACTTGGGG 125100 CATCCGCTAA llLll~AACA TTAGTCGGTT CGGTCCTCCA GTTAGTGTTA CCCAACCTTC 125400 -77.76-SUBSTmJTE SHEET tRULE 26) CA 022l874l l997-l0-2l W O 96/33276 . PCTAUS96105320 CTGACCCATT ATACA~AAGG TACGCAGTCA CAAGGTTGCC CTCGCTCCCA CTGCTTGTAC 125580 GTACAAGGTT TCAGGTTCTA TTTCACTCCC CTCACCGGGG '11~1L11CGC CTTTCCTTCA 125640 CTTCA~ACAG GATATCACGT GTCCCGCCCT ACTTCTCGTT AGCTTAGTAC CACAATATGG 125760 TTTTTAGATA CGGGATTATC ACC~'1'~'1"L'1'~ ATTGTGCTTC CCAACACATT CTCCTCACTA 125820 GA111~1111 CCTCGGGGTA CTTAGATGTT TCAGTTCTCC CGGTtTGCCT CAACAAGCTA 125940 TGAATTCACT TGTTGATAGT AGA11~11~A TCTACTGGGT TTCCCCATTC GGATATCTTG 126000 GATTA~ACGC CTCTTATCGA CTCATCCAAG ~L111CGCAG ATTAGCACGT C~L1~LLCGC 126060 CTCTGATTGC CAAGGCATCC AC~'L'1'~'1'ACG CTTAGTCACT TAACTATACA ACCTCAAATG 126120 TTTTCAATCA CTTTACGTTT TCACTTCA~A GTGCGGTCAA TTTGATGCGT ATTTTCATTC 126180 AACTAAACAC TTGATTGCTT TtGTTCAATC AAGATTTTTT TACA~AACAG ~'L'L'L'L~'L'L'L'1' 126240 TAGAGTTTCC TTTTCAGTTC TCTCTtTCAC TTTACTGTTt TGCCTACTCA GACTTTCTCT 126300 CGA~AATCTC '1''L~'1''L'11~AG ~LL~LLLCCA A'1"L'L'1"1"1'A~A GAACAGTAAG ACAATCTAAT 126360 A~AGTTATCT TTAATTGGCG TCCCCACGGG GATTCGAACC CCGGTTACCG CCGTGA~AGG 126420 GCGATGTCCT AGGCCTCTAG ACGATGGGGA CATCAATTAA AGATACTCTA 'L'L'1''1'~''1"1"1"1''1' 126480 A'L~'1"1''L'LAAC GTTTATTTTT CAACGTTGCT TTCGCTTCGT TTTTAATCTT GTCTACAACT 126540 ATCAGCCAAT ~1~L~1GAGC ACTCGCTGTC ~L~LC~L~L~LC AGTAAGGAGG TGATCCAACC 126600 GCAGGTTCCC CTACGGTTAC ~11~L1ACGA CTTCACCCCA GTCATGAATC ATACCGTGGT 126660 A~ACGCCCTC CAAAAGGTTA AGCTATCTAC TTCTGGTACA ACCCACTCCC A'l'G~l~'L~AC 126720 GAGATTCGCT CCACCTCGCA GCTTCGCTTC C~L~L~LATA CGCCATTGTA GCAC~L~L~1 126900 CTGGCAGTCT CCTTTGAGTT CCCGACCAAG TCGCTGGCAA CA~AGGATAA GGGTTGCGCT 127020 C~LLGC~GGA CTTAACCCAA CATTTCACAA CACGAGCTGA CGACAGCCAT GCAGCACCTG 127080 -77.77-SUBSmUTE S~EFr tRULE 26) -CA 02218741 l997-l0-2l W 096/33276 PCTrUS96/05320 GTGGAATTCT ACCCCTCCCT A~AGTACTCT AGTTACCCAG TCTGAAATGC AATTCCTAGG 127500 TG~ll~l-l-~l GTATTTAACG TCAATTTGAT GTACTATTAA CACATCAACC TTCCTCAATA 127680 TCCCCCCATT GCGCAATATT CCCCACTGCT GCCTCCCGTA GGAGTCTGGA CC~-1~1~'1~A 127800 CCATAAGCCA GATTCCCAAG CATTACTCAC CCGTCCGCCA ~-lC~l~AGCA AGAAAGCAAG 128040 CCATGATCAA A~-l~ll-AAT TCAAGTTCAA TCGCTCAATA AACTGCTTAG CTATAAATAA 128160 AGCTATAGCC ACCATTAAAA ~-ll~ll~ACTG CATTGACCTG GCGCGCTCGA CAAGATTCGA 128520 TGC~lC~-llG CGGAGGCGTA TATTAATGAT TTAATAAAAC CTTGTCTAGC A~l-l--l-l-l~AA 128640 AAAAAATGTT TGAGCGATAG ~l-l-l-lllATTC A~-l-~ll~lllA A~ATACACTA L~lll-llCGAC 128700 TATTTTTACA ACTTGGCGAA TCATTATATA TGTgGAATCA TCCAACAATT ATGAATTTGT 128760 -77.78-SU8S i ITUTE SHEET tRULE 26) W 096/33276 PCTrUS96/05320 TTATTACGTT CAAAATCTAG CGGTAACGTT TTATGCGA~A TTTCTATTGC ACTTAAGCCT 128820 AATTCTTCCA ACGCAACTAA ATTCATTTTG AATCCACGTT TATTATTCGA A~AAACAATT 128880 GTGCCATTAT TCGACA~AAC 1C~111LA~A TTGCGCATTA ATTTCACATG A1~1C~11GC 128940 ACATCCCAAC 1~1~LLC~AT ACGTTTAGAA TTCGA~AACG TCGGTGGATC CGCA~ATATC 129000 A~ATCA~ATT GACGATCACA 1LLLL~LAAC CATTGAAGGC AATCTGCTTG AATTAATTTA 129060 TGTgGTTTAC CTTCAATATC ATTCAAAATA AGATTTTGCT CCGCCCAATT AAGATAAGTA 129120 GAACCTGTAT AAGCA~ATAA GTTCAAGA~A TCTTTACCCT TTGCCAACTC ACCAATCATT 129240 LL1~1L~L1A AACGGTGATC TAAGAATAAT CCA~L~L~1A AATAATCTGT CA~ATTTACC 129300 CAAAGTTGCG TGCCATATTC ATTCACATAA AAGTATTCGC CTTTATTGGC TAA~11~L~A 129360 TATTGATTTG TAC~L1"LLLG L11~L~ACGA ACTTTGAGGA TCAACTTATT CGTTTCCACA 129420 C~L~L~ACTT GCA~AGTTGC AGTAACGGCA TCTAACA~AC GCTGACGAGC TTTATTTTCA 129480 GCTAAATTAT ATTCTGGCAA ATCAGCATCA TATA~ACGAT AAGCGTCTAA LL~LL~LLGC 129600 TTTGCCCATT TGCTAATTTT CTTAATATTT L1LL~-LAATC GATTAGCA~A ATCGGGGGCG 129660 ACCTCCGAAG TGCGGTTA~A TTCTAGTTCC TTTTCATCTG TAATTGCGTC AGA'L1LLC~L 129720 TCTGA~ACTT GATAATTCTT TTGCACACAA TCTAGTGGGC CALLLLLLGC TTTA~ACTGT 129780 CGGCTGGCAC GCATTCTCAA ACAATCAAGC AATGTGGATT CGCTACTA~A AACAGA~ACA 129840 TTCCAACCGC A~AATTCTTT TTTAAGTCTT TGCCCA~ATA CAGAATAGAG CGCGATTA~A 129900 GCTGGTGTTG TTCCTA~ACG TTCGCCATAA GGTGGATTAC AGATAACCGT ACCGACTTCA 129960 TTTA~ACGAG GALLL11LAA CGCTGCCACA TCAGCTTGCT GCCATTTAAT TA~ATGTGAA 130020 ACACCTGCAT TTTGTGCATT TTTCTGCGCC L1LLLL~ATA CGCGGTGATC GAGGTCA~AT 130080 CCATA~AAGT GCGGTTGAAT TTCACGTTGT '1LL1~LL~LG CTAATTCAAT CGCTTCATTT 130140 TTTACTTTTT CCCAAGCCGA TTGATTATGC GCTTTCCA~A AATCA~ATCC CCAATGTA~A 130200 CGATA~AGTT GCGGCGCAAT TTTGGCTTCC ATTTGTGCCG CTTCAATTAA AAGCGTACCT 130260 ATGTAATGCT TCCCCACTTA AATCTA~AGA AATCACTA~A TTTTCACGAT TCA~ATAAGC 130440 -77.79-SUBST~UTE S~E~T tRULE 2 W 096/33276 PCTrUS96/05320 i:
TTGGTTGGTT CCATTAAAAT CGACA~AGAA TGTCACTCGT TCATCA~ATT GTGCTAACCA 130620 ATTAAAGCCT GA~ACAGCCG CATA~AGATC CA~ATCACTG TA~ATTTTGG TTTCAATCAA 130680 AGGA~ATAAA ATGCGTGAAG CAAGGCGTGA CCA~AGCA~A GTGCGGTATA AA~lllC~lC 130740 GAGTTCAACT TTTAATAATT CTTCAAAGCC ACGAGAAGTC GTTGCA~ATA A~ l~AT 130860 GATCATCATA GCGAGTTA~A CTGTA~AAAG A~AAGCCCTG A~llll~llAA ATCAGGGCTT 130980 CGAGCTACCA AGCTGCTCCA CCCCGCgtCT GATGGGGCGT ACTATACTCG CTTA~AATTG 131100 AaTTGCAAGA ATTAAACAAA ACTTGATGTA t~ LA ATAAAATGTT CAATATGTGG 131160 TTTTATTAAT CAACTTCGCT AAATAACACT G~'1"1'~'1"L'1"1'C AGTAAATTTT GATAGCGTAT 131220 GCAGCCCTAT TGTrGCTTAC TTTAGAATTA AAAAATGTCG ATGCTTAAAC ~lll~l~GTT 131280 CA~AACTTTT TCTATCTCAA TTATTACCGC ACTTTTGGTA GCTTGTACCT CTAACACA~n 131340 A~ACACTCAG ATTCCAACCn CCTCA~ATGG GAGTGATCCT CAACAATTCG GTGTGCA~AA 131400 TATACCAATC GAACTTATCA GCA~ACCGCT CTTGTGCCTG lLlC~lATAT AGAAAACCAA 131460 AGTGCGGTAA TAAATCAAGG CGA~llllllA ACACAGCTTT CCAATATA~A A~ATTATTCA 131520 AGTAAACTTT CCACAAATTT TTACGATAAT TATGAAAAGA ATTACA~ATT GGGTTCTTTC 131580 TGGGGCAAAT ATTAATGAAC TCACTCAATT TAATATCCAA CCACA~ATTA TGCGTGGCTT 131640 TGATGGATTT CA~AATGTGC TGATGACAGG CTATTATTCG CCTATACTTT ATGCTCGTCA 131700 TCGAGCACAA ATTTATGCGG GAGCATTAGC GGA~AAAGAT TAGAGTTAGC ATATAGCGAT 131820 CGTTTATTAG TAGAAGATGG CGAAATTCCA A~AGA~AAAA TGTCTATTCA AGCAATTCGA 132000 GAATGGGGTA ATCGTAATCC ~l~lC~lATA CAAAGCTTGT TAGAACGCAA TGAAGCTTAT 132060 GTAll~lllA AAAATGATCC AAGTGGCA~A GTGA~AGGCT CTGCGGGCGT TC~'1'~''1"1'~'1'A 132120 -77. 80-SU~S i 11 UTE ~E~ (RULE 2~i~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GCAATGGCTT CAGTGGCATC AGATCGCAAT ATTATCCCAT CTG~lLCl~l GCTTTTAGTC 132180 GAAGTACCCG ACATTGATAA TAACGGA~AC TGGCTTGGCA CACACA~ATT ACACTTAATG 132240 GTTGCACTTG ATGTAGGCGG TGCAGTGA~A GGTCATCACT TTGACTTATA TCGTGGTATC 132300 GGTGCTAGAG CAGGACATAT TGCAGGGCTT TCA~AACACT ACGGTAGAGT ATGGGTATTA 132360 TGG~LL~llG GGTCGTGGAG GCCTTAGCAC GATCTGGCAT TGGCGAACTC ACATTAATTG 132540 ATATGGATGA TATTTGCGTC ACA~ATATCA ATCGCCAACT TCCTGCGATG AGCGGCACAA 132600 TCGGCA~ATT A~AAACTGAA GTCATGTCAG AGCGAGTA~A ATTAATTAAC CCAGAATGTA 132660 GCTATGACTA CGTCATTGAT GCCATTGACA ATGTGA~AAC TA~AGCGTCG CTGATTGCTT 13?.780 ATTGTA~ACG TAACA~AATT AATGTGATTA CTATTGGCGG TGCTGGCGGT CA~ACTGATC 132840 CAACCCAAAT TCA~ATTGCC GATCTCAGTA A~ACCATTCA AGATCCGCTG CTCGCCAAAG 132900 TGCGGTCAGT TTTACGCAAG GATTACAATT TTAGCCA~AA TCCA~AGCGT A~ATTTAGTA 132960 TCGATGCGGT ATTTTCAACA CAACCTTTAA TATTCCCACA AATGACTGAA GG~L~Ll~lA 133020 TTG~LLLLLL TGCC~LLL~L CGTGTAATAG ATA~ATTACT A~AGA~AAAA TCTTAATCAC 133140 ~l~LL~AAAA TGCACATTGA CCATA~ATGT GCALLLLLLA TTGAATGA~A CCTATTGACT 133200 TTGA~AATGA A~AATTTTCC ~'L~'L'l''L'L'l'AC TATA~AATCG TTGCAATTTA TATA~AAAGG 133260 CGTACTCTTT TTTCCCTTTG AGAATTACTA CCAACAAGTA AGGA~ACATA AATATGA~AA 133320 CCGATGTATT AGCATCAGTA A~ACCTTTAG GCTTTATTGT TTCATCTATT GCAGATGGCG 133440 TAACTGGTAC ACAAGTCCTT GTTCCTGCTG GCGCCTCTCC GCATGATTAC AATTTGA~AT 133500 TATCTGATAT TCA~AAAGTA A~ATCTGCAG ATTTAGTTGT ATGGATTGGT GAAGACATTG 133560 ATTCATTCTT AGACA~ACCA ATTAGCCA~A TTGAACGTAA A~AAGTGATT ACCATTGCCG 133620 ATCTTGCGGA TGTA~AACCT TTATTAAGTA AAGCTCACCA TGAGCATTTC CATGAAGATG 133680 GCGATCATGA TCATGACCAT AAGCACGAAC ACA~ACATGA TCATA~ACAC GACCATGACC 133740 ATGATCATGA TCATA~ACAC GAGCATA~AC ACGACCACGA ACATCATGAT CACGATCATC 133800 -77. 8 1 -SUE~S i 11 UTE S~tE~T (RULE 2~i) CA 022l874l l997-l0-2l 096/33276 PCTrUS96/05320 ACGAGGGTTT AACAACAAAC TGGCACGTTT GGTATTCTCC AGCTATCAGC A~AATTGTTG 133860 CACA~AAAGT AGCGGATA~A TTAACTGCAC AATTCCCAGA TAAAAAAGCG TTAATTGCAC 133920 AAAATCTTTC AGATTTTAAC CGCACTTTGG CAGAACA~AG TGAAAAAATT ACGGCACAAC 133980 TTGCAAATGT TA~AGATA~A GGTTTCTACG TTTTCCACGA TGCTTATGGT TATTTCAACG 134040 CA~AAACTTT AGCGCACATT A~AGAAGAAA TTGATGAACA TAAAGTA~AT TGCTTATTCG 134160 CAGAGCCTCA ATTTACGCCA A~AGTGATTG A~l~lLlAGC GAAAAATACT A~AGTCAATG 134220 TAGGACAACT CGACCCAATT GGCGATA~AG TTACTTTAGG TAAAAATTCT TATGCAACAT 134280 CAATGACCGC ACATAAAAGT GCGGTCATTT ~llllll~lAA ATTTGATATT TAGTTTTATC 134400 TCCAATATCA AAATGCA~AG GCATTCGCCA 'l"l"l"l"l'~'l'ATC GCTAAAACTA A~AGTAATAC 134460 CAAGCAAGCC ACAAATATCG GCTGTAAATT TAGCA~AGGC ACGCGGA~AC AAAAATATTC 134580 TTTAAAACAC A~ACCACCTA AAGTAAGTAA CGCACCGCCA AGAGCCAACG CAGGATAATG 134640 ATTAATATAA AAAAGTAGTC CAATCCAAGT TGCA~ATTGA AAAAGCAATC GAAAAGATTT 134700 TAAGTA~ATG TGTAACGAAG AGGCACAACA GGTTGCCGCA ATTAATATAA ATGTGAGTGA 134760 CATTGTATAA ATGTTCCTTT TTATGAATTA CA~ATTAAAA ATA~ATATAT CCTAAAAGTC 134940 AGAAATAAAA AGTACAGTCA ATTTA~AAAC AGGTTCTA~A TTAACCGCAC TTTTATTATT 135000 TCAGTTTTAG CTTATCAAGA All"llllGAT GAATGCCACC AAAACTGCCG TTAGACATCA 135060 CTAAAATATG ATCCGTAGGT TGAGCCTTTG CAACAATCAT ATCCACTAAT CGATCTA~AT 135120 TTGCATTCCA ATAAGCAGGT TGTACACATT GGTTTGCAAT ATCTGCCACT TCCCAAGA~A 135180 ~'l''l'~'l"l'~AGG TTGAAGCATA AACACGGCAT CAGCTCGACC AAGTGCAGGC GCGATGTCAT 135240 CTTTATGAAC ACCCATTTTC All~l~llAG AACGAGGTTC AAGCACTGCA AGAATACGAA 135300 CACCACCACC AACTTTATCT CGTA~AGCGG TTAGCGTAGC AAGAATAGCT TCTGGATGAT 135360 GCGCAAAATC ATCATA~ACC GTAATGCTAT TAACTTCGCC TTTCACTTCT A~ACGACGTT 135420 -77.82-SUBSTITUTE SHE~T tRULE 2~

CA 022l874l l997-l0-2l W 096133276 PCTrUS96/05320 TTACTTCTGC CA~lll-ll~l CCATGATGGA AAACCGCAAA ATGTGAAGCA TCATTTGTAA 135600 TACGTTCAGC A~ACCACTCG TTATCTTTGC CTAAAAATTG ~l~llGAGAC CAACATCCCA 135660 ATGCCAAAGT ll~llllGCA ~'ll-l~ll'~'AC TCGCCGAACT TAATACCAAG CCACTGGCTG 135720 GGATAGTTCG AATCATATGA TGAAATTGGC GTTGGATCGC TTTGAGATCA TCA~AAATAT 135780 CAGCGTGATC AAAACTAATA ll~lllACGA TAAGTGTACG TGGATTGTAA TGGACAAATT 135840 TATCTCCTAA ACGAGCTGAA ATGCCAAAAT TACCCGCAAT TCCGCCGATT A~AAAACCTG 135960 ATTTTAAGCC A'1-L11'~'1"1~'1' AAGACCCACG TTAGCATACC TGTGGTCGTT ~lllllCCAT 136020 TTGGAATAAT CTCGATACCT TG~l~ll~-lA AAAAAGTGCT CATTGGAGGG TAAACATTAG 136260 ATGTGCCACA AATACCTAAG ATATGAATAT GTTTCATTGT Alll~l~l~l TGATTAAGGA 136380 AAACGAA~AA TATGATAAAA CAACTTCTAT GAACTTTCAA AAGAAAAGAC CATCATACCA 136440 ACAATGAAAT TTAAGCGATA AAGCAATTTC AGAAGCACAA TGGCTCACTA TTTACA~AGA 136560 A~ATAATCAG CCGTTCTATG TAGCAAATCT TCCTGCATTA CAATTTGGAA AAAGTATTCA 136620 TTTAAGCAAT TCGCTCA~AA CCAGCTTTCA AATCTGCAAT TAGTTCATCC ACATTTTCAA 136800 GTGCAATTTC TT~lG~-L-lGA TTACAAAGAA TTAGAGACTC A~ATCCTCCC CATGAATAAG 136920 CCATAGCGAA CAGTTGA~AA TGATCCATAA ATTTTGATAC TTGCTCTGAA GTTAATCGCT 136980 GGGTTAATTC A~AAGAAAAT A~ACCACTGC TTCCACTA~A ATCACGTA~A AAGAATTCAT 137040 ACCATTTTGC CACTTTAATA CTGCTTTCCT GAl~ll~lll TAATCGTACC CCCA~TGTAC 137160 -77.83 -SUBST~TUTE SHFET tRULE 2 CA 02218741 l997-l0-2l AA1~11-~1~1 AAGTTGATCC CAAGTTCGCG CATTCGCAAC GGCAGTACCA ATCATAATAT 137280 TCGGTGCTTC TAAGAAAAGT A~11-11~1AT 1CG~11GAAT AAGCGTTGCA ATATCTTCAC 137520 CCCCCTCCAT TTCGCACATT A~A1~11~1A AAGCAAAATG TGTTAGCGTC C~l~ll~lGC 137760 CATAAAATAA TTCGCCTTTT GCTCTACGTT GAGTAGCGTG ~11~1111ATCT TCAATACTGT 137820 CAAATAGTAA TGAAGAAGCT CGCTGTA~AA CAGGGTTTAC CGA1C~-L-L~1 GAAAAACGTT 137880 TTTGACGACC AGAATGAATA AACATTGTTG AAAGATCATA 11-1--1-~1--1--1GC ATATATTTCC 137940 TTATTTAAAT TAACTTATAG GGCA~AAATA ACTATGGTTT CAATTCCTAT CCGCACCTGA 138000 TTTTACTTCA TCTGCGGTAT TAGGCAATGG A~AAAATAAA GAGAAAACAA CAAATAATTC 138060 ATAAAAAGCG ACCTTAGGTG G~-L-L-L-L-L-L1A TCATCAGAGA TAATTTAGAA TAAACCATCT 138180 TTAGCTAAAG TGCGGTCAAT 1LL1-~1ATGA AATTCAATAT CCCAATTTTC CTAACGATCT 138240 TTCGAGTCAT TTTGATTCCT '1-L-1-L1C~LGA TTGCATTTTA TTTACCCATT GAATCATCTC 138300 TGGCAGAGCT TGGGGAACGT AGCAAAATCG CA~-1~-1~-1-LG GTGGGGAAAA TGGA~AACCA 138600 CAGCGCA~AT GTTAGCACTA GGCGGATTAT TATGGCGTTA TAACAACTAT ATGGAAATAG 138660 TACAAGTAGC A~AAGGAAGC TTGCTAGATA ATATTCAATT ATAAATTTAA ATAAAACACA 138780 r GTTATTTTTT ATGATAACCA TCTATATTTG AGTTATTTTT AATCAAATAA AATATTTTTT 138840 -77.84-SUBSTITUTE SHEET ~RULE 26) ~ =
CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 A'1'1"1"1"1"1"1'CG TTTGACAGCA ATATATA~AT CCGTAAAATA CGCCCC~1"1G TCACGCAGTA 138900 CGGGGTCGCG AGTTCGAGCC '1'C~'1''1''1'CCCG CTCCAATTTG CCCGAGTGGT GGAATCGGTA 139020 CACGACCCAC CACTTAAAAA TAAAGTAAGC ACCGAAAGGT ~1L11111AT TATCTAAATC 139260 CTTCTACATC GCCCCAATGA GTTACTTTCG TTGAGCCAGG '1''1"1'~'1''1'AAGC GCTTTATAGT 139440 ATGGTTGGCG AGTGATTAAT AACACATCTA ACTCATCGCC ATCTTCATCT AAA~111~1G 139680 ATGCCGCAAC TTTACGGTTC CATTCGATTT TATGGCAGCT AC~'1''1'~'LGGA ATTTCATTTA 139800 CTACATTGAT AATGCCAGCA TCTACATCGC CTGGCGTTAA AATTTGATTA A~ATCAGCCA 139860 '1"L'1"1'~'1''L'1'CC TTCATTTTAT CAAGTTAAAA AACGCAACAA GTATAGCAGn lLll~LGCGA 139920 TTTTGACCGC ACTTTATCCT AAATAAAACT CACGCAAACG TTTACTTATC ~L1111ATGA 140040 AACTTTAGAA AAAACATTTG AGCTCAAACA ACGTGGTTCA A~'L~'L'LC~'LC AAGAAATTAT 140160 TGGTGCTGCA GGTTTCCCTG CGGAATCTGT CTTTATTGCC AC~'L~'1"1"LAG TTGCAGGATT 140280 AGGCTCTATC TTAATCGGCT TATGGGCA~A TGCACCAATG GCAATTGGTT GTGCAATTTC 140340 TCTTACTGCT TTTACAGCAT TTAGCTTAGT GATTGGTCAA AAGGTCGCCA TTCCCGTnGC 140400 -77.85-SUB~ 111 UTE ~i~ FET tRULE 2~i~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 A~1~11111A CTTTTAATTG CCGCA~ACGG TGTTGGTTTA GTCGTCAGCA ACCAAGCTGG 140580 AGCGTTAATT ATTGGCCTTG AAAAAATGAA AATTA~AGGC GGCATTTTAT GGGTAATTAT 140700 CGCTATTACT ATCGTAGGTT TAATTTTTGA TCCA~ATGTA A~ATTTGGCG GAGAGATTTT 140760 CA~AATGCCA ACCTTTGGTG A~AATTCTCT ~11--1~11ACAA TTAGACTTTA TGGGCGCACT 140820 CGGTACAATT CGTGCAGTTG CAGGTCAAGC AGACTTGCTT GATA~AGATG GTCA~ATTAT 140940 AGGTATTACT GCTATCGTTG TTG~1-~1-~-11 ATTCCTATTA ATG~-11L-1~1 TCCAACCATT 141120 AG~11-1~11A GTGCCAGGCT ACGCAACTGC TCCAGCATTA ATGTATGTTG GTTTATTAAT 141180 GTTAAGCAAT GTAAGCAAAT TAGATTTCGA TGA'11-1C'~11' GGCGCGATGA GCGGATTAAT 141240 ATAAGA~AAG GGAAAAGCCT TCCCCTCAAT TTTAATCACA AAAGTGCGGT GA~ATTTTAC 141480 ATTTACATAA G~-11~1111A AAATTGGCAT TAAAATCCCT CTGGTTTACA ATTTACCAGT 141600 A~ATCTTTGC CCCGCCCAGT TTGCAACCAC TTCCCCAATG GTTGCCCCAT ATAAACCGCA 141660 ACAGAGTAAC CATTAATATC CGCCACGCCA 111-1~-1AATT TTCCATCGAA AATACTGGAT 141840 TCGCCCATAA AGTTAGCCAA A~ACAGAGAA TTTGGTCGGA GATA~AGCTC TTTCGCCGGC 141900 G~-LLLLLGCA TAATTTTACC TTTATTCATC ACAATCACTT CATCAGATAC CGCAAATGCC 141g60 T~1~11--LGAT C~-L~L~-L~AC ATA~AGCGAA GTAATGCCTA AAC~11~11~ CAATTCACGG 142020 A111-L-1-1~AC GCATAGAACG ACGTAAGTTT GCATCTAAAT TACTTAATGG TTCATCAAAC 142080 -77.86-SUBS i ~ ~ UTE SHEET ~RULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 'L~-l-ll-lACAC GCTGAGCGCG LL~ll~ll-lG CCAATGCCTT GCATTTTTAA GCCGTAGCCC lg2260 ACGTTATCGC CAATGCTCAT ATGCGGGA~A AGCGCGTAAG ATTGGA~AAC AATACAAATA 142320 TCTCGATTCT GAATAGAGGA LLll~-llACA TCTTCGCCAT CAATAAATAT TTGACCTGAT 142380 GTTGGATTTT CTAATCCTGC CACTA~ACGT AATACGGTGG TTTTACCACA GCCT.GATGGC 142440 GCTTTACCAA ATG~L-ll-l~l GATATTTTTT AATACTAAGA AATCATTATT ACTCATAATT 142560 TTTACCTACA ACTTAACGAG TTAATTCATT LllllCGCTT TAGAACGGGA AATACGCGTA 142620 TCGCCTACAA TCCAGTCGAA A~ACAAAATA ATTGCCATCA TCACAACAAT TAAAATAGAA 142680 CCGTATGCAA TCGCAATGCC GTA~Ll-~lCCG l~llC~ACAC GATTTAAAAT ATATGCGGTA 142740 GACGCGAGTn TCTGCTGTCA CTAAGAATAT AATCGCACTT ACC~1C~1~A TTGCACGAAC 142800 GA~ACTAGTC ACTA~AGCAG A~AGCAACGC AGGTTTTAAT AATGGCAATA CGATAAAGCA 142860 CAAl~l-lllC CACGAACTCC CTTTTA~AGA AAGCGATGCT TCATCAAGGG ATTTATCAAG 142920 CTGTCCTAAC CCAGCAATCG CTGCTCGCAT ACCAATGGGT A~ATCACGCA TTACCATTGA 142980 GGA~lllLllA C~lLG~A~AT CTTTACGCAC CACAATATAC GCAATCAATA ATCCAAAGAA 143160 TACGCCCCAG TTTACAGTGA AA~llCC'~lA GA~AATACTA CCGTAAAGTG CCATATTA~A 143340 CACATCGCCA CGATAAGATT TCCCCGA~AC AGTGACATAA GAGCGGTTAC CAATCCA~AT 143460 TGAAGCATAA TCAAGTTGTG AACCCGCAAT ATAGAAATAA A~l-ll~l~lGG CAATCACATC 143580 GA~ACTTCCA CCTAACACTA AAGGATTACT AAAGTCCGCC AATGATTGAA TGAATACAAT 143640 TAAGA~AGAA TTTGCTAATG CTGGACGCAG TAACGGAAAA ATAATCTGAT AGAACGTTTG 143700 ATAACGATTA GCACGCAACG TATAAGACGC LL~LL~AATA GACGGGTGTA CGGATTTTAA 143,60 CCCATTAAAA CCATAAAGCC AATTATGACT AGAAAAACCA AaATTCGTAC TTAAAAATTC 143880 -77.87-SUE~STmJTE S~EET tRULE 2~i~

CA 022l874l l997-l0-2l GGTTACATAA CCAGAACGTC CGAGCATTAA AGTAACCCCA AGTCCTACAA CAAATGGGGG' 143940 CGTGGTATAG AGCGCAAAGG CTAAACCA~A TACAGTAGAA ACGATGCCCA CAAAGCCCGA 144060 TAAGA~AAGC GAATTGGTAA TTACGCGGAC AATATAGCTC TGCGTTAAAA TTCGCATCAC 144120 ll~ll~lGGC GCAAAGGTAT CGCCGTCATA A~ACATTGAA ACGAAAATCG CCAATGTTGG 144180 ATAAACGATA AAGAAGA~AA TGAGCAAGAT AATGCA~AGC A~AGAAGCGA TGATAAATTT 144240 AAGTAACACA ATCACAGAAT AGCCCATACT AAllll~lAC ACCGTCGCAC TGATAAACAT 144360 AAACAGTACA GAAAGTGCGG TCA~AAATAG ~'l'~'l'~'l"l"l''L'l' GCTTGGGTTT GCTGTGGCAA 144420 GAAAGAAGCC CAGCCCATTG CCTCTAAATA TTATCTGAAG TACTTTCAAA CA~ACCGTAA 144540 TCAAGTGCAT TGGAAGGCAG AAGTGCA~AC GCTAACAAGG ATA~AATAAT CCA~AAATAA 144600 GCAGAATGCA TTATGGAAAG lllLlllGCG TTCATACAAC CTCGCAGTAA AGAAAACCTG 144660 AAGGCTTTGC ~ TGCACCGTAT TTTTCAAAGT CATAATTGAT TAATTTGAGT 144900 GAATCCCCTT GTTTCCAAGC TAAll~ll~A ~~ "l"lG ATAAAGCCCA ATCGACGAAT 145020 AATTTTGCAT TATCAATATT ACGCGCACCT TTTAAGAnAC TCACGCCACC TAATTCATAG 145080 CCC~llC~ll CGCACGGCAC AACTAATTCT AATGGCGCAC CATTGCGTTT TTCTAAAGCA 145140 TAAlC~l~LA AGAAACCCAC CCCAATTGTC nTTCGCCACG CGCAGAGTTA CGTGATGGCG 145200 TGATACCCGA TTTGGTATAT TGAGAAACAT TAGGATGTAA ~'l'~''l''l''l"l'AGG A~ATCGAATG 145260 C~l~lrlllC GCCCCATAAT TGAACGAAAG TTGCCAATGC AGTGTAAGCA GTACCCGCAC 145320 ATTTTGGCAC ll~lllAATA CCTAATTTTG CCAAACGTTC AGTATTCACA CCGA~ACCTA 145440 AGATCCCCAT ATAAATTGAG GAAACATAAT GGC~lllC~l' TTTCGCTGGT TCACGGAAAC 145500 -77.88-SUBSTI~UTE 5}~EET tRULE 2~) CA 022l874l l997-l0-2l W 096133276 PCT~US96/05320 CTTGAGCTTG AGGGTCAAAA GTACCGCCGA ACCA~ACATC CGCTTGAGGG TTALlllLll 145620 CAGCTTCAAC TTTAGCAAAA GTACTGCCTG AACCATTACG AATA~AGGAT ~Llll~ACAT 145680 TA~AATGTTT GAATCCTACT TGA~AAATAG A~ATAATACC GTGATGAAGT TCACAGTTTT 145920 TAAAATTCAA GTGAA~AAAT AnACGTGA~A TTCACCGCAC llll~LLlAT AATTGCAAGA 145980 AL-L-L-LC~L-1A CATCGA~ACA CGATTATGTC A~ATCCCTCT TGTATCATCA TCGCCATCAC 146040 AGGTGCATCT GCATCAGGCA A~AGTTCTAT CGCTTCCACT GTTCACA~AG AG~L~L~LAA 146100 TGAACTAGGC TGCCAAGA~A TTGGTATCAT TACTGAAGAC AGTTACTATA AAGATCA~AG 146160 TCATTTAGAA ATGACTGAGC GGGTA~AAAC GAATTACGAT CATCCA~ACT CTATGGATCG 146220 CGATTTACTT ATCCAACATT TAA~AAATCT A~AAAATGGC AGTGCAGTAG ATGTGCCTGT 146280 TTATAGCTAT GTAGAACATA CTCGCACCAA CGA~ACAACG CATTTCACAC CA~AACGAAT 146340 LL~L~LATTC GTAGACACAC CACTTGATAT LL~LLL~ATC CGCC~LLlAC AACGTGATAT 146460 GGAAGAACGT GGTCGCTCTC TACAATCAGT GATTGATCAA TALC~LG~AA CCGTGCGTCC 146520 AAL~LL~LlA CAATTTATTG AGCCGTCTAA ACAATATGCG GATATTGTCA TTCCTCGTGG 146580 TGGTAA~AAT CGCATTGCGA TCAATATGTT AAAAGCTCAA ATCCTTCATT TATTGAATCA 146640 ATTATTTCTT TAACACCACG TCCAAATAAT GACA~AATCA ACGGTGCGAC AATTGATGTT 146760 CGCTTGGGGA ALL~LLLCCG TGTATTTCGT GAACACTCTG CACCTTTTAT TGATCTAAGC 146820 TCCGTGA~AT TGCCAGCCAA TATTATCGGT TGGTTAGATG GCC~L-L~LLC TTTAGCCCGT 147000 GGTGCGTTAA ~-L-L-LL~AAGT ATTAAGTGGC GAAssAAAAC GACCATACAG TAGCCGCA~A 147180 GATGCAAAAT ATAA~AnTCA ACAAAGTGCA GTAGCCAGTC GTATTGACGA AGACAAGGAA 147240 -77 . 89-SUBSTTTUTE S~EET tRULE 26 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TAATCGATGA A~AAGTTCGC ACTTATCGTA GGGATCGTCG CTTTGGCGAT ~llll~llll 147300 TTATATATTC AACTTTACCG CGTGCA~AGT GCTATTAATG mACAACTGGC ACAACA~AAC 147360 ATTGCCGTTC AGTCAATCAA TTTATCATTA llll~lCCCG CACTTTCCCT TGA~AATATA 147420 AAAACTACGC AATTTTCAGC TCAAAAAATT GAAGCTA7.~AT TTA~Llllll GC~l~llLlG 147480 TATGGA~ACG CAGCACTTCA TTCACTGAAT ATTCAACAGC TCAAATTAAC TCAAAACACA 147540 CA7.~AATCCTG CCAATGTATC GATAGAGATT TCGCCTTTTT CATTAAAACA GCTTTTATCA 147600 A~AAAAGTAA TATTA~ATGG CGAAAACCAT ATTCGCATTG AATTTAATAA ACCTATTTAT 147660 GGAAAAACAA A~ACTTTCCA TTTTTCTTTC CATA7.~AGCGA ATTTAGACTT CTCAACATCA 147720 GAATCAACCC CACTTCAATT TGTAGATGCA AGCCTA~ATA ATCAGCCTAT CGGTTATATT 147780 GA7.~ACTCACA CAGCCCACCA ACA~ATAGTG ACTTATATAA AACCACAATG CGATAACGAT 147840 TGTTTAGCCG TATTGA~ATA TCAACA~ATA GACAATCA~A GTGCGGTA~A TTTTTCGGGT 147900 A7iATATTTCC ~l~ll~AACG CTTATTCGCA CTATTA~ATT TGCCAGA~AT GTTAAGTGGA 147960 CACGCCGATT TTGATCTTGA TTTCAGCTTT TCATCTTCCT CGCTTATTCA AGGA~AATTA 148020 AA~ AG CGCA~AATGG CGA~ATTCTT GGTGTGAATT TATTGGATAT GGTAGCGCAA 148080 TATTTCCCGA TTAATTACAA CAATGATTTG TTACA~AACA AAGAATTA7.~A CACTCGCTTT 148140 GAACAATTTT ACTTACAATT A~lll~lC~AA CA~AATCAAC TCATTGCTGA AAAAATCGAA 148200 TTA~AAACGC CCGCACTTTT GGGGCAAGGA A~AGGCATCA TTGATTTA~A TCGAATGGAA 148260 TGCAATGTGG ATATTAATTT A7~ATTCTACG GATCAACGCT ATCA~AATTT GACACTTCCA 148320 ATCAATTTTT TTGGTAACTG CAATTCTCCA CAATACAAAA TTAATTTTAC GAAGA7~ATTC 148380 CGCCATCAAT TAATTGATGC GATTA~AGAA AAGTTACGTT AATGTCGTTA TATTTA~AAG 148440 CTGA~AAAAT CCAATCATGG CGCGTGCTTA TTATGGCTTG CGCAGGATTT ATTTTTAATA 148500 CTACAGAATT TGTACCCGTT GCAATGTTAA GCGATATTGC ACA~AGTTTT GATATGCA7.~A 148560 CTGCGATGCT TGCCACGGGC AATATGGAAC GTA~AAGTCT GCTTATTAAG ~llll~ATTA 148680 TATTTATTGT TGGGCATATT TTATCGGTCA TTGCATGGAA llL~lG~ATA TTACTTCTCG 148740 CTCGAATGTG TATTGCATTA GCACATTCGG l~llllGGTC AATTACTGCC TCACTTGTGA 148800 TGCGCATCTC ACCTAAACAC AAGA7.~AACTC AAGCATTAGG AATGCTCGCT ATTGGCACCG 148860 -77.90-SUE~5 111 UTE 5~E~T ~RULE 2~

-CA 022l874l l997-l0-2l W 096~33276 PCTrUS96/05320 GGGTCACTTT TGGCATTATT GCGGTACTGG CATTATCCAT CA'1'~'1"1"1"1"1'A ATTATTCGAT 148980 TATTGCCA~A TTTACCCAGT AAAAATGCTG GCTCTATTGC AAGTTTACCC TTGCTTGCTA 149040 CTGCTTATAC TTATATCGAA CCATTTATGA TTGATGTAGG GCATTTAGAT CCA~ATTTTG 149160 CCACGGCTGT ATTATTAGTT '1''1''1'~'1''1"1'~'1' CAGGCATTGC AGCAAGCCTA TTATTTAACA 149220 GATTATACCG ATTTGCTCCC ACAAAATTTA Ll~ll~lllC GATGAGTTTA TTGATGTTCT 149280 CC~'1'~'1"1'GCT ACTCCTCTTT TCGACCA~AA CAATAATAGC AATGTTCAGC ~'1''L~'1'~'1"1"1'A 149340 TTTGGGGGAT TGGCATTTCT TGTATCGGAC TATCTCTACA AATGCGCGTA CTA~AACTTG 149400 GCGCAGGCGC ATTATTTGGA AACCTTGCGA CAACCTATTT AGGATTA~AT GA~ATTGGTT 149520 ATACAGGCGC AGCATTAGGT TTAATCGGTT TCATCATTTT TATTACAACG CACTTA~AAT 149580 ATCGCCATAC A'L'1''L~'L'1'~'1'G CA~AACA~AT A~AAAAATAA CCGCACTTTA GTTCTCCAAA 149640 AAGAGTTTTA A~AGTGCGGT TA~ATCTTGC TAAGTTTTAT TTATCTTGCG TTTAACGTTT 149700 CG~LLL~LLA ATA~ATTTCA TCA~ACGTTT ACGTTTACGC AA'L'1'G~'L'LCG GAGTGAGTTT 149760 ATTTTTGCGT CCTGCA~ATG GGTTTGAGCC TTCTTGGAAA AGCAGACGAA TCGGTGAACC 143820 AATAATTTTT AAGCTCTTAC GATAATAATT AGATA~ATAA CGTTTATAAG AATCTGGTAG 149880 TTGCA~AATA CGAGTTA~AA GCGAAGTCGT CA'L'L'1''1"1''L~A GTGGCACAAG CATAGGCTTC 150060 TTTAATCGAA TCAAAAAGAT TACCTACACC A~'1''1'CC~'LGC AAGGCTGA~A TA~AATGCAC 150120 CCGAGCAAAA TCAATA~AAT CTA~ACGACG ATCAAGTTCA GATTTCACAC GA~L~LLL~Ac 150180 ATCTTGATCT A~ACCATCCC ATTTATTCAC GACGATCACC A~AGAACGCC CTGCATTTAA 150240 AATA~AGCCG AGCA~AGATA AATCCTGATC AGA~ATGTTC 'L~''L~'1'CGCAT CAATAGTCAG 150300 CAATACAACA TTAGCATCTT GAATCGCTTG TAAG~'1"1"L'1'A ATCACAGAGA ATTTTTCCAC 150360 TGCCA~ATGC ACTTTACCAC GCTTACGCAC ACCAGCCGTA TCAATCAAGG TATATTGCTG 150420 CCCATCACGC TCCATTGGAA TATA~ATACT GTCACGTGTC GTACCTGGCA TATCAAAAAC 150480 CACGACACGA TCTTCGCCTA A~ATACGATT GGTTA~AGTA GATTTACCCA CATTTGGACG 150540 ACCAACAATG GCAATCTTAA TATTTTTATC 'L'L~'L'L~'1''1'~'1' TCAAGTTCTT CGTCTAACGC 150600 -77.91-SUBS i 11 UTE ~E~EET tRULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/05320 ATCATCAATT AATGCCGTAT CTTCTTCTGA ATTCAAAATC GAAll-ll~l TCCCATTCGT' 150660 ~'l''l'~'l"L~'l"l'C CTCAGAAGTG CGGTCATTTT CATCGGCGTT TTCCATTTTT TCCGCAAAAG 150720 GssGCAAGTA ~ll~llCCAT TAATTGAGTA ACACCACGGC CTTGTGAGGC TGCGATTTGC 150780 TCAATTTCCC CTAAACCTAA CTGATA~AAT TCAGCACAAT GGGAATCCGC ATCAATACCA 150840 nCAGTTTTAT TTGCCACCAC CACAGTAATT ll~llllGAC GTTGGCGTAA ATAATTAGCA 150900 ATACCAATAT CAGCTGCCGT TAAACCCGCT CTAGCATCCA CAAGGA~AAG AACAATATCC 150g60 TAllll~lAT CACGAGTTAA ACCGGGA~AA TCAGCGACTA ACGCATCTCT CGTACGAGTA 151140 GTTGCCATAA A~AATCTCTT Allll~l~AA A~ATGGCGAC TATTATATCG GAAGTTA~AG 151260 GATTGGTAAA AAATCATTTC ATAAAGA~AA GA~AAAGCCA CAGGATACAA TCCTATGGCT 151320 CAGCTTGAAA GCGAGTGTTG CG~lllll~G CAAC~lll~A AGAGGATAAG AAAATGATTA 151440 AGATCATTAT C~ ~l'C~l~A CTACTATTAT TAGTGAGCCA GCCCGCTTAC TAATAACACG 151500 ACATACTAGG GAGTAACCGC TCCCTAGTTC TTCAAATATT A~AAGTTTAC TTTATTTTTG 151560 TTTATTAAAT TTTACTTACC TGCTTA~ATT CCACACGATT AATGCACATT ATTATTGCCA 151920 AAACGTTTAT CCCAAAGGCA ATTATTTCCA ~lllllllAT TCATCATCTT TAAGAATTCT 151980 AAATGCGCTT GTAGCTCATC ATTAGTAGGT TGAAGTAATT TCA~ATTGTG CGAAAAATCT 152040 ACCGCACTTT TTAlll-ll~ CGCC~lllll TCTTGCATAA CACGGATAAC TCCAGACTCA 152100 ACAGATTCTT CTTCATCGAA TA~ATTTGTT TGCCCTCCCG TCATCATCAA ATAAACATCC 152160 AAACGATCAC AAAGTGCATC CA~ATTATTG C~llllCCAG GATACATCTG ACGCGCCATT 152280 -77.92-SUBS i 11 UTE ~HEE~ tRULE 26) -=
CA 022l874l l997-l0-2l W 096/33276 PCTrUS96105320 TGTAGCGTAT CTGTCACCAA ACA~ATATCG TCAGTTTTCA CATTGAGGTT AAGTTTACGA 152340 TTAATATAAT CCA~AAAATC TTGGGCAACT TCTTTGAATT CAGGTTTATC CGCTAACATT 152460 TCATCAGTAA TTCCATGAAC TTTAATCGCA TCAGGATCAn CGGGGCGATC TGGCTTAATA 152520 TAAATATGAn AATTATTACC TGTGTAacGA CGATTTATTA ATTCAACTGC ACCAATtTCA 152580 TTGCCATTCT ACACAACAAC ~-l"l"l"l"l'~'l"l'A TGCCnAAACA GATTGAAATT TTTACTGATG 152760 ATGAA~AAAC ACTCTCCAAA GGCTATTTCC AAACCACCAA TAATCGAATG GAATTACGCG 152880 GCCAATATAT GAAAAATGGC ATAaCcAAAT GGATCTTTAA CTGGA~AAAA AATAATTGGA 153000 TCCAACgTCA TAAAATTAAT TGGCAATGGG TAAAAGGCCA TGCTGGACAC AGAGAAAATG 153120 AAATTTGCGA TGAATTAGCA A~AAAAGGGG CAGAAAATCC GACATTGGAA GATATGGGGT 153180 ACATAGnAGA ATAATACAAC TGATATAACG TCATATTTTT CGATACCTAA AAATATTTAA 153240 TACTTAAACC TAAAACAGAA TAAAAAATAA TCAAATTCAT TTaAAAAATG TGATCTCGAT 153300 CAGATTTCAA GnAAATTAAA ATTTTGGAGT ATTGACATCA AAAATTTTTT TTGTAAAGAT 153360 GCAGCTCGTC C~llllGGCG ATTGGACAAT TCTATTGGAG AAAAGTTCAA TCATAGATAG 153420 TAAACAACCA TAAGGnATAC AAATTATGAA AAAAACACTT GCAGCATTAA TCGTTGGTGC 153480 CTTCGGTGAT G~llL~lATG CACAAGGTTA TTTAGA~ACT C~11L1~11A CAAAAGCCTC 153720 TGAAAACGGT TCAGATAACT TCGGTGATAT TACAAGCA~A TATGCTTATG TTACTTTAGG 153780 -77.93-SUE~STITUTE ~EET ~RULE 26) CA 02218741 l997-l0-2l W 096/33276 PCT~US96/05320 ATTAGCACAA AAGCGTGAGG GTGCAAAAAA TACA~ATAAG CAGCCTAATG ATAAGGCTGG 154020 TGAAGTACGT ATAGGTGA~A TCAATAATGG AATTCAAGTT GGTGCAAAAT ATGATGCA~A 154080 CGACATCGTT GCA~AAATTG CTTATGGTAG AACTAACTAC A~ATATAACG AAGCTGACGA 154140 GCATACACAG CAATTA~ATG GTGTATTAGC AACTTTAGGC TA'LC~lLLlA GTGATTTAGG 154200 CTTATTAGTG TCTCTAGATA GTGGCTATGC AAAAACTAAA AACTATAAAA CTA~ACACGA 154260 TGGCAACTTC A~ATATGAnC GCA~ll~l~l AGATCAAGGT GAAAAAACAC GTGAACAAGC 154380 AGTATTATTC GGTGTAGATC ATA~ACTTCA CAAACAACTA TTAACCTATA TTGAaGGTGC 154440 TTACGCTAGA nCTAAAACAA CTAATGGAGG CGTAAAAACT GA~AAAGAAA AATCAGTGGG 154500 AATCGAAAGA TTCGCTtTTT TTTTTGCTCA A~ATCAAGTT AAAAAATGAT TAAGTTAAAA 154620 GTGTATAAAT ATTTAGGCTA TTTTATAATT AATAAAAAAt CTGTGATATA TATCACAGAT 154680 TTTTAAATCA ATTAACTATT TAA~L~lllA CTATTAATTC T~LllC~ACT TTCCGTTTAC 154740 TACTGTGCCG ATTACTTGGT AATTTGGCGT A~ACACGGCT AAGTTTGCTA TCTTACCTTT 154800 TTCTACCGAA CCTA~ACGAT CATCTATACC AATTGCTCGT GCAGGATAAA GGTTACTCAT 154860 CATTGTGATT GATGCCCCTG CAATTGTGTC ATTCGCATCA TAGCAACGCC ~LL~lll~AT 154980 GCCGTAATTG ATATGCACAC CATCGACGAT AATGCCAGTG TA~ACATCAG AATCTAATAC 155160 GCG GCAATGGTCA Lllll~LAAT CACATCACCA TTTTCGCAGA GAAAATCTTT 155400 GA~ACTTGTA CAACCTGATT TTAAGTTAGT TTCCTGCATA ATTTCCAAGG TTTCAACGCT 155640 -77.94-SUBS i 11 UTE S~EET (RULE ~6) CA 022l874l l997-l0-2l CGTTA~ATTA TTACCTTGTA AATCAATGGT TTTGATACCT ~'1"1"1'~'1'AATT CAGCTTGGGG 155760 GATCACTGCT TCAATAATTT CACCGTTAAT AATTACAGCA A~ATCACGTA A~ACATCATA 155~20 '1"1"1"1'~'1'~'1'AA ATTACACAAT TAATTAATGC GTATTTCATA Ll~l~llC~l AATATCAACA 155880 TTGTGATTAT AGGGCGAATG TAATTCGCCC CTACATA~AG ATGAAGAATA GATCTCTATT 156000 TATCCTGATA ATCCGTACCA GCAACCGCGC CTTCTAATTC AGTA~AATAT TTCACGGTTT 156060 TCACTTTTAG ~'1'~'L'L~'L'L~A GATTATAGGG CGAATGTAAT TCGCCCCTAC ATA~AGATGA 156120 A~ATATTTCA CG~LLLL.AC TTTTAACTCT TGTTGAGCAG CTTCATCACA AACAAGCAAG 156240 A~ATGACGGT GCATTTGTAA TGCACTGACT GTCCATA~AT GGTTAATACT GCCTTCAACT 156300 GCAGCTTGCA CTGCCAGTGC ~LL1L1~ATGT CCTGTTGCTA A~ATCATCAC 'L'l ~'L'L~'l'GCA 156360 TCTAATAATG TGCCAACACC AATGGTTA~A GCATATTTCG GCACTTGAGT AACATCATTA 156420 TTAAAGAAGC GTGAATTTGC AATCAATGTA TCTTGCGTTA GC~L~L~LAAT ACGGGTGCGA 156480 GAACTTAATG AAGAAGCAGG TTCATTA~AT GCGATATGTC CATCTACGCC AACCCCCCCC 156540 ATA~ACAGAT GAATTTTGCC GTAGGATTTA A'L'L'L'L'L'L~'L'L CATAACGACG GCATTCTGCA 156600 TTGAAAAAAT TGTTATACAT A~AGCTGTGG TAACTTTCAG G~'L~'1"LCCTC TGGTA~AGCC 156720 ACATATTCAT CCATATTGAA AGTCACTACG 'L~L11~A~AC TCACTTTGCC TGCTTGATAA 156780 AGTCGAATCA ~LL~1LGATA A~'1"1"L'1"LAGT GGTGTGCCAC CAGTAGGTAA CCCCAATACA 156840 A~AGGACGCT CGGCGGTAGG TTTA~AATCG TTGATACGAT TGATGATATG TTGTGCAGCC 156900 CAACAACTGA ~ L~L~L~L~1~C ~L~L~L~L~1~AAT GGAATAAAAC GCATATTAGC ~LLC~l'L'LAT 156960 GGATCATTAT AAGTGCGGCA A'1"1''L'L~'LATC 'LL~LL1LLAA A~AGA~ATTC TTTTGCTCCA 157080 A~ACAGGGGA AGGA~AGTGC TTGCTGACTT G~'L~'1"1'~'L~'L TTGTAACGGA ATA~AACAGG 157200 GGGAGGTAAG '1"1"L'1''1"1'~'LAA TTTAAATATT TATGACA~AA ATTTCGCTTT CAAGTCTTTT 157260 GCTTTTGCAA G~'1'~'L'L~'L'1'C TGTTGCTTTT GATGTCATTG GTTCACGGCA ATAACCTGCA 157320 -77.95-SU85 i I i UTE S~EE~ ~RULE ~6) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TTTACCCCTA ATA~lllCGG ~lllllATAA AGTTCACCGA AlL~Ll~AAT GCCCATATTC 157680 ACGCCAGTTA AGAACGGGAT AGAGTACACA ATCATATTGT TGC-lvlllC AGCGATGATG 157740 ~l~l~lAAT AATGTTTAAT TTCAGGGAAG CTAAATTTGT AATAGAATGG CGTCACTGCA 157800 GATAAGCAGT CGTAGCCTAA ~ll~l~llGCA TATTTACCTA ATTCCACCGC 'll~llllAAG 157860 CGGAAGATTT ~llllllCTC TTCCGTTGAA AGCATAAAGT TTTCGCCTGT TGAACCGCCC 157980 AAATCACGCA TAA~lllL~ CCTATTTTAT AC~11~11~A AGAATTACAT TGAGAGTTTT 158160 ll~lllAGTT TGAGCGGCAA TAl~Ll~llC GCCCTGCACT AACAAAGCAT AAATTAAATC 158220 TAATACAA~A AGCTGTGCAA TTTTGGTGCC AATAGAATCG CCTTGTAACT TGC~ll~lll 158280 ATTACCATTT ACCAAAACAT AATCAGCATA TTCTGTCACG GGGGAACGCA AACTATGCGT 15~340 CAATGCCACT ~ll~llGCAC CAllll~lll TGCGATTTTG ATGGTATGCG ~C~lll~AGC 158400 TG~llllllA AGTACTTTAA CGACTTCTTC AAG~l~llll AAATCAAGTA AATTAATCGT 158640 l~l~LlC~ATT ACATTAGCAA CCGCCGTTTG CAAlllLl~l~ GCAATAGTGA GCGAATCATC 158700 ACTTGGCATA Alll~l~lll CAAGTATGCT TTCATCTTGA TTATCTTTCG TCGCAAGTTC 158760 GACGAGCGTA G~ll~lCCAA CTTGCAAATG TTTAGCGATT TCTGAAAGGG AGCATTGAGA 158880 GACTAAATCA GGCGAACGCA A~ATCGTATC GGCAATTTTT ~ ~ATT TAGTTAAACT 158940 -77.96-SUBS 111 UTE ~i~{E~T tRULE 2fi) CA 022l874l l997-l0-2l GTCCAAATTT AGCGGTTTCA ATTTCACAAC AATATATCGA AGGAAAATCT TGTA~ATATT 159120 GAATATCTAA ACTAATCACT A~ATCAGCAA TTAAATTAGC AATGGCTTTC GCAGAACGCT 159240 CGACAAGTGC GGTCGCTTTT TCATCATTTT TTCTAAAACG CTCAAACACT l~llllGGAT 159300 CGCACGGTTC TTCCCATTGG GAAGA~ACTG CTTCAATTGC TCGCCCTGAA GCAATCGCTT 159360 CAATATGCCC AGCAATACCA CGAGAACCTG TCTGCAAAAT TTGGTTCAGC ACAATCCCTC 15g480 CGCCAACTCC TGTTGAAACG GTAATA~AAA CAAAATTTGA TAC~l~ll~A GAATTTTGCA 159540 TAL~llllGC AATACTCGCT TTAAGTGGAA ATTCCGCCAA GCCACCTAAG lllllCGGAT 159660 TTAATGCACT TA~AATGCCA TTATTGATGA TCCCCGTAGA TGCTACCGCT ACATAATCAA 159720 TAAAGTCkTT nTCTCACACG TCTTACGACT ATCTTGCAGA TTTCACTGAA TTAGCAAACC 159960 CTTCTTCTAA ATTAGGaACA ATCTGCCATT GCCAAACAGC CCA~lllC~LG GA~lllllllC 160260 TCAGGCAAAT CAC~llllAC AATTCCGATA ATCGGGACAT TCACAAAAGG ACGGGTTGCT 160440 GCCATAGCAG A~ACGATTTC AGGTTTATCC ATTGGGCCAT CATCGACAGG TTGGCAAGaA 160560 GAAATAAGAC CATATTGAAT TTGAGA~AGC A~ll~ll~AT AAGATAATTT AGACATATA~ 160620 CACCCCTCAT TTAAATCTGA ATAAATCACT TTA~AATTAA TTTAATCCAC ACA~AACAAT 160680 -77.97-SUB5TITUTE SHE~T tRULE 2~) W O 96/33276 PCTnUS96105320 ATGCCATTTT AAAGAATATT TTTGAAGTGT Llll-l~ATAA ATGTGATCAA CTTCTCATTT 160800 TGGAAATAAA ACTCGTA~AA CTATTTTA~A 'l"l"l'~'l"l"l"L'L'L TACTCTTAGA ATTGCTCTCG 160860 GTTAATcTAT GCCCCTTTCC AACATAAGTT CACACAGGAG CGAATATGAT GAAATTGACA 160980 AAACTTTTCC TTGCCACCGC CA'LlLClllA GGCGTATCTT CTGCTGtTCT TGCCGCTGAT 161040 AGTTCACAAT TAGGTGATGA CCGTGCAATG TTAAAACAAT TAAAAGACGG ~Ll~L~lCGAC 161220 TTTACCTTTG CAGAATCTGC TCGCTTCCAG ~L~LlllACC CTGAAGCGGC AGTATTTGCC 161280 TTACCTTATG TTATTAGCAA CTACAATGTT GCACAAAAAG CCTTATTCGA TACAGAATTC 161~40 GGCTTA~AAC LlC~L~LGCC AAATGCAGCA ACA~ACTTAG CCTATGCTAA ATATGTTGGT 161520 GCATCACCAA CACCAATGGC ALlll~lGAA GTTTATCTTG CGTTACAAAC CAATGCCGTC 161580 AAATATCACA CTAAATTATT CGTAGATGGA GAGA~AGATT TAGTCACATT CTTTGAAAAA 161820 TATGCTGAGT TTGTAAAACA AACTGGTCAA AAAGGTGAAT CAGCTTTAAA ACA~ATTGAA 161940 TATCAGCGTT GCTGTGAGAA AACAAGAACA CGTATTTATT GALllLlLAA CTAATCTAAT 162240 GCCCGAAAAA ATCAGAAAAT TCACA~ATAC ~Lll~lACAA TTATTAGTCT TTATATGTAT 162300 -77.98-SUBS 111 UTE ~HEET tRULE 2h~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 CTTAGGAGGC ATTTCTGAAA AATGGATTTT CGCAGCACTG C~L~ll~LCG CAATATTAAT 162420 GAL~lllCGC TTTATCCAAG CGCA~ACCCT A~ACTTTAAG ACTGGGAAAA GCTATTTACC 162480 TTGGTTCAAA GTATTGCGTA TTAGCAATTA TATA~AACTC GGTTCAAGTT CAGTCTATGT 162600 CGCCTTACTC GTTTGGCTAA TCATTATGTT TALCG~L~lC CCTGTAGGTT GGTCCTTATT 162660 TATTGCTACT CTACTTTATT TTTCTATGAC ACGTTGGAAC GTCGTA~ATG CCGCAACTGA 162720 GGGCATTCTA ATGAATACAG GTGGGATTAC CGAACGTATT TTTAATTTTG CTA~AGCCTT 162840 ACTCGGTCAT TACACAGGAG GAATGGGACA CGTTAATATC GGCGCAAGTT TALl~LL~LC 162900 TGGTATGTCA GGTTCAGCAC TTGCTGATGC GGGGGGCTTA GGTCAATTGG A~ATCA~AGC 162960 AATGCGTGAT GCTGGTTATG ACGATGATAT TTGCGGAGGA ATTACTGCTG ~ll~LL~lAT 163020 ATCTATCGCA AAA~L~lllA TTGCAGGTTT TATTCCAGGT GTATTAATTA CTTTAGCTTT 163140 GAGAGAaCAA CTTTGCAGCA GCTTTAAACA Al~llLLlGG GCAATCTTAA CGCCGTTATT 163260 AGCATACTCT GTAATTATTG GTAAATTCGT GTATA~AGAA TTAACCTTAA AAAGCTTATT 163380 GA~LLL~LLl GGCGATATGA TTGCGCGTGA ACAAGTCGCA ATGC~l~LLG CTGATGTGTT 163500 TATCGCAATG CAGTTCAATA TTGACTTAAT ~LL~llLGGT GTAATGACCA CATTAAATAT 163680 GATGGTTGGT ATTCTTACCC CACCAATGGG AATGGCTCTC Lll~lL~LLG ~LC~L~lAGG 163740 AAATATGTCA GTTTCCACGG TAACCAAAGG CGTATTACCG TTCTTGATTC C~111LC~L 163800 ACCATAATAA AAAGTGCGGT TGAAAAACAT TAAATTTTTT AACCGCACTT TCALC~LLLL 163920 CGCCTATTCA ATGCC~lLlA ATGAATAGAA AACTGTAAAC ACAACTCA~A ATGGGGTTTA 164040 -77.99-SUBSmUTE SHE~T ~RULE 2~) CA 022l874l l997-l0-2l TTATGAAACT AACTA~AACA GCATTATGTA CTGCACTTTT TGCCACCTTT A~lllLl~AG 164100 TTGGCGACAC AGTTTATGTG GGATTAGGTT CTGGTGGCGA TA~ATTCTAT ACCTTAGACC 164220 GAGATA~AGT TTATATTTTA GGCGGCTCTA ATCTCTCTAT ATTTAATGGC TTCTTCCAAG 164520 ATCAACGTCC AGAAGATTAT 'l'l~'l''l"l'ACAA CAGAATTATT GAGCTATGAA CCATCAACCA 164640 ATA~ATGGCG CAATGAAGGT CGTATTCCAT TCTCTGGTCG TGCTGGTGCA GCCTTTACAA 164700 TTCAAGGTAA TGAGCTAGTG ~ll~l~AATG GCGA~ATTAA ACCTGGACTT CGCACCGCTG 164760 CTGCTCCA~A AGGCAAATCA CAAGATGGTT TAGCTGGTGC GCTTTCAGGC TATAGTAACG 164880 GAAAACTTCA CGCACATA~A GGTTTAAGCA AAGCTTGGCA TAACGAAGTT TATACGTTGA 165000 ATA~AAGTAA TTAAAGCAAA ATTAAGACAA ATTTTGACCG CACTTTAAAT GCGCTATAAA 165300 TTTATTCATT GCCATAGCAA TGTATTTTTT GCCA~AGATT GCTAGTTATT CTGTCCATTT 165420 TTCAGTGATT ~'l''l"l''l''l'~'l''l'A TTTCCCTTTC A~ llGATT GCTTTAAGCA GCGTTATGCA 165480 ATCTTTATAT GTAAAACCTC CATTAATCCT CGTGACTTTA AAGGCACAAC A~AATTAGTT 165540 TTAGTGATAA ACCAGTTTCA AATAGCCCGA GAAGAAACCT ATTTGGAAAG TA~ATTTGGC 165720 -77.100-SUBST~UTE SHEET ~RULE 26~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GATGAATATC ~lC~llACAA ACA~AAAGTA AGACGTTGGC TATA~AAAAA CACCTTCACA 165780 AGGAAGGTGT TTTTATCA~A TTA~ACTCTA llllllCGGT GCCTGCATAA AGCGGAAGAA 165840 ATCACTATCT GGTTTTAAAA TCATTATATT GTCAGAATTT GCA~AACTCG CTTCATAGGC 165900 TTTTAAGCTA CGCACA~AAG TA~AGAATTG TG~ll~ll~A GCA~AAGCAT CTGAATATAA 165960 TTTTGCTGCA GCTGCATCGC CTGAACCTCG TAAll~ll~l GCAGTTTTAT TTGCATTAGC 166020 AAGAATTAAC GTCACTTTGC GATCTACATC AGCTTGAATA AATGCTGCTT lll~lllCCC 166080 TTGAGAACGA TGTTCACGCG CCACTGCATC ACGTTCTGCA CGCATACGTT GGTA~ATTGA 1661.40 TAATTCTGCC GTACTGTCTT GTCCTGAACT TA~AGCTTTT TTTGCCCCTT CCATTAATTC 166260 TCCACGTGTA CCAGA~ACAA TATCTTTAAT CGTGCGTGAA CCAATTTCAG AACGTAAACG 166320 GTCGTTTACT TTACGACTTA ATA~ATTTGC AGCTTGAGCA TAATCGCCAC CGCCAGTAGA 166380 TGTGTAGAAT CGACCA~AAT CACTGATTTT CCATTTCACA TAAGAATCCA CTAGCA~ATC 166440 'l"l"l"l"l"l'~'l'~'A ACAGTAACAA AAC~l~llGC AGAGCCATCT A~AGTACGAA TACGTGCATC 166500 TAAAACTTTG ATGCTATCAA TTA~AGGCAC TTTA~AATGC AAGCCCG~Ll CATATACAAC 166560 CA~lll~llA TCAGCATCAC GCTGTACTTT GTTA~ATCGT AACATAATGC CACGCGTACC 166620 llCC~llACA ACGACGATAC TAGAATA~AC GACTGCCGCA ATCACGA~AA TAACAGGTAA 166680 TA~AAATCTA CGCATTAGTT A~ATCTCCCT TGACGAATCG GCGCAACGGT AGTCGGCTGA 166740 GGCTGATAAG AATTTTGACG TTCTGGTGCA GTA~AAGCAG GCGAAGAATT GACCGCACTT 166800 TGAATATATA AACGCTCACG CAGTA~ATCT GGCGCAGCCT TA~ATTCTGG CAACAAGCGT 166980 TGCA~ACGTT CCACTTCACC TTTTGCATCT AACACGATAC GATCTTTATA AGCTGTTGCT 167040 TCCGCTTCAC GAATA~AACG TTGTTCATCT TCCTGCGCTT TAATTGCATC ATCA~ACGCA 167160 'L~llllAcTT CTTCAGGTGG GCGCGCAGAT TGGAAGTTCA CATCAATAAC CTCAAGTCCC 167220 l~l~lCGCTT GATTCA~ACT ATCATCTGCA lll~llACGC TA~AAAGATA TTTTGCAGGA 167400 -77.101-SUBSTITUTE S~tEET (RULE

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96105320 ATTGCACCTT GTGTACGCAA ~l~llllACT TGCTCCACAT TTACTGGCAA TACTTTATCT 167520 ACA~ATGTTG ~lllC~AGTT CAAACCAGGT TGAACAATAG AATGTAACTC GCCAAAACGA 167580 AGCACCACAC CGCGTTCAGC ~l~LllAATG GTGTAAAAAC CGTTTACGCC CCAAATAATC 167640 GCACCAATCG CTACAGCAAG TGGAATAACT TTACCAAAAT GA~ATGGCGT ATTGCCTTGA 167700 GAACTGCCAT TATTTTGACC G~'1'~-1"1"1L'1'A TTTCCACCAC CTAATTTTTT AAGCAGATTA 167760 TTAAAAATCT CCTCAATATC TGGTGGAGAT TG~l~llGAT TTCCACGATT TTGATTGTTA 167820 CTCCAAGGAT CGCGATCTGA ACCGTTCTGT GACATTTCAT TCTCCATTTG TCA~AAAATT 167940 GTTAAGAGTT TAGCTAAATA AATGGGGCAC GTCTATGA~A ATACAAGGCT TTTTAGGCAA 168000 TAAAAAATCC TTGATTTTAT ATAAGGATTT TTTTGATTAA TTCACTTCAT A~AGAACATA 168060 AGT 'l~llllATCT GTA~ACTTTC TCTATTCCAT TCATAAAAGT GCGGTAATTT 168120 ll~ll~ATGA TTGACAAAAG CGGCTAAATA AATAGGGAGT TCATCAGTAA ACCACAACTG 168180 CCCCTGCGGA CAATAATCTG AAAAAATTTT ~ A GGAAAATGAC GAACATTGGA 168240 TAATTTTACG ATCCCA~ATC CTTGAGATTT CAATACAGCC TCTCGCAAAC ACCAACAACG 168300 ATA~AAAGCG TTCAAAGAAT CCTGCTGATG ATGAAACCAA TCA~TTTCTT CTTTTGGTGC 168360 GCCGTAGGCG ATGTAGGTTG TCATA~AATA A~AGCACCAT TCAAAGGTGC TTTTATATTA 168780 AAAGGATTTA ~-L-l-l'G'l'~'l~'l- AAATTAGCGA ATCACTAATT CCGCCACAGA AACACCGACC 168840 AAGCAAGCAA CAACAACCCC AATTA~ACCT GGCACCATAA AACTGTGGTT A~AATAATAT 168900 TTACCAATTT 'l'-l'~'l'l~'l'ACC CGTTACGTCA AAGTTTACTG TTGCAATATC TGACGGATAA 168960 TTTGGAATGA AGArATACGC ATAAGTTGCA GGCATTA~AC CAACTAAGAT TGGCGCAGGA 169020 -77.102-SUBSmUTE SHEET ~RULE 26) W 096133276 PCTrUS96/05320 ATTTGAGGAT TC~llllC~l TGCAAGTA~A ATCACACCAC CAAAACAAAG CATCATCATT 169320 ATCGCAATCG CAACAATCAC AACTA~AGCA AGTAAAAATA GGTAAACAGA LllllllGCC 169440 CCTTGCGGAA GGGTTTCATT CAA1~L1~1A CTGGTAGTAT TTAAAATACG TTCGCGCCAT 169500 ACTGGATCTT GTAAACGACG TTGATATTCA GGA1~11~11 CTAACTCTTT ACCACGACGC 169560 GCCATTGGAC GTTCTGGACG AA1111~111 TTCAATGCAA CATCGCCGAT GATTGGCATA 169800 AL1~1~1AAA CAGAGTGACC TGTACCAAGC ATAAAGGTTA ATAAATAGAC GACTAATGGG 169860 TTAATAGTAA AAATAAAAAT TCTAAATA~A GCATA~ACAC CTCAAAAATG GAAAACTATG 170160 CAAATAATAC 1L~L1L11AG GCATATAACT AAATTATTTT TTAAAATTTA AACCAAGATT 170220 TTGATTGTTT TGCACGTAAT CAATCGCAGA TTGAACAGTG GTAATTTTTT CAG~11~1LC 170400 ATCAGGAATT TCAATATCAA AL1~L1~LLC TAAAGCCATT ACTAATTCAA CTGTGTCTAA 170460 TGAATCTGCA CCTAAATCTT CAACAAAAGA AGCTTCAGGT TTAACATCTT CTTCTTTAAC 17~5Z0 ACCTAATTGT TCAACGATGA 1LLLL1~1~AC GCGTTCTTCA ATACTCATTT GTTTTTCCTA 170580 ~11L~11AGTT TTAACTCATA AAAGAGTGGT TAGTGTATGT A~1L1111AGT AACTTGCAAC 170640 -77.103-SUBST~TUTE S~{EET (RULE 2~i~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 TTATCTAAAA TCTTTGGCTA TGATTTTATT GCTTAGAAAT CCCCCATA~A TCAATGTCAA 170820 ATCATCAGAA GCTAAGAAAG CAACGGCTTT AGCTATGTCT TTnGCTTCGC CTAAACGTCC 170940 AGCTGGAACA TTAGATAAGA TCCCCGCTTT TkGTTCATCC GTAAGCACTT CTGTCATATC 171000 TGTTGCAATA AAACCAGGAG CAACCACATT TACAGTAATA CCACGTGCAG CTA~l~l~lll 171060 CGCTAAAGAT TTAGAAAAAC CAACCACACC CGCTTTTGCC GCACAATAGT TA~lll~lCC 171120 TGGATTACCC GTTGAACCAA CCACTGAACC AATATTGATG ATACGACCAA AAC~llLlll 171180 GTTATTCACG AGAATATCAA TATCGCCAAA ATCATTTTTA A'lll~ll~AA GTAAGGTTTC 171360 CGAGATCGCC TCTGCACCCT TTTCAGAGGI TGCTGTACCA ATTACAAATG CAC-lll~l~A 171480 ACTAAGTTCT TCTGCAATCG CACGACCGAT ACCACGGGTA GATCLl~l~A CTAAAGCAAT 171540 TTTACCTTGC Allllll~ll CCTTTTACTT ACACTAAAAA 'l''l'~'l"l'~'l'ACC GCATTGAATG 171600 GCATTAATTT TCCGCGCAAT TCCACTAATT TAATCGCATC TTGGA~ATCC AACACGCCAG 172200 CACAAACTAA CGCAGAATAC TCACCTAAGC TATGACCTGC CATCACTTCT G~lllLAATT 172260 GAGGA~ATTT ~lL~lllC-AT ACGCGATAAA TAGCGACTGA AGCAGCTAAA AGTGCGGGCT 172320 GAGTTTGCCA AGTTTTATTA A~ll~ll-AG CTGGACCTTG TTGAACAAGA TACCATAAAT 172380 CATAACCAAG CGCATCAGAT G~ll~lllAA Al~lll~AAT AACGATTGGA TATTCAGTTG 172440 -77.10~-SUB ST7T~JTE ~ EET ~RULE 26 CA 022l874l l997-l0-2l W 096133276 PCTrUS96/05320 TTTTCATTAT ~Llll~lCCT A'1"1'~ 1"1 1 L 1"1' AATTGAAAAT T~'1"1'~'L'LCGG TAATTA~AAT 172560 CGGGTTTCGC CGATGGCGAG CTTACTTTTT CTTTGCTTCG CCAAAGAAAA AGTAAGCA~A 172620 AAGA~AGGCG CCCCTACTTT TCL'L'1'~'L'L'1'C ~LLL~LLCCA TTGAATTTGC CTTAACGGAA 172680ATTTtCTGAA CTCGCTACGC TCA~ACAGAC GA~AATTTCC TACA~ATTCA ATTCCACAAA 172740 GGTGGAAAAG AAGGGAACCC AA'L'L'1'~'1"L~'L TTATCCGATT TAAAGTGCGG TCAAAACTCA 172800AAATATTTTT '1~L1~L1AAA ATGAATTTAA AATTAACCGC A~''L'L'L'L'LA~A TAATGCTCTG 172860ATA~ATTCGG GGCCCCATAT AAATCACCTT TGCGACTTTC AATTTTCAGG CAATTTGCGT 172920 ~L~1LL~AGC GCAGCGAGTT CAGCA~ATTG CCGTTAAGAA AATTGAAACA AAGCAAAGAA 172980 CAGCGATTTA ACTGGGGCGT ~'1"L'L'L~'L'L'LG CCTACTTTCT TTTACACGAG TA~AAGAAAG 173040TGAGTCGCCG TCAGGCGAAC CCCTGACATT TAACACA~AA AGTGCGGTCA ATTTTTACCG 173100 CACTTTAAAA TCATCAATAA TTATATCA~A TCAACTAAAA TCTCACTAAC GCTGAACCCC 173160 AAGTCCAACC ACCGCCA~AG GCTTCTAATA ATAGTAACTG CCCACGTTGA ATACGGCCAT 173220 CTCGAATAGC CTCATCTA~A GCAACAGGAA CAGTTGCTGC ACTGTTATTA GCGTATTTAT 173280 TACGTAAATT TGCTTGGTGT GGCACAAGCC AGTCTAAATC rL'1''L'L'L'1'ATCT AAATTATTGG 173400 CTAAAAGTGT TTCTTCCACC ACATTTGAAA GTTCACGAAC TGCCAATTTG AAC~'L'1"LC~'1' 173460 GGGCATTATT TTTATCTGCT GAAGCGTGTA AATGGGTGGA GATAATTCCT T~'L'1'~'L'L~AC 173580 TCGCTTCTAA AATTACAGCA CCCGCACCAT CACCA~ATAG CACAACAGTG CTGCGATCTG 173640 CTGCACGAAT AAATTGATCA GCTACGCTCA AAGCATAGAC A~AGCCTGTG CAAGCTGCCG 173760 CCAAATCAAA AGaAATCGCA TCATCAATAT TTAATA~ACC TTGCACTTGG CAAGCCGCAC 173820 TAATTTGAGC AGCTTCGATC GCA'1"1"1''1''L'LG CCGCTTCA~A TCCCATTGTT GCAACAGTTT 173940 ATGTATCAAC CA'1''L'1"L'L'1'~'1' AAATCCGCAT TTGTGCGAAT ATGGCTCGGC AGATAGCTAC 174060 CGGTGGATAA AATTCTACTA TTCATACTCA ATAAGATAAG CGATTA~AAA GGAAAAAATC 174120 -77.105-SUBSmUTE S}~EET tRULE :2~i3 -CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/0~320 TACAGCAGCA ~L~ AAAG CATCGTGTGA ACGACGCATA TCACGACGTG AACGAGATTT 174420 ~Ll-l~ll-ll~l TGAACAGCCA TTGGCTATAC TCCTAAATTT AATTTACTTT TGCTTTA~AT 174480 C~l~-l-LCCTG CGCGGACACT TCACAGTGTT CAGATGAATG CATTGGTACA AGCGGCAAAG 174600 AAGTAAACTC ACATTCCAAT ~Lll~ll-l~l AAG~LlC~l--l ACAACGCTGA CATTCAAGAT 174780 GATTTGCCGC ATAATAACCA ACATAATCAA GCC~-L~LllG AGCATCTTTT ATGGGATCAA 174960 CAGTGAGGGG TAGTTTTk~C T~TTG~TAG GGCGTGAATA TTACCTGTTG TTGCGAAGAT 175020 AGTCA~AGGG AAATCACATT TTTTATTGGA TAACTCAATA AAGGAAATTA TCCGCTAACT 175080 AAAAAGGTTG GAACTATAAC A~AAATTGCT ATAATCACGC ~L-lL-l--l-lll AACAAGGAAA 175140 GCCACAAATT TATTTAACTC AAATTGCTGG CTGGTTTGCT A~ACA~AAAT GGGGCAAAAT 175260 AAAAGAACAA LLl--l~l-GATT ACGCAAGTTT TAATGAATTT TTTATTCGTC CGTTAAAAGA 175380 TAGTGAGTGC GGTCATATTG ACGATAATCT TTTATTGCAA GCTAAGGGGC AL-l-l-ll-lCAG 175500 TGTAACTACT TAT~L-LL~l-C CTCGTGATTA TCACCGAGTG CATATGCCAT GCGATGCTAC 175620 -77. 1 06-SUBS 111 UTE ~E~T (RULE 263 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GGCAGGCGTA ATTAATCCTC CACGCCACAA CGAAGTGA~A ACTTGGACTT ATGAAGGCGA 175860 TGTTCGCATG GGCGAAATCT TGGCATATAA AAAATA~ACA GGATTTATTT CCATA~ATGA 176040 CAGA~ACA~A TCCTGA~AGT AGATATTTCT CA~-Ll~lllA AAGGCAGTAT AACCTTACTG 176100 C~L1111~11 CTTTCATTTG AACAATTAAC GCATTGTTAC A~ATTCCTCT GAACCTGTTG 176160 GATGAATTGC CACCGTATTG TCA~AATCAG ~Llll~llGC ACCCATTTTG ATTGCTACAG 176220 CA~ATCCTTG AATCATTTCA TCTACACCAA AACCAATACC ATGTA~ACCC ACAACTTTTT 176280 CATCTTTACC CACACA~ACT AATTTCATTT TGCACGGTTG GCGATGTTGA GTTACCGCAG 176340 TGTACATCGC TGTGA~AGAA GATTTATATA CCTTAACATT TTCTGCGCCG TACTGCTCAA 176400 TCGCTTGCGG TTCAGTTA~A CCTACAGTGC CGATAGGCGG ATGGCTA~AT ACAACGGTTG 176460 GAACTA~ACT GTAATCTA~A TAtTCAGTCG GTTTATTATT A~ATA~ACGC TCAGA~AGGC 176520 GACGACCTGC TGCAACTGCA ACTGGTGTTA ATTCAATGCC ~llllC~ATA ATATCGCCTA 176580 CCGCATA~AT GCCTTTCACA TTAGTATTTT GATATTTATC TACTTTGACA TAGCCATGTT 176640 ~'~LlC~lllC TACGCCAGCA llll~lAAGC CAATTTTATC L~lC~llGGA ACACGACCCG 176700 CAGCCCA~AT AACGCAATCT ACGGTAACAT CAGATTGACC ATCACATCTT ACAGTAAGTG 176760 AACCATCTGC ALLllllACA ATTTCAGATG GGGTAGAATT GGTATGTAAT TGAATTCCAT 176820 CTTGCGCAAG CACTTCCACT AAL~lll~lA CGATTAATGG ATCCTGATTA CGCATTGGCG 176880 CATGGCGACG CACTAATA~A l~l~LllCCA CGCCTAAGCT ATTTAATACG CCAGA~AGTT 176940 AGA~ACCATC TGAATCAATG CCGTATTCTT ~LC~lllAAT ATTTGGACGA TATGGACGAC 177060 CACCAGTTGC GATTA~AATA TGATCTGCGG TTA~Ll~llC ~Llll~lACCA TCAGCAAGTG 177120 TTACTTCAAT GGTATGGGCA TCGACA~ATT TTCCGA~ACC ATTAATTACA TCAATATTAT 177180 CAATCAGTTT TGA~AAATCA AALlllllCA CTTCAACATC A~AACCATAA TCTGGCGCAT 177300 AArLl~ll~AT TGCTTCTGCA ATATGCGCAC CATA~AACAT CA~llLLLlA GGTACACAAC 177360 CGACATTTAC ACAAGTTCCG CCAAGATGTT TTGCtTCAAT GATTGCACAT TTTTTtCCAT 177420 -77. 1 07-SUBS i 11 UTE SH~Fr (RULE 2~i3 CA 022l874l l997-l0-2l W 096133276 PCTrUS96/05320 CATAATGTTT AGTCATAGTT TGAACCTTTT TTA~ACTAAA Alllllll~l ATTCTGCCTA 177540 ATATTGGTTT ATCGCAGCCG CAA ll~llG ATCTTGATAA ATAll~ll~A CAATATCATT 177780 CGCTTGAATT TTGGTATTAA GTTTATAACG AAGATTACCT ~ lACTT GCGTACCAAA 177960 TTTACTAATT AAATTTTGCT GCATCACTTG CTGA~ATAAT TGTGTAACAC TTGGGGATGC 178080 ATTTAATTTA ATCAGTTCCC C~l~lllCGT ATAACTCGCA ATCTCTTGTA TTGCACGGCT 178140 Al~llll~ll GTCACAGATA CAACGGCAGT TCGATTAACA TTCATTGAAG CACTTGGTGC 178200 CGCTAGAATA CCTACTGATG ATAATGTTTT AA~llll~lll ACTAATGCCA TAATTTCCCC 178320 ATAAATCAAT TAGAATTGTG CTATTCTTAC AAA~llC~ll ATTAATGTAT AGC~lll~AT 178380 CGAGGTTCTG AATCACATTT TA~ATGCGTT ATTGTCAGCG CAGACTTTAA AAATATTCGA 178560 CACGCATTAG CATTACATTT ATTCACTCCA GAAGAATGGA AAGCACA~AA TGA~ACTGTA 178680 TTGATATATC GCAAAAAGTT CTAACAAAAA ACC~l~l~ll TAAGTAGCGA AAAACAGAGA 178800 TTTTCGCTAG AATGAGGCGT TTAATTTAGT CCAAATTCGA lll~lCGGTA AAATTATTAA 178860 CTGTGAAATC AATCCATTTG A~llllllAT TTTGTGACAT TAAL~lllll TTAGCGGTTT 178920 TAACCTTGAA AAGTAGTGCA AATAGTATGA TTACAATTAA GA~AGGTTTG GATCTCCCAA 179040 TTGCGGGA~A ACCAGCACAA GTAATCCATA GCGGCAACGC TGTGAATCAA GTTGCGATTC 179100 TAGGTGAGGA GTATGTGGGG ATGC~lC~ll CAATGAAGGT GCGCGAAGGC GA~l~ll~lGA 179160 -77.108-SUBSmUTE SHEET tRULE 26 -CA 022l874l l997-l0-2l CAAGCGGTAC CATCACTGCA ATCAATCGTG GCGAAAAACG TGTATTACAA ~L~L~L~L~1~A 179280 TTAATGTAGA AGGTGATGAA AAAATCACTT TTGCAAAATA TAGCACAGaA CAATTGAATA 179340 CA~LLL~1LC TGAACAAGTA AAACAAAACT TGATAGAATC TGGCTTATGG ACGGCATTAC 179400 GTACTCGTCC ATTTAGTA~A GTTCCATCCA TTGAAAGTGA AGCATCTTCT A'L'L'L'1"1'~'LAA 179460 ATGCGATGGA TACCAATCCA TTAGCAGCCG ATCC~L~L~L CGTATTAAAA GAATATTCGC 179520 AAGACTTCAC TAACGGTTTA ACCGTATTAA ~LC~1~L~TT CCCTTCAAAA CCATTACACT 179580 TATGTA~AGC AGGCGATTCT AATATTCCAA CTGCTGATCT TGAAAATTTA CAGATTCATG 179640 TCGGTATTCA AAAAACTGTA TGGCATATCA ATTATCAAGA TGTGATCGCT GTAGGTA~AT 179760 AATTAAGTGC AGGTAAAAAT CGTGTAATTT CTGGCTCAGT '1~LLL~LGGT CA~ATAGCAA 179940 ATGAAAAAGA A'L'1"L'L'L'LGGT TGGATTATGC CACAAGCCAA TAAATATTCT GTGACTCGTA 180060 CCGTATTAGG GCCACTTCAG TA~AAAATTG TTTAATTTTA CTACTTCAGA AAATGGTGGC 180120 CTGGAATTAG ACGAAGAAGA CTTGGCGTTA '1~L1~1LLCG TTTGTCCAGG CA~ATATGAA 180300 TGAAAAATCT TTTTGAAAAA ATGGAACCCG C~'L'L'L'L'L~CC CGGTGGTAAA TACAGCAAGC 180420 AAAACACTCA C~'L'LC~'1'~AT GCGTTAGATT CAAAACGTAT GATGATTACG GTTTTCCTTG 180540 C~'L'1'~'L'LCCC TGCGATTTTC TATGGGATGT ACAATGTGGG TAACCAAGCG ATTCCAGCGT 180600 TA~L~L~ GGTTCGTGGT CACGAAGTAA ATGAaGGAAT GTtCGTTTCA ACCATTTTAT 180840 -77.109-SUE~S i 1 1 UTE S~EET ~RULE 2fi3 CA 02218741 l997-l0-2l W 096/33276 PCTrUS96/05320 TTG~-lG~lCG TGC~ll~llA TTCTTCGCAT ATCCAGCTCA AATTTCAGGC GATACGGTTT 181020 AAGGTGCATT GCAACATACC GTAACAGGGG CTCCAATTAC TTGGATGGAT G~1-L-11-~1'1G 181140 TTGCAACCTC AAC~-l--l~-ll-l- AACCTAATTG GCTCAGAGAC TAACCCTATG TTCTCAATGC 181320 CTTGGCATTG GCA~l-l-L~ll- TTAGGTGGAT TTGCATTGGG TATGGTATTT ATGGCGACCG 181380 TTTTATTTGC AAACTTATTT GCACCGATTT TCGACTACAT C~-~ lCAA GCAAATATCA 181560 ~-l-l~-l-l~-lGC TACTACTGAG TTTAGTTTGT TCCATTATTG TTG~-lG~-l-lC CGCAGTAATG 181680 C~ll--lC~llG ATTTAGCAAC GGGTGAATAC ACACAACAAG CAGATGATAG CCAACAAGCA 181860 ATTCCTGCTG ATGCGGATAA AGCACGTATT C~ll~l-C~lA GCAAAACAAC TGAAGTTTAT 181920 TTGTGGTCAG TGATGTATGG CTTAGTATCT GTTCAACCAG ATGGTAATAC TATTAATGGA 18''040 TTAACAGGTA ATG~-l-~ll~A AGGTACCTTT AATTATTGGT TCAGCAAAGA TGGCTTTGGT 182280 Al~-l-~-l-l~l-l AGCGCCAATT GCTAAAAACA ACCCTATTGC ATTGCAAATC TTAGGGATTT 182400 -77.110-SUBSTITUTE ~EET tRULE 26) CA 022l874l l997-l0-2l GCATTCGTAT TATTGTACAG CTCGCAATCA TCGCTCGCTT GTtATCGTAG TGGATCA~AT 182580 TCTAAAAGCC TATGCTTATG GTTTATCTAA ACAACTTTCA GTA1LC~11G GTTTGATTAT 182640 TACTAACTGT ATCGTAATGG GGCGTGCTGA AGCATTTGCG ATGA~ATCCC CTCCAGTTGA 182700 AA~1111~1A GATGGTATCG GA~ATGGCTT AGGTTATGGT TCAATGTTAA TTATCGTAGC 182760 AL1111CC~1 GAACTTATCG GTTCAGGTAA ATTATTTGGT ATGACGATTT TCGA~ACTAT 182820 TCAAAATGGT GGCTGGTATC AAGCA~ATGG TTTATTCCTA CTTGCACCAA GTGCATTCTT 182880 TATCATCGGA LL1~L~ATCT GGGGATTAAG AACTTGGA~A CCAGAACAAC AGGAGAAGTA 182940 ATCAATGGAA CATTATATTA GCCTATTTGT TAAGGCAGTC TTCATTGA~A ATATGGCACT 183000 ll~lll~llC TTAGGAATGT GTA~1L1~11 AGCGGTATCT AAAAAGGTGT CCCCTGCGTT 183060 'LG~1~1LGGG ATTGCGGTAA ~111C~1L~1 TGGGATCGCA GTGCCAGTAA ACCAATTAAT 183120 TTATGCA~AT GTACTA~AAG AGAATGCTTT AATTGAAGGT GTAGATTTAT CATTCTTA~A 183180 CTTCATCACT TTCATTGGGG TTATTGCTGG TTTAGTGCAA ATTCTTGA~A TGGTATTAGA 183240 TA~ATTTATG CCA1~1~111 ATAACGCATT AGGGATTtCT TACCTTTAAT CGCAGTA~AC 183300 TGTGCGATCT TTGGTGGGGT AL~111~ATG GTTCAACGTG ATTACAATTT CCCTGAATCT 183360 A1C~1~1ATG GTTTCGGCTC AGGTTTAGGT TGGATGTTAG CGATTGTAGC GCTTGCTGGC 183420 TTAACGGAAA AAATGA~ATA CGCTGATATT CCTGCTGGAT TA~AAGGTTT AGGTATTACC 183480 ATTGTATTAG TGTTAGTGGC AATCATCTTA TTTGCGA~AT CA~AATTAGT CGATTCTGGT 183660 A~ATTATTAG GGGCTTTAGC AAGTA~AGGT ATTTtCGTGT CTTCTGCTTG CGGCGGCGGT 183780 GG~1~11~1G GTCAATGTAT TGTTA~AGTG A~AAATGGTG GCGGAGA~AT TCTTCCAACC 183840 GAA~111~1C ACATTAACAA ACGTGAAGCA A~AGAGGGAT ATCGCTTAGC TTGTCAAGTT 183900 AATGTA~AAG GTAATATGGA AGTTGAACTT CCAGAAGA~A TCTTCGGCGT GA~AAAATGG 183960 GAATGTACTG TTATTTCTAA CGATAACA~A GCAACCTTTA TCA~AGAGCT TA~ATTGGCT 184020 A'11C~1~AAG GCGAGGAAGT GCCTTTCCGT GCAGGTGGTT ATATCCAAAT CGAAGCTGAA 184080 A~ATATGATT TATGGCGTTA 1~L~L~1AAA GTGGACGAGC ATATTATCCG TGCTTACTCA 184200 -77.111-SU8S 111 UTE S}~EET ~RULE 26) CA 022l874l l997-l0-2l ATGGCTTCAT ACCCTGAAGA GA~AGGTATC ATTATGCTTA ACGTTCGTAT TGCGACTCCA 184260 CCACCACGCC AACCTGATGC GCCTCCGGGT CA~ATGTCTT CTTACATTTG GTCATTAAAA 184320 GACCAATTAA AACGTTTACA TTCTA~ACGT AA~ATGTCGT TCTGGTATGG TGCACGTTCT 184500 tTTATTCACA ATGTACTTTA TGAAAACTAC TTGAAAAATC ATGAAGCACC AGAAGACTGT 184680 AATTCATCAT AAAAGCTGcC CGCACTTTGT GATAAAGTGC GGnCsAAATT TAAGATGTTT 184860 TTAAACATTT TCTATGATTA CAGGTAAGTT Ll~ll~AGTT TGCCAGTAAT TCACCAATTT 184920 TTGCTGCTTG TCAAA~AGAA ACAAAAGTTA l~l-lllAAG CGGTAAAACA ATGGGGACAA 185040 AGCAACCTAC ACCAGAACAA TTAGCTGAAC GCCAAGCGTG GGTTGGCATT GATA~AATTA 185400 CCCTAGATAC TAACAAAGAA AAAGCTACAT TAAGTAAAGC A~ll~l-AA GTTTACGTAG 185460 ATTTATCGTC AATTGCTAAA GGCTTTGGCG TTGATCAGGT GGCTGAA~AG TTAGAACAAT 185520 TA~ATGCTCA GAATTACATG GTTGAAATCG GCGGTGAAAT TCGTGCGA~A GGAAAAAATA 185580 TTGAAGGTAA ACCTTGGCAG ATTGCCATTG AA~AACCAAC TACAACAGGC GAAAGAGCGG 185640 -77.1 12-SUBSmUTE ~H~ET tRULE 2~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 ATCTTGCCGT TTATTTAATC ATTAGAACAG ATAATGGTTT TGTTACCA~A TCATCCTCTG 185940 CTTTCAAAAA ATTAACAGAA ACA~AAGAAT AGTTATGCAA ACTTTATTTT TTACTTTAAT 186000 CG~LLLC~LC GCAATTATAT TGTTGATGTC TATCGGATTT ATTATCAAAA AACAAAGTTT 186060 A~AAGGCAGC TGCGGTGGTT TATCTACCCT TGGTATTGCC A~AGCTTGCG ATTGTGATAA 186120 ACCTTGCGAC ACGCnTCAaT CAAAATTAGA TGCAGGCGAT GrACAAGCGA AAGCTGAATA 186180 TCAAAAATGA CCGCACTTTA TGTGCAAAAT A~AATTAACG GCAAAATTAT TTTGCCGTTT 186300 ACA~AAAAAG TCATTTGTGG TATGTCTGGT GGCGTGGATT ~Ll~-l~-L~LC AGCGTTTATT 186480 CTTCAACAGC AAGGCTATCA GGTGGAAGGC ~l~LLLATGr A~AACTGGGA AGAAGATGAT 186540 TTGGGGATCA AACTACATAA AATTAATTTT GCGGCAGAAT ATTGGGATAA L~L~LLL~AG 186660 TTAGATCCCA ATA~AGATCA AAGTTATTTT CTTTATACTT TAAGCCATAA ACAAGTGGGG 186900 CA~AGTTTAT TCCCC~LLGG TGAAATCGAG AAGCCCATTG TTCGTGCTAT TGCTGAAGAT 186960 CTTGGCTTAA TTACGGCGAA GAAAAAAGAT TCTACAGGGA Lll~llLLAT TGGTGAGCGT 187020 A~ATTTAAGG ALLL~LlAGC ACGCTATTTA CCAGCTCAAC CAGGTAATAT TCGCACTGTA 187080 GGATTAGGCA TTGGTGGTCT AAAAAATGCG GGAGATGAAG ~LLG~LATGT AGTAGATAAA 187200 CGTTGCACGG TGAAAACGCG TTATCGCCAA CAAGATATTC ~Ll~l~L~AT TGAACCAATT 187380 GATGATGA~A CCATTCGAGT TALLLLL~AT GAACCTCAAT CAGCAGTAAC CCCAGGGCAA 187440 TCTGCCGTAT TTTACCTTGG CGAAGTTTGT TTGGGTGGCG GTATTATCGC AGA~AGAATA 187500 -77.1 13-SUE~S i 11 UTE SHEE~ ~RULE 26 W 096/33276 PCTAuS96/05320 TGACGCTCGC CATTCGTCCC GTTTGATTGT CCCTGCGATA AGAAAAGAAC 'l"ll"l'~'l"lLll' 187620 AGGCGAGTTT GG-lllll-A TCTACTACAA CAAACTTTTC TACAACATCA ATCCCAACTT 187800 GAAAATATTT CA~L~lll-l TCTAGTACAC CATCGCATAA ACCACGCCAG CCAGCATGTG 187920 TTGCAGCCAC TTCATTGCCA GAl~ll~lAG TGAATAGAAC TGGCA~ACAG TCTGCCGTCA 187980 TAACAACGCA AACTTGATTG GGAACATTTG TATAAACTGC ATCCGCTTCA AGALlll~lC 188040 CTGAATAAGG TAATTGAATC ACTCGAGTAC L~l~l~lllG AGTTAGA~AT ATAGGTGTTT 188100 GTGGCAAACC AAA'Lllll~l ACTAATAAAG TGCGGTTGGT TTTTACCGCA ~Llll~llAT 188160 GAGTAGTGGT AAAGGCATGA ATALl~lllG GAACATTCCA ATTGGGGTTA ATTGCTTGCA 188280 TCAACGAAAT CATCTGGTAA TGGTGCATAC CATTCCATCA ~L~LCCC~l~l GATTGGATGA 188400 GCTAAGCGTA ACATGACCGC ATGTAAAGCT TGGC~LllGA AATTACGCAA TACTTCCATA 188460 AGTGGATGGG CAATATGTGC CATATGAACG CGGATTTGAT GGGTGCGCCC C~'l"l"l'-''l'AAA 188580 G~llllCCCA TTGGATGAAC CGCCATTAAA GTACGTTTGG TTGCATGACG AGCCATAGGT 188700 ATTTTACGTT $TTGTAGGTC ACGTACTAAC TTAGTTTGAG CAGGAATGGT TTTAGCaACA 188820 ACCATTAGAC ~L~llGlATC TTTATCTAAT CGATGCACAA TTCCTGCTCT CGGTACTTCT 188880 ACGATATTCA ATGGAATATT TTCTGCTTCA AAAC~L~lll CATCTTCCAC TTCAACAATA 189060 ATCTCTATTC TCTCTCCTCC AAGCACTTTC TCACGCGGAA TATTAGTAAT GCG~LC~llA 189120 AACTCTGCAA ~L~lLlGGTC TAAACGTTGT CCCATTTGTT CTGGCTGCAC TTCAGCCGAA 189240 -77.1 14-SU8S 111 UTE S~tEET (RULE ~6) CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/05320 AGGGTAATTT GTGGCATA~A TAGCTCTCAA AAATTTTAAA AGTTGGCTTA TTGATTAATG 189300 AACAATGCGT A~AATA~AAT CTTTGGCATT GCTTGCCGTG GCAGCATTGG TTATTGGATG 189420 TTCAAGTGGT TCA~AAGATG TTGAACAAGC ATCGGTAAAT GAATTATACA CA~AAGGTAC 189480 AACATCATTA CAAGAAGGTA GTTACTCTGA AGCCATTCGC TATTTA~AAG CGACGACTGA 189540 GCGTTTTCCA GGTAGCGTTT ATCAAGAACA AGCAATGTTA GATTTAATTT ATGCA~ATTA 189600 TAAAACACAA GATTATACGC AAGTATTATT GATGGTAGAT AG~111-1-1AC ATCAATTTAC 189660 ACA~AGCCCA AATCAAGCCT ATGCGGTATA TATGGCTGGC TTAACTAATG CAGCAACAGG 189720 CGATAATTTC ATTCAAGATT TTTTTGGAAT TGACCGTGCT ACACGTGA~A CAACCTCTAT 189780 GCGTACCGCT TTTTCTAATT TCCA~AACTT A~L1C~-1~-1A TTCCCTAATA GCCCTTACTC 189840 ACAAGATGCT TTAGCTCGTA TGGCTTATAT TA~AGATGCA CTGGCTCGTC ACGAATTAGA 189900 GATTGCA~AA TTCTATGCAA AACGTA~AGC GTGGGTAGCA GTTGCA~ATC GTGTGGTAGG 189960 AATGTTAAAA CAATATCCTG ATACTA~AGC aACTTATGAA GGATTATTTC TGATGCAGGA 190020 AGCTTATGAA A~AATGGGTT TAACCGCATT AGCA~ATGAT ACTCA~AAAA TTATTGATGC 190 080 GAATA~AGAT AAAACTTTTG CACCAATTGA A~AACCA~AC GAGCCAGACT TAAAAGTGCC 190140 AGCAGTA~AA TAGCAATAAC TGCAGAAAAA TCGAATACTC TCTGCACCCT AAAAATTGAA 190200 TA~AATTTAA ACTAATTAAG GTGCAGATTT TTTTATTTTT TATCAACTGA AAATGCTTTA 190260 CCATAATTTG CACA~ATAAT CTGAGCAGCA TTATA~AGCG TTGTATCAGG TGTTA~ACTT 190 320 AACGTATGTT ~1-~-1-1-1-1-GCTT TTTAGGTGCT GCCCGCAAAC CCTGTCCCCA A~ATTCATCA 190 380 TAGA~ATCAG TTCGTATTTG AGTTAAATGA TAATTTGCAC AATTCAAAAT CTTATACTGA 190440 CGAACAGAAC GTGCATAACG TTTAGGCTCA GGATA~ACAT ACAATCCCCT ATCTA~ATTC 190 500 ACCACAGCAT CA~AATGTAC AATTTGTGGC TCTTGGTTAT CCACCCAGAT CGATTCACTA 190560 TCGATGTAAT AATTCACATT CTTTACCA~A CGTATATATC CG~-1~C~1AC ATCAGTCGGC 190620 GGTGCCAGCT TCACATCATT 11~-1-1-~'AGCC TTTTGGATTT GAGCAGAACA AGCGGTAAGT 190680 TTTATTCTAG AATTTTACAG TGTGTCCATA ACCTTCTAGG ALl~llllAA TAL~ll~lAA 190800 GGAL-L~-1--L-1A GTTGGCGGTA ATACATTTTC AAGCTCATAA TCTAACCCAA GGGTTTTCCA 190860 -77.115-SUBS 1 1 1 UTE S~{EET tRULE 2~

W 096t33276 PCTtUS96/05320 AACATAACGA ATCCAGGTAT GTTGATTACG TTTTTGCA~A TATTTTGCAA ATTCAAGGGT 191040 ACGTTTATTT GGCACCCCAA TAAGATTTTG ATGAACTTGA TCATTAAGTT CTTTTAAATC l91100 A~AACCATTT GTATCTAAGC AAGTATTAAT CCCTTCCTCT TTACAAGCAC GGAACCAATC 191220 AGCATTCATA AAATGGCGAT AAGTCACGAC ~Ll~lLL~ATT AAATCTTCGA CACTGATTTC 191340 AGAGTGAATT CGTCCAAGAA CTGACATACA TAAATTTCCT A~AATTAGAT ATAGCTAAAT 191520 TTTACCAAAG ATTTAGTCTA TA~AAAATGA GCCTGATTTA AATCAGGCTC ATACATATTA 191580 TGTTCCCGCC AAAGTGCGGT CA~AAATAAA CAl~LllllA CATTGACTCT GTGAAAGTTC 191640 TAGTAATTAC ~'L~'L'l'~'L'l'~'l' TG~L~lLlAG TTAAAGAGTT APAAACGTACT GCGTAACCTG 191700 AGTAACCATC CATTAAGCCA GCAAGGTTGC GAC~ll~lGC TTCTGCATCT TTACCTAAGG 191880 TAGCTACAGA AGTTAATGAT GCTACCGCAC ~LLLllGGTC ACGACCGTGC ATTGGGTTCG 192000 CACCTGGTCC GAATGGTGCA CCAGCACGAC GACCATCAGG GGTGTTACCC ~'l"l"l"l'~'l"l'AC 192060 CGTTAGTTGC AACAACATTG CCATCTTTAT CTTTGATGTC GCCACGAACT GGTTTAACTT 19?.300 TATCGTGCAT ATAGTGGATT ACGTTTAAGG CAGTCACATA Ll~l"l"llGCC AACCAATCCA 192480 TA~AGCTATC CATACGAGTC ATTACTGTAT CGA~ATCTAA TACTTCATCA GTAATTGGTG 192540 CA~LlllCGG ACCTACTTGC ATACCTAATT TTTCATCGAT ACCGCCGTTG ATTGCGTATA 192600 -77.1 16-SU~SmUTE ~}~EET tRULE 26 CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/05320 ACAATGTTTT CGCTAAGTTT GCACGTGCAC CGAAGAATTG CA'111~111A CCCACAATCA 192660 TTGGTGATAC ACAACATGCG ATTGCGTAGT CA'1'C~'1''1'~'1"1' GAAGTCTGGA CGCATTA~AT 192720 CA'1'C~'1''1''1"1'C GTATTGAACT GATGAGGTAT CAATCGATAC TTTTGCACAG A~ACGTTTGA 192780 A~'L'1''L'1'~AGG TAATTGTTCA GACCAAAGAA TGGTTAAGTT TGGCTCTGGA GAAGTACCCA 192840 1~11~1AAAG G~1~1~1A~A ATACGGAATG TATTTTTGGT TACTAATGTA CGACCATCTA 19 2900 ATTCAGGTGT ACGTAAGA~A CGAACCATAC GAAGTTTCAT AACTAAGTGG TCAACTAATT 193020 CTTGCGCTTC AGTTTCAGTA ATTTTTCCTG CTTTTA~ATC AC~'1''LC~ATG TACACGTCAA 193080 TA~AGGTTGC GGTACGACCG AATGACATTG CAGCACCATT TTGTGATTTT ATTGCAGCAA 193140 GATAAGCA~A GTACATCCAT TGAATGGCTT CTTGAGCATT AGTTGCTGGG TTAGA~ATAT 19 3200 CATAACCATA GCTTGCTGCC A'1''1''L~'1"1''L'1'A ATTGACCTAA TGCACGGTGT L~Ll~LGCGA 193260 'L11~LL~ACG TA~ACGAATT GTTGCTTCAA GATTTACGCC A'L~'1''L~'LA~A 'L~'L'L'L'L'L~'LA 193320 AAGAAGAGAA TTGTGCGTAT TTA'L~'L'L'1'~A TTAAGA~ATC TACACCATAA AGTGCTACAC 193380 CAGATTTACG GCAACGTA~A ATATCTGGCG TGTA~ACATC GAATACACCT TGGTTATGTG 193500 TTTTACGGTA TTCAGTGAAG A'L'L'L'1''L'1''L~'A CTTTTGGATC AAGTTCACGA CCATA~ACTT 193560 TACAAGAACC TTCCACCATT TTGATACCAC CGAATGGCAT AATGGCACGT TTTA~AGGTT 193620 CATCAGTTTG AAGACCAACG A'1''1''1''L'L'L~'1'A AA'L~'L'L'1'~'L'L AATGTAACCA GGTGCGTGAG 193680 AGATAATGGT AGATGGTGTA TGTTCATCAA AATCTAATGG CGCGTGAGTA CG~'L L'L l ~AA 193740 TTTTAATACC TTCCATCACA GATTCCCA~A GCTTGGTTGT TGCTTCGGTT GGACCTGCTA 193800 AGA~AGAGTC ATCGCCTTCA TAAGGGGTAT A~11L1LL1G GATA~AGTCA CGTACATTGA 193860 CA'1''1"L'1'~'1"1'G CCAATCGCCA CCAGCA~AAC CAGCCCACGC CAATTTTTGC ATTTCATTAA 193920 GTTCTGACAT AGTCATTTCC '1LL~11AATT AATA~ATA~A TCTTTAATGT GTTTTGGTTA 193980 GGATTA~ATT CTTCACGATG A~ATGGTACA AATCTA~ATC TGCGTATTTC ATCGGATCAA 194100 CACCGATTTG TTGCCA~AAT TCAGGTGTAC TA~AATGTGC GGTAATAATT CCCATCGGAA 194160 TCATA~ACAT ATTAGCCACA CA~'1'~'L'L~'AA ATCCTGACGC GACA~ACA~A CCAATCGGCA 194220 TAATCATAAT A~ATGCTTTG TCTGTAACAG TCTTACCAGA ATAAGACATC CAAACCGCCA 194280 -77.117-SUBS 111 UTE S}~E~T (RULE 2~) CACACACCAT AATGTTACAT AAAATACCTA GGTTAAAAGC TTCA~ACCAA GTGTGATGAA 194340 CCACGATCCA ATTTCGAATC A'lll~l~lCG TGGTGATTCT ACCGCCTACA CGGGCGACTA 194520 'l"l"l'~'l'~'l"l'~'l' CGTGTAAAAT ACAAAGGCTA AGGCAATACA AGCACCGGCA CTAATACCGG 194700 AAAAGCAAAA ATTATTTCAA CAAACTTTGA TATTTTGCAA G~'1''1"1'~'1"1''1'A ATTAAAGACA 195000 TGAAACTTGT TTTATTCGCG TAATACCGTG AATTCCCCCA GATAATCATC CA~llllC~A 195120 TATAGACTTG CTATTTTGAG TAATTAATAG CATTATTTTG Al~lllll~A AGAAAAAGGC 195240 GAl~lll~lC ATAAAATAAT GATTTAAGTG CGGTTAAAAT TTGGTTAATT TTAAGTGCAC 195300 ll~lllATAC AGGAGCAGAT TATGTATTAT GGTTTAGATA TTGGTGGCAC GAAAATAGAG 195360 'l"llG~l~AGG TGGGCACCGT AGGTTTGGGC GTACCTGGTT TTGTTAATCA ACAAACTGGA 195540 TTAGCCGAAA TTGCCAATAT lC~l~lGGCA GATAATAAAC CAATTTTATG CGAlll~l~l 195600 ACGCGTTTGG GCCGTGAAGT GCGGGCAGAA AATGACGCAA All~llllGC GTTATCTGAA 195660 TTTGGTGGTG G-lll~lCTT AAACGGTAAA GTTCATTCAG GTCAAGTGGG AATGGCGGGA 195780 CCAATTTATC AATGCGGTTG CGGCAACAAG G~ll~lll~G ATAATTATCT GTCTGGTCGC 195900 -77.1 18-SUBS i I i UTE ~}~E~T (RULE Z6) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/OS320 AA~LLL~Ll~L ATCAAAGCAA TGA~AGTGCG GTAGATTTTG TGAATCTTTT TGTTGAGTTG 196020 GCGGCGATTT CTATTGGCAA TATCATTACG GCATTTGATC CGCATATGAT l~l~LLAGGT 196080 GGTGGATTAT CTAATTTTGA TTACCTTTAT GAGGCTTTAC CAAAAGCnCT TCCGCCTCAT 196140 GTGCGTGGTG CGGCAGCGTT ~~ AACC AAATAATTCA ACAAACTAGT GGGGCGTATT 196260 T~11~LL1~1 GTTTCTTTCT TTAGAGAAAT TATTAAAAAA TCTCGCCTTT TCATTGAAAA 196380 LCC~lLLATT CCCAGCAAGC ~LLC~L~AAA TGTGGTTTGG LC~LlCGGTG GAGGGGAGTT 196620 AAATTCAAGA TAAAGATGGA TCA~lLCC~LG GCGGCCCTGC TTATTATATT GTGCAAGGTT 196860 AAGGGGAATA L~LCG~LATT TCATTAGTAA TTTTTACCGC ACTTATTATT TTCGGTGGCG 197040 'lL~LL~AAAG TGCATTTAGT TTTGATGCTG CCGCTGGCGG AATGTTTGGT GCATTGGTAT 197220 CGAAAGCAAT GATGATGGGG ATTA~ACGTG GTTTATTCTC A~ACGAAGCA GGGATGGGAT 197280 AAATGCTCGG G~1~11L~11 GATACAATGA LC~Lll~lAC TTGTACTGCC GTTATTATTT 197400 TGCTTTCGAA TAATTATGGT AGCGA~ACGC TCAAAAGTAT ~L~~ ACG CA~AATGCTT 197460 -77.119-SUE~S i 11 UTE SHEET (RULE 2~i) CA 022l874l l997-l0-2l W O 96/33276 PCTnUS96/05320 TCATTAACTT GATCGCAATT TTGATGTTGT CGCCAATCGT ATGGA~ATTA ATGAAAGATT 197760 ATCAACGCCA GCTTAAAGAA GGA~AAACGC CAGAGTTTAA AATTGATGAA TACCCTGAAT 197820 TTATCTACCT TTCCAAAAAG AGTTAGATTA TTATTTAAAG A~ALlllll~ ATATTGTTTC 197940 CCTTTATGGA AGCGCACATC GACTGGCTGA TTTGCCACTC GACAGGTTTC TATA~AATCT 198180 TCGGTACGCA All~l~lCGG TAAAAACTCA TCTTCCAAGC CCTGATCAAT GCGCATACCT 198240 TGCACTTTAT AGC~ll~llG AATGAGCGAG CTGGCATCAT ATTGCTGCCA TTTTTCACGA 198300 GCACC~l~lC CACCCATTGA A~l~lCC~ATA ATGGAACGTT TGCC~ll~l AGGGAAATTT 198480 GCTT~TCA A~TCAG~-C~ TTCATTCAAG ATATAATCA-T ACATTTGATA AllC~lCGCC 198540 CAAGGCTGCT CGGTCGCATT AAGATAAAAG CCCGCTCCCT GCCCTA~ATC GTAAGCCGCA 198600 CCTGAAAGCC AATA~ATCAC ACCAAGCGGT CGA~ lG GATTATTTGG CAAATAAACG 198780 GCAAATTTCA TTTCACATTG AA~l~lllGA GCATTATGCG CCCAAACTTG CTGCGAACCG 198840 CCAAAAATTT GA'l~ll~llC AATTAGTTTC ATAGCGTACC TTAGTAGTGA ATAACAGTAC 198900 TGTGAGTCAC AAACG~ll~l AACTGGATGT CGC~lll~AT TGAATCTTCC ACCATTTGCG 199020 CCAATTGGAA CGGACGCGTT GA~ATTTCTT GTCCTGCACC CGCTACGCCG ATGATAATGG 199140 ATTGTCCCCA GCCACGGTGA GCA~lll~lA ATGCTTGACG CATTACGTTT ACATTACCGA 199200 TACATTCAAA GGTATGGTCA ATGCCCCATT TATTAATATC TAACAACACA ~l~-l"l'-l'~ATCG 199260 ,GCTTATCGTA ATCATTAGGG TTTA~ACAAT CCGTTGCACC A~A~L~llll GCCAACTCAA 199320 -77. 1 20-SUBSTIl~JTE ~tEET tRULE 26) CA 022l874l l997-l0-2l W 096r33276 PCTrUS96/05320 GCACTACCGC TAAACCAATC GCACCCAAGC CAAACACGGC AACAGAGTCG C~'1--1'~'1"L~'LA 199440 ~L1~-L-LC~-LG GTTCGCTTCA GGGTTGATTT TCGCCAGTGA AACTTCCGCA ACAACTGAGT 199560 ATTCACTGAA GGTTGAACAG CCCATATAGT GATAGATCGG CTGACCTTGA TAAGA~AAAC 199620 ~1~LC~1-GCA ATCAGGCATT AAGCCTTTAC CTTGCGTGTC ACGCACTGAG ACGCATAAGT 199680 ~-L'1'C~-L~'LCC TAGCACCACA GGGAATACCC CTTCAGGATC GCTTCCTGAT AACGTAAACG 199 860 GAGATTTGAT GGTTGAATTG A'L'L'1'~'L'1"1'AA TTTCCATTGT TTTTCCTCTT AATTCATTGA 200040 AA~'1'~'L'L'L-1''1- TTATCATTTT TGTTTA~AGG GAATAAAAAG TGACTTACAC CACCGCTAAA 200160 GCTGCTGA~A A~ATAGGCAT TTCCGCCTAC ACCTTACGCT TTTATGACAA AGAAGGCTTG 200220 AATCAAACAA AAAATGTA~A GTGTCA~ATT GCCGAATTAA AACGTTATTT AGATTTGCTT 200460 GAATACAAAT TAGC~-L-L-L-1-A CCAAAAAGCG A~AGCACTAG GCTCGGTA~A AGCTGTGAAT 200520 TTACCGCA~A ~L-LC~-L~AAAC GAGCTA~AAG GGTAAAAGTG TTCACATCAC AGAATTAGAA 200580 AAATCAGGTT TTGTGATCAA GATCAGGATA ACATA~AAAT AA1-~'LCCGAT AGCTATTGTT 200700 CTAAATGGCT AAAAAGAGTA TATTCCGAGC CA~ATTTTTT ~-1-LL1L-LACA GAACGGAGTT 200760 TTTTGGCACG aAAAAATTAA GAAATGCTGG CTCAGATCTT GGTGCAGCAG TGA~AGGTTT 200880 CA~AAAGGCG ATGAAAGAAG ATGAAA~AGT A~AAGATGCG GAATTTAAGT CTATAGATAA 200940 TGAAACAGCG TCTGCAAAAA AAGGA~AATA TA~AAGAGAA AGGAACAGGC TTAATCCGTG 201000 -77.121-SUBSTiTUTE S~EET tRULE 2~i) CA 022l874l l997-l0-2l CCGA~ACGTT TGCCTATAGC AATTCGCACT GTAATGGATT GGGTAAAAAC AATTCGTGGT 201120 TTAGCTGCTA ACGTTCA~AA TGAGTTGAAA CAAGAGCTAA AATTGCAAGA ATTACAAGAT 201180 GTGGAAGAAT TAAAAGCTCA AGCAGATAAG ATGAAAGCGG AGCTAGAAGA TA~AGCAGCT 201300 GAAAAGTCTC AAAATGCAAT CTCAGTTGAG GAGGCTGCAG A~ACTTTATC TGAAGCAGAA 201420 TCAAAAACTA AATCATAGCG A~lllllATG AGTAATGTGG ATGAATCTCA ACCTTTAATT 201600 ACGCACCTTG TTGAACTAAG A~ACCGTTTA TTACGCTGTG TGALll~L~l AGTGTTGGTT 201660 Lll~ll~CTT TGGTGTATTT TTCCAATGAT ATTTATCATT TTGTTGCTGC ACCTTTAACG 201720 GCTGTTATGC CAAAAGGCGC AACAATGATT GCAACCAATA TTCAAACGCC lLl~lllACG 201780 CCAATTAAAT TAACTGCGAT TGTTGCAATT TTTATTTCTG LCC-llATTT GCTTTATCAA 201840 ATTTGGGCTT TTATTGCACC TGCTTTATAT CAGCACGA~A AACGGATGAT TTATCCGTTG 201900 TTAllllC~A GTACGATTTT ATTTTATTGC GGTGTTGCTT TTGCTTACTA TATC~L~lll 201960 C~l~lL~LAT TCAGCTTCTT TACACAAACA GCCCCAGAAG GCGTTACCAT CGCAACAGAT 20'020 ATTAGTAGTT ATTTAGATTT TGCTTTAGCG TTATTTTTAG ~LLllGGCGT Ll~LlLl~AA 202080 GTGCCAATTG CGATTATTCT ACTTTGCTGG ACTGGTATTA CCACTGTAAA GG~L~llLCC 202140 GAAAAACGCC CTTATATTAT TGTTGCGGCA LlllllATTG GTATGCTTTT AACGCCTCCT 202200 GAL~LLllLl CACAAACTTT GCTTGCCATA CCGATGTGCT TG~L~lllGA GCTCGGTCTA 202260 TTGGTCGCTC GATTTTATCA ACCAAAAGAC GACGA~AGTG CGGTTAAAAA TAATGATGAA 202320 TATTATATTG ATATAACCCT AAllll~lll TTTCATAAAA CATATTTTCG TAGTGATTTA 202440 'l"l"l'~'L~'LC~'l' TTTTTATTTT TTATCTAATA AATACGATAT TTTTTAGATA AL11~111AC 202560 ATALl~L~lA TGCGCCTCAC GAGGCGAATA CAATAAAAAT ACAATACACA CAACATCAAC 202680 -77. 1 22-SUB~TtTUTE 5}tE~T tRULE 26) -CA 022l874l l997-l0-2l AAAGAGGGAA ATTCATTATG TCA~AAGTTG CTTCCTTAGA CGCATTTTTA ACA~AAGTTG 202740 TTTGGCCTTT TTTAGAAGCC AATCCTA~AT A'1'C~'1"1'~AGA AGCATTATTA GAACGTTTAG 202860 TTGAGCCTGA ACGTGCATTT CAATTCCGTG TGGCGTGGAC TGACGATA~A GGGCAAGTGC 202920 AAGTA~ACAG AGCA111C~1 GTACAATTTA ATAGTGCCAT AGGCCCATTT A~AGGGGGAA 202980 TGC~111CCA TCCATCAGTA AATTTATCTA TCTTA~AATT CTTAGGTTTT GAGCA~ATCT 203040 TTA~AAATGC TTTAACAACA TTGCCTATGG GCGGGGCA~A AGGCGGTTCA GATTTTGATC 203100 CTA~AGGCAA ATCTGATGCT GAAGTTATGC ~'L'L'L'L'LGCCA AGCATTAATG GCTGAACTTT 203160 AAGTTGGCTA TTTAGCTGGC TATATGA~AA AATTATCA~A CCAATCAGCC '1'~'L~'L'L'L'L~'A 203280 CTGGTCGCGG 'L~'1''1"1'~'1"L'LC GGTGGTAGTT TAALLC~LCC GGAAGCAACG GGATATGGAT 203340 TAATTTATTT TGCTCAAGCA ATGCTTGCTG A~AAAGGCGA TAGTTTTGCA GGTA~AGTAG 203400 TTTCAGTTTC TGGTTCTGGT AATGTAGCAC AATATGCTAT TGA~AAAGCA TTAl~L~LLG 203460 GTGCA~AAGT AGTAACTTGT TCTGATTCAT CAGGTTATGT TTATGAtCCA AATGGATTTA 203520 CTACTGA~AA ATTAGCCGCA CTTTTCGATA TTA~AAATAC A~AACGTGGG CGTGTGA~AG 203580 TTGATATTGC G~'L'LC~'1''L~'1' GCAACTCA~A ATGAATTAGA A~'1"L'L~'LGAT GCACAACGTT 203700 TAATTA~AAA TGGTGTGA~A TTAGTGGCTG AAGGTGCGAA TATGCCAACA ACAATTGAAG 203760 CAACAGAAGC ATTACTAGCT GCAGATGTAT TATTTGGCCC GGGTA~AGCT GCCAACGCTG 203820 GTGGTGTTGC TACTTCTGGT TTAGA~ATGG CACA~AGTTC ACAACGTTTA TATTGGACAG 203880 AATACGGCAC AATTGAAGGT CAAGAAAACA,TTAACTATGT TGTTGGGGCA AATGTAGCAG 204000 G~'L'1''L~'1''LAA GGTGGCTGAT GCAATGTTAG CCCAAGGCGT TTATTAACAA ATA~AAAAGT 204060TAAACTAAAT AACCGCACTG TAATAAAGTG CGGTTATTTT TTTAGGATGA AATTTGAATA 204120 TAAGA~AGCG ACATTTTGTC GCCTTAGATA TTATTTATTT TGAATTGTTT TCGTCACAAT 204180 GATTAATATC ACTGCATTTG CCGTALAGAT ACACGTTATG C~'1''1"L'L'1'AAT TTTATGCCGT 204240A'L'L'L'L'1'~'ACT GATTTCACGC TGACGTTGTT CAATAATATT ATCCGTAAAT TCAAATACTT 204300TACCGCAATC TTCACAAATA ATATGATCGT GA~L~L~L~ L TGGAGCAAGC TCA~AAACGG 204360 -77.123-SUBSTTTUTE S~ EET (RULE 2~

:

CACGATAAAC TGTGGCTAAT CCAATTTCAC AAC~-l-l~llC CAGGAAAATT TTATAAACAT 204480 G~l-~l~-lAAT TTTTAATCCC A~ll--ll-llGA GTAATTTAAT ATTTCCTTCA GACATAATTT 204600 TCCTTCCTAT TATGCACA~A ATGCTAAGCC AATTCAGCTA AGCACATTTC ATCATAAATT 204660 TGTTTACACC A1-1-1-11~-1AC ACGCTCTGCG GTAAGCTCTG GTTGGCGATC TTCATCAATA 204720 ~l~l~-l-l-GGCC AAl--l-lC~-lAC CACAATTGCA CCGTGTGGCT CTATAATATC GCGCACAGTT 204840 CCGATAGCAT CACAGAAATA ATCTGCATAA l~-L-l~-L-l~AT CGCCACAACC GAAAATACCT 204900 ACAAGTTTAT CTGTAA~ATC AAlll~llCG AGTGTTGGGA AAAAGTCATC CCAGTCTGCT 204960 l~l--l-~ll-LGC TACTTTTGGC AATATCACGA ATATCAATTA AATCACTACC TAA~ll~-l-lll 205080 AAl-CG-ll-lAA TTGCACGAAT AACAAAATCA G~-l-l-l-l--lC~G CGTGAACCCA GTGTCCACTG 205320 CCATTAATCG TAAAGGCAGT TGCATTAGGA AAll~-l-L~lA GAA~l-l-lll-lC GCTATTTTCT 205380 TTTTCCCAAT CCATAATATT GGCATAATTG TTAAAAAGCG CGGTAAGATT AAAACGA~AA 205500 All-l~l--lG-l--l TTAAAATCGG TTTGGCTTGC TGACGATTTT CAGGCTTTGC A1-11111ACC 205620 CCGAGATTAT CCATATCGCC GAATAAACCG TGAATAAAAA TTA~AACAGG TGTATTAATC 205980 ~-l-ll~-l-l-l-lA CTTGATGAAA TTGATAATTG AGTAATGATT TTGCCATAAT TTTTACGTGA 206040 -77.124-SUBS-~ I I UTE SH EF~ (RULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GAATTTGTAA AGAAGTCGTT ATAATTGA~A A~AATTTTAG CA~ACAGAGA GATA~AAATG 206100 GGAGA~AGTG CTTCGGATAT TTTACGCCGT TTGCTTAGTT TACCTGTGCA TACTTCAATT 206220 GTTAATGATT TAATTATTAC TTCAGCAGAA ACAGATCA~A AGCCA~AACA GGCTATCAAT 206280 GTGA~AGAAG TA~ATATCAA AACAACAAAA AAGCAATCAA TAACCGCAAT TAATCAGATT 206340 GTAGA~AAAG TCCAAACTTT ATTA~ATTCA ACTGAATTTC AAGAAGAAAG TAAGGCTGTT 206400 GTAC~l-ll~l TAGCGATTTT ACGTGTGCTT TATCGTACAA ATCCTGAAAG TTTTGCGCAA 206460 TTAATGGCAG GTAACCATAC TAAACCA~AA CA~ATTCCAG ATACGCCTTA TTGGGTTATT 206580 ACCAATACAA ATAGTGGACG A~AAATGTTA ATGCTAGAAG GTGCAATGCA ATCTATGGAA 206640 TTACCTGA~A CATTGATTGA TGAAGTGCGA TCATATTTCA CGGTA~ATTA ATAATGTATC 206700 AGGGCGATAT GCTTACTTGG ATAGAATTGA CTACA~AGAT TAACCAAACA GTGGCTTTTT 20 b 820 TACA~AAAAA AGGCGTA~AT GCAGAAAGTG CGGTTGCTTT TGTGGGA~AA AATTCAGAGA 206880 A~ATTTTATT TTTATATCTG GCGACAATTC AGCTTGGCGC A~AAGTTTTA GGCATAAACC 206940 CTG~llllCC ACAAGA~AAA ATTGCA~AAT TATGTGAGTT TTATCA~ATT GALlllL~ll 207000 TTTATGATAA AGATTTACTG AATTTGCAAG AAATTGATGT TTTTACTCAA A~AGCCGATT 207060 lllLlC~lCC TGCGACGATG ACGCTAACGT CTGGCTCGAC AGGTTTACCA AAAGCAGTTG 207120 TGCATAATGT CCAAGCACAT TTGGATAATG CA~AAGGGGT ATGTAACTTA ATGAAGTTTG 207180 ATTGTAATCA ATCTTGGTTA CTTTCATTAC CCTTATATCA C~lll~AGGG CAAGGTATTG 207240 CATTATTAAA GACGACCCAC ~'L'l"l'~'L~'l''l'G TGCCAACGCA ATTACAGCGT TTATTAGATT 207360 ATTTACAGGA A~ATCCGAGC ATTTCATTTG CTACACGCCA TATTTTACTG GGCGGTGCGC 207420 ATATTCCGAC AGAACTTACA CAAAATATGT TGA~ATATGG TATCGA~ACG TATTCTGGCT 207480 ACGGAATGAC GGAAATGGCT TCGACAGTTT TTGCTA~AAA ATCTGACAGA A~ACAAGGCG 207540 TAGGGCAACC GCTCTTAGGT AGAGAGTATT GTTTAGTAAA TGATGA~ATT TGGCTGA~AG 207600 GTGCAGGTTT GGCGATGGGT TATTGGAAAG ATCGACAAAT l~llC~ATTA ACGAATAACC 207660 AAGGCTGGAT TCAGACA~AA GATA~AGGCA TTTGGCAAGA GGGCGAACTT GTTATTATCG 207720 -77 . 1 25 -SU8S~ I I UTE ~ EET (RULE ~6 GACGACTTGA TAATATGTTT ATTTCAGGTG GCGA~AATAT TCAGCCAGAA GA~ATTGAAC 207780 AAGTGATTAT TCAACATTCT TCAGTTAATC AAGTATTTGT TTTACCACAA A7.~AAACA~AG 207840 AATTTGGTCA GCGTCCTGTC GCTTTAGTGG ATTTTAATGA GCCCTTTAGC A~AAGTGCGG 207900 TTGAAAATTT AALC;lll-lll TTACAAGATA AACTTGCACG TTTTA7.~ACAA CCTATTGCAT 207960 ATTATCCTTT GCCACTGATG CTTGAGA7~AG GCATTAAGAT CTCACGTA7~A CAGCTTGCTG 208020 AL LG~ l l GGC A~AGCGAGAT GAGATA7iATT AATTTACCAT TTAGATTAGG GA~AAATAAT 208080 GATTAGGA~A CTTATGA~AA TACCTCCATT TTTTACCGCA (:LLlllGCCT CGGCAATGTT 208140 TACCCTTAGC GTTTCGCAAG GGGTATTGGC GGCA~ATTCA ACA~ATGTAT TACCAACGGA 208200 GCAATCGCTT A7.~AGCCGATT TGGCTAACGC TCA~A~AATG AGTGAGGGGG AGGCA~AAA 208260 TAG~lL~llA GCAGAATTAC A~ACATCAAT TGATTTATTG CAGCA~ATTC AAGCCCAACA 208320 A~ATCAAT GATGCATTGC A~ACAACATT AAGCCATTCA GAGAGTGA7.~A TTAGA~AGAA 208380 TAATGCAGAA ATTCAAGCAT TA~AAAAACA ACAAGA~ACG GCAACAAGTA CTGATGATAA 208440 TGCGCAATCA CAGGACTATT TACA7.~AATAG TCTCACTAAG TTA~ATGATC AATTACAAGA 208500 TACGCA7.~AAC GCATTAAGCA CAGCA7.~ATGC ACAATTGGCA GGGCA~AGTT CTALLLI :L~A 208560 ACGAGCACAA GCGGCATTAA CAGA~AATGT TGTACGCACA CAGCA~ATCA ATCAACAATT 208620 TGATTTA7.~AG AATAGTTATA ATCA7~AACTT ATTA~AAAT AATGATCAGC LLL(_LLlACT 208740 CTATCA7.~AGC CGATATAACC TATTGAATTT ACGTTTGCAA GTACAGCAGC A~AATATTAT 208800 TGCGATTCAA GAAGTCATTA ATCA~AAAAA TCTTCAGCAA TCACA7~AATC AAGTAGAACA 208860 AGCTCAGCAA CAGCA7.~AAAA CTGTGCA7.~aA TGATTACATT CAAA~AGAAC TTGATCGCAA 208920 TGCACAGCTT GGTCAGTATT TATTACAACA AACAGA~AAA GCGAATTCAT TAACTCAAGA 208980 ACA~ATTAGT GCATTACAAG GCACGTTAGT TCTTTCACGT ATTATCCAGC AACA7.~AACA 209100 A7.~AATTACCG ACTAACTTAA ATATTCAAGG TTTATCA~AA CA~ATTGCCG ATTTGCGTGT 209160 ACATATTTTT GACATTACTC A7.~AAACGCAA TGAACTTTAT GATCTAGATA ACTATATTAA 209220 TA7.~AGTTGAA AGTGAAGATG GA~AACAATT TACTGAGGCA GA7.~AGAACGC AAGTTAPAAC 209280 GCTATTAACT GAGCGTCGGA AAATGACATC TGATCTGATT A~ATCTTTAA ATAATCAATT 209340 AAATCTCGCG A~L l l ~ l L l GG AATTAACACA GCTGCA~ATT ACACA7.~ATCA GTGATCA7.~AT 209400 -77. 1 26-SUBS 111 UTE S~tEET ~RULE 2~) CA 022l874l l997-l0-2l TCAATCTAAA TTAGAGCAGC A~A~1-1111G GGTGAAAAGT AATAATCCTA TTAATTTAGA 209460 CGG~11~-11-1 11~1-L~A~AA ATCCAGAAGA ATTTTGGCAT TGGTCATTTA GTATGGCGGG 209820 TTATTGGTGG ~ 1-1ACAT TTTGGATTTC AL-L~-L-LCC~-1~ CCAAATGGTA 'L-L-L-L-l~L-LAA 209880 TCATTTTGAA TCTTCAAAAG AGAATGCACA AC~'L'L-L-LC~-L G~1-~-1LATCC AGCGCATTAT 209940 '1~L-L~-1GGTT GTATTGCTTT TA~ATACTTC ~1'~-L~-L'L'LAGC AATGTCACTG ATGCAGGTTT 210000 ~1-LG~-1-LAATA AGAATTGTAC AAATTGGTTT TAGATTAATT CCTGTGGGAT TAATCGTACT 210180 TA~L-L~1L-LLA GGCTATTACT ACACCGCTTT AAATTTAATT GAGCATTTTA TTCATTCTTA 210240 '1'-1~-LC~'1'C~'1' TTAGCACATC GCCGTTTAGC AGAAAAACGT CGTCA~AAAG CACTTGAAAA 210360 GGCGTTAAAT GATGTGCGTA GCCAATTATT AC~'L-L-L-L~-LA GA~1~-L~-LL1A TTTGGACAGC 210480 ATTATTAGGG A1~1-L~-1ACT ATGTATGGTC AGATTTAGTC ACCGTAGTGA GCTATTTACG 210540 TACTTTATTT AAL~LL~-LLG TTGCTTTGGT TATCGTAGGA ATTACTTATG TGTTGGTTCG 210660 TAATATTTCA GGCATTTTGG AAGTATTAAT 'L-L-L-L'L~-LCGC GTGAATCTTT CACAAGGTAC 210720 ATTTGCAACC TTAGGGATGT CTTGGTCAAA ATTACAATGG TTATTCGCCG CA~'LL-L~'l~'L 210840 TGGTCTTGGT TTTGGTATGC AAGAGATTTT TGCAAACTTT GTGTCAGGTA TCA1111~1-1 210900 AGCGAAAATT CGTATCCGTG CAATTACATT GATTGATTTT GATCGCA~AG AAGTGATTGT 211020 GCCAAATA~A '1'~'L-L-L-1~-1'~A CTGGTCAAGT GACCAACTGG GCATTATCTA ACACTATGAC 211080 -77. 1 27-SUBS i 11 UTE S~}E~T tRULE 2~i3 CA 02218741 l997-l0-2l W 096/33276 PCTnUS96/05320 ACGTTTAGTG ATTAGCGTTG GTGTTGCTTA LG~ll~lGAT TTAACACTCG TGCGCCAATT 211140 LlLlllAACT LllG~lGCAA GTACACTGGA TCACGAGTTA C~L~lllATG TAGAACAAGT 211260 CGAAGAAATT C~LL11~11~ ATGTAAAAAA ATAAGGGCAA ATTATGGCTG GTAATACAAT 211440 TGGACAACTT TTCC~L~L~A CAACCTTTGG AGAGTCACAT GGTATTGCAT TAGGCTGTAT 211500 L~lC~lAAA CCAGGAACAT CTCGATATAC GACGCCTCGT CGTGAAGATG ACGAAGTTCA 211620 AATTTTATCT G~L~l~lllG AAGGAAAAAC CACAGGCACA AGTATTGGGA TGATCATTAA 211680 AAATGGAGAT CAGCGTTCGC AAGATTATGG TGACATTAAA GALC~lllCC GCCCAGGTCA 211740 TCCGCAGAAA GTGGGACAAA TTGATTGGGA AAAGGTAAAC AGTAATCCAT L~ll~ CC 211980 TG~LC~ll~A ATCAATCTTA ATGGTGAAGC CGTAGAAGTT GTAACAAAAG GTCGTCACGA 212400 'l'C~'l''l'~'L~'l'G GGGATTCGTG CTGTGCCAAT TGCGGAAGCT ATGGTGGCGA Ll~l~llATT 212460 AGATCATCTC TTAC~lLllA AGGCACAGTG TAAATAATCC TGTACCTAGG GTAGTATACT 212520 AATGAATAAA ATTTTATTAA AAACAACCAT AATTTTTACC GCA~Llll~L CTCTGAACGT 212640 -77.128-SU8STTTUTE SHEET (RULE 26 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GA~AGGTGAA GGTTACCAAG TGATTCGCAT GAATCGCAAT CGTTATTATG GTCATCCAAA 212820 TATGATTCAG TATCTTGAAC GTTTGGGGCA GCGAGCTA~A GCTGCTGGGT TGCCAACGAT 212880 TCAGATGGGA TTAGATGCGG ATA'1"1'-1G~'L-1' AAGAATGGGC GA~ATGTCAG ATGCCGATGC 213000 GCTCAATTCT GATGGTA~AG GTTTATTAGT TGTGGATAGA AAGGCGCAAC GAGTAGATGA 213060 GACGCGTATT ~11-1~-1LAATC CTGCGATTAA GGTAAAATTA TGTCAAACCG CTGGCAATGA 213180 TCGCGGTTGG CTACACAAAA ~1-LC~1C~11G GCATGGACAC AACTCTCATT TTCATGTTCG 213240 TTTAACTTGC CCAGCAGATG CATCTTATTG TGA~AATCAA GCGCCTGTGC CTG~LG~lGA 213300 CAAACCTAAA GTTACACCGC CTGAGCCGTT TTTGTGCCA~ CAGATTTTGA ACTCACCGAA 213420 TTAGCAATAT ~l~-l-l'-l'-L~'l~-L TG~'l"l-l L~'LC GCATCATTTA TCGATGCAAT TGCTGGCGGT 213540 GGCACCAACA AATTGCAAGC TATGGGCGGT GCATTATCCG CAAGCCTTTA 'l'-L-L~-l--LGCGA 213660 AAAAGAGCGG TCAATTTACG CGATATTTGG TTTATTTTGA ~1-L-LGG~-L-1-1-L CTTAGGTTCT 213720 CGAAAACAAC GATTAAGTTA 1~L~-L-1ATTT G~-L~-L-L-L-LAG TTAGCCCATT TTTAGGTTTT 213900 CTAGGATTTA ATCTCCCGAA AGCGGCAGCA CATGCA~AAG TGATGAACTT CACTTCGAAC 214020 CTTGCTTCTT TTGCACTTTT CTTATTGGGC GGACA~ATTC TTTGGA~AGT GG~L1LC~LG 214080 ATGATGGCTG GGAGCATTTT AGGTGCA~AT TTAGGTGCCA AAATGGTGAT GACGA~AGGT 214140 AAAACCTTGA TTCGACCGAT G~-LL~1-1ATC A'L~-L~-L1'-L-LA TGATGACGGC TA~AATGGTT 214200 TACGATCAGG GTTGGTTTCA TTTTTAATTC GGA~AGCGCG CA~AAGTGCG GTTAAAATTA 214260 ATTACATTTT ATTATGTCGG ATAATCAACA A~ATTTACGT TTGACGGCGA GAGTGGGCTA 214320 ,~L~ ~1L~LL1~ ~LL~LL~LLAG CATTTGTGCC '1"1"11C~1~LG CGCGATAAAT TGACGGGAAA 214440 -77.129-SU85TI~UTE S~EET tRULE 2~

CA 022l874l l997-l0-2l W 096/33276 PCT~US96/05320 ATTAGGTATT TGGATTGGGC ATA~AGCAAA GAAACAGCGT ACGCGTGCAC A~ACTAACTT 214500 GCAATATTGT TTCCCTCATT GGACTGAACA ACAACGTGAG CAAGTGATTG ATA~AATGTT 214560 TGCGGTTGTC GCTCAGGTTA '1'~'1"1"1'G~'1'AT TGGTGAGATT GCCATCCGTT CAAAGAAACA 21~620 TTTGCAAAAA CGCAGCGAAT TTA1'CG~'1'~"1' TGAACATATC GAACAGGCAA AAGCTGAAGG 214680 TATTAAACCT TTTTTAAGTC A'1'~'1''1'C~'LAA AGGCGAAATG GGTTATTACT TACCCGATGA 214920 AGATTTTGGG GCGGAACAAA GCGTATTTGT TGA'L'L'1'~'1''1"1' GGGACTTATA AAGCGACATT 214980 ACCAGGGTTA AATAAAATGG CAAAACTTTC TAAAGCCGTT GTTATTCCAA 'l~l LlC~lCG 215040 TGATCCTGAA CAATCAGCCC GAGCAATGAA CGAAGAAATA GAA'L~''1''L'L'1'G TTACGCCAGC 215160 TTATGATTAA AAATAGGGTT TGAAAGTCAT A'L'L~'LC~AAA ACGGATATTC AATAAGGTAA 215280 '1"LL'1'GGACGA ATTGCTGCGA CCAATGCCAT CAGTGATATT TTTGCTATGG GCGGTAAGCC 215580 GATAATGGGA ATTGCTATTT TAG~'1"1''1"LCC AACCAATGTA TTACCTGCAG AAGTTGCACA 215640 GGATGGCGTC ACCGCAATGA CGGATGTCAC TGGATTTGGT TTA~L~LG~1~C ATTTAATTGA 216000 AATCTGTGAA GGTTCAAATC TAAGTGCGGT A~'L'L'L'L'1''1'CG GACAAAATTA A~ACCTTGGA 216060 ,CGGTGTAAAA GATTATATTG CTCAAGGTTG CGTACCGGGT GGAACAGGGC GTAATTTTGA 216120 _77.130-SUBSTTTUTE SHE~T tRuLE 2~1 CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 ATCCGATATC ~11~11~AAG TAAAATAAGG AATTTTAATC GATCCTCCCT AATGATTAAT 216360 CATTAAATAT AATGAATTAT GCGCCTAAAC G~'1'~'1"1"1'AAT ACGAGCTGAT TTACCTGAAC 216480 CTGGGCGGAA GCTAGGTACG '1"1"1"1'~'1"1"1"1'A A'L'L~'L'1'~''L'LG TTCAAGTTGT TTGATAATGT 216780 CTTGCGCCTC TTTTAACAGC TTAC~'L'L~'1"1' CGTCAGTCAG AGCTAGGCCT TCTAAGAGCT 216900 CAGGGCGTCG GAGCCACGTT ~L~L~LAGCG A'L'1'~'L'L'L'LAA TCGCCATTTC CGAATTTCTT 216960CGTGATGTCC CGACATCAGC ACGGGTGGTA CAGTTAATCC TTCTAACACT 'L~'L~'1'~'LAG 217020 TGTAATGCGG GCAATCTAAT AAACCATCTG CA~AAGAATC '1''L~'L'L~'1'GCC GAGGCTTGTT 217080TGCCTAATAC ACCGGGAATA AAACGTGCAA CAGCATCAAT TAATGTCATT GCCGGCAATT 217140 ACC~'1"L~'ATC AATCCCTTCG TAACGTCCAC ATACTAAAAT CAA'L'L'L~'1'~A TTTTGAGCAA 217260 G~'LCG~'L'1'AC GCCGCCTTGA TCGAGTTTAC GTCCTTGTGG CGAAAGGTAA ATCACCTTTG 217320 TAAAATCTCT TGGATTCCAA CATTCAACTT TCAGAAGATT A'L~'L'1"L'LACG GCTCTACCTG 217500 ACATAAAAAG CCTACTACAT TAC~'1"1"L~'LG CATACTTGAG ATTAGAAACC AGCGTCCCAA 217620 TCCACTTCAA TA~'L'L'L'LC~'1' GGTGAGATCG A~L~L~L~L~L~A CTACTTGTTC ATACAAAAAC 217680 GGAATTAACC G~'1'~'L'1'~'L'1''1' TCCAAAAGCA TCTTTGGTAT TGGCTTTAAC CACTAATACA 217740 TCATTAGAAC CCGTTTCCAT CA'L'L'1'~'1'~'L'1' A~'1'~'L'LCC~'A TTGTATAACC TTCTAAGTTT 217800 -77.131-SUBSmUTE S}~EET (RUI E 2~i~

CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 ACGACTGTAC AACCGATTAA ATCGTGCCAG TAATAATCGC C~'1'~'1"1'~'1'AG TTCTGGGA~A 217860ACAGATAAAT CTACACCAAT TTCAACATTC GCTA~AATTT GTGCAGCTTC ACGGTCATCA 217920 GATTGCCATT CGCCTTTGAT TTTTA~AAAC CAAGGTTGAT AATCA~AAAT GCTTTCAGCT 218040 '1'~'1'-1'~'1'~'1"1'G ATGAATAAAT ACGCAACCAC CCACGAATAC CGTAGGTTGA GCCTAATTTG 218100 CCCACAACTT CAATATGTTG TTGTTCCATA '11111~ACCT ATCTTAGTTT GAGAACTAAA 218160 TCAAAAAGCA AAATTATGCT G~''1"1"1''1"1'~'1'G ~11~1111AC CAAGCTCGCA ACACGATCAG 218220 GAGGTGAACG ACTGTCAGCG ACTACGATTT GATAAAATGG GC'~'1"1"1"1''1"1'A GCTCCGCCAC 218400 TCAAATTCGA AAGTGATTTG AGAATATAGC TTA~''1"1''1"1"1''L ~1~1~1ATAT ATAGACAAAA 218520 GTA'1"1'C~'1'1''1' TAATTATCAT TCACAATTTA '1"1"L'1'~'1"1''L'1'A CGATATAATA CGAGGCATCC 218640 AG~''L~'1''1''1''1'A GGTCAAATTT ACGCGTATAG CGGTATTTTA GCTTGATAAA ATATCAGTTA 218700 AATGAGGTTT ATATATGAAA ATTAGTTTTC A'L'1'~''1'~'1'~'1"1' AATTGGATTA GCATCATTTA 218760 '1''1'G~'1'~'1"1'~'A ACAAGGTGTA ATAGCTAATC C~'1'~'1"1'CTCA TCAATCAATA TCCACTGAAT 218820 TTACAAATTT ACA~IU~AA CTTACCGCAC 'l''l''l"l'l''l'~'l''L''l' ACCTCCCCAA '1''1"1'~'1"1'GATA 218940 ATCAGATCCA AATAAGCGAA AAA~nCCTCA CTCGCATTTT TAAAACAGAT AAAAATCTCA 219000 CGCCTAbATT TCTTGATTAC TTATACTTTG AGCCAATA~A TA~'1'~'1"1'~AT GCTAATTTAA 219060 TTCAGGAAAT GAAGAAAAAC TTACTGGTGT ~111111AGC AAATGATCAG GCA~AAATTT 219120 AAGCAGATCA AATTATATTA CTGTCTTTGA ATGCCA~AGG TATATTTCAA AAAATTATTG 219240 AACA~ATACG TCAAGATTTT CCGAATCAGA CTA'1"1"1"1''1''1'C GATTACTGAA AATCGTATTA 219300 GTTTGATTAC TC~11~11~A GAAATTAAGT CTCGCCTTGC TTTAGCAAAT ATGATGTTCA 219360 ATCGCCAATT TAAAGGTGTG GAAGTTGATG A'1"1''1'~'1'~ATA TTTAGATCAA CCTCGAGAAA 219420ATTTACAGCA CAATAATGAT GCAATTCGTT ACA~AACCTT TCAAGCAATG CTAGAAGGTT 219480 -77.132-SUBST~UTE SHEET tRULE ;~6) CA 022l874l l997-l0-2l W 096133276 PCTrUS96/0~320 TAAATTAATC CCTTACCAAT AGGAGTTTTT ATGCTTTTAT CCA~AAAATC AGCCTCCTTT 219540 GCACTCAGTG CATTTGCGAT G~L111~ACT AGTGTAGCTC TTGCCAAAGA GGCACCACAA 219600 CCGCACGA~A CACGGATTAA TTTAAATGGT CAGCAAACCA AAGTGGATAT TGGTGGTTTT 219720 TCTGCTGTCA ATGCAAAACT TAACAAATTG CGTAAAAAAT ACAA~AATCC ATTAGTACTG 219780 AATGTGATTC CTGATAAAAA TTCAATTTTG TATAACAAAT GGA~ACCTTA CGATATTTTC 220020 TCCTCTTCTC CGGGTAAGGA TGTGAAGTTC TACGATGAAA TTGCTACTGC ACA~ATTATG 220140 GAAA~AAATA TCGAAATTGC TCAAAAAGTA AATGATATTG ATGTGATCGT TACTGGCGAT 220260 TATTCTGCCG TGGTGGGGGA TTTGGGTGTT A~ATTCAGTC CTGAAGGTAT AGCGTCTATT 220440 ATGAAGAGTA TTTCACTTGA TGATCATGAT GCA~AAACAG ACATGCTTAT TTCAAAATAT 220620 A~AAGTGAAA AAGATCGTTT AGCACAAGAA ATTGTTGGTG TCATCACAGG TTCTGCAATG 220680 CCGGGTGGTT CAGCAAACCG TATCCCAAAT AAAGCAGGCT CAAATCCAGA AG~lL~lATT 220740 CAAAATGCTG GCG~1~1ACG CGCAGATATT TTACCGGGTA ATGTAACCTT TAACGATGCT 220860 A~ACAAGTGC TTGAAGATGC AATGCAATTT G~1L1G~11G ATGGCTCTAC AGGCGCATTC 220980 TTAGTGAGTG TTGAAGTCTT GAATA~ACAA ACCCAACAAT GGGAACCGAT TGATGATAAC 221100 AAACGTTATC TTGTCGGAAC AAATGCTTAT GTTGCAGGCG GTA~AGACGG TTATAAAACC 221160 -77.133-SUBSTlTtJTE S~E}~T tRULE 2fi~

CA 022l874l l997-l0-2l W 096/33276 PCT~US96/05320 GAAAGTTTCA TAAAATTTAT GAAAAAACAT CCGCACTTTG AGGCTTACAC TTcATcAAAT 221280 ATGATTAAGA ATTTTAACTA TTCCATATTT AGATGCTTTC TCGTGGAAAA TA~ATTCCCT 221460 ATAGAGGTTG AAAAATAGGG TGATTTATTG CGATAATCTA CCCCATTTTT TGGGAGATcT 221520 AAATGCAAGG TATTGTACTT TCAACTGGTG GGGGAGCAGT G~lll~lAAG GAAAACCGTA 221880 AACGCACTCA ACGTGATAAA AAACGTCCAT TGCTCCAAGA TGCAGAGAAT C~lC~L~AAG 222000 TATTGGAAGA TTTAGCA~AA ATTCGCAATC CGCTTTATGA AGAAATTGCG GACATCACTT 222060 TGCCAACCGA TGAACAAAAT GCCAAAATAA TGGTA~ATCA AAlL~ll~AT TTAATTGATA 222120 GCACAGTTTT ATCTTGATAC AGTCATCTAT GC~llGGAAA AACGTGGTTG CGTAGTCGAT 222360 CAl~lLllAT TGCCAGATGG CGA~AAATAC A~AACACTTG AATCTTTAAA CTTAATTTTC 222420 CAAATTCCAA CAACATTGCT TTCACAAGTG GAll~Ll~AG TGGGCGGTAA AACGGCGGTT 222600 GATACGCTCA CGCTTAATAC ACTTCCTA~A CGTGAAGTAA ACGCGGGGCT TGCCGAAGTT 222720 ATCAAATATG GTGCCATTTT AGATTACGAA llllllGAAT GGCTAGAGCA ACATATTGAT 222780 -77. 1 34-SUBSTITUTE S~EET (RULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/0~320 A~AGCAGATG TTGTCGCGAG AGATGA~ACA GAAAAAGGCG ATCGTGCATT GCTTAATCTT 222900 TCTATTGCAG A1-~1~-1~-1CG CCTTGAAAAA TTACTTGCTC GTGCCAATTT GCCCACCGTA 223080 TCTCCAGATA CGATGCAGCC GGAGGACTAT TTACCGCATA TGATGCGTGA TAAA~AAGTT 223140 GATACCGAAC ATACCCTCGT GTTAAACGCA A11C~1C~1--1- GTACTCAAAC GGATTAAGAT 223260 GTTACGTCCG AAAAAACAAT CTTTAAAACC TAAGTTAAAA CACCGTCCAT TTTTA~AATG 223320 GGCGGGGGGA AAA~111C~L-1 TAACGGACGA GATAAATAAA GCCTTTCCAA ACAA L~AA~ 223380 CTATATTTTG GCAGATATCA ATCCTGATTT AATCAATCTA TTCAATATTG TGAAAGnAAA 223500 CGATTATTAC TATGCTAAAC~GTCGCCAATT CAATGCATCA ACAGAACCTT TCGAACGTTC 223620 GATTATTTTT TTGTATTTGA A1C~-1--1-1--1GG TTTTAATGGA TTATGCCGTT ATAACAGCAA 223680 ACGTTATTTT GCGCATAAAG CGCAAAGTGC G~L~1111LA TGCTGTGATT TTCAAAAAAC 223800 TTTGGCAGAT TTAGCGAAAT CTATACAAAA AGAAA~ACAA ATTTCGATAT TGATCTCGAA 223980 TCACGATACT AAATTTACGC GTGA~ATTTA TAACGGTGCT AAATTTAAAC GGGTAAAAGT 224040 CCAACGTTCT ATTAGCCA~A ACCCAGA~AA ACGCGTAAAA GTGAAAGAAT TGATTGCGAT 224100 ATTTGGTGCT CGTAAATAAT AAAAATAACC CTTACTTTAT ACTA~AAGTA CCAAAATCGT 224160 111~1111AT CAGAATGATT ATCTAGAAAA CTCATCCAAT CATCAGAATA ATTAACAAAT 224340 AATTCATCAA AATTTAAGCC TGTTATGCTT TA11-~1-1LAG TGTATAACAA ATAGGATAAA 224460 AATGGAAAAA GCA~AACCAT CCAAGCAAAG A~ATTTTAAT CACTGTCAAG GAGTACATTA 224520 -77.135-SUBS I ~ I UTE SHE~ ~RULE 26~

CA 022l874l l997-l0-2l W 096/33276 PCT~US96/05320 TTGAATTTGG TAATA~ACCG TTAGGTTTAA AAGATACTAC ACCCAAATGC CACTGCCCTA 224580 TTTGTGCTCA AGTTTTATTT GAGA~AAATG TTAATACAGT GCCATCCTCT AATAGCAATT 224640 TTTCTAATTA CCCAAAAAGC GAATTCTGCC CCATA~AATT A~ACTA~AGC AATTTATACC 224700 AATCATATTT TCCATTATCA CCA~ATAAAA CGCATGGACT GAATTA~AAA ATTTATTCAG 224760 AAAAAATTGG CAAAAATATT ATCGTCA~AT TA~l~ llG GCAAAAAACT TATAACCTAT 224820 TGAATTTATT ATATTAGCTA ATCAACA~AA AATTTGGGAA TACGATAAAC TTGAAGAGTA 224880 TCAAATTCCT TATATTCTAT TAACATTAGC AGACTGTCCT AACCA~AAAG GAACATATAA 224940 AAATAAACGT CACTGCTGGT TTAGATTTTG GTTTGATGCT TCAATTCA~A GATATGAAGA 225000 ACA~AGAAAA CCTTCAGAAA TA~ATCTAAA A~ACATGAAT TATTTCATCA TGGATAAAAC 225120 Tll-llAGAA CAAGAAATAT TACTTCCCCA ATTTATTATT CA~AATATAG AACGGTGGTT 225180 TA~AACACAC AAllll~lAT AGACAAGTCA GCACCTAATA CTATTTCATG ACGAAGATCG 225240 C~1L111~11 TAAAAAGGCA AAAATAATGC TATTAATCAA CCATGCCAGT AATGTCGCCA 225300 CCCACACTGC AATACCCACC ACCAGCAATT TTGCTTTA~A AGAACGGTTA CCCAATAATT 225420 GGGTAAAGCC AACAGCAAGC ATTAGCCAAG TTGCTGCA~A AATCGTATGT CCAGAAGGGA 225480 ACGAATACCC C~lll~ATTT TCATAATGAT GAACTAACCA AGCTGGTGTA ATGGCATCCA 225540 TCGAATAAAA ATTCTTAGCT ATTTCAGCAC GCA~AGTGCG GTCATTTTTA TAA~AGTTTT 225600 CAGGCGTTGA ATGAGTTTGC TCAGCTAGAT A~ACGGTGAA TGGACGAGGT TCTTCAAATA 225660 ATGCTTTTGC CC~l~lllll GCGGCTTGAG TTGCAATAAC TGAAATCCCC ATCACAATTA 225720 CGCCTAATAT CCAll~llll GGATTTTTAA ATAAAAACGC AAACA~AAGC GTAAACAACA 225780 77.136-SUBS i H UTE SHEET (RULE 2~) CA 022l874l l997-l0-2l W 096133276 PCTnUS96/05320 CACAGCTTAA AATGCGATTG TGG~-L-LC~AA CTGGCGACAG CATTA~AACA AATTCAAGAA 226260 AAAATCCGTG CTTATTCTTT ACAAGATA~A GGAATGGATA CCATTGAAGC TAATCTTGCT 226380 TTAGGTTTCA AAGCGGATGA ACGCAACTTT GAA~L~-L~LG CCGATATGTT TGAGCTACTT 226440 GGTGTAAAAA AAGTTCGCTT AATGACCAAC AACCCAGAAA AAGTAGA~AC CATGA~AAAA 226500 GCAGGTATCA ACGTGGTTGA ACGAGTA~CG CTTAATGTAG GCGA~AACCG CTACAACACA 226560 A~ATATCTTG ATACA~AAGC GA~AAAAATG GGGCATTACA TTGTGCATAA CAATGACGAA 226620 CAACATTTAA TGACCTGTCC ACATTGCCAG GAAGAGATTA TTTAACA~AT AAGATATGTT 226680 TA~AAAGCCA TACTGTTATA TTGAACAGTA TGG~L1-L-L-L-L ATTTAAACTT TATGTTATGG 2267gO
AATAATCAAA AGA~1LL-L-11A GCATATTGCT A~AAACGGGA AACCCCGTCT CGTATTCCAA 226800 AGATCGGGGC TTATCAGGAG TAAGTAAAAT GA~AAAAATT GC~ L 'L-1--1 -L~'A 'L-L L L ~-L L ~AT ' 226860 TA1~1~-1-L~1 TTAGTTAGCT GTTCCGGAAC AGTTATCTAA GATAATCGCA AGGGGACGAT 226920 GTAGGAGTTG TCCCCAATGC CTCCACCAAT CTTAAAGAAT ~L~1L1C~-L-1G ATTGCAAGGG 226980 TACTTGCGCA CCCATTATAC TCGGTACAAG ATA~ACAGGC GTACTATATT GA~AAATAGG 227100 TAACACTAAA TG~-L~-11-~-1L GAACTATCCC TTTTAATTTC GCGTAATTTT CTAACCGCAC 227160 ~11-1-1-1CGGAT ATCGTCGTCA TTGCACTTTC AAATA~ACGA TCAAATTCCG CATTTTTATA 227220 GCCATTTTTG TTATCTGGGC TTTTTGAATA GAATAAATTT AGA~ATGCTG CAGGATCATT 227280 AAAATCAGCA CACCAGCCAG AACGAATTAA TTGAAAATCG C~Llll~lGC GGGCGGTTTG 227340 CAATTCTTGC CAGCTCATCC CTTGATTTTC AACTCGTAAT A~ATCAGATT GTGATAATTG 227400 ATGATTTAAT CGCATTGCAA TGGTTTGATT CAGAGATAAA TCATCATA~C GAATACGTAA 227460 TTTCAATGGA CGAGTTTCAC TAATTTGATT TTGGGAAAAG AG~-1~-L-L~1G CAACAACTGG 227520 AAGATGAGCA ATATCTGCAA CCA~ATTATT GGTAGAAATC ATCGA~ACAA TCG~ L L L-L~-L 227640 TACCGCACTT 1L1L~-1AACA CAGGATCGGA AAGATTAAAC TCATAGAAGT AAGTACAAAG 227700 AGACAAATCT GCATCAACGG AAA1-1-L1L1G ATACTTCACT TGCTGAAATA TCA~-l l-L-L-LC 227820 TTTCGCCCAA TAATAAGGAT TGGTAGTTAA AATGTGCTGA TTTTCAGCCT GC~L11~LAA 227880 -77. 1 37-SUBS i 11 UTE S~tEET (RULE 2~i) .

CA 022l874l l997-l0-2l TTGATATGCA CCATTGCTGA TA~ATATTTC AGTCGATTTA GCATAGTGAG GCA~AAGACT 227940 CTTCGCATTT TTCAGATTCA TA~AAGCCAA ATAATTTTTA AGTGGGCTTT CAGATTGAGA 228120 AA~1~1-L1GC CAAGATTGTA CAAAATCTGA TGCAGTGATA GGCTCGCCAT TTGACCATTT 228180 AGCATTTTCA CGCA~AGTGA A~ATCCAAGT TTTATTGTCT TCGGTTTGCC AA'1'111~1GC 228240 TACAGCTGGA ACAAGATTAC CCTGCACATC ATAAGCTGTT AATCCTTCAA A~AGATCTCG 228300 TAATAATTGA ~111~11~11 CG~L11~1~C TTGCCAAGGT TGCA~AGTCA AATCGCTATA 228360 AACGCCACGT TTTAATTCAA CTCGGTTAGA TTCCAATTGA GTALLlllll ~L~L-l-AAT 228420 TCCA~AATAA GAAGAACCAA AACTTAATAC AAATCAACGC AACAATAACA CTACGCCCTA 228600 TTACACTTGG CGTGA~ATAA AAACCAATTA GTAGCATTGT GGTAACA~AA GTCAAAATAA 2286~0 AAATTTTGGT AL1L11~111 AATGATCGAT TTTCATGA~A GGACTTGAGA L~lllLl~AT 228720 A~ATACTTGT GCCTAAAAAC CA11~11~1'A AGC~L111GA A~-1111~1G AAGA~AAATA 228780 AAGTAAGTAA TAAAAAAGGC GTGGTAGGCA AAAGAGGAAG GA~AAATCCC AATGATGCCA 228840 ATTGCAAGTG AAAGA~AACC TAAAATAATG TA~ATAATTT TCATAATGTT CCTAATAAAA 228900 TTTGCCGTCA CATAAAAAAA CA~1111~AA A~AAGGAACA TTTATGTCTA TGTCAAATCC 229020 ATTACTTAAC ATTCAAGGCC TACCGCCATT TTCACA~ATC AAGCCAGAAC ACATTCGACC 229080 TGCTTGGTCG CCC~lll~lC ATCTCAATTC AGTAAAAAAT AGCACTGAAT TACGTGAAGC 229260 CTATCAAACG TGCTTGCCGT TA~111~LGA ATACAGCACT TGGGTTGGTC AGCATAAGGG 229320 ACA~AAGA~A GCCATTGAAA ATTCACTGCG TGATTTTGAA CTTTCAGGCA TTGGGCTTTC 229440 CGAAGAGAAA CAACAACGTT ATGGCGA~AT TGTGGCACGC TTATCGGAAT TA~ATTCACA 229500 ATTTAGCAAT AACGTATTAG ATGCCACCAT GGGTTGGGAA AAACTCATTG A~AACGAAGC 229560 -77.138-SUBS 1 i 1 UTE SHEET (RULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 AGAACTTGCT GGTTTACCTG AATCCGCACT ACAAGCTGCA CAACAATCTG CCGA~AGTAA 229620 ACAAGGCCCT AACGCTGGCA AATGGGACAA CAGTA~AGTT ATGGAAGAAA TTCTGACGTT 229800 A~AAATGGCA GAAAACCCAC AACAAGTGCT TGA1L1~11A GATCATCTTG CCGAACGTGC 229920 TGTCACTGAA CTTGCACCTT GGGATATTGG TTTTTACAGC GA~AAACA~A AACAACATTT 230040 ATACGCCATT AATGATGAAG AACTTCGCCC ATA1L11C~A GAAAATCGCG TGATTTCAGG 230100 A~11~111~AA TTAATTAAAC GCATTTTTAA TATTCGTGCA GTGGAACGCA AAGGTGTGGA 230160 TACTTGGCAT AAAGATGTAC ~'L'1''1'~'1"1"1'~A TTTAATCGAT GA~AATGATC AACTCCGTGG 230220 CA~'LL1~1AT CTTGATTTAT ATGCACGCGA ACACAAACGT GGTGGTGCGT GGATGGATGA 230280 GGAAAACTGG TGCTGGGAAG AAGAGGCTTT GGC~LLLATT TCAGGACATT ACGAAACAGG 230580 CGAGCCGTTG CCAAAAGAAA AACTCACGCA ATTGTTA~AA GCGAAAAATT TCCAAGCTGC 230640 GATGTTTATC TTACGTCAGC TTGAATTTGG TALLLLL~AT TTCCGTTTAC ATCACACCTT 230700 TGATGCGGAA A~AACCAATC AAATTTTGGA TACACTTAAA TCAGTGA~AT CACAAGTTGC 230760 AATTCTCACC CGTGGCGGCT CAGAAGAACC AATGGAACTC TTCA~ACGCT TCCGTGGCCG 231000 TGAACCGCAA TTAGATGCGT TGTTAAGACA TA~AGGAATT ATGAACTAAT ACGTCAAACT 231060 ATAGGGCATG CACAACATGC C~'L'L'L~'L~'AA ATATTTTCCT CGACATAAAA ACATAGTAAA 231120 TTTTAACCGC ACTTTATCTA GACAA~ACCT GCA~ACGAGA CATTATTTTT ACAAATAGCT 231180 -77.139-SUBSl 11 UTE ~HE~T (RULE 2~i~

CA 022l874l l997-l0-2l W 096133276 PCTrUS96/05320 TGGCTGGGAT TTCAAACAAT ATGTGCTTGG CACACTTTTT TACC~-LlllA TTAGCGAAAA 231420 CGCTTAACGG ~l~ll-llGAA AGGCGTGGCT GAACTTGATT TTGGCAAATT TGAAGATAAC 231780 CTTTTGCTTC AAGCCAAAAA ACAATTTGAT GAACATATTA TTGAAGAAGG ~LlLlL~GGG 232020 CAGGAAATTA ACCATACCAC ATACAACCTT GCCCGTATGA ATAl~lllll GCATAACATC 232080 AATAAACCTT TCGATGCCAT 'i~lllC~AAC CCGCCTTACT CCGTGAAATG GGCTGGCTCC 232200 ATCCAAAGCG GACTTTGCCT TTATTTTACA TGCGTTAAGT TA~L~llL~AG CAAAAGGCCG 232320 TC~LllGAAG AAATCGCCCA AAATGACTAC AACCTTGCAG TAA~LlC~lA TGTGGAACAA 232680 AAAGACACTC GTGAAGTGAT TAATATTGAT GAACTCAATG CTCAAATTCG TGaAACTGTT 232740 AATGTAGGGT GGGCTTCAGC CCAnaTTTAC GATAACAGGT AGTGGGCTAA AGCCCaCCCT 232860 ACGAGGAACA ATAAAAAAAC ACCATGAAAA ACAACCGCAC llllllAGAA AAATTATTGG 232920 -77. 1 40-SUB5 i 11 UTE ~}~EET (RULE 2~) W 096/33276 PCTrUS96/05320 AGGG~1~-L~A GGTTGAGTGG AAGCCTTTAG ATGAAGTTGC CAATATCGTC AATAAtGCAA 232980 GA~AACCAGT CAAATCATCC TTACGAGTGT CAGGGAATAT TCCATATTAT GGTGCTA~TA 233040 A1G~11~-1GC TAGTCTAGAA AATTACTCTA TTCAATGGGC TGTAGGTAAA TTTTGGGCAA 233160 ATAACCACGT CCATGTAGTA AATGGCAAAG A~AAATTAAA TAA1C~-1-1-11 TTATACCATT 233220 ATTTAACTAA TATGAATTTC ATTCCATTCT TAGCTGGAAA GGAACGTGCA A~ATTAACAA 233280 AAGCTA~ACT GCAACA~ATT CCAATCCCCA TCCCCCCACT CTCCGTCCAA ACCGAAATCG 233340 TA~AAATTTT GGACGCATTG ACAGCACTTA CCAGCGAGCT TACCAGCGAG CTTACCAGCG 233400 TA~ATATTGA TGA~ATGAAC AAGGTTATTG AA~1LG~1~A TGTAGGGCCT ~LlC~lATGT 233520 GTA~ACGAAT TCTTAAAAAC CA~ACAGCAA GCTCTGGAGA TATTCCATTT TATAAGATTG 233580 GAACTTTTGG GA~AAAGCCT GATGCCTATA TTTCAAATGA G~-L-1-1-1C~AA GAATATAAAC 233640 AAAAATATAG CTATCCTAAA A~AGGAGATA TTCTTATATC TGCTAGCGGA ACTATTGGTA 233700 ATAATGATGA AA~L~LC~-1L CTTAATAAAT ATTTATATCA TTTCTATAAG ATTGCTA~AT 233820 GGGGAATTGC AGAAGGAGGC ACCATTCAAC GTTTATATAA CGACAATTTG A~AAAAGTAA 233880 AAATTTCTAT TCCTCCATTA AAGGAACAAC ACCGCATCGT TTCAATCCTA GATA~ATTTG 233940 AAACCTTAAC CAATTCCATC ACTGAAGGCT TACCTTTAGC GATTGAACAA AGCCA~AAGC 234000 GGTATGAATA TTACCGAGAA TTGCTATTAA AL-L-1~-1-C~1A ACCCGTAGTG GGCTTCAGCC 234060 TCGGCGCGAT TTTACTAAAG GTGGATTATA 1-L-L-L-L-L~ACA AL-L~-L-LL-LAC AAGATAGAAC 234240 A~AATCTTAT CTAACTGACT ATATCAATGA ATTTAGATCT GCATATAAAC A~A~l--L~-L~A 234300 ACATTATCCA TTCGA~ACAG TAGCAATTTG TATTTTGCCC GATCATATTC ATTTACTGAT 234360 GCAATTACCT GA~AATGATG ATAATTACGC AATACGCATC GCATATTTAA AAACACAATT 234420 TACACGACAA CTTCCA~AAG AATGCCGACA ATTTAATA~A AATAGACA~A AATATCGAGA 234480 GAATCATTTA GATTATATTT ATTACAATCC TGTGA~ACAC GGCTATGTTG AGGTAGTAAA 234600 -77.141-SUBSTI~VTE S}tEET ~RULE 2~

CA 022l874l l997-l0-2l W 096/33276 PCTruS96/05320 CAGCCCACAA TTAACCATAA CAAACGGTGG GCTAAAGCcc ACCCTACAAT GTAATGAGAA 234780 CGATGAACTG ATTAAAAACT TACGGGCGCA ATTACAACGC TTAAATAACG TG~Llll~LC 235080 TGAGAAAACC CGCAAAATTC ACGATGATTA TATTTATGAT lll~l~LlCG ATAACGGACG 235200 TGGTTTACCC CTTTATTGAA TTAAAAAAAC GCGGCGTGGC GAllC~l~AA GCCTTTAACC 235380 AAATTCACCG TTACAGCAAA GAAAGTTTCA ATAAAGaAAA Ll~l~l~lll AAATATATTC 235440 AGALllll~l CATTTCTAAT GGCACGGATA CTCGCTATTT TGCTAATACG ACTAAACGCA 235500 ATTTAAAGGA TTTTACCGCG A~Lll~llGC AAAAGAATAC TTTGCTCAAT GTGTTGGTAA 235620 CAACAGAACG TATTTTATGG AAAATtCAAA llL~llACTT AGCA~AAAAT TGGAGTAATC 235740 AAGC~L~lCG CCTTGCGACT GAACTTGATT TTATTGATAA A~L~1L1111 GTGGTCGATC 235860 GTAAAGACTT AGACTACCAA ACGATGAAAG AATATCAGCG LLlllCGCCT GATAGCGTGA 235920 ATGGGTCGGA AAGTACCGCT GGGCTTAAAC GCAATATTGA AAAAGATGAT AACA~AATTA 235980 TCGTAACCAC CATTCAAAAA TTGAATAATT TAATGAAAAG TGAAGAAAAC ~L~L-lATTT 236040 ATCAAAAACA GGTGGTCTTT AllllC~ATG AAGCACATCG CTCTCAATTT GGCGAAGCAC 236100 -77. 1 42-SUBSmUTE ~HEET tRULE :Z6 W 096/33276 PCTrUS96/05320 ACAACGATGT CCGCCCACAA TTTA~AGCCT TAGAAACAGA AAAAGATCCT GAAAAATTGA 236340 CCGCACTTGA GCAGA~ACAA GC~L111LAC ACCCTGAGCG TATTAAAGAA ATCTCGCAAT 236400 ATTTGCTTAA CAATTTTA~A CAGAaAACCC ACCG~-ll~AA TGCCACAGGT A~AGGCTTTA 236~60 ATGCAATGTT TGCGGTAAGC AGTGTAGAAG CAGCAAAACG TTATTACGAA ACCTTACA~A 236520 ATTTACAGGC AGAGCAGGAA TATCCGTTAA A~ATTGCAAC AAL~llllCG TTTGCCGCCA 236580 ATGAAGA~CA AGATGCGATT GGCGATATTC CAGATGAGAC CTTTGAACCC ACTGCTCTAA 236640 ACAGTACGGC AAAAGAATTT TTAACA~AAG CCATTGATGA TTACAATCAC TACTTTGGCA 236700 CGAATTATGG CGTAGATAGT CAATCATTCC AA~ATTACTA TCGCGATCTT GCCAAACGTG 236760 TGA~AAATCA GGAAGTGGAT TTACTGATTG LG~lCGGAAT ~Ll~llAACA GGCTTTGATG 236820 CCCCTACGTT GAATACTCTT TTCGTGGACA A~AACTTGCG TTATCACGGA TTAATGCAGG 236880 -L-lll~lCG CACCAACCGC ATTTATGACA CAACTAAAAC CTTTGGGAAT ATCGTCACTT 236940 TCCGCGATTT GGAACAAAAT ACCATTGATG CAATCACGCT ATTTGGCGAT AA~AATACGA 237000 AGAATGTCGT ACTAGA~AAA AGCTACGACA GCTATTTTAA CGGTGATGAC AATCAACGTG 237060 GCTATGCAGA AATCGTGA~A GAATTA~AAG A~AGCTTTCC TGATCCAACA GAAATCGA~A 237120 CAGAGCAAGA TAA~AAAGAG TTTGTAAAAT TATTTGGCGA ATATTTGCGT GTCGAAAATA 237180 ATCCGATTGC AATGGA~AAA TTCAAGCAAG TACATTATGT GAATGATGAA CA~ATTGCAG 237300 ATGATATTCG CGATTGGTTA CGCCA~AGAA AAGAGGGGAA TGATAAGGAT AATTCGCCGA 237420 TA~ATTGGGA TGATGTCGTG TTTGAAGTGG ATTTATTA~A ATCTCAAGAA ATCAATTTGG 237480 ATTATATTCT TGCGTTAATT TTCGAACATC ATAAGA~AAA CCAAGACAAA GAGGTGTTAA 237540 TTGATGA~AT CCGCCGCACA ~LlC~-lL~AA GTTTGGGTAA CCGTGCGAAA GAGAGCTTGA 237600 TTGTCGATTT TATCAACCAA ACA~ATTTAG ATGATATTCC CGATA~AGCG ACTTTAATTG 237660 AAGAAAATTT GAATGTCGAT GCAGCA~AAC GCTATATCAG CACTTCATTA A~ACGGGAAT 237780 ATGCCAGTGA AAACGGCACG GCACTTAATG AAGTATTGCC A~AAATGAGT CTACTTAAGC 237840 CACAATATCT CACTAAAAAG CAGAAGATTT TCCA~AAAAT TGCTGCATTT GTAGAGAAAT 237900 TTA~AGGGGT TGGAGGAAAG ATTTA~ATTT AATATATCAA CAATTAGACA TCTTATTAAG 237960 -77.143-SUB5 i 11 UTE 5~}E~T ~RULE 26) _ W 096/33276 PCTrUS96/05320 ACATA~AGGC ATTATGAATT ATGAATTAAT AATACAAAAC ATACTGGTCA ATATTTAACT 238020 A~1C~1GATA ATAAAAACAG CTCCAATTTA TACTTGGAGC 1~11-1L11AT ATCGATA~AC 238080 TTA~1111LA CGTGCTAAAA TTCGATTTGC ACACTCTGCT GCAGCTGTTA AGCCACCTGC 238140 CATCATAATA ATATCTTTAA TCACTA~ACG ACCAACTCCA GATAAATAAG GGAAACCATA 238200 A~ATGACAGC GTGACTATTG ACATGCCAAA TGTCAGTAGG CCTCCTGCCA AACCTGCCGT 238320 GTAAGAAGCC GTATAGGTGC CA1111~111 ATGCCATTCG A1~111111G CAACCATTTT 238440 ~1C~11~AGGA 11111~1~1A GTGTATATTC CATCACTAAC TCTCCTTTAT CATTCGGCAC 238500 TAAATTTGGC C~L1111~AT ACATATAGCT AAAAAACGGG CTATTTGATA CAAAGTGAGC 238560 A~ATTCAACA AATGTATTAA ATACTGACAT ATA~ATTTCC ACATAAAAGT AAATAAAATT 238740 TTATCAATCA ATTCTCCACA ATTAAAAACA TCAGAATTTT TAGCCGCACT TTCTA~AGTA 239040 GCGGTATCTT ~1~111~111 CATATTATCT TTTGATAATT GAGCCAGATA ATTTGGCATA 239160 ~111~11L~A ATAAAGATAA A1L11~1A~A ATTTGGGATT TTCCAAGTGT TTCTATCAGC 239220 GCTAAATCAA A~1~L1~L~A AAGCTCATTA TCATCATTCA TTTCTATAAT AGATTCGCTT 239280 TCATCCGCAA AAAATTGCTG TAGACAATGG TGTAAATCCT TAATTGA~AT GGGTTTACGT 239340 AATACGCCAT CCATGCCCAT TTCTA~ATAT TCTTGCTCGC TTTGCATAAC ATTGGCGGTA 239400 -ACA11L1L~1 CAAATA~AGT AATCGCCTGC TTGCCATTTG TCGCAACATC AACATGATGC 239580 -77.144-SUBSTrrUTE SI~EET tRULE 2~) -CA 022l874l l997-l0-2l AGAGTATTCA AGGATGGTAT ATTTTnCTTA ACAGATTCTT TTTCAGA~AT TTCCTGAGCG 239700 TGGAGAGTnA GATGGA~AGT CGCGCCTTTT C~1C~11~AC TTTCAACTGT TA~ATCCCCT 239760 TCCCATTAAC TGAGCAAGAT TTTTAGA~AT AGCCAACCCA ATACCGCTAC CCGCACTTTG 239820 CTGGCGGCTT TCTTTCACTT GATAATACAT TTCA~AAATA l'~'L'l''l"l"l'~'L'L CTTCAGGTGA 239880 AATCCCCATT CCTGTATCTT TCACAATA~A ATGGTAACAA TCCTGATTTC TCATAATTTT Z39940 TTGGCTCAAG CGAACACGAT CAAGATTCAA CCAATTAGGC A~ATTAGGTT CAAGCTCTAA 240060 AGAAAAAATA AGALlLLLLl CTTTGGCGAG GA~ACTAGCA A~ATTATA~A TALC~LLLAA 240120 TAAGGCAGGG AAAL~L~LLG GCTGGCGATT TAATTCAATT CGGCTGGCAT CAALLLLLLC 240180 CAAATCAATA ATATCGCTAA AAATATAGCC TA~ACTGACC GcACTTATGT TGATAGTTTT 240240 TAAATAATTA CGCTGGAGAT CATCCAATTC ATCATCAAGT A~AATCTGGC TAAGCCCGAC 240300 AATCCCATTC AATGGCGTGC GA~ATTCATG GCTTATTGTG GCAAGTAAGG TACTTTTATC 240360 ACGGCTATTT ~LlLL~LAACT TTTCCAATGC TTGGGATAAT LLLLL~l~AG CAGCAATTCG 240420 AA~LLLLL~l ACTAATA~AG TGAAAAAATA AATAACA~AA GGCGCAGTGA GTAAGCCA~A 240540 AGTTACCGAA CGAAAAATAT CTACCCAAGA TATCTGATGA ACAATA~ATA GACTAAATAA 240600 AATCTGAGTA CA~AGAGCTA A~ACCGCGAG AATCATCACG CCTAAAAGAG A~AAACGAAG 240660 ACGCCCAAGA CGAATAACCC AATCCACATA ACTCTGAGCA AAATATTTGA AALLLlL~AT 240720 CA~ATCTCCT AAAACATTAT TATCGTTATA A~AAAAACCT GTGCATATAG GCTTTATTAT 240780 ATCCATAAAG TAAACGAGAT TGTTATTACT ATGTATGCGT AAGA~ATGAA A~ACTTAATC 240840 TTTATTAATT AT~L~LlL~A CTAAAATTTG TAATTCAGGA ATAACTTGCT CTTCA~ACCA 240900 AGGALL~Lll GTTACCCAAA GCTGATTACG TGGGGAAGGG TGCACGAGAG GCATAAAGTG 240960 TA~AATCATT GGATGCCATC TTTCTGCA~A ACCTTGACGA GGTGGTAAAT CACCCGATTT 241140 ACCTTTTCCA GGATAATAGA AATCCATTGG AAGAACCGCA AATATCCCAG AATTATA~AA 241200 CA~ACGAGAT TGCTCAGCTT TTAACCCAGG AGCTTGACCA ACAATATTAA TTCGAGCTGT 241320 -77.145-SUBST~TUTE S~{EET tRUI E 2~i) CA 022l874l l997-l0-2l TTTAGGAGCC GAAAATA~AG GGA~AATTCC ACC3-11~1C~1A AAATCTTTAT TTTGAGGATC 241380 TGAATATATA AAGTCTATTT GA~AAATATG AAAAATCAAA ACTCTA~ATG ATGTA~ATAG 241500 AATCTCTATT TTCTACTTTA A~lCCllll~A TGA~ATAATG AATA~ATTCC CA~AAGCTAA 241620 AACCCCATAT clllC~ACAC GGGGCCCTTC l~lllllATT TAACTTAGAT AAGTATTTGG 241680 AA~ll~lllC~A TAA~lCC,l~l 'lll~lCllll AlC_l~lCc~lC l~llll~TCT C_lCC,llACTC 241860 A~lC_lllCCT CTACCTTTCA C_lCC,ll~llA TTGGTCACAA GCTGAATCCG AllllC_lllC 241920 TATTAAGTCT TCTATATTTA C_llllc_lllG TTTAGTCTTT TAC_llc_l~ll TCGCTCTGCT 241980 TTTATTTGCT TCGC_Llll~A lCl~llACTT CACTTAGCTC CCAAAAACAC TTGAGCGTTG 242040 TATAGTTAAG CC_~lc-lCGGGC AATTAGTATT GGTTAGCTCA ATGACTCACA TCACTTACAC 242100 ACCCAACCTA TCTACGTCGT AGTCTACAAC AACCCTTACT GACTTA~AGT CAGGGATGAC 242160 TCATCTCTTG GCAAGTTTCG TGCTTAGATG CTTTCAGCAC TTAl~l~llC CGCATTTAGC 242220 TACCCGGCAA TGCGTCTGGC GACACAACCG GAACACCAGT GATGCGTCCA ~lCCG~LC~l 242280 GTCTCACGAC GTTCTA~ACC CAGCTCGCGT ACCACTTTAA ATGGCGAACA GCCATACCCT 242400 CGATGGCCCT TCCATTCAGA ACCACCGGAT CACTATGACC TA~lllC~lA CCTGCTCGAC 242580 'll~l~l~l~l CGCAGTTAAG CTTGCTTATA CCATTGCACT AACCTCACGA 'l~lCCC,ACCG 242640 TGATTAGCAA AC~llC~lGC TCCTCCGTTA CGCTTTGGGA GGAGACCGCC CCAGTCA~AC 242,00 TACCCACCAG ACACTGTCCG AGACCACGTT TCGTCATCTT CGTTAGAACA TCA~ACGTTA 242760 CCTATCCTAC ACATCAAAAT TCAATGTTCA GTGTCAAGCT ATAGTA~AGG TTCACGGGGT 242880 -77. 1 46-SUBSTlTUTE SHEET ~RULE 2~) -CA 022l874l l997-l0-2l W 096/33276 PCTrUS96/05320 GTG~Ll~l~l TTCGATGACA CCATCAATTA AC~L-lC~'AGC ACCGGGCAGG CATCACACCC 243120 TATACGTCCA CTTTCGTGTT TGCAGAGTGC 'L~'L~'l"l"l''l''l'A ATA~ACAGTT GCAGCCAGCT 243180 L~lCCCGAAG TTACGGTGCT ATTTTGCCTA GTTCCTTCAC CCGAGTTCTC TCAAGCGCCT 243300 GAGTATTCTC TACCTGACCA C~L~l~lCGG TTTTCAGTAC GGTTTAGTAA AGCCTTTCGC 243360 TTAGTGGCTT TTCCTGGAAG TGTGGTATCA GTTACTTCAG CTCCGTAGAG C~LC~l ATC 243420 A~L~1~1~1~1 GTTAAGGAAG TCCGGATTTG CCTA~ACTTC CCACCTACCA ACTTA~ACGC 243480 ACATATCCAA CAGTGCGATA ACCTAACCTA ~''LCC~'LCCCC ACATCGCAGC TTTACCAAGT 243540 ACAGGAATAT TAACCTGTTT CCCATCGACT ACG~LLLL~A GCCTCGCCTT AGGAGCCGAC 243600 TCACCCTGCC CCGATTAACG TTGGACAGGA ACCCTTGGTC TTCCGGCGAA CGG~LLlLLC 243660 ACCC~'L'L'L'LA TCGTTACTTA TGTCAGCATT CGCACTTGTG ATACGTCCAG CCCACCTCTC 243720 GATGAACCTT CTTCCGCTTA CACAACGCTC CCCTACCCAA CAGAATA~AT TCTGATGCCG 243780 CAG~LLCG~L GCTATATTTC AGCCCCGTTA CAL~LlCCGC GCAGGCCGAC TCGACTAGTG 243840 AGCTATTACG ~LLL~LLLAA ATGATGGCTG CTTCTAAGCC AACATCCTAG ~L~L~lAAGC 243900 ~'L'LCC~ACTT CGTTTCCCAC TTAATATAGA CTTGGGGACC TTAGCTGGCG GTCTGGGTTG 243960 'L'L'LCC~L~LC CACGACGGAC GTTAGCACCC G~C~'L~L~'LC TCCTGAGTAT CA~L~LLLGG 244020 ACCCCCA~AG GTGTCACCTC AAGGCTCTAC CTA~ATAGAT TTCGGGGAGA ACCAGCTATC 244140 CCCCTATTCG GTTAACCTCG CTACA~AATA TAAGTCGCTG ACCCATTATA CAAAAGGTAC 244380 ATCAGGAGTA TTTAGCCTTG GAGGATGGGC CCCCCTTCTT CA~ACAGGAT ATCACGTGTC 244560 ~L~LLLGATT GTGCTTCCCA ACACATTCTC CTCACTATAT TGCTATCACT TACTGGCTCT 244680 -77. 1 47-SU~STITUTE S~}EET (RULE 2~i) CA 022l874l l997-l0-2l W 096133276 PCTnUS96/0~320 TTCGCTTTCG CTCGCCGCTA CTGACGAAAT CTCGGTTGAT LlCllllCCT CGGGGTACTT 244740 AGA1~111~A GTTCTCCCGG TTTGCCTCAA CAAGCTATGA ATTCACTTGT TGATAGTAGA 244800 11~11~ATCT ACTGGGTTTC CCCATTCGGA TATCTTGGAT TAAACGCCTC TTATCGACTC 244860 TTCAATCAAG A~1111111AC AAAACAGGTT 11~LL1L1AG A~11LC~L1L TCA~1L~L~1 245100 CTTTCACTTT A~L~L111GC CTACTCAGAC 111~1~1CGA AAATCTCTTG TTTTCAGCTT 245160 GTTTCCAATT TTTTA~AGAA CAGTAAGACA ATCTAATAAA GTTATCTTTA ATTGGCGTCC 245220 CCACGGGGAT TCGAACCCCG GTTACCGCCG TGAAAGGGCG A1~1C~1AGG CCTCTAGACG 245280 ATGGGGACAT CAATTAAAGA TACTCTATTT 1~LL111ATC TTTTAACGtT TAL L 1 L L ~AA 245340 CGTTGCTTTC G~L1C~1111 TAA1~11~LC TACAACTATC AGCCAATCTG TGTGAGCACT 245400 CG~L~1~1~1 C~1~11~AGT AAGGAGGTGA TCCAACCGCA GGTTCCCCTA CGGTTACCTT 245460 GTTACGACTT CACCCCAGTC ATGAATCATA CC~1-G~LAAA CGCCCTCCAA AAGGTTAAGC 245520 TATCTACTTC TGGTACAACC CACTCCCATG GTGTGACGGG CG~-1~1~1AC AAGGCCCGGG 245580 AGTTGCAGAC TCCAATCCGG ACTTAGACGT ACTTTATGAG ATTCGCTCCA CCTCGCAGCT z45700 TCGCTTCCCT CTGTATACGC CATTGTAGCA C~1~L~1AGC CCTACTCGTA AGGGCCATGA 245760 TGACTTGACG TCATCCCCAC CTTCCTCCAG TTTATCACTG GCA~1~1C~1 TTGAGTTCCC 245820 GCTCATCTCT GAG~1~L1~1 TAGGATGTCA AGAGTAGGTA AG~L1~LLCG CGTTGCATCG 246000 GCCCAATCCC CAAATCGACA GCGTTTACAG CGTGGACTAC CAGGGTATCT AA~Lc~L~l"l L 246180 -77.148-SUBS 111 UTE SHE~T (RULE 26~
-W 096/33276 PCTnUS96/05320 CACTTA~ATA ACCGCCTGCG TGCCCTTTAC GCCCAGTTAT TCCGATTAAC GCTCGCACCC 246420 TCCGTATTAC CGCGGCTGCT GGCACGGAGT TAGCCGGTGC 'l 'l ~'l"l'~'l'~'l'A TTTAACGTCA 246480 GGC~11~11C ATTCACGCGG CATGGCTGCG TCAGGGTTCC CCCCATTGCG CAATATTCCC 246600 CACTGCTGCC 1CCC~1AGGA GTCTGGACCG 1~L~1~AGTT CCAGTGTGGC TGGTCATCCT 246660 CGCGGTATTA GCGACAGTTT CCC~LC~11A TCCCCCTCCA TAAGCCAGAT TCCCAAGCAT 246840 TACTCACCCG TCCGCCACTC GTCAGCAAGA AAGCAAGCTT 1~1C~LGCTA CCGTTCGACT 246900 TGCA1~1~11 AAGCCTGCCG CCAGCGTTCA ATCTGAGCCA TGATCAAACT CTTCAATTCA 246960 AGTTCAATCG CTCAATAAAC TGCTTAGCTA TAAATA~AAC ACTACTTAAA A~AGTAATGA 247020 TGAATTTTCA GTTAAGCACC TATTAAGACT TCAAAATTAA AAATAGTTTT A~AACAAGTC 247080 AATCAACAAG TGCCCACACA GA11~1~LGA TATATTGTTA AAGAGCAAAA AATAACGACG 247140 CACTTGGAAA CTTAAAAAAC TTCACAACAG TGC~1C~11G TGTGCGGTGC ATTATAGAGA 247200 TTTTCAAATC CCTTGCAAGT A~1L1111~1 AAAAATATTT A~AAAAATGA 'l ~ L L L'L~ATG 247260 GAAATATAAA CATTTTATTA AAAAGTGCGG TTAGAATAGT CA~ACTTTTA TTGCTATTAT 247320 TTCTTACGTA ATGAAACtTC TCCACCATTA AACATCTGAA TTTTATTGCC ACATAATACT 247380 TCATCAATAC CA1111~L1C A~AGATATTT AAACGTGTAT ATAhATGTTG TATAAGTTTG 247560 GGTAATAAAG L11~LCGCTC TACATCAGGA TCAATTTCAC ACACTTCCGC ATAAGGCTGA 247620 CTAATTTCTG L1L~LLLLGA CAACGACACA TTAATACCTA TGCCAATCAC TAAATTGAGC 247680 AAAATATCAT TTGGCCATTT CACTTGTACA TTTAGCACTT CCGCAATCGC CA~ACCGATG 247800 ACTA~ACTTA ACCCCTCAAT TGA1111LLA GGATCAAATG CCCAATA~AA ACTA~ACATG 247860 TATTCAGCCA CACAAAGATC GC~L111LLL AATGAAAGAA TALLLL~LAG TATCCATTCA 247980 r TTTGTAGAGG AAATAATCGG CTGATAATGG ATACTATAAG GA~AAAGTGC GGTTGAAATT 248040 -77. 1 49-SUBSTITUTE S} tF:~T (RULE 2 CA 022l874l l997-l0-2l W 096/33276 PCT~US96/05320 ATATCCAAAC CAATTTCACG TAAll~l"l'GA ATAl~llC~l CTAGATTTTT AGAAAATTTT 248160 TCCAATTCAG ACCGCACTTT CGGCTGACAA TCCGCTA~AT ATGTCAATAA CGTAAAATTC 248220 ATCATTCATT CCTTATGGCA AATAGTATGA A~ATCATAGC ATAAATCCTA A~ATTnnGTT 248280 GCGAGAATAT TGCAATGTCA TTACGCATTA AACAAGAnGC CCTTACTTTT GACGATGTTC 248400 TACTCGTCCC AGCTCACTCA ACTGTGCTTC CA~ATACTGC CAACCTTTCA ACTCAACTTA 248460 CTAAAGAAAT TcGTTTAAAT ATCCCAATGC TTTCAGCAGC AATGGaTACC GTAACTGA~A 248520 CCAAACTTGC GAl~l~lllA GCACAAGAAG GCGGTATTGG CTTTATTCAT AAAAATATGA 248580 CGATCGAACG CCAAGCAGAT CGCGTGCGTA AAGTA~AAAA ATTCGAAAGT GGTATCGTTT 248640 CTGAACCAGT AA~l~llllA CCAAATTTAA CGCTTGCCGA ACTTGCTGAA ATGGTGAAGA 248700 AAAACGGATT TGCGGGCTAC C~l~ll~lAG ATGGGGAAAA TAATTTAATC GGTATCATTA 24~760 A~AAAGAAGA CTTGGTGACC GTAAAAGAAG GGGCGAGTCG CGAAGAAATT TTGGaATTAA 248880 TGCATCAACA CC~l~ll~AA AAAGTATTAG TGGTTAATGA TAGTTTCAAA CTTAAAGGTA 248940 TGATTACCGT TAAAGACTTC CAAAAAGCAG AACA~AAACC AAATGCATGT AAAGATGAAT 249000 TCG~lC~lll ACGTGTCGGT GCGGCTGTAG GTGCAGGTGC TGGCAACGAA GAACGTATTG 249060 ATGCCTTAGT GAAAGCAGGC GTAGATGTAC TATTAATTGA 'l"l'~'L'l'~'l'~AC GGTCACTCAG 249120 AAGGCGTATT ACAACGCGTT CGTGAAACTC GTGCAAAATA TCCA~ATTTG CCTATCGTTG 249180 CAAGCTGTGT AATGGTTGGC TCGATGTTTG CGGGTACAGA AGAGGCtCCA GGTGAAATCG 249480 AACTTTATCA AGGTCGTGCA TTTA~ATCTT ACCGTGGTAT GGGCTCATTA GGTGCCATGG 249540 CGAAAGGCTC ATCAGACCGT TATTTCCAAT CGGATAACGC GGCAGATA~A CTCGTACCGG 249600 AAGGTATTGA AGGCCGTATT CCATATA~AG GTTACTTAAA AGAAATCATC CACCAACAAA 249660 TGGGTGGCTT AC~'1''1'L1"1'~'1' ATGGGCTTAA CGGGCTGTGC AACTATTGAT GAACTACGCA 249720 -77.150-SU~S i 11 UTE ~EET tRULE 26) W 096/33276 PCTrUS96/05320 CCAAAGCGGA A~LLl~llCGC ATTAGCGGTG CAGGCATTAA AGAAAGCCAC GTTCACGATG 249780 CCTGCCTTTT G~L~lllAAA GTGCGGTTGG tTTTTGCAAA GTTTTAAATA ATATGAACCG 249900 CTTACACTAT CAATAATAAG AGCATTATAA ATGACA~ATA TCCACTATCA CA~AATCCTA 249960 ALC~lC~ACT TTGGTTCACA ATACACTCAA CTGATTGCGC ~-LC~l~l~CG TGA~ATCGGT 250020 GTGTACTGCG AACTTTGGGC TTGGGATGTA ACCGAACAAn A~ATCCGTGA ATTTGCTCCC 250080 GAAGGTATTG AAGGCCGTAT TCCATATAAA GGTTACTTAA AAGA~ATCAT CCACCAACAA 250260 ATGGGTGGCT TAC~-l-L~LlG TATGGGCTTA ACGGGCTGTG CAACTATTGA TGAACTACGC 250320 ACCAAAGCGG AALL-l~L-LCG CATTAGCGGT GCAGGCATTA AAGA~AGCCA CGTTCACGAT 250380 GTTGCTATTA CTA~AGAAGC ACCTAACTAT CGTATGGGCT AATCTTTAAG GTGGGCTTTA 250440 GCCTGCCTTT TG~-L~LLLAA AGTGCGGTTG ~L-L-L-LlGCAA AGTTTTA~AT AATATGAACC 250500 AATCCTCGAC LL-l-G~-L-L~AC AATACACTCA ACTGATTGCG CGTCGTGTGC GTGAAATCGG 250620 AACGGGTATC ALL~-L-L-L~LG GCA~-LC~LGA AAGCACAACT GAAGA~AATA GCC~1C~LGC 250740 ACCGGAATAT GTATTTAATG ~L~L~LACC AGTATTAGGC ATTTGCTATG GAATGCAAAC 250800 GATGGCGATG CAACTTGGCG GCTTAACCGA AAC~-L~-LGAT CACAGAGAGT TCGGCTATGC 250860 ~L-LCC~-L-L-L~-L CTTGAAAATT CCACCGCACT TTTTGCAAAT CTTAACGATA ATTTAACCGC 250920 ATTATTAACC AA~lLC~lAG TA~ACATCTG TGGTTGCGAA ACCA~ATGGA CAGCAGA~AA 251160 AGGCTTATCT GGTGGTGTGG A~L~LL~-L~L GGTTGCATTA CTTTTACACC GTGCTATCGG 251280 CA~AAACTTA CACTGCGTAT TTGTGGATAA CGGTTTACTC CGCTTACACG AAGGCGACCA 251340 AGTCATGGAA ATGTTTGGCG ATAAATTCGG TTTAAACATC A~-LC~L~-Ll-G ATGCTGAAAG 251400 -77. 1 5 1 -SU8STITUTE S}{EET ~RULE 26) CA 022l874l l997-l0-2l W 096/33276 PCTrUS96105320 ~1C~1-11~11A GGTGAACTTG CAGGCGTATC~TGATCCTGA~ GCGAAACGTA AAATTATCGG 251460 TAAAGTGTTC GTGGATGTAT TCGATGATGA ATCGA~AAAA CTCACTAATG TGAAATGGTT 251520 GGCACAAGGT ACGATTTACC CTGACGTAAT CGAATCTGCA GCAAGCA~AA CTGGTAAAGC 251580 ACATGTGATT A~ATCACACC ACAACGTAGG TGGCTTACCA GACTATATGA AACTTGGTTT 251640 AGTTGAACCT TTACGTGAAT TATTTAAAGA TGAAGTACGT A~AATCGGTT TAGCATTAGG 251700 CTTACCAGCT GAAATGATCA ACCGCCACCC ATTCCCTGGC CCAGGCTTAG GTGTGCGTGT 25~760 CGAAGAATTA CGCAACAGCG ~11G~1ATGA AAAAACCAGC CAAGCCTTCA GCGTATTCTT 251880 ACCAGTGA~A TCTGTAGGTG TGATGGGCGA TGGCCGTA~A TACGATTGGG TTATTTCCCT 251940 ATTAGGCA~A ~1~1~1AACC GTATCATCAA CGAAGTGAAT GGAATTTCCC GC~LC~1ATA 252060 TA~111~1AA TTATTTCAGT AACTTTAATA AGTGCGGTTA ATTTTCACCG CA~11L~LLL 252180 LL~LL1AAAA GCCCTTCTAT GCCAATCACA ATGAGACTTA ACCAAATAGG CACATAAGTA 252240 AAATAGTCAC TTGTGGTTAT TTGATTATCT AGCACA~AGA CAGCTATTAA AAAAAGCAAT 252300 ATGGGTTCAA TATAACTCAA CACCGCA~AA ATACTAACTG GAA~LLL~LLG GCTTGATTTT 252360 GGAATCGAAA TTAAAATAAT ATCCAATGTA ALLC~L1~1A GAGCAGGGAT TTTCATCCAT 252540 TTACGGCTTA GATAATAAAA TGGATAAACC GTACA~ACCC ACAAGCTTGT CCATGAAAAA 252600 GAATA~ATGA TAAACGTTCT TTTAACCAAG CCCATCCTAA AACAGCCATA ATCAGCGGAA 252720 AAAGA~AATA TCCCATCGCA ATATTTATCC CTTCGCCATT TAGCGGTGCC CACATA~AGA 252780 GCCAGAATTG ACTTCCCGCA TCTAGTGTCC CCAGTAAAAA TA~AACCCAA CGCGTCCAAC 252840 TTTTTCCTAA AGTTGTCGTA ATAAGAGACA A~AGAGAGCG GCAACCAATA GTCGGAAATA 252900 GAATTA~AAG TAACCCAAAG ATCATGGTCA GCATACGCCA CGCAAAAACA TCCGTTCCGC 252960 TAAGTGGTTG GAGCCATATA CTA~ATAAAT ACAATATGCC AAATA~ACAT TGTGAAAAAA 253020 -77.152-SUBST~TUTE ~HEET ~RULE 2b~

CA 022l874l l997-l0-2l W 096~3276 PCTAUS9610S320 TGATTATTAT AAAAGCCCAA GGCAATAAAA AATCTCAACT TTA~ llA TTGTGATAAT 253140 A11111~1~A ATAGTTACAT TTTTGAGA~A TTATCTTATG CA~ACACTGG ATAAATTAGA 253200 TCGTCATATT TTGAATGTAT TACAACAAGA TGCCATGATT CCGTTA~AAG AACTGTCAGA 253260 GAAAGTGAAT AGTTCCGTTG CAAC~l~l~A ACGACGTGTG CAATCATTAA CTGATTCAGG 253320 CATTATTACA A~ACGAGTTG CA~ll~lllC CCCA~AAGCC GTTGGGCGTA CGATTAGCGT 253380 Alll~l~ATG GTCGAAATGG ATAATCAACA TTCTTATTAT CAAGAGCAAT TTGAACGGAA 253440 AATGCGTCAA GAAGACGAAG TGGTGAGCTG TTACGA~ATC TCAGGGGACT ATGATTTTAT 253500 GTTGCTACTC CATGCA~AAG ATATGGA~AG CTATCACGCA TTCACACGCC GAGTATTGAC 253560 GGGTGAATTT CATGTAAGAA CTTATA~AAG TTTATTTGTA ATGAATTTTA CCAAAGCAGA 253620 GTTTAGTTTT GTC~llL~ll TTAAGAATAA ATACCCAAGT ATTGCCGA~A CCGTTGATCC 253740 AAGTAGAATA CCTAAACGAG A~AGAGTATT GACACTTTCC CCCGCATTAG CATCA~ACGC 253800 AAGGCTTGCT AAGAACATTG ACATCGTA~A ACCGATTCCA CATA~AACCG CAACAGCAAA 253860 AAlll~lllA AAATTAATTC CATCCGGTnA TTTAGCTAAT CCCAATTTAA CAGAAATATA 253920 ACTAAATCCA AATATACCGA ~lG~lllACC AATAATTaAA CCG-llGCTA TAGCCAATAA 253980 TAATGGCGAC GAAATCATAT TCACATCTAT GCCTGCA~AA CTCACACCAG CATTGGCAAA 254040 TGCGrAAAGT GGTAAAATAA CGA~AGATGA CCAAGAGGCT rAAATATGCT CGA~ATCATC 254100 TAATGGGCGT T~lC~lllll TACCTTTCAA TGGAATGCTA AAACCAATAA TAACGCCTGC 254160 TA~AGTAGCA TGCACACCAG ACTTTAATAC GGAAGCCCAT AAAATTGCAC CTACGACCAT 254220 ATAAGCGCAA AGTGCAGA~A CTCTGA~ACG ATTTAGTAAT ATCAGcACAA TAATTGCCAC 25~280 TATCGCACCG AGGTCATCAA TAATAGCAAG GGCAAGTA~A AATATTTTCA GTGGAAGTGG 254400 CA~ll~lllA CTCAATAACG CCATAATTCC CAGTGCAAAA GCAATGTCTG TTGCCATTGG 254460 AATTGCCCAG CCATTAGCTA AACTTGGATC ll~lllAGCG ATA~ACCAAT A~ACTACAGC 254520 CGGTATAACC ATTCCGCCAA TAGCTGCAAT AGCAGGGA~A ATAGCTTGTT GATAGGTAGA 254580 AAGCGCGCCT TCA~ATAATT ~'l''l"l''l"l"l'~AC TTCCATTCCC ACTAATACAA A~AACACCGC 254640 CATAAAACCA TCGTTAATCC AGTGAATTAA GGTTTTATTA ATTGAGA~AC TACCAATTTG 254700 TA~ACTTACA GGCA~ATTTA A~AAATCATT ATATTGGTTG CTTAACGGCG AATTAGCCAG 254760 -77.153-SU85 11 i UTE ~ EET tRULE 2~i~

, CA 02218741 l997-l0-2l W 096133276 PCTrUS96/05320 AAAGGAAGCA TCCTAGCATA Ll-l--lC~AAGT TAAAGGAAAA AGTGCGGTAG ALll-l~-l-CGG 254940 TTACACAATA GAGATTTTAT CTA~Lll~-lA GTAGAATGCG GACCTTTTAT TTTTAGAATC 255060 AAAAACTATG TTTTCACGCA AAGATATTAT ~-l-l-l--lAGGA ATGATGATCT TCGCCTTATT 255120 GACGAGTGCT TCCTTAGGCT ~L-l~-l-l-ll-AAC TGGC~Ll--l--l-A ATGCCATTTA TTACGCTTGT 255240 CACAGGTTTC ~-LC~-llATAC TTTATTTAAC CATTGGCTCT ACCTTTGCAA TGCCCCGCAT 255360 ~L~-llC~L-l-Ll GTATTCTCAC TCATTTTTAA CTTAATCGCG ATGGGCTTTA TGATTAGCCC 255480 AAAAACCAAA GATATTGTGA AATACACCAT TTCAGCAGGA ~Ll-l-~l-LL~AG TCATCTTACT 255780 TGCGGGTTTA TAL-l--Ll-l-CGC L-l--l-l-~-l-ATCT AGGCGCAACT AGTGCTGCAG TTGCAGAAGG 255840 GGCAACGAAT GGTGGACAAA L-l-l-l-~l-~-lCG TTATGTAAAT GTCTTATTCG GTTCAGCTGG 255900 GACTTGGATT ATGGCAGGTA TTALl-~L~-ll AGCGAGCTTA ACAACACTTG TTGGTGTAAC 255960 TAGCGCATCT GCTGATTATT TTTCAAAATT ~-L~L~-lGCGT ~L-L l L~'-L-l-ATC CATTCTGGGC 256020 A~-L-L-L~11-1-L AGTTTATGTG ACAGCTTAAA TAACGTTAAA ATGTTACCAG AAAGCATCAA 256260 TTCATTATTG AAACACTTCC ~-L~-lLl-~ATC TGAAGGAATG GCTTGGTTGG TTCCGACTTT 256320 TCACAAAGTG TTTTATTTAT CAGCCCTGTG CCGTA~AACT CCGTCCTTCA GGGCGGAGAT 256440 -77. 1 54-SUBSmUTE S~{EET tRULE 2~) CA 022l874l l997-l0-2l W 096/33276 PCTnUS96/OS320 ATAAGGCACA GGGCTGATAA ATTTCTAACC GCA~L~lllC AAAAATCAAA TTAATTTAAC 256500 AGGTACTTTT ACGACTAATT TTTTAATTTT ~ CCATTCACTA CACAGCAAGG 256560 TTTATCATCA ATATCTGCAC A~AGTTGATA ATCATCCGCT ~LC~ll~lAAT CTTCATACTT 256680 TACATCTAAG TATTCATGAT GTAATTCTGC LLllllACTG ~LlG~ll~l~ CA~LlL~l~G 256800 TTCCATTACG TTCATATA~A TTTGATCGTT AATATCATGG CGACCATTCT CTAACGCATT 256860 CAAATCTAAC GTATTTA~AT AATCACATAC TTCAGCAATC ACTTTTGGTA AACCAACTTT 256920 AAAATTTGGG l"lG~l"lA~AC TGCTAATAAT CATAGAATTT TCCTTATAGT GGATAAAAGT 256980 TACACTATGA TACCAAGTCA GTTA~ATGAA ATAAAGCCAC CGATTACATC AL~l~l~llG 257040 TGACGCATAA AGTCTA~ACA ATGA~ATTAC GGCATTAACA CAAGCATTTT CAGAAAAAAT 257160 ATTATCAAGA GGCTTATGAG GACCTGTA~A ATGAAAAATA TTAGGAGAAG TATCAAGAGT 257220 AAGATCATTT TGCCACGATT CAGAaATATC TCCTGTATGT A~AATA~AAA CAGAGAGATT 257340 TTCATTGTGC ATTAATA~AG ATTTCAGTGT AATTTCTACA TTAAGGAAGA TAATTAGCAT 257400 CACTAGCCAT CATTACATTA TATTTCATAT A~AAGAACCT A~TTTCAGAG AGrACAATCA 257460 TTAGCCATTA AAGCCA~ACA LC~l~LATA~ TGCACGGGCT TTALll-l-~lA CATTAGCGTG 257580 CGGCTATCAA AAGAAATTTT TAAACGCCCA AAGTGCGGTC ALLL~L~L~LC~A AAGATTTCTT 257640 TTGCTAGTCG CAATCTGGGA AATAAGGCAT L~LLLllAAT ATA~ATTTTA AGGAAAACAT 257700 TGTGAATCCA ATTGTTAAAC AATTTA~ATA CGGTCAGCAT ACCGTTACTC TAGAAACTGG 257760 CGTGACTGTT GTTGCTAAAA AAGATGTGAA AGAAGGTCAA GA~LL~llCC CATTAACCGT 257880 ATTATTCCCA GAAGGTTTCT TCAATGA~AT CCAAGTTGTG GCAACTGTGG ~LLL~L~lAAA 258060 -77.155-SUBS i I i UTE SHE~T (RULE 26 W 096t33276 PCT~US96105320 CGTATTAAAC CCAACTATGG CAGAACA~AA ACAAAGCCGT TTGGACTTAG TGGTTGCAGG 258240 TTTAATCAAC AAAGTA~AAG CGATTGCTGA AGCACGTTTA GGCGATGCAT ACCGCATTAC 253480 TGAAAAACAA TTACGTTACG AACAGATCGA TGCGATTAAA GCGGATGTAA yTGCGCAAAT 258540 CACAGCTGAA GATGAAGAAA yCAGCGAAGG TAAAATCGTG GATATTTTCA CCGCACTTGA 258600 AAGCCAAATC GTTC~lG~lC GTATCATTGC AGGCGAACCA CGTATTGACG GTCGTACCGT 258660 TGATACTGTT CGTGCATTAG ATATTTGCAC lG~l~lATTA CCACGTACTC ACGGTTCTGC 258720 TGCACAAATC ATTGATGAAT TAACGGGTGA ACGTCAAGAT CA~ll~llAT TCCATTATAA 258840 TTTCCCTCCA TAll~l~lAG GCGAAACAGG TATGATCGGC TCGCCAAAAC GTCGTGAGAT 258900 ~ ~lATGT GGTGCGTCTT TAGCATTAAT GGATGCGGGC GTTCCAATCA AAGCTGCTGT 259080 TCCTGCTCCA CGTGCTGATA lll~l~ACTA CGCACCGCGC ATCTATACAA TGAAAATCGA 259380 CGTTGGAAAT AAAGAAGGTT TAGTTCATAT TTCTCAAATT GCTGAAGAGC GTGTAGA~AA 259680 AGTTAGCGAT TACCTTCAAG TGGGTCAAGA AGTA~ACGTA AAA~ll~llG AAATCGATCG 259740 TCAAGGTCGT ATTCGTTTAA CAATGAAAGA CTTGGCTCCA A~ACAAGAAA CTGAAATTAA 259800 -77.156-SUBSmUTE ~{~EET tRULE 26) W 096133276 PCTrUS96/05320 CATTCGCTGC CAA~11L1~1 1~11L1CCAA CTTTTAGGCA TAAAGAAAGC AAATGCGGTG 25g920 TGCTGGCTGT GTTCAGTCTA GGGGCGGTTT '1~1~1~1AAA AATCATGTCG TGTTGGCTGA 260040 TTACGACGGC GCATTGGATG CTTTCAATAC G~L~111~AA TTAGATTCAG GTTATGACTA 260 40 TACCCACCTT AATCGTGGTT TA~ATTTTTA TTATGTAGGG CGCTACCATC TTGCTCAGCA 260400 AGA11L~11A CAGTTCTACC AAGCCGATAA AAAAGATCCC TA'1C~1~1~1 TATGGCTATA 260460 TTTGAACGAA CAAAAATTAA AACCACAAGA AGCCCAAACA AAC~11~11G AACGAGCAAA 260520 AGGGCTATCA GAGGACTTCT GGGGTACACA TA1C~11~AA TATTACTTAG GACACATCTC 260580 1C~1111GCC GC~111~AAC TCATGAAATT AAAACCGGTT CAAACAGAAG ACGAAAAAGA 260820 ~1~111~AGC 111C~L1ATT TATATTCGAG TATTTTAATG ACTGACAAAA TTACTTTCAA 261000 TGACTTAGGC TTACCTGAGT TCATCTTAAA AG~1~111~L GACTTAGGTT TTGAAACACC 261060 AGTTGCCGAT GCGTGCGAAC TA111~11AA ATATGCACAG GGCACTCGCA TTGTTACCTT 261300 TGTGGGTACA CCAGGCCGTA 11~L1~ACCA TA11C~1CGC GGAACATTAA AT~lll~l~A 261420 A~11C~1111 ATCGTATTAG ATGAAGCCGA TGA~ATGCTA CGCATGGGTT TCATTGATGA 261480 -77.157-SUBS 111 UTE S~{EET tRULE 2~) . CA 02218741 1997-10-21 , . . .

DEMANDES OU ~3R~VETS VOLUMINEI~X

LA PRÉ~;~3YTE PARTIE DE C~ E DEMANDE OU CE BREVET
COMPRE~lD PLUS D'UN TOME.

CECI EST LE TC~ME ¦ DE S

NO~E: Pour les tomes additiorlels, veuillez c~ntac~er le 8~reau canadi~n des brevets ~2J~7~1 JUMBO APPLICATIO~S/PATENTS - .

THtS SECTION OF THE APPLICATIONJPATENT CONTAINS MORE
THAN ONE VOLUME

T~IS ~S VOLUME f / OF 5_~

.
NO~E: For addibcnal ~ srnes-pleas~ c~ntac~~the Canadian PatPnt Off~ca

Claims (20)

What Is Claimed Is:

1. Computer readable medium having recorded thereon the nucleotide sequence depicted in SEQ ID NO:1, a representative fragment thereof or a nucleotide sequence at least 99.9% identical to the nucleotide sequence depicted in SEQ ID NO: 1.

2. computer readable medium having recorded thereon any one of the fragments of SEQ ID NO: 1 depicted in Table 1a or a degenerate variant thereof, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b.

3. The computer readable medium of claim 1, wherein said medium is selected from the group consisting of a floppy disc, a hard disc, random access memory (RAM), read only memory (ROM), and CD-ROM.

4. The computer readable medium of claim 3, wherein said medium is selected from the group consisting of a floppy disc, a hard disc, random access memory (RAM), read only memory (ROM), and CD-ROM.

5. A computer-based system for identifying fragments of the Haemophilus genome of commercial importance comprising the following elements;
a) a data storage means comprising the nucleotide sequence of SEQ ID NO: 1, a representative fragment thereof, or a nucleotide sequence at least 99.9% identical to the nucleotide sequence of SEQ ID NO: 1;
b) search means for comparing a target sequence to the nucleotide sequence of the data storage means of step (a) to identify homologous sequence(s), and c) retrieval means for obtaining said homologous sequence(s) of step (b).

6. A method for identifying commercially important nucleic acid fragments of the Haemophilus genome comprising the step of comparing a database comprising the nucleotide sequence depicted in SEQ ID NO: 1, a representative fragment thereof, or a nucleotide sequence at least 99.9%
identical to the nucleotide sequence of SEQ ID NO: 1 with a target sequence to obtain a nucleic acid molecule comprised of a complementary nucleotide sequence to said target sequence, wherein said target sequence is not randomly selected.

7. A method for identifying an expression modulating fragment of Haemophilus genome comprising the step of comparing a database comprising the nucleotide sequence depicted in SEQ ID NO: 1, a representative fragment thereof, or a nucleotide sequence at least 99.9% identical to the nucleotide sequence of SEQ ID NO: 1 with a target sequence to obtain a nucleic acid molecule comprised of a complementary nucleotide sequence to said target sequence, wherein said target sequence comprises sequences known to regulate gene expression.

8. An isolated protein-encoding nucleic acid fragment of the Haemophilus influenzae Rd genome, wherein said fragment consists of the nucleotide sequence of any one of the fragments of SEQ ID NO: 1 depicted in Table 1a or a degenerate variant thereof, excluding the fragments of SEQ ID
NO: 1 depicted in Table 1b.

9. A vector comprising any one of the fragments of the Haemophilus influenzae Rd genome depicted in Table 1a or a degenerate variant thereof, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b.

10. An isolated fragment of the Haemophilus influenzae Rd genome, wherein said fragment modulates the expression of an operably linked open reading frame, wherein said fragment consists of the nucleotide sequence from about 10 to 200 bases in length which is 5' to any one of the open reading frames depicted in Table 1a or a degenerate variant thereof, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b.

11. A vector comprising any one of the fragments of the Haemophilus influenzae Rd genome of claim 8.

12. An organism which has been altered to contain any one of the fragments of the Haemophilus genome of claim 8.

13. An organism which has been altered to contain any one of the fragments of the Haemophilus genome of claim 10.

14. A method for regulating the expression of a nucleic acid molecule comprising the step of covalently attaching 5' to said nucleic acid molecule a nucleic acid molecule consisting of the nucleotide sequence from about 10 to 100 bases 5' to any one of the fragments of the Haemophilus genome depicted in Table 1a or a degenerate variant thereof, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b.

15. An isolated nucleic acid molecule encoding a homolog of any one of the fragment of the Haemophilus genome depicted in Table 1a, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b wherein said nucleic acid molecule is produced by the steps of:
a) screening a genomic DNA library using any one of the fragments of the Haemophilus genome depicted in Table 1a as a target sequence;
b) identifying members of said library which contain sequences which hybridize to said target sequence;

c) isolating the nucleic acid molecules from said members identified in step (b).

16. An isolated DNA molecule encoding a homolog of any one of the fragments of the Haemophilus genome depicted in Table 1a, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b wherein said nucleic acid molecule is produced by the steps of:
a) isolating mRNA, DNA, or cDNA produced from an organism;
b) amplifying nucleic acid molecules whose nucleotide sequence is homologous to amplification primers derived from said fragment of said Haemophilus genome to prime said amplification;
c) isolating said amplified sequences produced in step (b).

17. An isolated polypeptide encoded by any one of the fragments of the Haemophilus influenzae Rd genome depicted in Table 1a or by a degenerate variant of said fragment, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b.

18. An isolated polynucleotide molecule encoding any one of the polypeptides of claim 17.

19. An antibody which selectively binds to any one of the polypeptides of claim 17.

20. A method for producing a polypeptide in a host cell comprising the steps of:

a) incubating a host containing a heterologous nucleic acid molecule whose nucleotide sequence consists of any one of the fragments of the Haemophilus influenzae Rd genome depicted in Table 1a or a degenerate variant thereof, excluding the fragments of SEQ ID NO: 1 depicted in Table 1b under conditions where said heterologous nucleic acid molecule is expressed to produce said protein, and b ) isolating said protein.