Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 1 of 212 PageID
`#: 32749
`
`EXHIBIT 1
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 2 of 212 PageID
`#: 32750
`
`(12) United States Patent
`Zsebo et al.
`US006759215B1
`(io) Patent No. :
`US 6, 759, 215 Bl
`(45) Date of Patent:
`:l!Jul. 6, 2004
`(54) METHOD OF PREPAMNG HUMAN STEM
`CELL FACTOR POLYPEPTIDE
`(75) Inventors: Krisztlna M. Zselo, Thousand Oaks,
`CA (US); Robert A. Bosselman,
`Thousand Dales, CA (US); Sidney V.
`Suggs, Newbury Puk, CA (US);
`Francis H. Martin, Thousand Oaks,
`CA(US)
`(73) Assignee: Amgen Inc., Thousand Oaks, CA (US)
`( * ) Notice: Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is subject to a terminal dis-
`claimer.
`(21) Appl. No. : 09/635, 251
`(22) Filed:
`Aug. 7, 2000
`Related U. S. Application Data
`(63) Contmuation of application No. 08/449,182, filed on May
`24. 1995. now abandoned, wMch is a continuadon of appli-
`cation No. 08/172,329, filed on Dec. 21, 1993, now Pat. No.
`6. 218. 148. which is a continuation of application No.
`07/982,255, filed on Nov. 25, 1992, now Pat. No 6 204,363
`which is a continuation of application No. 07/684^35, ffled
`on Aor. 10. 1991, now abandoned, which is a contmuation-
`in-part of applicatioil No. 07/589 701 filed on Oct 1, 1990,
`now abandoned, which is a contmuation-m-part of applica-
`tion No. 07/573, 616, ffled on Aug. 24, 1990, now abm-
`doned, which is a continuation-in-part of application No.
`07/537, 198, ffled on Jun. 11, 1990, 'now abandoned, which
`is a contmuation-m-part of application No. 07/422,383, filed
`on Oct. 16. 1989. now abandoned.
`(51) Int. Cl. 7 ........................ C12N 15/09; C07H 21/04;
`C07K 1/00; C07K 2/00; C07K 14/00
`(52) U. S. Cl. ..................... 435/69. 5; 435/70. 1; 435/243;
`435/252. 3; 435/320. 1; 435/325; 435/69. 1;
`530/350; 530/351; 536/23. 1; 536/23.5
`(58) Field of Search ............................... 536/23. 1, 23. 5;
`530/300, 350, 351; 435/69. 1, 70. 1, 252.3,
`320. 1, 325, 243, 69.5
`(56)
`References Cited
`U.S. PATENT DOCUMENTS
`6,218,148 Bl * 4/2001 Zsebo et al.
`OTHER PUBLICAHONS
`435/69.1
`Skoluick et al. From genes to protein structure and fanction:
`novel applications of computational approaches in the
`genomic era. Trends in Biotech 18(1): 34-39, 2000.*
`Bork, A. Powers and pitfalls in sequence analysis: the 70%
`huidle. Genome Res 10: 398^00, 2000.*
`Doerks et al. Protein annotation: detective work for fuactiou
`predictiou. Trends in Genetics 14(6): 248-250, 1998.*
`Smith et al. The chaUenges of genome sequence annotation
`or "The devil is in the details". Nature Biotech 15:
`1222-1223, 1997.*
`Brenner, S.E. Errors in genome function. Trends in Genetics
`15(4): 132-133, 1999.*
`Bork et al. Go hunting in sequence databases but watch out
`for the traps. Trends in Geuetics. 12(10): 425-427, 1996.*
`Wells. J.A. Additivity of mutational efEects in proteiDs.
`Biochemistry 29 (37): 8509-8517, 1990.*
`Ngo et al. Computational complexity, protein stnicture pre -
`diction, and the Levinthal paradox. The Protein Folding
`Problem and Tertiary Stmctuie Piediction, pp. 492-^95,
`1994.*
`Lewin, B. Genes. New York: John Wiley and Sons, Second
`edition, 1985, p. 681.*
`* cited by examiner
`Primary Examiner - Lorraine Spector
`Assistant Examiner-Budget E. Bunner
`(74) Anorney, Agent, or-Fimi-MarshaU, Gerstein & Bonm
`LLP
`(57)
`ABSTRACT
`Novel stem ceU factors, oUgonucleo tides encoding the same,
`and methods of production, are disclosed. Pharmaceuticil
`compositions aiid methods of treating disorders involving
`blood cells are also disclosed.
`13 Claims, 119 Drawing Sheets
`EXHIBIT
`,
`2-
`Planet Depos, LLC
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 3 of 212 PageID
`#: 32751
`
`U. S. Patent
`Jul. 6, 2004
`Sheet I of 119
`US 6, 759, 215 Bl
`FIG.I
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 4 of 212 PageID
`#: 32752
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 2 of 119
`US 6, 759, 215 Bl
`Q
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 5 of 212 PageID
`#: 32753
`
`U. S. Patent
`jui. 6, 2004
`Sheet 3 of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 6 of 212 PageID
`#: 32754
`
`U. S. Patent
`jui. 6, 2004
`Sheet 4 of 119
`US 6, 759, 215 Bl
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`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 7 of 212 PageID
`#: 32755
`
`U. S. Patent
`jui. 6, 2004
`Sheet S of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 8 of 212 PageID
`#: 32756
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 6 of 119
`US 6, 759, 215 Bl
`31.0
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`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 9 of 212 PageID
`#: 32757
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 7 of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 10 of 212
`PageID #: 32758
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 8 of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 11 of 212
`PageID #: 32759
`
`U. S. Patent
`jui. 6, 2004
`Sheet 9 of 119
`US 6, 759, 215 Bl
`FIG. 9
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 12 of 212
`PageID #: 32760
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`U. S. Patent
`jui. 6, 2004
`Sheet 10 of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 13 of 212
`PageID #: 32761
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`U. S. Patent
`jui. 6, 2004
`Sheet 11 of 119
`US 6, 759, 215 Bl
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`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 14 of 212
`PageID #: 32762
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 12 of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 15 of 212
`PageID #: 32763
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 13 of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 16 of 212
`PageID #: 32764
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 14 of 119
`US 6, 759, 215 Bl
`OL2GO
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`233-14
`235-29
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`LOCATION
`CTTAATGTTGAACAAACC
`7 03-6 £.6
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`GCGCCGCGGCTCCrATAGGTGCTAATTGG
`CCTCACCACTGTTTSTGCTGG^TCGCA
`153-179
`GGTGTCrAGACrTGTSTCTTCTTCATAAGGA
`209-190
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 17 of 212
`PageID #: 32765
`
`U. S. Patent
`Jiri. 6, 2004
`Sheet 15 of 119
`US 6, 759, 215 Bl
`FIG. 12C
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`'CG
`221-11
`TTCGGCCS^TCAGGCCCCCCCCCC
`221-12
`TTCGGCCGGATAGGCCTTTTTTTTTTTTTT
`22B-28
`GSCCGGATAGGCCTCACNNNNNNT
`22 8-2 S
`GGCCGGA^AGGCCTC?IC
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 18 of 212
`PageID #: 32766
`
`U. S. Patent
`jui. 6, 2004
`Sheet 16 of 119
`US 6, 759, 215 Bl
`200
`I
`PCR90.6
`222-n
`PCR96^ 222-JLL
`<3(C)
`PCR90.3
`12
`PCP96.6
`201-7
`FIG. 13A
`400
`223-6
`'215-25
`.
`219*25
`21&-21"'
`223-6
`600
`)
`533
`PCRs yielding
`5'raicDNA'
`(or secuer;ce
`analyas
`PCF1S25.1
`201*7
`PCR90.4
`21&. 25
`224-27
`224. 28
`222-11
`PC R630. 1. 630.2
`227. 29
`224. 24 .
`219-25
`222*12
`PCRs yrelding
`3' rat'cONA"
`tar sequence
`analysis
`PCR64. 1. 84.2
`227. 29
`PCR1
`219.26
`227-30
`PCRs
`used
`(or
`expressic
`230-25
`PCR2
`222. 11
`223.6
`PCRs used (or
`hybndization
`probes
`219-21
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 19 of 212
`PageID #: 32767
`
`U. S. Patent
`jui. 6, 2004
`Sheet 17 of 119
`US 6, 759, 215 Bl
`1
`PCR22.7
`7. 29
`200
`PCR24.3
`222-J1
`FIG. 13B
`400
`600
`700
`228-29
`PCRs yielding
`human cDNA
`for seauence
`analysis
`PCR24.7
`224.25
`228-29
`PCR25. 10{33. 1)
`222-11
`228. 29
`224. 24
`PCR41J1 (42. 3}
`224-25
`233*13
`PCR39. 1 (A1. 1. 51 1. 58. 1)
`227-29
`233-13
`PCR58.5
`233-13
`227-30
`227. 30
`227-30
`PCRs used
`tor
`expression
`PCR96. 1 (PCR 7}
`233-13
`227-30
`PCRs used
`for
`hybrid^ation
`proves
`231. 27
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 20 of 212
`PageID #: 32768
`
`U. S. Patent
`jui. 6, 2004
`Sheet 18 of 119
`US 6, 759, 215 Bl
`10
`»,
`s
`?
`r*.
`0»
`i
`1
`<
`^
`0
`Li-
`^
`0
`.
`s'
`0'
`D
`0>
`CD
`p
`cv
`t ,
`1
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 21 of 212
`PageID #: 32769
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 19 of 119
`US 6, 759, 215 Bl
`FIG. 14B
`AAAGTATCTTTC;A;TS3CGAAGGACATG7TTTCC=ATAAGTGG<:
`AAACAnACTGTCTGCAC&TAATAATTATCTTGCTGCCSTAAAGAT
`TAGGTTAAATTCTGcCTTCGATCTAAAAACACACCCTTCTGTCAA
`TCCGAGSAGCAGTGTGCTAGTCTAGAGGTCTAAATGAAGGCTCCT
`TTCA. CG3TTGTATTTCTGCTCCCCAAATTGTCCACATT7AAAAGG
`AGAGTGCTTCTTTTCAGCCTTAGGCTC7GAATTTCATGCArTCC7
`CCATTTTCCSASGTCCCccCcAAGTGA. TAATTCTGTTACA. CGTTG
`CTACAAGTTCATCCCTAATTGCCGTCAAGAAACTGACTGTAGAAG
`GCTTACCACAGACGTTGTAACCGACAGTAAAGCCATTGAAAGAGT
`AATTCAAACAGSATGGAAGCCAGGAGTArTTTGTGGCTGTTGCTC
`TTTTTCTTTTCAGTTTGGTGAGAGCAGCTTGAATtGCTTAACATTT
`AAGCCATCAGCTTAAAACAAAACAAAACAAAACAAAAAAAAACCC
`CGCTCIGGCATATTTGCACTTAACACATACGGTA.
`TAAGGTGTTAC
`TGGTTTGCATAGTTCTGGATTTTrTTTTTTTAAAAACTGATGGAC
`-20
`ThrTrpIleIleThrC
`ACC?AGAAATGTTTCTGTTCrTTGTTTAGACTTGGATTATCACTT
`-10
`ysIleTyrLeuGlnLeuLeuLe'-PheAsnProLeuValLysThrG
`GCATTTATCTTC/=ACTGCTCCTATTTAATCCTCTCGTCAAAACTC
`1
`lO
`InGlttlleCysAr^AsnP^oValThrAspAsnVa.
`lLysAspZleT
`AGGAGATCTGCAGGAATCCTGTGACTSATAA. TGT^AAAG^CATTA
`45
`90
`135
`1BO
`225
`270
`31$
`3 0
`405
`450
`495
`540
`585
`630
`675
`-72G
`765
`18
`hrLvsLeu
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 22 of 212
`PageID #: 32770
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 20 of 119
`US 6, 759, 215 Bl
`IV^'i'i:
`FIG. I4B CONT.'
`CAAAACTGGT&&S7AAAGAATSAT7TT3SCATCTATAAG7CTTCC
`610
`CTGTGCTTSCTSACCACATAGGTICAGGGCACTCCCGACAGSAGT
`8 5 5
`TCCCAGCrrTCTAASATAAGGAATCACTSTACSAGTCTGAAGTGC
`TTCTTCTGGGCAAATGG5AGATGCITAG3TCATGGAGG3TTTATC
`TGTATAACTGSCCCTTTGCACACCAACAAAGTG&CTGACTG5C-:
`TTGCCTGTTACCSACTG
`Intervftning sequence of unsown length
`TCTCCAGTCCTGG3CATGGTATATACTTAGGCACCCAAGATTGGA
`4 S
`TTTACAACTCAAGCATTATATATTGGACAACnACGGGGTATGAGA
`9 0
`TATTAATGATATGTCAGGTTGGATGSATGAGTTTTCTCAAGAAAT
`135
`19
`Val
`TCTCTTGTATTTACTCACGTTTTCATrrCTTGGTCTCTGTAGGTG
`30
`900
`945
`990
`1007
`39
`tetAspValLeu
`^_ _______ ^.^
`GGGATGGATGTTTTGGTATGTAG-CCACACAC-7CTGAGTTGCCT
`1BO
`AlaAsnLeuProAs^AspTyrMetIleThr^uAs^y^V^lA^
`SC
`^AT^TTCCAAATGACTATATGAT^CCCTCAACTATGTCGCC
`225
`270
`315
`360
`TTTAG7AGCTAATGGGTSACCTGTGCTTATTCACATTGAAGACAT
`TATTTGCTCTTTGTCGTTTTTAG^GT^GACCTATAATTTTTCCT
`TCAAGCTGCTGCTAAGATTATCAGTGAGCATTTCAGT^TGTGTTT
`405
`TAAGCCTACTCATTAAAAGG^. ^TGGC7CATCTTAGACGTAGCAA
`450
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 23 of 212
`PageID #: 32771
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 21 of 119
`US 6, 759, 215 Bl
`*»»n<». » <j
`. . i-rf^* U
`rv»»ui-/k. -. -
`FIG. 14B CONT-
`CC5ATGTTAA7TTTTCCCC&G5CATC?CTCAGAG5GACTT3^A:
`TTAAAATCATGTTAAATTTCCTCCTTG5CTATGTTA7TTC:
`GCTATGTTATTCCTATTCGTATTTCATTTAAAGGSACGSn^.:
`TATTGTATTTCTSAACTTTTTCAGGCATGCATCCGGGTCTTTGAA
`TAAAA
`Intervening sequence of unknown length
`CACTAAGACTCCTTCTAGTAATGTTTGTAATCCTGTCTGTATCGA
`ATGTCTTTGAAAACGCAGTGACTAAGCCATAAATAATCTTCCACA
`GAACGTCCA. GTSGTTCATGAA. CTTTGTATGTGGGGGTGGGGCAAG
`AATTGTCTCACTATTGGTCAAGGAAGAGAAGGTAAGGTATGCAAG
`I
`GGTGGTTTAATCTTCTTCCGTGGAAGGACAAAATCATCTATCA. TT
`TCCTCTGATCTCTATGCA. TTTGTTTGTTTTGAACTGAATCTGACT
`TGAGCAAGAGTTGGCGTCCTGTGTTCTGAGGAAACTCTTTGTCCT
`GCAGTCAGTGACTAJJAGTGCTSAGAGATCTGAAGAGCACTCTGA
`ATCTGCCA. TATTTTTAATAGATGCTTTGTCTTCTCTTTGAATTTC
`40.
`50
`ProSerSisCysTrpLeuArgAspMetValThrEisLeu
`TTCCAGCCTAGTCATTGTTGGTTACGAGATATGGTAACACACTTA
`60
`Ses-ValSerLeuThrThrLeuLeuAspLysPheSerAsnIleSer
`TCAGTCAGCTTGACFACTCTTCTGGACAAGTTTTCAAATATTTCT
`70
`80
`GluGlyLeuSerAsnTyrSerIldleAspLysLeuGlyLysIle
`.
`t?5
`540
`585
`630
`
`35
`45
`90
`135
`180
`225
`270
`315
`360
`405
`450
`495
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 24 of 212
`PageID #: 32772
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 22 of 119
`US 6, 759, 215 Bl
`FIG. 14B. CONT.'
`GAAGSCTTGAGTAATTATTCCATCATA.SJlCAAACTTGSaAAAATA 5^:
`90 .
`96
`ValAspAspI'euValAlaCysMetGluGluAsnAl&ProLys
`GTSSATGACCTCGT55CATGTATGGAASAAAATSCACCTAAG3TA 585
`ACTTSGTATTCATCh. GAATTATTTTTCITATACT
`619
`Intervening sequence "of unknown length
`GAGCTCATGATGAGCAATTCACAACCACTTGTAATTCCAGCTCCA
`'4 5
`GAGGACATTATCCCCTCTTTGGATGCCATAGGAATCTGCTCTCAA
`9 0
`ATATGTASATACCACCTCTGCCACCTCAGCACATACATACACATA
`135
`ATTAAAAAATAGAAACATTAAAGGAGTTCCAATCAATCCTTATTC
`180
`TTTTCTGTArTCAGTATGCCCAGATGTAAATTCTAGGAATATGTT
`22 5
`TTAAAGGCTAATTCTTATTTTGTAATAAGCAGCTITAAAATTCTT
`270
`AATTGTTTTTTCGGGTCA.CTTTATTGTCCTATTGCCACSACATTG
`315
`TCCTGTCCCATTGTCTGTTATTCCrTCTGTTTTGTTTATTGTTCC
`360
`CTAGTTACTTTGATCAT^AGATTGACCTGTTACCCGTTGTTA-TTC
`405
`TCTGTAGCCA-TTTTGAGTTGTGTCTATTAGAACAGCTGTTAAATT
`450
`ACTTGAATCATTGAGGACA^AGTCrtATAATCTATTATGCTGATCC
`495
`AGTCAAGTCTATGASTTATTTGAAAACTAGAATCTTTGTTAATTA
`540
`97
`AsnValLys
`TTTGTTTGCTTGTTTGTTTGTTTATTATTTGTCTAGAATGTAAAA
`585
`100
`110
`GluSerLeuLysLysFroGluThrArgAsnPheThrProGl-uGlu
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 25 of 212
`PageID #: 32773
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 23 of 119
`US 6, 759, 215 Bl
`FIG. 14B CONT-
`GAATCACTSAASAAGCCAGAAACTAGAJACTTTACTCCTGAAS^A
`$30
`120
`PhePheSerIle?h<sAsnAr-gSerIleAspAlaPbeLysAsp?he
`TTCTTTAGTATTTTCAATAGA.TCaiTTGATGCCTTCAAGGACTTC
`7 5
`130 .
`140
`MetValAlsSerAspThrSerAspCysValLeuSerSerThrLeu
`AIGGTGGCATCTGACACTAGTGATTSTSTGCTCTCTTCAACATTA
`720
`148
`GlyProGluLysA
`GGTCCTSASAAAGGTAAGGCTTTTAAGCATTTCTTGTTTAAAT5T
`7 65
`ACATAGAAASCCTGAACTTCTGTAAGCCTCTACTGCTGAATCAAC
`810
`TAAA.TGTGTTGCTGTAGAAAGAACGTGTGGGTTTTTCTGATAAAA
`855
`ACAAAAAGCAAATATCAATGACTACCAATGATTATTATCTAGCTT
`900
`GAGA-GXTATGCCCTAAGACAGCGATTCTCGATATTTCTAAATTAA
`945
`AGAATTGTGTGATGG7GGCTCACATATTTTCTAACTGTGATATTT
`990
`GCC?LGGAGAGTAGAATAATGTTATTCTTCATCCCCAGAATTCCTA
`1035
`AGATTTCACGTCTCATGTCTT7TCCATAAGGTTCAAACTCTGAGA
`1080
`CTTGAGTTCTGAGCCTCAGCAGGTCATTCTGAATCCCCACTCTCC
`1125
`CCGAGCTG3GTCCCTATGGGGGAACTAACTTCA. TTGCTTTCTTTT
`1170
`AAAACATGACGAGTTACCAAC^GCTCCTCGCTATTATAAACATGT
`1215
`TCCTAAGCATGTCTGTGCATGCaATAAGCCTTCACTCTACAAGAC
`1260
`AGTTATGGTGTATCGCTTGACAAAACTGAGCAGCCAAGCTGAGTA
`1305
`TGAAATAATAATCTAGACTT3GSAG3CAGACCCAGCACCTACTGT
`1350
`GATATTGCACrTC3CCTTTGGSGGACTCTATGATTCAAAAGTTCA
`1395
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 26 of 212
`PageID #: 32774
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 24 of 119
`US 6, 759, 215 Bl
`FI'G. t4B CONT-
`ISO
`spSczAr-g-V
`CCATGTAACACTSACACATTATTGCTTTCTA.TTTAGATTCCAGAG
`1440
`166
`alSerValThrLysProPheMetLeuProProV&lAlaAla.SerS
`TCAGTGTCACAAAACCATTTATGTTACCCCCTGTtGCAGCCAGTT
`1485
`170
`176
`erLeiA=-gAsrAspSerSerSer5erAsn_
`CCCTTA.SSAATGACAGCAGTAGC^GTAATAGTAAGTACACA.TATC
`1530
`TGATTTACTGCATGCATGGCTCCAAGTATCCTCTATAGSAGTGTI . 1575
`GCATGGACTTAAAGTITATAAATCACTACTAJlTAATGCTGTTCTG
`1620
`TCACTGTTATTCCTTGTATGSGCTTCCTGACAATTAAATATCTGG .
`1665
`TTTGTAGAATCGGATCTCCTTAGAGGTTAASATGACCATGACAAA
`1710
`ATTAGGCCAATCAACTTTCTGC3AAGSTTATTTTAAATAAGGCAC
`1755
`GAAATTAATTGAAGGAAAAAAAAATACAAGCAAGGCCTTATTITG
`1800
`AATCATGGTAGGCTTAAAATAGACTTTGTGGA5AATGTCCCTGAT
`1845
`CAAAGTGGASTTTTCAGATTTCAAGTGCATGTGCTAACTCTCCAC
`1890
`AATGTCAAGGCTATTTTCAGTTTTGTGTCTCCATATTTACTACTG
`1935
`CATGT7TGGAAA.TTTGCTGATGCTGTTAGATTACCTAAGAATGTA
`1980
`TGTTGAAGAAGAATGGACTTCTTTCCCTAAAATTTCTGTCCTCTT
`2025
`TGcCCAAGAACCCAcGTTCCTGSAAGACTATCTTATTTTCATGTC
`2070
`TGTGCAATGATCA.TTATAAAGATTATTGAATATACTGGGAATACT
`2115
`CTGGTTTCTGTTTTTACAGATTCATJ'ATAGCTTATTCAGTCTTTA
`2160
`AAGAAAGTTCTCTGAAGTCCATGCTTTAGAATGTTTCTCTATCAA
`2205
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 27 of 212
`PageID #: 32775
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 25 of 119
`US 6, 759, 215 Bl
`FIG. 14B CONT."
`AACTTSACCTGGACCTTAAATAAAGCTATATTTAGTCTTTTTATC
`2250
`CCTGAAAAATATATTTCACAGTGTAGACATTTGATATACATCTAA 22 95
`GGGAAGGATGCTGCCAGAATGCTCGGGCTGGCAGTCTACAAAGTC
`2340
`CACTGCTCTCAGGATGGACTTCTGAAAGCGGAAATTGTGAACTGC
`2385
`ATGCATATAACATATCAGATCCTCGAGC
`2413
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 28 of 212
`PageID #: 32776
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 26 of 119
`US 6, 759, 215 Bl
`»<
`e
`n
`0
`w
`n
`B
`N
`0
`^-
`0
`LL.
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 29 of 212
`PageID #: 32777
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 27 of 119
`US 6, 759, 215 Bl
`»n
`w
`<J»
`N
`t»
`h-
`z
`Q
`u
`0
`^
`0
`:i
`<
`<
`>j
`&'§
`0 J »<
`^
`t;
`<t>
`r^
`t?
`r-
`x
`-I
`ft.
`K
`1
`w
`J
`0 0
`1ft
`v^
`'°3
`k;
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 30 of 212
`PageID #: 32778
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 28 of 119
`US 6, 759, 215 Bl
`<
`10
`0
`u.
`0
`ffl
`8,
`?I
`h.
`0>
`s
`0
`^
`s I
`0>
`0
`0
`N
`t
`ll
`.
`11
`CM
`(
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 31 of 212
`PageID #: 32779
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 29 of 119
`US 6, 759, 215 Bl
`FIG. 15B
`-21
`hrGln
`CACAAGTGAGTAGG5CSCGCCCG55&. GCTCCCAG3CTCTCCAGGA
`4 5
`AAJATCGCGCCCGGTGCCCCGGGGaAGCCSGCGCTCCCTGGGACT
`90
`TGCAGCTGCGSCGTGCA.GGGCTGTGCCTGCCGGGTG
`126
`Intervening sequence of unknown length
`AGATACTAC&AAGATAAATCAGTTGCACAAGTTCTTGAAACTCTA
`4 5
`CAGTGTAJITAAGSAAAAATAAGTCATGCATAAAAGCAACTATAAT
`90
`ACATAATAGAAAATGTTATTTTCAAGCCGATGTGTAGGTTATGTG
`135
`TGTTCGAGAGAGAGAGAGAGAAGACAGATTACTTTCTGCTAGGGT
`180
`TCAASAATGCCTTCCTGTTGGCTAAGCAAATATTTTCCTTAAGTG
`225
`GCTAAAAAGCTGTGTTTCAAAATATTCTTTTGATGTCTCACAAAT
`270
`TCAGTGGAATTCTCTrAGGTCTAAAAA. 7ATACATCTCTCTCACTT
`315
`TAACTTGGTGTGCTATTGTAG^TTATTGGATTAAAGCACTGCTCA
`360
`GGGATTATGCTGCTTCTTGCCAAGCAGTCTACA.TTTAAAGTAGAA
`405
`ATAAGATGTTTCTTTTGGT3C CA7AAGGTATACATTTTATGCATT
`450
`CTCTAGTT'TTTAGAAGATACCC~/. LAGGGC-rAAGTCTTTAACATGC
`495
`TGCTACAAGTTTATTCCTAATTGCCATTGGGAAATTGGCTGAAGA
`540
`AAGTTTTTAACAAAAGTTAACAATATTGTCATTGAGAGAATAATT
`585
`CAAAATGGATTTTAACTAAAAGCTTTTAAAAACTTTGGTGAGCAT
`63 0
`AGCTTGUl73CGTAATATTTAA'rTGCATTTAAGCC?ATAACATAT
`67 5
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 32 of 212
`PageID #: 32780
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 30 of 119
`US 6, 759, 215 Bl
`FIG. 15B CONT."
`ATTAGACTGSrCTTTrT
`STGCATCAAG3CAT?A5ATGr;AAJA3T
`-
`2 0
`rTGAATSft.TTACA.GATCTTAACTGATSATCACCXAGCAATZ-TTTC
`7 .65
`-20
`'
`-10
`ThrTrpIl»L&uT^Cy9 llftTyrLeuGla.
`Le
`TSTTTTCATTTAGACTTGGATTCTG&CTTGCATTTATCTTCAGCT
`810
`1
`uL<tuLeuPheAsn?roLeuVallysThrGluGlyIleCysArgAs
`GCTCCTATTTAATCCTCTCGTCAAAACTGAAGGGATCTGCAGGAA
`855
`10
`18
`iiArgValThrAsnAsnValLysAspVa. lThrLysLeu
`TCGTGTGACTAATAATGTAAAAGACGTCACTAAATTGGTAAGTAA
`900
`GSAATSCTTTACCSTGCTGTG7AAAAAASAGCTGTGGCTCTTTTT
`945
`I
`CCTGTGCTTGTTGATAAAAGATTTAGATTTTTCTTGCCCCAAAGT
`990
`AATGTTTTCCTAAAGTGGGGAAAGTAATCACTGGGTTACAATAAA
`1035
`GGGTTTATACAAAGCAGGTAGTGA.GATATTTAGGGTCATGGATAA
`1080
`TT7GTTGGTAAAAC7GGCZAS7TGCACACCACTGCTGT5ACTGCT
`1125
`TCTTTGCTGGTCTTCTCCCCATCCTTCATAGGCAGTGAAGGACCT
`1170
`TGGAGAGTTCGCTGT5TGCTGA7GGGCTTGCCCCAGCTTGTTCCC
`1215
`CATAATCTCTCCAGTGGGTTTCCCAGCATGTTCTATTCCCCTTCA
`1260
`CATGTCTTCCTACTCTTCTTTAAAAAGCCTAACGAAAGGAAATCT
`13D5
`GAAATGGCTATTCTCCCAATTCAATCAGCAGGAAGACCCTGTCAC
`1350
`ATGTCAGTGSGTGTTTGCTCCTTCAGGGAACATAGAGAGGTGATT
`1395
`CATTGCCCACATGTTGAAGGGACTCATCTCCCTGGTTTGTCACAT
`1440
`TGAACTCTTCCCTCAGCGA/. AGCATTTGCATTGCTTCCC
`1479
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 33 of 212
`PageID #: 32781
`
`U. S. Patent
`jui. 6, 2004
`Sheet 31 of 119
`US 6, 759, 215 Bl
`FIG. 15B CONT.'
`Interveiiing sequence of unJcnown length
`GAATTCCAAGATCACAGGTGGAA(SCTGAAATTCAGATCATGT;TC
`45
`CAAAACTCAGTAGGTTATACCTAGCCAG^CATAACTGAATTTGSA
`9 0
`GTCTAAAAGATCTGTATrATCACTTTTTTAmTGAAGGATGCCT
`135
`TTTGATTACA-GAGGGAAATCAAGGATTAAAAATCAATATACATGT
`180
`AAATATTGAAATTCATTGSTAACTTTAAAAAGCACAACASTTTTG
`'225
`TGS'CCTTTTCTCCAAAGCACTACAAATATSATTAATTGATGTATA
`270
`19
`ValAlaA
`AGAATTTTCTTATGSAATTTTTTTTTTTGTCTCTGTAGGTGGCAA
`315
`30
`snLcuProLysAspTyrMctIleThrLeuLysTyrValProGlyM
`ATCTTCCAAAAGACTACATGATAACCCTCAAATATGTCCCCGGGA
`360
`39
`etAspValLeu
`TGGATGTTTTGGTATGTAAAC-ACATTTCTGAGTTTCAT7TTAGT
`405
`AGCTCATAGAAGAAATGGGATCATTCATATTGAGATAGTAC^CTA
`450
`GCTGCTATTTAGGAGCTTGCT-AT7GTCAGGATTTGAAGAATTTA
`495
`TCTTTGGAATTTGACTTGCAGGCr'r'rTTTTTCCCCCTCTT 535
`Intervening sequence of unk-nown leng'c.h
`CCTGTTACAAGAGTCCCTCCTCCTATTAGAATAGTCCCTCC7CCT .
`45
`CCTGTCACACTAGTCCCTTCTCTTCCTGTTACAATAACCCCTGTC
`90
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 34 of 212
`PageID #: 32782
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 32 of 119
`US 6, 759, 215 Bl
`FIG. 15B CONT.'
`CTCCTATTACAAC?lTTTTAA. STAA. TGTAATA'?TAATTTTAAA?AT
`CTGGCCAC3CACGGTGGTTCAT5CTTGTAATCCCAGCACATTGG3
`AAGCTGAGACGGGTSGATCA.
`r7TGAGGTCAGGAAGTTT5AGA. CAG
`CC7GGCCAACATG5TGAAACTTCCTCTCTACTAAAAA. TAAAAAAG
`TAGCCAGGCATGGTGGCAGGCACTTGTAATCTGAGCTACTCGASA
`GGCTSAGGCAG3A. GAATCACTTSAGTAACTAAAACGATASCTTTG
`AAGASTACTCCGAGTTTTATGGCACTTACTTATTAAAATAGCTGT
`40
`ProSerHisCysTrpIleS
`TTTGTCTCTTTTTTCft. TA.TCTTGCAGCCAAGTCATTGTTGSA.TAA.
`50 0
`erGluM«tVailValGlnLeuS<rAspS<^-LeuThrAspLeixLeuA
`GCGAGATGGTAGTACAATTSTCAGACAGCTTGACTGATCTTCTGG
`70
`spLysPheSerAsnIleSerGluGlyLeuSezAan. TyrSerIleI
`ACAA5TTTTCAAATATTTCTGAA. GGCTTGAGTAATTATTCCATCA
`80
`90
`l&AspLysLeuValAsnlleValAspAspLeuValGluCysValL
`TAGACAAACTTGTGAATATAGTGSATGACCTTGTGGAGTGCGTGA
`9
`ysGluAsnSerSerLys
`AAGAAAACTCATCTAAGGTAACTTTGTGTTCATTGGGATTATTTT
`TCATTACGCTTCTC7AAAAACCCATGCTTCTTGGTGCTGTTGGGG
`AAAATGAGGCACCTTTATTTATGATATTTTGATTGTATAAACTTC
`AAATTTAAAAATCTTGTTCAGATGAGCAAAGAAAACAAGTA. TTTG
`CAGTTATACTGCAATACTGAAGTGCACn-TTC 796
`135
`180
`225
`2-70
`315
`36'0
`405
`450
`495
`540
`585
`630
`675
`720
`765
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 35 of 212
`PageID #: 32783
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 33 of 119
`US 6, 759, 215 Bl
`FIG. 15B CONT."
`Intervening s«<?uence of unknown length
`TTGTGTTCACTGCCCCAGATTCAAC.
`ITGTGATCCCACTGGGA7CA
`4 5
`CTACCCTSCATIACCAATCTGAATTACA.TACGTTAAAACAGCCAT
`9 0
`CTAAAAGTGCTAGTTSTAAGAGTCTAAATACTTGAATCTTTGAGA
`135
`GACATATTTATAGTCCATTATCTTCACCTCAGTTAAGTCTGAAGA
`180
`97
`J^spLeuLysL
`CTATTTGAAAAATGTAATCCTATTTTTTCTTCTAGGATCTAAAAA
`225
`110
`ysSerPheLysSerProGluProArgLeuPheThrProGluGluP
`AATCA.TTCAAGAGCCCAGAACCCAGGCTCTTTACTCCTGAAGAAT
`270
`120
`130
`hcPbeArgIlePheAsnA^crSerZl&AspAla?heLysAspPheV
`TCTTTAGAATTTTTAATAGATCCA7TGATGCCTTCAAGGACTTTG
`315
`140
`alValAlaSerGluThrSerAspCysValValSerSerThrLeuS
`TAGTGGCA. TCTGAAACTAGTGATTGTSTGGTTTCTTCStft. CATTAA
`360
`148
`erProGluLysA
`GTCCTGAGAAAGGTAAGACATGT^AGCATTTCCAGTTCAAATGTA
`405
`AACAACAAACTTAAATCTTCCCT^TGTAGTAAGAATCTACCTCTG
`450
`TGTTAAGCTGTAGCAAGATACATGCATGTACGTCTAATAAAAAAG
`4 95
`CAGATATCAATAGCACAGAAGA?A
`519
`Intervening sequence of unknown length
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 36 of 212
`PageID #: 32784
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 34 of 119
`US 6, 759, 215 Bl
`FIG. 15B CONT.'
`CTCTATAACTCATACAAATCACCATATAACACTGACACATTATTG
`4 5
`150 .
`160
`spScrArgVa. lSerVa. lThsLysProPheMetL
`CTTTCTATTTAGATTCCAGAGTCAGTGTCACAAAACCATTTATGT
`9 0
`170
`euP ro? roVa.UU. aAl &S e r S erLexiArgAs nAsp Ser S erSer S
`TACCCCCT5TTGCA. GCCAGCTCCCTTAGGAATGACAGCAGTAGCA
`135
`176
`erAsnA
`GTAATAGTAAGTACA.TATATCTGATTTAATGCATGCATGGCTCCA
`180
`ATTAGCACCTATA. GGAGTATTGCATGGGCTTTCAA. GGAAACTTCT
`225
`ACATTTATTATTATTGATACTGTTCTGTTACTGTTATTCCTTTTA
`270
`TGGTCTTCTTGAGACTTAAGTTTGTAGAATTAAATTTCCCTAGAG
`315
`CTGGAGATAATGTrTAGAGAATTAGGCCAATAAATTT
`352
`

`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 37 of 212
`PageID #: 32785
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 35 of 119
`US 6, 759, 215 Bl
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`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 38 of 212
`PageID #: 32786
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 36 of 119
`US 6, 759, 215 Bl
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`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 39 of 212
`PageID #: 32787
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 37 of 119
`US 6, 759, 215 Bl
`RG. 15D
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`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 40 of 212
`PageID #: 32788
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 38 of 119
`US 6, 759, 215 Bl
`FIG. 15DCONT.
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`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 41 of 212
`PageID #: 32789
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 39 of 119
`US 6, 759, 215 Bl
`FIG. 15DCONT.
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`

`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 42 of 212
`PageID #: 32790
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 40 of 119
`US 6, 759, 215 Bl
`FIG. 15DCONT.
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 43 of 212
`PageID #: 32791
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`U. S. Patent
`Jul. 6, 2004
`Sheet 41 of 119
`US 6, 759, 215 Bl
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`Case 1:18-cv-00924-CFC-SRF Document 450-1 Filed 10/25/19 Page 44 of 212
`PageID #: 32792
`
`U. S. Patent
`Jul. 6, 2004
`Sheet 42 of 119
`US 6, 759, 215 Bl
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