US 20080222741A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0222741 A1 Chinnaiyan (43) Pub. Date: Sep. 11, 2008
(54) EXPRESSION PROFILE OF PROSTATE (60) Provisional application No. 60/309,581, filed on Aug. CANCER 2, 2001, provisional application No. 60/334,468, filed on Nov. 15, 2001. (75) Inventor: Arul M. Chinnaiyan, Plymouth, MI (US) Publication Classification Correspondence Address: (51) Int. Cl. Casimir Jones, S.C. AOIK 67/00 (2006.01) 440 Science Drive, Suite 203 CI2O I/68 (2006.01) Madison, WI 53711 (US) CI2N 5/00 (2006.01) (52) U.S. Cl...... 800/10; 435/6: 800/13; 800/18; (73) Assignee: The Regents of the University of 435/375 Michigan, Ann Arbor, MI (US) (21) Appl. No.: 11/924,415 (57) ABSTRACT The present invention relates to compositions and methods (22) Filed: Oct. 25, 2007 for cancer diagnostics, including but not limited to, cancer markers. In particular, the present invention provides gene Related U.S. Application Data expression profiles associated with prostate cancers. Genes (60) Continuation-in-part of application No. 1 1/343,797, identified as cancer markers using the methods of the present filed on Jan. 31, 2006, which is a division of applica invention find use in the diagnosis and characterization of tion No. 10/210,120, filed on Aug. 1, 2002, now Pat. prostate cancer. In addition, the genes provide targets for No. 7,229,774. cancer drug screens and therapeutic applications.
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Diagnosis Therapeutics Prognosis Patent Application Publication Sep. 11, 2008 Sheet 1 of 137 US 2008/0222741 A1
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FIGURE 2A
PIM1 oncogen MYC MYC PNUTL1 psanut PNUTL1 psalut 1 TRF2 MYB2 UBCEO TP30 Tal-interacting protein POF8 TPD53 turror protein 052 SEll suppressor of lin TRA CALLA CAA TGFB1 TGFbeta t IGFBP5 IGF binding protein 5 as IGFBP5 GF binding protein 5 TGFBR3 TGFbeta receptor || TGFBR3 TCF beta receptor ill CCFD2 cyclin D2 CCMD2 cyclin D3 GSN gelsolin amyloidosis GS) gelsohn aryloidosis Rhobras gene family Rho8 ras gene family GAS 1 growth arrest-specific s FGFR2 FGF receptor 2 FGFR3 FGF receptor 2 TGF83 GFbeta 3 - TGFB TGFbeta
TGFB2 TGFbeta 2
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-FCE TGF3 connective tissue GF3
FGF2 FGF basic
FP2 TNF inducible protein 4-3-3 era 4-3-3. eta SiOOA 1 catgizzarin St.00A 1 catgizzarin Patent Application Publication Sep. 11, 2008 Sheet 3 of 137 US 2008/0222741 A1
FIGURE 2A-2
Commercial Pool
LUMLumican LUM Lumican IGBTDIntegrin beta-1D ITGBD integrin beta-1D THBS1 Thrombospondin THBS1 Thrombospondin Hewin GA1 integrin alpha 1 GA integrin alpha ITGA2 integrin alpha2 O TGA2 integrin alpha2 .ru U FN1 Fibronectin () MCAM melanoma adhesion C C. FN1 Fibronectin r MSN Moesin MSN Moesin r r WCLVinculin C} AV2 Caveolin 2 () AV2 Caveolin 2 CTNNB1 Catenin beta 1 CDH1 E-Cadherin DH1 E-Cadherin ITGA4 Integrin beta4 TGA4 integrin beta 4 CD44 antigen CD24SPOCK antigen Sprosteonectin Tastin Patent Application Publication Sep. 11, 2008 Sheet 4 of 137 US 2008/0222741 A1
FIGURE 2A-3
Commercial Pool
HEPSIN
CALLAYNEP SPINT2 TMP2 CST3 cystatin C ELANH2 anti-elastase 2 i ADAMTS1/METH MMP7 matrilysin MMP7 matrilysin P6 t ? Selenoprotein P1 GS-P1 "O OY GST-M4 (U GST-M or g GST-M1 (1) ; GST-P1GSTM5 r
Patent Application Publication Sep. 11, 2008 Sheet 5 of 137 US 2008/0222741 A1
FIGURE 2B
SNAP or Other Localized PCA Metastatic BPH Cell Lines UGBUteroglobin IL1R2 Li receptor || CLU Clustern
Y PA262A Phospholipase A2 O SCYA2Small inducible cytokine A2 fi SCYA2Small inducible cytokine A2 i-r HLA-DQA1 E is HLA-DQA ?t HLA-DR - HLA-DRB - a HLA-DPB CIS Complement is (4BPA Complement 4-BPalpha HLA-DQB1 HLA-DQB1 IL1R1 Ll receptor IL1R1 (L1 receptor Patent Application Publication Sep. 11, 2008 Sheet 6 of 137 US 2008/0222741 A1
FIGURE 2B-2
Commercial Pool
NAP or Other I Localized PCA Metastatic i BPH Cell Lines
MAPK10 MAPK10 PTK9 tyrosine kinase 9 PTK9 tyrosine kinase 9 PPPCB phosphatase n PPP1CB phosphatase 1 S. PTPRK it 8 E. g SGKkinase O. : MAPK6 ga MYPT C PPAP2B PPAP2B PPP2CB PTPRF MAP3KO MAP3K10 STK15 Serine/threonine kinase Patent Application Publication Sep. 11, 2008 Sheet 7 of 137 US 2008/0222741 A1
FIGURE 2B-3
Contercial Pool NAP or Other as Localized PCA
BTF3 SK ATF3 FOSB 5 NR3C1 ETS2 MEIS2 NES SLUGMES1, zinc finger protein a SLUG zinc finger protein ZBRK MYC MYC EZH2 enhancer of Zeste 2 MYBL2 ERG Patent Application Publication Sep. 11, 2008 Sheet 8 of 137 US 2008/0222741 A1
FIGURE 2 B-4
Commercial Pool NAP or Other Localized PCA Metastatic BPH Cell Lines MPDZmultiple PDZ domain ARHEras family member E RAB2 ras oncogene family RAB2 ras oncogene family ANXA7 annexin A7 ANXA1 annexin A11 ANXA4 annexin A4 NBL1 tumor suppressor N-RAS FAT tumor suppressar FZD7 frizzled D7 ST5 tumor suppressor 5 FHL1 4 1/2 LIM domains RAP1A ras. Oncogene family TACC1 EPHA1 ANXA1 annexin At RG regulated in glioma Endothelin receptor type B Endothelin receptor type B Endothelin receptor type B PSMA ODC Ornithine decarboxylase 1 HS1-2 putative TM protein HS1-2putative TM protein FKBP5 FK506-binding protein 5 FKBP5FK506-binding protein 5 FASN fatty acid synthase FASN fatty acid synthase DDX1 DDX DDX TOP2A topoisomerase DNA alpha ESTs topoisomerase alpha ESTs topoisomerase lalpha MTA metastasis associated 1 FLS353 espressed in Colorectal ca. Patent Application Publication Sep. 11, 2008 Sheet 9 of 137 US 2008/0222741 A1
FIGURE 3C
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Figure 5
Norma Adjacent CommercialPod N Vou kara war sesse sease see ess - 234.31 TT1023 KIAA0203. KAA0203 gene. product D 3.33333 $31 W961.34R38383 ZFP36JUN '"zinc avianfinger sarcoma pfot eih virushomol 17go; oncogene to Zf p-36 homolog in Thouse 84.9944790 A.A48552862.179FOSBFBJ EGR1 early murine growth osteosarcoma response viral oncogene homol dig 51448309776 H210413455 ATF3FR activatingCASP8 and transcription FADD-like ages factor regulator 8980925394 AA-8553AA598794 dc T dopachroneconnective tasy tomerase tisse dopach 58 r or factordele isome rese, tyrosine-related protein2 2.78729 N62935 Homo sapiens mRNA, cDNA KFZp586M1418 from cone drcFZ2586M 1418 244307300 103 N7579W07099 PANAGL 1 asN-acetylglucosamin minogen, actival or gase,inhibitor alpha-Sanfi type ippo disease is 49.39350043, H1769.6AA93,513 MBP MMP7 gye matrixbasic met protein alloproteinase 7 matri Iys in, uterine 470393 AA03153 MMP matrix met alloproteinase 7 marilysin, uterine 1344.22 R31679. ESs 856. AA452966 RCP4 Pur kine cell protein 4 84916 AA48682 SGK serum glucocorticoid regulated kinase 83.823838: AA453712AAg31 UMM. lumium carcari 501854 AA 127965 St 593Q83 AA148641. MEIS2 Meis. Inguse homolog2 48.8434$343 W92594.DKFZP564BO769AAO47435 KIAA0203 KIAA0203 pKFZP564BO769 33 93. protein 95323g593 AA5416AA22839 TPRLSF translocated lens epithelium promoter derived region growth to actlyfactor a ted MET oncogene 502396366966 AA156946AA2353 HomoEST sapiens mRNA, cDNADKFZp53492063 from clone DKfzp564C2063 88938 4434 BPAgbulous pemphigoid antigen 1230f240kD 231.32 H54629 NFSFO not negrossfact organd superfamily member 10 l 30 1309 NO DATA FOR THIS CONE J N UN GENE BUILD 106. 2.951404072 R55750N71647 ESTSis Weakly similar to similar to pre-mRNA splicing factor SRP20 (C. elegans --- - 33333 72235 NNMonicot i nami de Ninethyltransferase - 365826 AAO25819 sis growth arrest specific 32489 W438. EWS edgpic viral hegration site 5 4.183341S833 W8853W86553 FKBP5SBR5 FK506-bindingFK593-binding protsprotein in 55 243989 N45364 ESTs 83.385 AA44880 A3 cabonic anhydrase ill, muscle spacific 1328281996 AA430545R27172 ESTsKAA0056 KIAA0056 protein 80734778. AA45700R19956 WEGF &B vascular eggie"53; b561 factor 25890876 N4984138859 SC2A5CCK cholecystokinin solute arrier family 2 facilitated glucose transporter, member 5 24.1274 h9216 Hora sapiens. mRNA, cDNA DKFZp586A0617 from clone dkfzp586A0617 - V - - 4D887338 08:35Ng DATA FOR THSCLONE haseNUN GENE, BUILD 106. 4347702 XR359340 MAP3K10CTBP C-terminalmitogen-activaled binding protein protein kinase kinase kinase 10 39811926. AA59851.750323FASN KRT8ker fatty atacid in synthase 485744Q82 AA939932BXA2R,46924 ABP1 ami orthrombokane. ide 3. A2prgte receptor in 1 amine oxidase copper-containing - 295.889 NS7917 Rieukemia inhibitisry factor recept or - - - BE256895 N26311 PLAB prostate differ entiation factor
expression fold change from pool Patent Application Publication Sep. 11, 2008 Sheet 12 of 137 US 2008/0222741 A1
Figure 6
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Figure 7
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Figure8
CEL ADHSON ANT-ROASE/ PROTEASE VE-cadherin mee2 wresp.-1. vrcystatin c RE. rcaveolin 2 wres SCANGER whoesin wePACALLA 4A seocit wires selenoproteia el CELL GROWTH 4aTAs an-epsin *Gs's f CELL, DEATH e HOSATASE 1ac Ya S. f KNASE 1ne-1 vre 1MBL-2 5 wrecks
TGF signaling s Wr FRAE2B GEF signaling se Wrzel wrofaes. X - Yi 3. a SERIS ERA, t & NY SGR vic-ere Epithaliua N A TW Met S PTR9 1aRAP2 & TRANSCRIPTION NAMMAON ACORS A MMUNITY 1ac, Pa2 A2 1a ERGO r Sceae vranted Ns 1a-Ya-2 * As 1a As wrist3 W Cls, CGBP WFR22ED 7 - SR WIL1R NMEIS Patent Application Publication Sep. 11, 2008 Sheet 15 of 137 US 2008/0222741 A1
Figure9
2 pin-1 M5495 3 FKBPs XM 004288 4 FASN NM004104 5 TFOLH M99487 6 TNFSF10 XM045049 8 S100A1 XM 047223 9 TIGFBP3 XM 004689 10 SLUG XM 01634 GSTM3 J05459 12 LR2 X59770 13 ITGB4 X53587
16 APP X06989 18 ANNEXINA XM 005665 19 EPHA M8391 20 NCK1 XM 051968 2 MAPK6 XM 017662 22 SGK XM 037045 23 HEVIN XM 011533 24 MEIS2 XM 012430 25 MYLK XM 04219 26 FZD7 NM 003507
29 ARHB XM 002689 30 PSG9 NM002784 3 GSTM NM00056 33 TIMP2 XM 027036
Patent Application Publication Sep. 11, 2008 Sheet 16 of 137 US 2008/0222741 A1
Figure 9 (cont.)
XM 005121
52 ANNEXN A11 XM 035906 54 IGFBP5 XM 04673 56 T COL15A XM 00:5592 58 SKI - XM 001535 60 FOSB NM006732 61 CFLAR XM 027980 YWHAB XM 00959 NRAS XM 001317 SCYA2 XM 038982 ITGA XM 032902
XM 03000 XM 0306 XM 037653 NM 002709 XM 05128. Patent Application Publication Sep. 11, 2008 Sheet 17 of 137 US 2008/0222741 A1
Figure 9 (cont.)
XM 047633
XM 012615 XM 009488
GP73 AF2360S6
Patent Application Publication Sep. 11, 2008 Sheet 23 of 137 US 2008/0222741 A1
Figure 10 (cont.)
96. tact ttgctc Ctggggtgaa gtoctato.ca gatggttgga atctitcctgg aggtggtgtc. lO2l cagogtggaa attatcCtaala totgaatggit 9CaggagaCC CtCCaCaCC aggttaccca 108l gCaaatgaat atgctta tag gcgtggaatt gCagaggct9 ttggtott.cc aagtattoct ill4l gttcatcCaa ttggatacta tgatgcacag aagct.cctag aaaaaatggg tggctoragca 120 ccaccagata gCagctggag aggaagttcto aaagtgccct acaatgttgg acctggctitt 26 actggaaact tt to taca Ca aaaagttcaag atgcacatcc actictaCCaa tgaagttgaca i32) agaatttaca atgttgatagg tact.ct Caga ggagcagtgg aaccagacag atatgtcatt l38 Ctgggaggto accgggactC atgggtgttt ggtgg tattg accCtcagag tggagcagot l441 gttgttcatg aaattgttgag gagct ttgga acactgaaaa aggaagggtg gaga CCtaga 150 agaacaattit tgtttgcaag Ctgggatgca gaagaatttg gtottcttgg ttoctactgag 56l tigcagagg aga attcaag actCct tccala gag.cgtgg.cg tggettatat taatgctgac l621 to atctatag aaggaaacta cactotgaga gttgattgta Caccgctgat gtacagottg l68l gtacacaacC taacaaaaga gctgaaaagc CCtgatgaag gctttgaagg Calaatctott l74l tatgaaagtt ggactaaaaa. aagttcct tcc Ccagagttca gtggCatgCC Caggataagc lBOl aaattgggat Ctggaaatga ttittgaggtg ttct tcCaac gaCttggaat tgct tcaggo B6l agagcacggit a tactaaaaa. ttgggaaa.ca aacaaattica gcggctatoc actgtatcac l921 agtgtctatg aaaCatatga gttggtggaa aagttt tatg atccaatgtt taaatatoac 98l citcactgtgg ccCaggttcg aggagggatg gtgtttgagc tagcCaattic Catagtgctc 204 cct tttgatt gtogagatta tgctgtagtt ttaagaaagt atgctgaCaa aatctacagt 2l Ol atttctatga aa CatcCaCa gga aatgaag acatacagtg tat catttga tetcactitt 2161 totgcagtaa agaattittac agaa attgct tCcaagttca gtgagagact cCaggact tt 2221 gacaaaag.ca accoaatagt attaagaatg atgaatgat C aactCatgtt totggaaaga 2281 goatttattg atcCattagg gttaccagac aggcctttitt a taggcatgt Catctatgct 234l ccaa.gcagoc acaacaagta, tgcag999ag toatt.cccag gaattitatga tgctotgttt 240l gatattgaaa gcaaagtgga cCottcCaag gCCt99ggag aagttgaagag acagattitat 24.61 gttgcagoct tCacagtgca ggcagctgca gagactittga gtgaagtagc Ctaagaggat 2521 tott tagaga. atc.cg tattg aatttgttgtg gtatgtcact Cagaaagaat cgtaatgggt 258 atattgataa attittaaaat tggtatattt gaaataaagt tgaatattat a tataaaaaa 264l aaaaaaaaaa aaa. SEO ID NO : 6 l Cotcactgac tataaaagaa tagaga agga agggcttcag teaccggctg. Cotggctgac 61 ttacagoagt cagacitctga caggat.catg gctatgatgg aggtocaggg gggacccago 2. Ctgggacaga CCtgcgtgct gatcgtgatc ttcacagtgc to CtgcagtC totctgttgttg 18 gCt9ta actt acgtgtactt taccaacgag Ctgaagcaga tgoaggaCaa gtact.ccaaa 24. agtggcattg cttgtttctt aaaagaagat gacagttatt gggacCCCaa tgacgaagag 3O. agtatgaaca gcc.cotgcts gcaagttcaag tggcaactcc gtcagotcgt. tagaaagatg 36. attttgagaa cCtctgagga aaCCatt tot acagttcaag 42 aaaagcaa.ca alaa tatt tot cCCC tagtga ga9aaagagg toctoragaga gtag cagotc acatalactgg 9accagagga 48 agaagcaa.ca cattgttct tc tCcaaactCC aagaatgaaa aggctotggg Cotgcaaaata 54 aactCctggg aatcatcaag gagtgggcat toatt.cctga goaact tyca Cttgaggaat 60. 99tgaactgg toatcCatga aaaagggttt taCta Catct 66. ttt Caggagg attocCCaaac atact ttcga aaataaaaga aaacacaaag ala C9a caaac aaatggtoca ata tatttac 72 aaa taca Caa 9ttatCCtga cc.ctatattg ttgatgaaaa gtgctagaaa tagttgttgg 78. tCtaaagatg Cagaatatgg actC tatt CC atctatoaa.g ggggaatatt tgagcttaag 34. gaaaatgaca gaattt ttgt ttctgtaa.ca aatgagcact 901 gccagtttitt tgataga cat ggacocatgaa ttggggcctt tttagttggc taactgacCt ggaaagaaaa agcaata acc 96. toaaagtgac tattgagttt totaggatgat a Cactatgaa gatgtttcaa aaaatctgac O2 caaacaaac aaacagaaaa Cagaaaacaa aaaaacctCt atgcaatctgagtagagcag 108 CCCCCs aaaattic tac 8acaca Cact gttctgaaag. tgactcactt atCCCaagag 4. aatgaaattg ctgaaagatc tttcaggact CtacctCata l2O tagalagactg toagtttgct agoagaaatc. toag Cttcca aacattaatg caatggitta a catcttctgt Ctttataatc 261 tacticcittgt aaag actgta gaagaaagag Caacaatcca totctoalagt 32 agtagtagcC agtg tatCac to caggtttc Ctta agggiac aa CatCCC ta. agtcaaaaga gaga agaggc
Patent Application Publication Sep. 11, 2008 Sheet 72 of 137 US 2008/0222741 A1
Figure 10 (cont.)
92 tagttaaagt gacCatgaat tttgagccala ataaagtgaa tatt caaaag aaaaactg.cC 1981 atatggaggg aaaggaaa.ca gtatgcatala atgctacagt gtgttttgat gtgaaattaa 204 agtctaaaga agacacgatt tatgaagctg atttgcagta ccgtgtcacc ctagattoac 210 taalgacaaat atcacgaagt tttt totctg galactoalaga gagaaaggtt caaagga aca 216 totacagttctg aaaatcagaa tgcactalagc actoct tcc ta. Catgttgaca agcatgactt 222 totaggactCt gtgagaataa Cgttggactt taatct tacc gatcCagaaa atgggcCt9t 2281 tottgatgat tcCtaccaa actcagtaca tgaata tatt ccCtttgc.ca aagattgttgg 234 aaataaggaa aaatgttatct Cagacctorag Cctgcatgtc. gCCaCCaCt9 aaaaggaCCt 24 O gctgattgtc. CgatccCaga atgataagtt caacgttagc Ctca cagtca aaaatacaaa 246 gga cagtgcC tata acaCCa ggacaa tagt gcattattot ccaaatctag ttttt toagg 2S2 aattgaggct atcCaaaaag acagttgttga atctaatcat. aatacca Cat gtaaagttgg 2SB attatcCCttic ctgagaagag gagagatggt aact ttcaaa a tattgtttc agttta acac 264 atCctatoctic atggaaaatg tgaccattta tttalagtgca acaagtgaca gC9aagaacc 270 toCtgaaacC ct ttctgata atgtag taala Catttctato: Cogg taaaat atgaagttgg 276 actacagttt tacagotctg Caagttgaata CCaCateca attgctgc.ca atgaga cagt 232 ccctgaagtt attaatticta CtgaggaCat tggaaatgaa attaatlatct totact tigat 2B81 tagaaaaagt ggat.ct tttc caatgccaga gct taagotg Caateticat tocccaatat 2941 gacatcaaat ggttaccCtg tgctgtaccc aactggattg toatcttctg agaatgcaaa 3OOl ctgoaga.ccc. cata totttg aggat.cctitt cagtatoaac totggaaaga aaatgactac 3O6 atcaactgac Catctoaaac gaggcacaat totggactgc aata catgta aatttgctac 32 catca catgt aatCtcact t Cttctgacat CagcCaagttc aatgtt togc ttatct tgtg 3.18. gaalaccalact tt tataaaat Catatttitc. Cagct taa at CttaCtataa ggggagaact 324 toggagtgaa aatgcatc to tggttttalag tagcagea at caaaaaagag agcttgctat 330 tCaaat atcC aaagatgggc taccgggcag agtgc.catta tgggtoat CC tgctgagtgc 336 ttittgc.cgga ttgttgctgt taatgctgct cattt tagca ctgttgga aga ttggattctt 342. caaaagacca ctgaaaaaga aaatggagaa a.
SEQ JD NO: 68 gtaticactica gaatctggca gCCagttcCg tCctgacaga gttcacagca tatattggtg 6. gattcttgtc. cata.gtgcat Ctgctttalag aattaa.cgaa agcagtgtca agaCagtaag 12 gattcaaacc atttgccaaa aatgagtCta agtgcattta c to tct tcct ggcattgatt 8. ggtggtacca gtggcCagta Ctatgattat gatttitc.ccc tatCaattta tgggCaatca 24 totaCCaaact gtgcaccaga atgtaactgc Cctgaaagct accCaagtgc catgtactgt O gatgagctga aattgaaaag tgtaccalatg gtgcctoct9. gaatcaagta cetacct 35 aggaataacC agattgacCa tattgatgaa aaggcctttg agaatgtaac tgatctgcag 42 tggCtcattc tagatcacaa cct tctagaa aactccaaga taaaagggag agttt totct 48 aaattgaaac aactgaagaa gcts catata ala CCaCat Ca acctsgacaga gtotgttgggc S4 ccacticoca aatctotgga ggatctgcag Caccata acaag at CaC aaagctgggc 60 tottttgaag gattggtaaa cctgacct tc atcCatcticc agcacaatcg gctgaaagag 661 gatgctgttt cagotgcttt taaaggtott aaatcactcg aatacct tea Cttgagottc 72 aatcagatag cCagactgcC ttCtggtotC cctgtctotc ttctaactict Ctact tagac 78. aacaataaga totagoaacat cCCtgatgag tatttcaa.gc gttittaatgc attgcagtat 84 ctg.cgtttat Ctcacaa.cga act990tgat agtggaatac Ctggaaattic titt caatgtg 90 totatcc.ctgg ttgagctgga totgtc.ctat aacaa.gotta aaaa.catacc aactgtcaat 96. gaaaaccttg aaaact atta CCt99aggto aatcaacttg agaagtttga Cataaagagc O2 ttctgca aga toctggggcc attatcCaC to caagat.ca agcatttgcg tttggatggC O8. aacgcatct Cagaalaccag tottccaccg gatatgtatg aatgtctacg tgttgctaac ill4. gaagttcactC ttaattaata totgttatcct ggaacaatat tt tatggitta tgtttittctg l2Ol tgtgtcagtt ttcatagtat cCatatt tta ttactgttta ttact tcCat gaattittaaa 261 atctgaggga aatgttttgt alaa Cattta t ttitttt taala gaaaagatga aag.9CaggcC 32 tatt totatoa caagaacaca CaCatata.ca Cgaataga.ca toaaactCaa tgct ttattt 3. gtaa atttag tgtttittitta tttctactgt caaatgatgt gcaaaacctt ttactggttg 44 Cat-ggaaatc agccaagttt tataatcCtt aaatct taat gttcCtcaaa gCttggatta 50 aataca tatg gatgttactic to ttgcacca aattatcttg attacattcaa atttgttctgg
Patent Application Publication Sep. 11, 2008 Sheet 77 of 137 US 2008/0222741 A1
Figure 10 (cont.)
738, aattagogag cacgccCCtc atgggcattt cgtgachtgt gtaaaa.goct atgatgcaga 4 cagttcagac atagacaagt tgcagtatto cattctgtct ggcaatgatc ataaa.cattt 7SO tgtcattgac agtgcaa.ca.g ggattatcac CCtect caaac CtgcaccggC acgc.cctgaa 756. gccattt tac agtotta acc tgtcagtgtc. tgatggagtt tttagaagtt cCaccCaggt 752 totatgtaact gtaattggag gcaatttgca cagtCctgct ttcc ttcaga acgaatatga 768 agtggalacta gctgaaaacg. etccocaca taccctggtg atggaggtga aaactacgga 774. tggggattct gg tatttatg gtcacgttac ttaccatatt gtaaatgact ttgccaaaga 78O cagattttac ataaatgaga gaggacagat atttactittg gaaaaacttg atcgagaaac 786 CCC9gcggag aaagttgatct cagtc.cgttt aatggctaa.g gatgctggag gaaaagttgc 792 tt totgcacc gtgaatgtca tect tacaga tgacaatgac aatgcaccac aattt Cagc 798 aaCCaaata gaagttgaata toggg to Cag tgctgctaaa gggact tcag togttaaagt BO tottgcaagt gatgc.cgatg agggctccala tgc.cgaCatc acctatgcca ttgaa.gcaga 801 ctctgaaagt gtaaaagaga. atttggaaat taacaaactg tCCggcgtaa tecacta Caaa. B5. ggaga.gcCtc attggCttgg aaaatga att Cttcactitt C tttgttagag Ctgttggataa 822 tgggtotCca toaaaagaat ctgttgttct tgttctatgtt aaaatcCttic Caccggaaat 828 gcagottc.ca aaattittcag aacct t t Cta tacct taca gtgtcagagg acgtgcctat 83. tggaacagag atagatctga tecsagcaga acategtggg actgttctitt acagotctggt 84 Ol caaagggaat actCcagaaa gcaataggga tgagtcCttt gtgattgaca gacagagegg 845 gagactgaag ttggagalaga gtottgatca tgaga caact aagttggtatC agttt tocat BS2 actggcCagg tgcactCaag atgacCatga gatggtgget totgtagatg ttagtatc.ca 858 agtgaaagat gCaaatgaca acagotc.cggit Ctttgaatct agtcCatatg aggcattcat 854 tSttgaaaac Ct9.cCagggg gaagtag agt aattcagatc agggcatctg atgctgacto 80 aggaacCaac ggccaagtta tgtatagoct ggat.ca.gtca Caaagttgttgg aagttcattga 86. atcCtttgcc attaa.catgg aaaCaggctg gattacaact ttaaaggaac ttgaCCatga 882 aaagagagac aattaccaga ttaaagttggt tgcatcagat Catggtgaaa agatcCagct 888 accecaca gccattgttgg atgttacCgt Caccgatgtc aacga tagtC CaCCaCgatt 894 cacgg.ccgag atctataaag gg actgttgag tgaggatgac CCCCaaggtg gggtgattgc 9 OOL Catcttaagt accacggatg ctgattctga agagatcaac agaCaagtta Catattt Cat 906 aa Caggaggg gatcCtttag gacagtttgc Cgttgaaact atacagaatg aatggaaggt 92. atatgttgaag aaacctetag acagggaaaa aagggacaat accetta citat cacggc 98. aactgatggc acct tctCat Caaaag.cgat agttgaagttg aaagttctgg atgcaaatga 24 caa.cagtc.ca gtttgttgaaa agactittata ttcagascact attcctgaag acgt.cctitcc SP3). tggaaaattg at catgcaga totctgctac agaC9Casac atcc.gctota acgctgaaat 936 tacttacacg ttattgggitt Caggtgcaga aaaatcaaa CtaaatcCag acacaggtga 92 actgaaaacg. totaacCCCCC ttgatcgtga ggagcaa.gct gtttatcatc ttctogtoag 948. ggCCacagat ggaggaggaa gatt.ctscCa agc.cagtatt gCgctCaCgc tagaagatgt. 9S4 gaacga taac gCCCCCyaat totctg.ccga toctitatgcc atcaccgtgt ttgaaaacac 950 agagcC999a acgctgctga Caagagtgca ggccacagat goCgacgcag gattaaatcg 966 gaagatttta tacticactga ttgaCtctgc tgatgggcag tCCCCatta acga attatc. 972 tggaattatt Cagittagaaa alacctittgga cagagaactic Caggcagtat acaccCtctC 978 tttgaaagct gtggatcaag gCttgccaag gaggctgact gccactggca ctgttgattgt 984 at cagttct gaCataaatg accCCCCC tgttgtttgag taccgtgaat atggtgccac 990 cgtgttctgag gacattctg ttggaactga agttct tcaa gtgtatgcag Caagttcggga 996 tattgaagca aatgagaaa totacctactic aataataagt ggaaatgaac atgggaaatt O2 cagotatagat totaaaa.cag OOB all Ol4 t all O2 Ol an 1026. lO32 O38 O44 OSO nnnn.nnngaia aataa.gc.cag tgggettcag OSs. cgtgctgcag Ctgg tagtaa cagatgagga CttCcCat aacgg tocac cottctitct t
Patent Application Publication Sep. 11, 2008 Sheet 80 of 137 US 2008/0222741 A1
Figure 10 (cont.)
222 agaattcata catgaatcca gaaaagaagt gcc.gggtttg gtgatct tca aaagaa.gcat 228 tgcagocctt ggctag actt gcca acacca Cagaaatggg gaattctota atcgaaagaa 234. aatgggCCCt aggggtoact gtactgactt gagggtgatt aacagagagg goaccatcac 24O1 aatacagata acattaggitt gtoctagaaa. gggt9t99ag ggaggaaggg ggtotalaggt 245 ctatocaagttc aatcat tot cactgttgtac a taatgctta atttctaaag attaatattac 2S2 tgtttatttc tgtttctoat atgg totacC agtttgctga tgtcCCtaga aaacaatgca 258 aaacCtttga ggtagaCCag gatt totaat caaaagggaia aagaagatgt tgaagaatac 2541 agttaggcac Cagaagaa.ca gtaggtgaca ctatagttta aaacacattg CCtaactact 27 O. agtttt tact tttatttgca acattta Cag totct tcaaaa to Cttccalaa gaattcttat 276 acacattggg gecttggagc ttacatagtt ttaalactCat ttttgccata catcagttat 282 to attctgttg atcatttatt ttaag cactc ttaaa.gcaaa aaatgaatgt ctaaaattgt 288 tttttgttgt acctgctttg actgatgctg agattctt.ca ggct tcctgc aattitcCtaa 2941. gcaatttctt gctctatotc toaaaacttg gtattt ttca gagatttata taaatgtaaa 3 OOl aataataatt tttatattta attatta act acatttatga gtaactatta ttataggtaa 3 O61 totaatgaata ttgaagtttc agcttaaaat aalacagttgt galaccalagat ctataaag.cg 321 atatacagat gaaaatttga gactatttaa. acttataa at catattgatg aaaagattta 3.81 agcacaaact ttagggtaaa aattgc.catt ggacagttgt ctagagatat atataCttgt 324l ggttt toaaa ttggactittc aaaattaaat ctgtc.cCtga gagtgttctot gataaaaggg 33 Ol caaatctgca CCtatgtage tetgcatcto ctgtc.ttt to aggtttgtca toagatggaa 335 a tattttgat aataaattga aattgttgaac toattgcticc Ctaagactgt gacaactgtc 342. taact ttaga agtgcatttc tgaatagaaa tgggaggcct Ctgatggacc ttctagaatt 348 ataagttcaca aagagttctg gaaaagaact gtt tactgct tgataggaat tecatcttittg 354. aggcttctgt toctictott tCctgttgta ttgactattt togttcatta Cttgattaag 360 attttacaaa. aga99 agcac ttccaaaatt ct tatttitt C ctaacaaaag atgaaag.cag 366 ggaatttcta totaaatgat gagtattagt tecctgttctic ttgaaaaatg cc.catttgcc 372 tttaaaaaaa. aaagttacag aaa tactata a catatgtac ataa attgca taaagcatala 37B gtatacagtt Caataaact t aactittaact gaacaatggc Cctgtagcca 9.Cacctgtaa 384 gaaacagagc agtaccagcg ctctaaaagc acctocttgt CaCtt tatta CtccCagaac 390 aacaactateC Ctgacttcta a tatCatcCa ctagotttgc Ctggttttgt Cttt tatgca 396 gatagaatca atcagtatgt attcttttgt gcctggct tc tt tetcticag CCttacattt 402 gtgagattico totgtattgt gctgattgttg gatct tttca ttcteattgc agaataatgt 408 totattgttgg gact tattac aatttgttca toctattgtt gatgggcact tgagaacttt 44 coattittggc gCtattacaa a tagtgcaac tatgaatgta Ct9.catgtta cCatCttact 420. tgagcCttta atggact tat ttct tcaaat CCttcCaaaa. attattatala gCattgaaat 426 tatagtttca agcCaactgt. ggattacCCtt a CCCttCct cCtttatcac alaccaccgtt 432 acaagtatac tta tatttocC Ctaaaata Ca tittaaaactt. acctaagttga Catttgtagt 4.38 tggagtaata ggagettcca gctictaataa aa.cagotgtc totaact tat tttatt tocca A 44 tCatgtcaga gotaggtgaag agccagaagt gaagagtgac tag tacaaat tataaaaag.c 450 Cactagacitc. ttcactgtta gCtttittaaa acattagget cCCatCCC ta. tggaggaa.ca 456 actic tocagt gcctggat.cc cCtctgtcta caaatataag attt totggg cctaaaggat 462. agatcaaagt Caaaaatago aatgcct.ccc. tatCCCtcac acatcCagac atcatgaatt 4681 tta catggta ctottgttga gttctgtaga gcct tctgat gtoctotaaag Cactaccgat 474. totttggagt tgtCaCatCa gataagaCat atctotaatt CCatCcatala atccagttct ABOl actatggctg agttctggto aaagaaagaa agtttagaag Ctgaga Caca aagggttggg 485 agctgatgaa actCacalaat 9atgg tagga agaa.gctotC gaCaata CCC 9ttggcaagg 492 agtctgcctC catgctgcag tgttcgagtg 9attgtaggt 9Caagatgga aaggattgta 498 ggtgcaa.gct gtCCagagaa aagagtc.ctt gttccagocc tattoctgcca CtcCtgacag SO4. ggtgaccttg gg tatttgca a tatteott gggcc tetgc tCC Cacc taaaaaaaga SO gaattagatt a tattggtgg ttcticagocaa. gaga aggagt atgttgtc.caa tgctgccttc Sl6 CCatgaatct gtotcc.cagt tatgaatcag t999 Caggat aaactgaaaa Ceccattta S221 C9tgttctgaa togagtgaga Caaaattitta gtocaaataa Caagta CCaa agttittatca S28. agtttgggto tgttgctgctg ttactgttaa ccatttaagt 99.99 Caaaac cittgcta att S34. ttctdaaaag Catttatcat to ttgttgcc aca 9Ct99ag Ctctcaaact aaaaga catt 540. tgttattttg gaaagaagaa agactotatt cticaaagttt CCtaatcaga aattitatic
Patent Application Publication Sep. 11, 2008 Sheet 83 of 137 US 2008/0222741 A1
Figure 10 (cont.)
'78. caca agggto agcataggca 999 totaCCCa gaga accgag a tatgccago aagtgaagat 84 ttacaagatt tacaaaagaa gctctgtcga. aagagatgta taaatcaatt actctgtaaa 90 ttgccCacag attcagagtt ggCtcc tagg agotgatgct gccattgtcg acatctgata 96. tttgaaaaaa Ca999 totgc aatcacctga cagtgtaaag aaaacct Cocc atctt tatgt O2 agctgacagg gactitcgggC agaggagaac ataactgaat cttgtcagtg acgtttgcct 108 coagctgcct gacaaataag toagcagott a taccca cag aa.gc.ca.gtgc Cagttgacgc 14 tgaaagaatc. aggcaaaaaa gtgagaatga CCttcaaac aaa tatttala aa taggaCat 2Ol acticCCCaat ttag totaga caca atttcai tt to cagoat ttittataaac taccaaatta 26. gtgaaccaaa aatagaaatt agatttgttgc aaa catggag aaatctactg aattggcttic 32 cagattittaa attt tatgtc a tagaaatat tgactcaaac catattt titt atgatggagc 1381 aactgaaagg tgattgcagc ttttggttaa tatgtct ttt titt totttt tocagtgttc 44 tatttgctitt aatgagaata gaaacgtaaa Ctatgaccta ggggtttctg ttgga taatt SO agcagtttag aatggaggaa gaacaacaaa gacatgcttt Ccatttitt ctt tact tatt S6 Ctctcaaaac aatat tactt tgtcttt toa atct totact tttalactaat aaaataagttg 62. gattttgtat tt talagatcc agaaa tactt aacacgtgaa tattttgcta aaaaa.gcata 68 tataaCtatt ttaalatatoc atttatct tt tgtatatota agacticatcc tgattitt tac 174 tatcacacat gaataaag.cc tttgttatctt tott cteta atgttgttatc a tactcttct 80 aaaacttgag tggctgtc.tt aaaagatata aggggaaaga taa tattgtc. tgttctotata 1861 ttgct tagta agtatttcca tag totaatga tggtttaata ggtaalaccala accota taala ls2 ccts acctoc tt tatggitta atact attaa. gCaagaatgc agta Cagaat tggata cagt ls 8 acggatttgt ccaaataaat totaataaaaa cct taala
SEQ ID NO : 78 l calaccacttg acaacctggit tagaagatgc cc.gc.cagoat tecaatticca acatggtoat 6. tatgct tatt gga aataaaa gtgatttaga atctagaaga gaagtaaaaa aagaagaagg 12 tgaa.gcttitt goa C.gagaac atggacticat ct tcatggaa acgtctgcta agactgctitc 28 caatgtagaa gaggcattta ttaatacago aaaagaaatt tatgaaaaaa ttcaagaagg 24 agtictittgac attaataatg aggcaaatgg Cattaaaatt ggcc.ctoagc atgctgctac 30 Caatgcaa.ca catgcaggca at Cagggagg acag caggct 99.999C99Ct gctgttgagt 36 ctgtttittac tgtctagotg CCCaacgggg cCtacticact tattott toa ccc.cc totcc 42 to Ct9.c toag ctgaga catg aaactatttg aaatggcttt atgtcacaga agactittaat 48 CC9 totalaatt cittgtataac tttgaataaa tggittaatgt to acttaaaa gacagattitt 54 ggagattgta ttcatatota tttgcatttg atttctaggt caattgatgt gattattt tt 6Ol gttaaatgtt gtotttgttgcC Cttaactacg aactgaattg tattaalacac tacaaagttca 66 tCttgagtat tttaaatcgg tttgttgtagt tagg tt tocc aaCatctgtg gttacctaat 72 gtttaa tatt atagaactgt cCtcagaaac tttgtcaatt ttcacggcta taaggaaa.ca 78. gaaggactct tttaattctg tatttatcat ttactittctg tatata tagt ttaataalCCt 84 gCttgggtgt aatttgcCaa gcttgaattic tittaatgcat ttgcataaat tota tact.gt 90. ttagagctta aagctacaga agcattgtta ggaattgctt 99 acactgaa ttittaa actt 96. tttgacattg ttaacaag.ca tgttcatctt ttcttgtcac tag to caaga aaaatatgct O2. taatgtata t tacaaaggct ttgtatatgt taacct titt taatgccaaa agtttgctitt 108 gtcCacaatt tocttaagac ctct tcagaa agggatttgt ttgcct taat gaatactgtt 4. 999 aaaaaac acagtataat gagtgaaaag 99 Caga agca agaaatttct acatcttago 2O gacticcaaga agaatgagta tocacattta gatggcacat tatgaggact taatlict titc 25 Cttaalacaca a taatgttt t ct t t t t tott tattocacat gatttctaag tata t t t tes 32 atgcaggada gtttt toaac Cttgatgtac agtgactgttg taaaattitt ctttcagtgg 38 caacCtectat aatCtttaaa a tatggtgag Catct t tot gttittgaagg ggatatgaca 44 ataaatctat Cagatggaaa atcctgtt SEO ID NO; 79 l CCtggg totg acgcggcCct gttctgagggg gcc totcttg titat tatt tattt tocgt. 6. gagtgttgcgc gCgctotcgc ggagggggtg 99.999 agggc 2. 99.99 agttgg agcC9999 to gtgacttgta 99tgagagaa Patent Application Publication Sep. 11, 2008 Sheet 84 of 137 US 2008/0222741 A1
Figure 10 (cont.)
Bl C9CC9agcC9 tcgcc.gcago Ctcc.gc.cgc.c gagaagccCt tgttccc.gct gCt999aagg 24 agag totgttg CCgacaagat ggCgga C999 gagctgaacg tggacagect Catcaccogg 301 Ct9Ctggagg tacgaggatg tcgtocagga aagattgttgc agatgactga a gCagaagtt 36 Cgaggctitat gta totaagttc togggagatc tttctgagcc agcctattot tttggaattg 42. gaag Caccgc tgaaaatttg tggaga tatt Catggacaat atacagattt actgagatta 48 tttgaatatg gaggttt CCC accagaagcc aac tact tottaggaga ttatgttggaC 54 agaggaaag.c agtct ttgga aaccatttgt ttgctattgg Cttataaaat CaaatcatCCa gagaact tct ttctCttaag aggaalaccat gagtgttgcta goatcaatcg catttatgga 66. ttctatgatg aatgcaaacg aagatttaat attaaattgt ggaagacCtt cactgattgt 72 tttaactgtc tgcctatago agc.cattgttg gatgaga aga tottctgttg toatggagga 78. ttgtcaccag acctgcaatc tatggagcag attcggaga a titatgaga CC tactgatgtc. 84 cCtgatacag gtttgctotg tgatttgcta tggtctgatc Cagataagga tgtgcaa.ggc 9 Ol tggggagaaa atgatcgtgg tgtttoctitt acttittggag ctgatgtagt cagtaaattt 96. ctgaatcgt.c atgatttaga tttgatttgt cgagetcatC aggtggtgga agatggata t O21 gaatttitttg ctaaacgaca gttggta acc ttattt totag CCCCalaatta Ctgtggcgag O8. tttgataatg ctggtggaat gatgagtgttg gatgaaactt tgatgtgttc. att toagata 14 l ttgaaagtCat Ctgaaaagaa agctaaatac Cagtatggtg gactgaattc tggacgtCCt 20 gtcacticcac Ctcgaa cagc taatcc.gcCg aagaaaaggt 9aagaaagga attctgtaaa 26 gaalaccatca gatttgttaa 99 acatactt cataatatat aagttgttgcac tgtaaaacca 321 toCagccatt tgaca CCCtt tatgatgtca CaCCttaac ttaaggagac gggtaaagga 138. tottaa attt titt totaata gaaagatgttg Ctacactgta ttgtaataag tatactctgt 144 tatag toaac aaagttalaat cCaaatetcaa. aattacca taaagttaca tott catgta SO tCacalattitt taaagttgaa aagcatcCCa gttaalactag atgttgatagt taalaccagat 561 9aaag.catga tgatcCatct gtgtaatgttg gttt tag tigt tgcttggttg teta attatt l62 ttgagcttgt tttgtttttg tttgttt toa ctagaataat ggcaaatact totaatttitt 68. ttCCCtaaac atttt taaaa. gtgaaatatg gga agagctt. tacaga catt caccalactat 14 tattt tocct tgtttatcta Cttagatato tgtttaatct tactaagaaa actttcgcct BOl Cattacatta aaaagga att ttagagattg attgttt taa aaaaaaataC gCacattgtc. 86. Caatccagtg attittaatca tacagtttga Ctgggcaaac tttacagotg a tagtgaata 92 ttittgcttta tacaggalatt gacactgatt tggatttgttg CactCta att tittalactitat 1981 tgatgctcta ttgttgcagta goattt catt taagata agg Ctcatatagt attacCCaac 204 tagttggtaa tgttgat tatg tgg taccttg gctt taggitt ttcattogca cggaacacct 2O. tttggcatgc taact toct ggta acacct toacctgcat tggttttctt ttctttitt 26. Cttcettitt ttittitt titt tttitttttga gttgttgttt gtttttagat cCacagtaca 222 tgagaatcct tttttgacaa gCCttggaala gCtgacactg totct ttt to CtcCCCta 228 acgaaggatg tatttaaatg aatgctggto agtgggaCat tttgtcaact atgggtattg 234. ggtgottaac tgtctaatat tgcCatgttga atgttgtata Cgattgtaag gct tatgtca 24 Ol ctaaagattt ttattotgat tttt Catala tCaaaggtoca tatgatactg tatagacaag 2461 Ctttgtagtg aagtatag ta gcaataattt ctgtacctga toaagtt tat tgcagocttt 252 Cttt tectat ttct tttt tt Caagggttag tattaacaala tggcaatgag tagaaaagtt 258 aa catgaaga ttt tagaagg agagaactta caggacacag atttgttgatt Ctttgactgt 264 gaCactattg gatgttgat to taaaagct tt tattgagcat tgtcaaattt gta agct tca 270. tagggatgga catcatcatct a taatgcc.ct totatatgttg Ctaccataga 276 tgttgacattt ttgacct taa tatcgtottt gaaaatgtta aattgagaaa cctgttaact tacatttitat 232 9aattggcac attg tattac ttactgcaa.g agatatttca ttt totagoac 288. agtgcaaaag ttctttaaaa tgcatatgtc. tett tecta attcc.gtttt gttittaaagc a catttitcaaa. 294 tg tagttt to toatt tagta aaagttgttct aattgatatg aa.goctgact gatttitt ttt 3OO ttcCttacag tgaga cattt aagcaca cat tt tattoca Ca taga tactat gtocttgaca 3Os tattgaaatg attic tect gaaagtatt C atgatctgca tatgatgtat tagg taggt 312. Cacaaaggtt ttatctgagg tgatttaaat aact tcc tiga ttggagtgttg taagctgagc 38 gatt totaat aaaattt tag ttgtacactt ttagtag tota tagtgaag.ca 324l ggtotagaaa ataagcc ttt gg Cagggaaa aagggcaatg ttgattaatc toagtattaa aCCaCattaa 33O. totgttatcco attgttctggC ttttgtaaat tcatcCaggt caagactaag tatgttggtt 336 aatagga at C cittittitt t tttaalagact aaatgttgaaa aaataat CaC tact taagct