111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20060134189Al
`
`(19) United States
`(12) Patent Application Publication
`MacLachlan et al.
`
`(10) Pub. No.: US 2006/0134189 A1
`Jun. 22, 2006
`(43) Pub. Date:
`
`(54) SIRNA SILENCING OF APOLIPOPROTEIN B
`
`Related U.S. Application Data
`
`(75)
`
`Inventors: Ian MacLachlan, Vancouver (CA);
`Lloyd B. Jeffs, Delta (CA); Adam
`Judge, Vancouver (CA); Amy C.H.
`Lee, Surrey (CA); Lorne R. Palmer,
`Vancouver (CA); Vandana Sood,
`Vancouver (CA)
`
`Correspondence Address:
`TOWNSEND AND TOWNSEND AND CREW,
`LLP
`TWO EMBARCADERO CENTER
`EIGHTH FLOOR
`SAN FRANCISCO, CA 94111-3834 (US)
`
`(73) Assignee: Protiva Biotherapeutics, Inc, Burnaby
`(CA)
`
`(21) Appl. No.:
`
`111283,550
`
`(22) Filed:
`
`Nov. 17, 2005
`
`(60) Provisional application No. 60/703,226, filed on Jul.
`27, 2005. Provisional application No. 60/629,808,
`filed on Nov. 17, 2004.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61K 48100
`(2006.01)
`A61K 91127
`(2006.01)
`C12N 15188
`(2006.01)
`C07H 21102
`(2006.01)
`(52) U.S. Cl ............................. 424/450; 435/458; 514/44;
`536/23.1
`
`(57)
`
`ABSTRACT
`
`The present invention provides nucleic acid-lipid particles
`comprising siRNA molecules that silence ApoB expression
`and methods of using such nucleic acid-lipid particles to
`silence ApoB expression.
`
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`~
`
`""d a ("!> = -> :a -.....
`== =-· Q = ""d = e::
`== --· Q =
`
`.....
`
`~
`
`~
`?
`N
`N
`
`N
`0
`0
`Q\
`
`00 =(cid:173)
`("!> a
`
`N
`
`Q -N w
`
`Q\
`
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`Patent Application Publication Jun. 22, 2006 Sheet 5 of 236
`
`US 2006/0134189 Al
`
`114%
`
`120%
`
`100%
`
`100%
`
`80%
`
`g
`c:
`8
`en 60%
`co a.
`!(.!
`
`40%
`
`20%
`
`0%
`
`63%
`
`Figure 5
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`e .. 100%
`c
`0
`0
`.!
`u :c
`Gl >
`11:1 a.
`'0
`fl.
`
`Cl)
`
`80%
`
`60%
`
`Patent Application Publication Jun. 22, 2006 Sheet 6 of 236
`
`US 2006/0134189 Al
`
`160%
`
`140%
`
`120%
`
`+mismatch SNALP
`+empty partides
`~apob-1 SNALP
`
`40%
`
`20%
`
`• • +
`
`-2
`
`0
`
`2
`
`4
`
`6
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`10
`
`8
`Study Day
`Figure 6
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`Patent Application Publication Jun. 22, 2006 Sheet 7 of 236
`
`US 2006/0134189 Al
`
`100%
`
`100%
`
`80%
`
`g 60%
`c::
`8
`co a.
`(/) >
`
`(/)
`
`40%
`
`20%
`
`0%
`
`1%
`
`56%
`
`22%
`
`15%
`
`PBS vehicle
`
`2:30:20
`+10%DODAC apob-1
`
`5:30:20 apob-1
`
`2:30:20 DODMA
`apob-1
`
`2:30:10 apob-1
`
`Figure 7
`
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`Patent Application Publication Jun. 22, 2006 Sheet 8 of 236
`
`US 2006/0134189 Al
`
`100%
`
`100%
`
`100%
`
`92%
`
`80%
`
`g 60%
`c
`0
`t)
`CJ)
`Ill
`ll.
`~ 40%
`
`20%
`
`0%
`
`21%
`
`29%
`
`PBS vehicle
`
`apob-1 2:30:20
`DODMA
`
`mismatch 2:30:20
`DODMA
`Figure 8
`
`apob-1 2:30:20
`Ole nOMA
`
`mismatch 2:30:20
`Ole nOMA
`
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`Patent Application Publication Jun. 22, 2006 Sheet 9 of 236
`
`US 2006/0134189 Al
`
`100%
`
`100%
`
`80%
`
`~ 60%
`8
`(/)
`m
`Q.
`(I) >
`
`40%
`
`20%
`
`0%
`
`65%
`
`13%
`
`PBS Vehicle
`
`2:30:20 DOPE
`apob-1
`
`2:30:20 DSPE
`apob-1
`
`2:30:20 DPPE
`apob-1
`Figure 9
`
`2:30:20 DOPE
`mismatch
`
`2:30:20 DSPE
`mismatch
`
`2:30:20 DPPE
`mismatch
`
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`Patent Application Publication Jun. 22, 2006 Sheet 10 of 236 US 2006/0134189 A1
`
`105%
`
`120%
`
`100%
`
`100%
`
`80%
`
`E c::
`8 60%
`Cl)
`ttl
`a.
`~
`
`40%
`
`20%
`
`16%
`
`87%
`
`72%
`
`51%
`
`0%
`
`PBS
`vehide
`
`apob-1
`SNALP
`Day1
`
`apob-1
`SNALP
`Day3
`
`apob-1
`SNALP
`Day7
`
`apob-1 mismatch mismatch mismatch mismatch
`SNALP
`SNALP
`SNALP
`SNALP
`SNALP
`Day10
`Day1
`Day3
`Day7
`Day10
`
`Figure 10
`
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`Patent Application Publication Jun. 22, 2006 Sheet 11 of 236 US 2006/0134189 Al
`
`120%
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`2 c 0 u
`
`en
`CXl
`ll.
`~
`
`......-apob-1 SNALP
`
`-<>-mismatCh SNALP
`
`0%+------.------~----~------~-----r------r------.----~
`24
`60
`36
`96
`48
`108
`12
`72
`84
`Hours After SNALP Administration
`Figure 11
`
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`Patent Application Publication Jun. 22, 2006 Sheet 12 of 236 US 2006/0134189 A1
`
`180
`
`160
`
`140
`
`120
`
`100
`
`60
`
`40
`
`20
`
`........
`~
`Ol g
`e
`.l!!
`Ul
`.9:! _g
`
`(.)
`Cll
`E
`Ul
`Cll
`0::
`
`... --··-··-"···-·--·"~~:;::;::.:+'\",
`J
`\ ',
`I
`\
`\
`\
`
`.... High Fat Diet+ mismatch SNALP
`
`--<:>- Normal Diet + mismatch SNALP
`
`-<'>-Normal Diet+ apob-1 SNALP
`
`.... High Fat Diet+ apob-1 SNALP
`
`'
`'a. ......... -~ .. /--0
`
`0
`
`5
`
`10
`
`15
`
`20
`Study Day
`Figure 12
`
`25
`
`30
`
`35
`
`40
`
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`Patent Application Publication Jun. 22, 2006 Sheet 13 of 236 US 2006/0134189 Al
`
`100%
`
`100%
`
`99%
`
`(,)
`
`~ 0
`CIJ en a.
`
`g!.
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`14%
`
`PBS Vehicle
`
`2:40:10 apob-1
`Figure 13
`
`2:40:10 mismatch
`
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`Patent Application Publication Jun. 22, 2006 Sheet 14 of 236 US 2006/0134189 A1
`
`160%
`
`120%
`
`e
`1:
`0
`~ 80%
`CJl a.
`~
`
`40%
`
`0%
`
`1!1 PBS
`Dapob-1 SNALP
`1§1 mismatch SNALP
`
`150%
`
`livermRNA
`
`plasma protein
`
`Figure 14
`
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`Patent Application Publication Jun. 22, 2006 Sheet 15 of 236 US 2006/0134189 A1
`
`128%
`
`115%
`
`100%
`
`66%
`
`51%
`
`120%
`
`·100%
`
`g 80%
`c:
`8
`~ 60%
`a.
`~
`
`40%
`
`20%
`
`0%
`
`PBS
`
`1 mg/kg apob-1 3 mg/kg apob-1 10 mg/kg apob-1
`SNALP
`SNALP
`SNALP
`
`3 mg/kg
`mismatch
`SNALP
`
`Figure 15
`
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`Patent Application Publication Jun. 22, 2006 Sheet 16 of 236 US 2006/0134189 A1
`
`160%
`
`140%
`
`120%
`
`~100%
`8 80%
`~ .. > 60%
`
`40%
`
`20%
`
`0%
`
`104%
`
`82%
`
`56%
`
`PBS
`VehiCle
`
`apob-1
`
`apol)-1 no- apob-1 u-
`P
`mod-sense
`
`Protlva
`apob-1
`
`· apob-1·
`Protlva
`apot>-1 no- mismatch
`p
`
`apoB-1514 apoB-2690 apol>-10851 apob-12192 apot>-13397
`
`Figure 16
`
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`Patent Application Publication Jun. 22, 2006 Sheet 17 of 236 US 2006/0134189 A1
`
`160%
`
`140%
`
`120%
`
`Ol
`
`Q. e 100%
`(/) co 80%
`Q.
`0
`'if!.
`
`60%
`
`100%
`
`151%
`
`136%
`
`125%
`
`105%
`
`65%
`
`40%
`
`20%
`
`0%
`
`PBS
`
`apob-1
`
`apob-1 no apob-1 u-
`phosphate mod-sense
`
`ProUva
`apob-1
`
`Prollva
`apob-1·
`apob-1 no miSmatch
`phosphate
`
`apoB-1514 apoB-2690
`
`apoB-
`10851
`
`apoB-
`12192
`
`apoB-
`13397
`
`Figure 17
`
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`Patent Application Publication Jun. 22, 2006 Sheet 18 of 236 US 2006/0134189 A1
`
`5,000
`
`4,000
`
`1,000
`
`Predlcteef lmmunostlmulatory activity by sequence motifs:
`
`1514=High
`2690=Low
`10851=Medium
`12192=Medium
`13397=High
`
`Pes
`
`apob-1
`
`apob-1 no
`phospl1ale
`
`apobo1U-<nod- Protllla apob-1 Protllla apob-1
`no phcspllalt
`.. ,..
`
`apob-1-
`ml.smlk:h
`
`apoB-1514
`
`apoB-2\lllO
`
`apoB-10851
`
`apoB-12192
`
`apoB-13397
`
`Figure 18
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`Patent Application Publication Jun. 22, 2006 Sheet 19 of 236
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`US 2006/0134189 A1
`
`180%
`
`180%
`
`D100nM20:1 I'QII11all:llld
`D100nM70:11'Q1111lllll80
`
`151%
`
`Figure 19
`
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`Patent Application Publication Jun. 22, 2006 Sheet 20 of 236 US 2006/0134189 Al
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`Figure 20
`Table 5
`
`SiRNA target sequence
`TGCGACCCGATTCAAGCACCTCC
`TGCCACCAGGATCAACTGCAAGG
`ACCTACTTACATCCTGAACATCA
`CTCCACTCACTTTACCGTCAAGA
`CATCAGCCCACTTGCTCTCATCA
`GAAGATGGGCCTCGCATTTGAGA
`GGGGATGAAGATTACACCTATTT
`CTCTACAAATCTGTTTCTCTTCC
`AATAACTACCTTCCTAAAGAAAG
`CTGGATTACAGTTGCAAATATCT
`GGGCATCATCATTCCGGACTTCG
`CTGGAGGCTCATGTTGCCCTAAA
`AGGCAACACATTACATTTGGTCT
`GGCCACCTAAGTTGTGACACAAA
`ATCAAGGGTGTTATTTCCATACC
`TGCCAAACTGCTTCTCCAAATGG
`AGGCACCAATGTAGATACCAAAA
`CTCCAGAGATCTAAAGATGTTAG
`CTCCACGAATGTCTACAGCAACT
`GTTGACCTGCTTTCCTACAATGT
`TATCAGGCTGATTACGAGTCATT
`AGACAGGCACCTGGAAACTCAAG
`CAAGACCCAATTTAACAACAATG
`CCTGAAGCACATCAATATTGATC
`AAGCACATCAATATTGATCAATT
`GATGAGCACTATCATATCCGTGT
`CAGCACCTAGCTGGAAAGTTAAA
`GCTAAGCAATGTCCTACAACAAG
`AAGCAATGTCCTACAACAAGTTA
`TAGCACACTTGTCACCTACATTT
`GAGCAATATTCTATCCAAGATTG
`TACAATTGACTTTGTCGAAATGA
`GAGAATCACCCTGCCAGACTTCC
`CCAGACTTCCGTTTACCAGAAAT
`ATGCACAACTCTCAAACCCTAAG
`GCGCAACGAGATCAAGACACTGT
`GAAGATAGACTTCCTGAATAACT
`CTGAATAACTATGCACTGTTTCT
`AOCAAGCAAGTTGGCAAGTAAGT
`CACCATAGAGATGTCGGCATTCG
`AACCAGTCAGATATTGTTGCTCA
`GTGGAGGGTAGTCATAACAGTAC
`GACCACAAGCTTAGCTTGGAAAG
`ATTGAGTCATCTACCAAAGGAGA
`GCTAACCTCTCTGAAAGACAACG
`GTCCATAATGGTT.CAGAAATACT
`GTATAGGGAACTGTTGAAAGATT
`CTCAAGTCAAGTTGAGCAATTTC
`CAGGAATATCTTAGCATCCTTAC
`CACCAGCAGTTTAGATATAAACT
`
`Position
`254
`344
`575
`686
`791
`1040
`1566
`2043
`2118
`2653
`2789
`2859
`2942
`3450
`3486
`3557
`3668
`4046
`4202
`4317
`4932
`6058
`6077
`6422
`6426
`6765
`6963
`7256
`7259
`7757 .
`7824
`8111
`8240
`8253
`8560
`8846
`9326
`9339
`9376
`9917
`10200
`10344
`10560
`10602
`12326
`12831
`12932
`13436
`13.473
`13602
`
`Imrnunostimulatory activity
`Low
`Med
`Low
`Low
`Med
`Med
`Med
`Med
`Med
`High
`Low
`Med
`High
`High
`Med
`med
`high
`low
`Med
`Med
`Low
`Med
`High
`High
`Low
`Med
`Low
`High
`High
`High
`Low
`Med
`Low
`Med
`High
`High
`Low
`Med
`Med
`High
`High
`Med
`High
`Med
`Med
`Med
`Med
`Med
`Low
`High
`
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`Patent Application Publication Jun. 22, 2006 Sheet 21 of 236 US 2006/0134189 A1
`
`Figure 21
`Table 6
`
`SiRNA target sequence
`GCGGACGCCGTTACTGCTGCTGT
`CCGAAAGTACGTGTACAACTATG
`ACCAACCAGTGTACCCTTAAAGA
`CATGACACGTGTTACACAGAAAC
`TTTGAAGACCCTTCAAGAACTGA
`AGCCACAGTGCTATACTCACATC
`TGTCACCTACCTGATGGCTCTGA
`AGCCACGCAGTTAACAGCTATTT
`GGGAAGAACCATGGAACAAGTAA
`GAAGAACTGTATGTCCAAGATCT
`CTGGAGAATTCTCAATTTCCAAC
`AAGCAGTTATCTTCCCAGAGAAA
`TTTGAGATTGGTTTAGAAGGAAA
`GTGGACCACTTTGGCTATACTAC
`GTGCACAAACTTTGCAGGGAATC
`GGGCATCATCATCCCAGACTTCG
`AAAGAGGCCAGTCAAGCTGTTCA
`CAGCAACACACTGCATCTGGTCT
`CAGGAGCTTACTCCAACGCCAGC
`GTGGAGCAGTATTCTGCCACTGC
`GTGCAGCAGTCTGAAGCTACTGT
`GATCACCTCAATAGCCTCTCAGA
`TTCCACAAATGTCTACAGCAATT
`TGTGAGAGAGATGTTACAACTGG
`AAGAACACAGCTTCCTTGAAATA
`TCTCACTGGACTTCTTCTCAAAA
`AGCTACAGCCCTATTCTTTCATA
`CTACAGCCCTATTCTTTCATAAC
`GGGCAGCTATATAGTAAGTTTCT
`CAAGACCAAACTGAATGACAAAG
`GCCTACAACACTAAAGACAAAAT
`TTAGAGGTAAATGATGCTGTTGA
`CACCATCAACCTCCCATTCTTCA
`TTGGAGAGAAATCGAAGAGGAAT
`CCTCAGCAGATTCATCATTATCT
`GAACAGTATCATATCCGTGTAAA
`ATTGACTGACATGTTGOTGAAGA
`TGACATGTTGGTGAAGAAGTTGA
`ATGAAAGACCATTTCCAAGATAC
`GCAGAGCAATATTCCATCCAAAA
`TTTGAGGTCAGTCTCCGTGCTCT
`ATTCACTCTTCTCAACACCTTCC
`TACAATTGACTTGCTGGAAATAA
`CATTAGAACTATCGACCAAATTT
`TGGTATGACTGTCAAAGTAAACA
`GCATACATTCGTCCCAAATTAGC
`GAGTACCAGATTCAATCAGTACA
`AAGAAACAGGCTTGAAAGAATTT
`CACCATTAGTTTAACCAAGAAAA
`GCCAACCTCCATGCTCCCATATT
`
`Position
`24
`174
`307
`861
`1002
`1187
`1257
`1363
`1512
`1837
`1882
`2016
`2089
`2230
`2432
`;2688
`2814
`2841
`2960
`3058
`3151
`3784
`4101
`4540
`4693
`5312
`5387
`5389
`5803
`5979
`6022
`6142
`6225
`6265
`6379
`6664
`7278
`7284
`7531
`7702
`7807
`7956
`7992
`8025
`8622
`8828
`9276
`9470
`10248
`10297
`
`Inununostimulatory activity
`Med
`High
`High
`High
`Med
`Med
`Low
`Low
`High
`Med
`Med
`Med
`High
`Med
`'Med
`Low
`Med
`High
`Med
`Low
`Med
`Low
`Med
`High
`High
`Low
`Low
`Low
`Med
`High
`High
`High .
`High
`Low
`Low
`Med
`High
`High
`Med
`Med
`Med
`High
`Med
`Med
`High
`Med
`Med
`Med
`High
`Med
`
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`Patent Application Publication Jun. 22, 2006 Sheet 22 of 236
`
`US 2006/0134189 Al
`
`Figure 22
`Table 7
`A B 'RNA
`sequences
`~po Sl
`Position
`Sequence
`1-23
`ATTCCCACCGGGACCTGCGGGGC
`2-24
`TTCCCACCGGGACCTGCGGGGCT
`3-25
`TCCCACCGGGACCTGCGGGGCTG
`4-26
`CCCACCGGGACCTGCGGGGCTGA
`5-27
`CCACCGGGACCTGCGGGGCTGAG
`6-28
`CACCGGGACCTGCGGGGCTGAGT
`7-29
`ACCGGGACCTGCGGGGCTGAGTG
`8-30
`CCGGGACCTGCGGGGCTGAGTGC
`9-31
`CGGGACCTGCGGGGCTGAGTGCC
`10-32
`GGGACCTGCGGGGCTGAGTGCCC
`11-33
`GGACCTGCGGGGCTGAGTGCCCT
`12-34
`GACCTGCGGGGCTGAGTGCCCTT
`13-35
`ACCTGCGGGGCTGAGTGCCCTTC
`14-36
`CCTGCGGGGCTGAGTGCCCTTCT
`15-37
`CTGCGGGGCTGAGTGCCCTTCTC
`16-38
`TGCGGGGCTGAGTGCCCTTCTCG
`17-39
`GCGGGGCTGAGTGCCCTTCTCGG
`18-40
`CGGGGCTGAGTGCCCTTCTCGGT
`19-41
`GGGGCTGAGTGCCCTTCTCGGTT
`20-42
`GGGCTGAGTGCCCTTCTCGGTTG
`21-43
`GGCTGAGTGCCCTTCTCGGTTGC
`22-44
`GCTGAGTGCCCTTCTCGGTTGCT
`23-45
`CTGAGTGCCCTTCTCGGTTGCTG
`24-46
`TGAGTGCCCTTCTCGGTTGCTGC
`25-47
`GAGTGCCCTTCTCGGTTGCTGCC
`26-48
`AGTGCCCTTCTCGGTTGCTGCCG
`27-49
`GTGCCCTTCTCGGTTGCTGCCGC
`28-50
`TGCCCTTCTCGGTTGCTGCCGCT
`29-51
`GCCCTTCTCGGTTGCTGCCGCTG
`30-52
`CCCTTCTCGGTTGCTGCCGCTGA
`31-53
`CCTTCTCGGTTGCTGCCGCTGAG
`32-54
`CTTCTCGGTTGCTGCCGCTGAGG
`33-55
`TTCTCGGTTGCTGCCGCTGAGGA
`34-56
`TCTCGGTTGCTGCCGCTGAGGAG
`35-57
`CTCGGTTGCTGCCGCTGAGGAGC
`36-58
`TCGGTTGCTGCCGCTGAGGAGCC
`37-59
`CGGTTGCTGCCGCTGAGGAGCCC
`38-60
`GGTTGCTGCCGCTGAGGAGCCCG
`39-61
`GTTGCTGCCGCTGAGGAGCCCGC
`40-62
`TTGCTGCCGCTGAGGAGCCCGCC
`41-63
`TGCTGCCGCTGAGGAGCCCGCCC
`42-64
`GCTGCCGCTGAGGAGCCCGCCCA
`43-65
`CTGCCGCTGAGGAGCCCGCCCAG
`44-66
`TGCCGCTGAGGAGCCCGCCCAGC
`45-67
`GCCGCTGAGGAGCCCGCCCAGCC
`46-68
`CCGCTGAGGAGCCCGCCCAGCCA
`47-69
`CGCTGAGGAGCCCGCCCAGCCAG
`48-70
`GCTGAGGAGCCCGCCCAGCCAGC
`49-71
`CTGAGGAGCCCGCCCAGCCAGCC
`50-72
`TGAGGAGCCCGCCCAGCCAGCCA
`51-73
`GAGGAGCCCGCCCAGCCAGCCAG
`52-74
`AGGAGCCCGCCCAGCCAGCCAGG
`53-75
`GGAGCCCGCCCAGCCAGCCAGGG
`54-76
`GAGCCCGCCCAGCCAGCCAGGGC
`55-77
`AGCCCGCCCAGCCAGCCAGGGCC
`56-78
`GCCCGCCCAGCCAGCCAGGGCCG
`57-79
`CCCGCCCAGCCAGCCAGGGCCGC
`CCGCCCAGCCAGCCAGGGCCGCG
`58-80
`59-81
`CGCCCAGCCAGCCAGGGCCGCGA
`60-82
`GCCCAGCCAGCCAGGGCCGCGAG
`61-83
`CCCAGCCAGCCAGGGCCGCGAGG
`62-84
`CCAGCCAGCCAGGGCCGCGAGGC
`
`Moderna Ex 1003-p. 23
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 23 of 236 US 2006/0134189 Al
`
`10333
`10380
`10417
`10528
`10800
`10849
`11353
`11439
`11451
`11452
`11767
`11788
`11868
`12190
`12243
`12363
`12715
`12925
`.13192
`13200
`13357
`13395
`13440
`13.449
`13595
`13671
`
`AAGCAGGAACTTAATGGAAATAC Med
`ATCCATTGAACTAAACTATGACT Med
`CTGCACTCTACTGCAACAGGAGG Med
`TCTCAGGAATATTCAGGAAGTGT Med
`GTCAACCTTGCTACAGGTTCATG Med
`CTCCATCACTTTGACCAGGAAGT Med
`TTTGAGGCAACTATACCTGAAAT Med
`TCTGAATAAGTTGGCCAACATGA High
`GGCCAACATGATTGCCGATGTTG Hifib
`GCCAACATGATTGCCGATGTTGA High
`CTTCAACACTGTGACTTCAATGT
`High
`GTGGAGTATAATGAAGATGGTCT Med
`ACTGACTGACTTTCATCTGTACT
`Low
`CTGGAATACGTTTCTTCAGAACT Med
`TGCCAGAAGGATGGTTGATGAAA High
`GAAGAGGGTGTTAGACAGTATAG Med
`GGCCAACAGGATATCAAGTTTAC Med
`AATGACTTTCTTCAATCCATACT Med
`AGAGAGTATCTTAGCATGCTTAC
`Low
`TCTTAGCATGCTTACTGATATAA
`Low
`GACCAACTCTCTAGCTACTATGA Med
`GTCCACAAGATTGATTGACCTGT High
`TCTCAGATACATCACCGAGTTAC Med
`CATCACCGAGTTACTGAGAAAGC
`Low
`GTAGACTACTATAAAGACCATCC Med
`TGCAACCAAGCTGGCATAAGAAC High
`
`Moderna Ex 1003-p. 24
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 24 of 236 US 2006/0134189 Al
`
`13638
`13935
`
`GACCAACTCTCTGATTACTATGA
`AGGCAGTAGACTATAAGCAGAAG
`
`Med
`Low
`
`Moderna Ex 1003-p. 25
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 25 of 236 US 2006/0134189 Al
`
`Position
`63-85
`64-86
`65-87
`66-88
`67-89
`68-90
`69-91
`70-92
`71-93
`72-94
`73-95
`74-96
`75-97
`76-98
`77-99
`78-100
`79-101
`80-102
`81-103
`82-104
`83-105
`84-106
`85-107
`86-108
`87-109
`88-110
`89-111
`90-112
`91-113
`92-114
`93-115
`94-116
`95-117
`96-118
`- 97-119
`98-120
`99-121
`100-122
`101-123
`102-124
`103-125
`104-126
`105-127
`129-151
`141-163
`142-164
`143-165
`144-166
`145-167
`146-168
`147-169
`148-170
`149-171
`150-172
`151-173
`152-174
`153-175
`154-176
`155-177
`156-178
`157-179
`158-180
`159-181
`160-182
`161-183
`162-184
`
`Sequence
`CAGCCAGCCAGGGCCGCGAGGCC
`AGCCAGCCAGGGCCGCGAGGCCG
`GCCAGCCAGGGCCGCGAGGCCGA
`CCAGCCAGGGCCGCGAGGCCGAG
`CAGCCAGGGCCGCGAGGCCGAGG
`AGCCAGGGCCGCGAGGCCGAGGC
`GCCAGGGCCGCGAGGCCGAGGCC
`CCAGGGCCGCGAGGCCGAGGCCA
`CAGGGCCGCGAGGCCGAGGCCAG
`AGGGCCGCGAGGCCGAGGCCAGG
`GGGCCGCGAGGCCGAGGCCAGGC
`GGCCGCGAGGCCGAGGCCAGGCC
`GCCGCGAGGCCGAGGCCAGGCCG
`CCGCGAGGCCGAGGCCAGGCCGC
`CGCGAGGCCGAGGCCAGGCCGCA
`GCGAGGCCGAGGCCAGGCCGCAG
`CGAGGCCGAGGCCAGGCCGCAGC
`GAGGCCGAGGCCAGGCCGCAGCC
`AGGCCGAGGCCAGGCCGCAGCCC
`GGCCGAGGCCAGGCCGCAGCCCA
`GCCGAGGCCAGGCCGCAGCCCAG
`CCGAGGCCAGGCCGCAGCCCAGG
`CGAGGCCAGGCCGCAGCCCAGGA
`GAGGCCAGGCCGCAGCCCAGGAG
`AGGCCAGGCCGCAGCCCAGGAGC
`GGCCAGGCCGCAGCCCAGGAGCC
`GCCAGGCCGCAGCCCAGGAGCCG
`CCAGGCCGCAGCCCAGGAGCCGC
`CAGGCCGCAGCCCAGGAGCCGCC
`AGGCCGCAGCCCAGGAGCCGCCC
`GGCCGCAGCCCAGGAGCCGCCCC
`GCCGCAGCCCAGGAGCCGCCCCA
`CCGCAGCCCAGGAGCCGCCCCAC
`CGCAGCCCAGGAGCCGCCCCACC
`GCAGCCCAGGAGCCGCCCCACCG
`·cAGCCCAGGAGCCGCCCCACCGC
`AGCCCAGGAGCCGCCCCACCGCA
`GCCCAGGAGCCGCCCCACCGCAG
`CCCAGGAGCCGCCCCACCGCAGC
`CCAGGAGCCGCCCCACCGCAGCT
`CAGGAGCCGCCCCACCGCAGCTG
`AGGAGCCGCCCCACCGCAGCTGG
`GGAGCCGCCCCACCGCAGCTGGC
`·ATGGACCCGCCGAGGCCCGCGCT
`AGGCCCGCGCTGCTGGCGCTGCT
`GGCCCGCGCTGCTGGCGCTGCTG
`GCCCGCGCTGCTGGCGCTGCTGG
`CCCGCGCTGCTGGCGCTGCTGGC
`CCGCGCTGCTGGCGCTGCTGGCG
`CGCGCTGCTGGCGCTGCTGGCGC
`GCGCTGCTGGCGCTGCTGGCGCT
`CGCTGCTGGCGCTGCTGGCGCTG
`GCTGCTGGCGCTGCTGGCGCTGC
`CTGCTGGCGCTGCTGGCGCTGCC
`TGCTGGCGCTGCTGGCGCTGCCT
`GCTGGCGCTGCTGGCGCTGCCTG
`CTGGCGCTGCTGGCGCTGCCTGC
`TGGCGCTGCTGGCGCTGCCTGCG
`GGCGCTGCTGGCGCTGCCTGCGC
`GCGCTGCTGGCGCTGCCTGCGCT
`CGCTGCTGGCGCTGCCTGCGCTG
`GCTGCTGGCGCTGCCTGCGCTGC
`CTGCTGGCGCTGCCTGCGCTGCT
`TGCTGGCGCTGCCTGCGCTGCTG
`GCTGGCGCTGCCTGCGCTGCTGC
`CTGGCGCTGCCTGCGCTGCTGCT
`
`Moderna Ex 1003-p. 26
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 26 of 236 US 2006/0134189 Al
`
`Position
`163-185
`164-186
`165-187
`166-188
`167-189
`168-190
`169-191
`170-192
`171-193
`172-194
`173-195
`174-196
`175-197
`176-198
`177-199
`178-200
`179-201
`180-202
`181-203
`194-216
`195-217
`196-218
`197-219
`198-220
`199-221
`200-222
`201-223
`202-224
`203-225
`204-226
`205-227
`206-228
`207-229
`208-230
`209-231
`210-232
`211-233
`212-234
`213-235
`214-236
`215-237
`216-238
`217-239
`218-240
`219-241
`220-242
`221-243
`222-244
`223-245
`224-246
`225-247
`226-248
`227-249
`228-250
`229-251
`230-252
`231-253
`232-254
`233-255
`234-256
`235-257
`236-258
`237-259
`238-260
`239-261
`240-262
`
`Sequence
`TGGCGCTGCCTGCGCTGCTGCTG
`GGCGCTGCCTGCGCTGCTGCTGC
`GCGCTGCCTGCGCTGCTGCTGCT
`CGCTGCCTGCGCTGCTGCTGCTG
`GCTGCCTGCGCTGCTGCTGCTGC
`CTGCCTGCGCTGCTGCTGCTGCT
`TGCCTGCGCTGCTGCTGCTGCTG
`GCCTGCGCTGCTGCTGCTGCTGC
`CCTGCGCTGCTGCTGCTGCTGCT
`CTGCGCTGCTGCTGCTGCTGCTG
`TGCGCTGCTGCTGCTGCTGCTGG
`GCGCTGCTGCTGCTGCTGCTGGC
`CGCTGCTGCTGCTGCTGCTGGCG
`GCTGCTGCTGCTGCTGCTGGCGG
`CTGCTGCTGCTGCTGCTGGCGGG
`TGCTGCTGCTGCTGCTGGCGGGC
`GCTGCTGCTGCTGCTGGCGGGCG
`CTGCTGCTGCTGCTGGCGGGCGC
`TGCTGCTGCTGCTGGCGGGCGCC
`GGCGGGCGCCAGGGCCGAAGAGG
`GCGGGCGCCAGGGCCGAAGAGGA
`CGGGCGCCAGGGCCGAAGAGGAA
`GGGCGCCAGGGCCGAAGAGGAAA
`GGCGCCAGGGCCGAAGAGGAAAT
`GCGCCAGGGCCGAAGAGGAAATG
`CGCCAGGGCCGAAGAGGAAATGC
`GCCAGGGCCGAAGAGGAAATGCT
`CCAGGGCCGAAGAGGAAATGCTG
`CAGGGCCGAAGAGGAAATGCTGG
`AGGGCCGAAGAGGAAATGCTGGA
`GGGCCGAAGAGGAAATGCTGGAA
`GGCCGAAGAGGAAATGCTGGAAA
`GCCGAAGAGGAAATGCTGGAAAA
`CCGAAGAGGAAATGCTGGAAAAT
`CGAAGAGGAAATGCTGGAAAATG
`GAAGAGGAAATGCTGGAAAATGT
`AAGAGGAAATGCTGGAAAATGTC
`AGAGGAAATGCTGGAAAATGTCA
`GAGGAAATGCTGGAAAATGTCAG
`AGGAAATGCTGGAAAATGTCAGC
`GGAAATGCTGGAAAATGTCAGCC
`GAAATGCTGGAAAATGTCAGCCT
`AAATGCTGGAAAATGTCAGCCTG
`AATGCTGGAAAATGTCAGCCTGG
`ATGCTGGAAAATGTCAGCCTGGT
`TGCTGGAAAATGTCAGCCTGGTC
`GCTGGAAAATGTCAGCCTGGTCT
`CTGGAAAATGTCAGCCTGGTCTG
`TGGAAAATGTCAGCCTGGTCTGT
`GGAAAATGTCAGCCTGGTCTGTC
`GAAAATGTCAGCCTGGTCTGTCC
`AAAATGTCAGCCTGGTCTGTCCA
`AAATGTCAGCCTGGTCTGTCCAA
`AATGTCAGCCTGGTCTGTCC~
`ATGTCAGCCTGGTCTGTCCAAAA
`TGTCAGCCTGGTCTGTCCAAAAG
`GTCAGCCTGGTCTGTCCAAAAGA
`TCAGCCTGGTCTGTCCAAAAGAT
`CAGCCTGGTCTGTCCAAAAGATG
`AGCCTGGTCTGTCCAAAAGATGC
`GCCTGGTCTGTCCAAAAGATGCG
`CCTGGTCTGTCCAAAAGATGCGA
`CTGGTCTGTCCAAAAGATGCGAC
`TGGTCTGTCCAAAAGATGCGACC
`GGTCTGTCCAAAAGATGCGACCC
`GTCTGTCCAAAAGATGCGACCCG
`
`Moderna Ex 1003-p. 27
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 27 of 236 US 2006/0134189 Al
`
`Position
`241-263
`242-264
`243-265
`244-266
`245-267
`246-268
`247-269
`248-270
`249-271
`250-272
`251-273
`252-274
`'253-275
`254-276
`255-277
`256-278
`257-279
`258-280
`259-281
`260-282
`261-283
`262-284
`263-285
`264-286
`265-287
`266-288
`267-289
`268-290
`269-291
`270-292
`271-293
`272-294
`273-295
`274-296
`275-297
`276-298
`277-299
`278-300
`279-301
`280-302
`281-303
`282-304
`283-305
`284-306
`285-307
`286-308
`287-309
`288-310
`289-311
`290-312
`291-313
`292-314
`293-315
`294-316
`295-317
`296-318
`297-319
`298-320
`299-321
`300-322
`301-323
`302-324
`303-325
`304-326
`305-327
`306-328
`
`Sequence
`TCTGTCCAAAAGATGCGACCCGA
`CTGTCCAAAAGATGCGACCCGAT
`TGTCCAAAAGATGCGACCCGATT
`GTCCAAAAGATGCGACCCGATTC
`TCCAAAAGATGCGACCCGATTCA
`CCAAAAGATGCGACCCGATTCAA
`CAAAAGATGCGACCCGATTCAAG
`AAAAGATGCGACCCGATTCAAGC
`AAAGATGCGACCCGATTCAAGCA
`AAGATGCGACCCGATTCAAGCAC
`AGATGCGACCCGATTCAAGCACC
`GATGCGACCCGATTCAAGCACCT
`ATGCGACCCGATTCAAGCACCTC
`TGCGACCCGATTCAAGCACCTCC
`GCGACCCGATTCAAGCACCTCCG
`CGACCCGATTCAAGCACCTCCGG
`GACCCGATTCAAGCACCTCCGGA
`ACCCGATTCAAGCACCTCCGGAA
`CCCGATTCAAGCACCTCCGGAAG
`CCGATTCAAGCACCTCCGGAAGT
`CGATTCAAGCACCTCCGGAAGTA
`GATTCAAGCACCTCCGGAAGTAC
`ATTCAAGCACCTCCGGAAGTACA
`TTCAAGCACCTCCGGAAGTACAC
`TCAAGCACCTCCGGAAGTACACA
`CAAGCACCTCCGGAAGTACACAT
`AAGCACCTCCGGAAGTACACATA
`AGCACCTCCGGAAGTACACATAC
`GCACCTCCGGAAGTACACATACA
`CACCTCCGGAAGTACACATACAA
`ACCTCCGGAAGTACACATACAAC
`CCTCCGGAAGTACACATACAACT
`CTCCGGAAGTACACATACAACTA
`TCCGGAAGTACACATACAACTAT
`CCGGAAGTACACATACAACTATG
`CGGAAGTACACATACAACTATGA
`GGAAGTACACATACAACTATGAG
`GAAGTACACATACAACTATGAGG
`AAGTACACATACAACTATGAGGC
`AGTACACATACAACTATGAGGCT
`GTACACATACAACTATGAGGCTG
`TACACATACAACTATGAGGCTGA
`ACACATACAACTATGAGGCTGAG
`CACATACAACTATGAGGCTGAGA
`ACATACAACTATGAGGCTGAGAG
`CATACAACTATGAGGCTGAGAGT
`ATACAACTATGAGGCTGAGAGTT
`TACAACTATGAGGCTGAGAGTTC
`ACAACTATGAGGCTGAGAGTTCC
`CAACTATGAGGCTGAGAGTTCCA
`AACTATGAGGCTGAGAGTTCCAG
`ACTATGAGGCTGAGAGTTCCAGT
`CTATGAGGCTGAGAGTTCCAGTG
`TATGAGGCTGAGAGTTCCAGTGG
`ATGAGGCTGAGAGTTCCAGTGGA
`TGAGGCTGAGAGTTCCAGTGGAG
`GAGGCTGAGAGTTCCAGTGGAGT
`AGGCTGAGAGTTCCAGTGGAGTC
`GGCTGAGAGTTCCAGTGGAGTCC
`GCTGAGAGTTCCAGTGGAGTCCC
`CTGAGAGTTCCAGTGGAGTCCCT
`TGAGAGTTCCAGTGGAGTCCCTG
`GAGAGTTCCAGTGGAGTCCCTGG
`AGAGTTCCAGTGGAGTCCCTGGG
`GAGTTCCAGTGGAGTCCCTGGGA
`AGTTCCAGTGGAGTCCCTGGGAC
`
`Moderna Ex 1003-p. 28
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 28 of 236 US 2006/0134189 Al
`
`Position
`307-329
`308-330
`309-331
`310-332
`311-333
`312-334
`313-335
`314-336
`315-337
`316-338
`317-339
`318-340
`319-341
`320-342
`321-343
`322-344
`323-345
`324-346
`325-347
`326-348
`327-349
`328-350
`329-351
`330-352
`331-353
`332-354
`333-355
`334-356
`335-357
`336-358
`337-359
`338-360
`339-361
`340-362
`341-363
`342-364
`343-365
`344-366
`345-367
`346-368
`347-369
`348-370
`349-371
`350-372
`351-373
`352-374
`353-375
`354-376
`355-377
`356-378
`357-379
`358-380
`359-381
`360-382
`361-383
`362-384
`363-385
`364-386
`365-387
`366-388
`367-389
`368-390
`369-391
`370-392
`371-393
`372-394
`
`Sequence
`GTTCCAGTGGAGTCCCTGGGACT
`TTCCAGTGGAGTCCCTGGGACTG
`TCCAGTGGAGTCCCTGGGACTGC
`CCAGTGGAGTCCCTGGGACTGCT
`CAGTGGAGTCCCTGGGACTGCTG
`AGTGGAGTCCCTGGGACTGCTGA
`GTGGAGTCCCTGGGACTGCTGAT
`TGGAGTCCCTGGGACTGCTGATT
`GGAGTCCCTGGGACTGCTGATTC
`GAGTCCCTGGGACTGCTGATTCA
`AGTCCCTGGGACTGCTGATTCAA
`GTCCCTGGGACTGCTGATTCAAG
`TCCCTGGGACTGCTGATTCAAGA
`CCCTGGGACTGCTGATTCAAGAA
`CCTGGGACTGCTGATTCAAGAAG
`CTGGGACTGCTGATTCAAGAAGT
`TGGGACTGCTGATTCAAGAAGTG
`GGGACTGCTGATTCAAGAAGTGC
`GGACTGCTGATTCAAGAAGTGCC
`GACTGCTGATTCAAGAAGTGCCA
`ACTGCTGATTCAAGAAGTGCCAC
`CTGCTGATTCAAGAAGTGCCACC
`TGCTGATTCAAGAAGTGCCACCA
`GCTGATTCAAGAAGTGCCACCAG
`CTGATTCAAGAAGTGCCACCAGG
`TGATTCAAGAAGTGCCACCAGGA
`GATTCAAGAAGTGCCACCAGGAT
`ATTCAAGAAGTGCCACCAGGATC
`TTCAAGAAGTGCCACCAGGATCA
`TCAAGAAGTGCCACCAGGATCAA
`CAAGAAGTGCCACCAGGATCAAC
`AAGAAGTGCCACCAGGATCAACT
`AGAAGTGCCACCAGGATCAACTG
`GAAGTGCCACCAGGATCAACTGC
`AAGTGCCACCAGGATCAACTGCA
`AGTGCCACCAGGATCAACTGCAA
`GTGCCACCAGGATCAACTGCAAG
`TGCCACCAGGATCAACTGCAAGG
`GCCACCAGGATCAACTGCAAGGT
`CCACCAGGATCAACTGCAAGGTT·
`CACCAGGATCAACTGCAAGGTTG
`ACCAGGATCAACTGCAAGGTTGA
`CCAGGATCAACTGCAAGGTTGAG
`CAGGATCAACTGCAAGGTTGAGC
`AGGATCAACTGCAAGGTTGAGCT
`GGATCAACTGCAAGGTTGAGCTG
`GATCAACTGCAAGGTTGAGCTGG
`ATCAACTGCAAGGTTGAGCTGGA
`TCAACTGCAAGGTTGAGCTGGAG
`CAACTGCAAGGTTGAGCTGGAGG
`AACTGCAAGGTTGAGCTGGAGGT
`ACTGCAAGGTTGAGCTGGAGGTT
`CTGCAAGGTTGAGCTGGAGGTTC
`TGCAAGGTTGAGCTGGAGGTTCC
`GCAAGGTTGAGCTGGAGGTTCCC
`CAAGGTTGAGCTGGAGGTTCCCC
`AAGGTTGAGCTGGAGGTTCCCCA
`AGGTTGAGCTGGAGGTTCCCCAG
`.GGTTGAGCTGGAGGTTCCCCAGC
`GTTGAGCTGGAGGTTCCCCAGCT
`TTGAGCTGGAGGTTCCCCAGCTC
`TGAGCTGGAGGTTCCCCAGCTCT
`GAGCTGGAGGTTCCCCAGCTCTG
`AGCTGGAGGTTCCCCAGCTCTGC
`GCTGGAGGTTCCCCAGCTCTGCA
`CTGGAGGTTCCCCAGCTCTGCAG
`
`Moderna Ex 1003-p. 29
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 29 of 236 US 2006/0134189 Al
`
`Position
`373-395
`374-396
`375-397
`376-398
`377-399
`378-400
`379-401
`380-402
`381-403
`382-404
`383-405
`384-406
`385-407
`386-408
`387-409
`388-410·
`389-411
`390-412
`391-413
`392-414
`393-415
`394-416
`395-417
`396-418
`397-419
`398-420
`399-421
`400-422
`401-423
`402-424
`403-425
`404-426
`405-427
`406-428
`407-429
`408-430
`409-431
`410-432
`411-433
`412-434
`413-435
`414-436
`415-437
`416-438
`417-439
`418-440
`419-441
`420-442
`421-443
`422-444
`423-445
`424-446
`425-447
`426-448
`427-449
`428-450
`429-451
`430-452
`431-453
`432-454
`433-455
`434-456
`435-457
`436-458
`437-459
`438-460
`
`Sequence
`TGGAGGTTCCCCAGCTCTGCAGC
`GGAGGTTCCCCAGCTCTGCAGCT
`GAGGTTCCCCAGCTCTGCAGCTT
`AGGTTCCCCAGCTCTGCAGCTTC
`GGTTCCCCAGCTCTGCAGCTTCA
`GTTCCCCAGCTCTGCAGCTTCAT
`TTCCCCAGCTCTGCAGCTTCATC
`TCCCCAGCTCTGCAGCTTCATCC
`CCCCAGCTCTGCAGCTTCATCCT
`CCCAGCTCTGCAGCTTCATCCTG
`CCAGCTCTGCAGCTTCATCCTGA
`CAGCTCTGCAGCTTCATCCTGAA
`AGCTCTGCAGCTTCATCCTGAAG
`GCTCTGCAGCTTCATCCTGAAGA
`CTCTGCAGCTTCATCCTGAAGAC
`TCTGCAGCTTCATCCTGAAGACC
`CTGCAGCTTCATCCTGAAGACCA
`TGCAGCTTCATCCTGAAGACCAG
`GCAGCTTCATCCTGAAGACCAGC
`CAGCTTCATCCTGAAGACCAGCC
`AGCTTCATCCTGAAGACCAGCCA
`GCTTCATCCTGAAGACCAGCCAG
`CTTCATCCTGAAGACCAGCCAGT
`TTCATCCTGAAGACCAGCCAGTG
`TCATCCTGAAGACCAGCCAGTGC
`CATCCTGAAGACCAGCCAGTGCA
`ATCCTGAAGACCAGCCAGTGCAC
`TCCTGAAGACCAGCCAGTGCACC
`CCTGAAGACCAGCCAGTGCACCC
`CTGAAGACCAGCCAGTGCACCCT
`TGAAGACCAGCCAGTGCACCCTG
`GAAGACCAGCCAGTGCACCCTGA
`AAGACCAGCCAGTGCACCCTGAA
`AGACCAGCCAGTGCACCCTGAAA
`GACCAGCCAGTGCACCCTGAAAG
`ACCAGCCAGTGCACCCTGAAAGA
`CCAGCCAGTGCACCCTGAAAGAG
`CAGCCAGTGCACCCTGAAAGAGG
`AGCCAGTGCACCCTGAAAGAGGT
`GCCAGTGCACCCTGAAAGAGGTG
`CCAGTGCACCCTGAAAGAGGTGT
`CAGTGCACCCTGAAAGAGGTGTA
`AGTGCACCCTGAAAGAGGTGTAT
`GTGCACCCTGAAAGAGGTGTATG
`TGCACCCTGAAAGAGGTGTATGG
`GCACCCTGAAAGAGGTGTATGGC
`CACCCTGAAAGAGGTGTATGGCT
`ACCCTGAAAGAGGTGTATGGCTT
`CCCTGAAAGAGGTGTATGGCTTC
`CCTGAAAGAGGTGTATGGCTTCA
`CTGAAAGAGGTGTATGGCTTCAA
`TGAAAGAGGTGTATGGCTTCAAC
`GAAAGAGGTGTATGGCTTCAACC
`AAAGAGGTGTATGGCTTCAACCC
`AAGAGGTGTATGGCTTCAACCCT
`AGAGGTGTATGGCTTCAACCCTG
`GAGGTGTATGGCTTCAACCCTGA
`AGGTGTATGGCTTCAACCCTGAG
`GGTGTATGGCTTCAACCCTGAGG
`GTGTATGGCTTCAACCCTGAGGG
`TGTATGGCTTCAACCCTGAGGGC
`GTATGGCTTCAACCCTGAGGGCA
`TATGGCTTCAACCCTGAGGGCAA
`ATGGCTTCAACCCTGAGGGCAAA
`TGGCTTCAACCCTGAGGGCAAAG
`GGCTTCAACCCTGAGGGCAAAGC
`
`Moderna Ex 1003-p. 30
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 30 of 236 US 2006/0134189 Al
`
`Position
`439-461
`440-462
`441-463
`442-464
`443-465
`444-466
`445-467
`446-468
`447-469
`448-470
`449-471
`450-472
`451-473
`452-474
`453-475
`454-476
`455-477
`456-478
`457-479
`458-480
`459-481
`460-482
`461-483
`462-484
`463-485
`464-486
`465-487
`466-488
`467-489
`4 68-4 90
`469-491
`470-492
`471-493
`472-494
`473-495
`474-496
`475-497
`476-498
`477-499
`478-500
`479-501
`480-502
`481-503
`482-504
`483-505
`484-506
`485-507
`486-508
`487-509
`488-510
`489-511
`490-512
`491-513
`492-514
`493-515
`494-516
`495-517
`496-518
`497-519
`498-520
`499-521
`500-522
`501-523
`502-524
`503-525
`504-526
`
`Sequence
`GCTTCAACCCTGAGGGCAAAGCC
`CTTCAACCCTGAGGGCAAAGCCT
`TTCAACCCTGAGGGCAAAGCCTT
`TCAACCCTGAGGGCAAAGCCTTG
`CAACCCTGAGGGCAAAGCCTTGC
`AACCCTGAGGGCAAAGCCTTGCT
`ACCCTGAGGGCAAAGCCTTGCTG
`CCCTGAGGGCAAAGCCTTGCTGA
`CCTGAGGGCAAAGCCTTGCTGAA
`CTGAGGGCAAAGCCTTGCTGAAG
`TGAGGGCAAAGCCTTGCTGAAGA
`GAGGGCAAAGCCTTGCTGAAGAA
`AGGGCAAAGCCTTGCTGAAGAAA
`GGGCAAAGCCTTGCTGAAGAAAA
`GGCAAAGCCTTGCTGAAGAAAAC
`GCAAAGCCTTGCTGAAGAAAACC
`CAAAGCCTTGCTGAAGAAAACCA
`AAAGCCTTGCTGAAGAAAACCAA
`AAGCCTTGCTGAAGAAAACCAAG
`AGCCTTGCTGAAGAAAACCAAGA
`GCCTTGCTGAAGAAAACCAAGAA
`CCTTGCTGAAGAAAACCAAGAAC
`CTTGCTGAAGAAAACCAAGAACT
`TTGCTGAAGAAAACCAAGAACTC
`TGCTGAAGAAAACCAAGAACTCT
`GCTGAAGAAAACCAAGAACTCTG
`CTGAAGAAAACCAAGAACTCTGA
`TGAAGAAAACCAAGAACTCTGAG
`GAAGAAAACCAAGAACTCTGAGG
`AAGAAAACCAAGAACTCTGAGGA
`AGAAAACCAAGAACTCTGAGGAG
`GAAAACCAAGAACTCTGAGGAGT
`AAAACCAAGAACTCTGAGGAGTT
`AAACCAAGAACTCTGAGGAGTTT
`AACCAAGAACTCTGAGGAGTTTG
`ACCAAGAACTCTGAGGAGTTTGC
`CCAAGAACTCTGAGGAGTTTGCT
`CAAGAACTCTGAGGAGTTTGCTG
`AAGAACTCTGAGGAGTTTGCTGC
`AGAACTCTGAGGAGTTTGCTGCA
`GAACTCTGAGGAGTTTGCTGCAG
`AACTCTGAGGAGTTTGCTGCAGC
`ACTCTGAGGAGTTTGCTGCAGCC
`CTCTGAGGAGTTTGCTGCAGCCA
`TCTGAGGAGTTTGCTGCAGCCAT
`CTGAGGAGTTTGCTGCAGCCATG
`TGAGGAGTTTGCTGCAGCCATGT
`GAGGAGTTTGCTGCAGCCATGTC
`AGGAGTTTGCTGCAGCCATGTCC
`GGAGTTTGCTGCAGCCATGTCCA
`GAGTTTGCTGCAGCCATGTCCAG
`AGTTTGCTGCAGCCATGTCCAGG
`GTTTGCTGCAGCCATGTCCAGGT
`TTTGCTGCAGCCATGTCCAGGTA
`TTGCTGCAGCCATGTCCAGGTAT
`TGCTGCAGCCATGTCCAGGTATG
`GCTGCAGCCATGTCCAGGTATGA
`CTGCAGCCATGTCCAGGTATGAG
`TGCAGCCATGTCCAGGTATGAGC
`GCAGCCATGTCCAGGTATGAGCT
`CAGCCATGTCCAGGTATGAGCTC
`AGCCATGTCCAGGTATGAGCTCA
`GCCATGTCCAGGTATGAGCTCAA
`CCATGTCCAGGTATGAGCTCAAG
`CATGTCCAGGTATGAGCTCAAGC
`.,ATGTCCAGGTATGAGCTCAAGCT
`
`Moderna Ex 1003-p. 31
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 31 of 236 US 2006/0134189 A1
`
`Position
`505-527
`506-528
`507-529
`508-530
`509-531
`510-532
`511-533
`512-534
`513-535
`514-536
`515-537
`516-538
`517-539
`518-540
`519-541
`520-542
`521-543
`522-544
`523-545
`524-546
`525-547
`526-548
`527-549
`528-550
`529-551
`530-552
`531-553
`532-554
`533-555
`534-556
`535-557
`536-558
`537-559
`538-560
`539-561
`540-562
`541-563
`542-564
`543-565
`544-566
`545-567
`546-568
`547-569
`548-570
`549-571
`550-572
`551-573
`552-574
`553-575
`554-576
`555-577
`556-578
`557-579
`558-580
`559-581
`560-582
`561-583
`562-584
`563-585
`564-586
`565-587
`566-588
`567-589
`568-590
`569-591
`570-592
`
`Sequence
`TGTCCAGGTATGAGCTCAAGCTG
`GTCCAGGTATGAGCTCAAGCTGG
`TCCAGGTATGAGCTCAAGCTGGC
`CCAGGTATGAGCTCAAGCTGGCC
`CAGGTATGAGCTCAAGCTGGCCA
`AGGTATGAGCTCAAGCTGGCCAT
`GGTATGAGCTCAAGCTGGCCATT
`GTATGAGCTCAAGCTGGCCATTC
`TATGAGCTCAAGCTGGCCATTCC
`ATGAGCTCAAGCTGGCCATTCCA
`TGAGCTCAAGCTGGCCATTCCAG
`GAGCTCAAGCTGGCCATTCCAGA
`AGCTCAAGCTGGCCATTCCAGAA
`GCTCAAGCTGGCCATTCCAGAAG
`CTCAAGCTGGCCATTCCAGAAGG
`TCAAGCTGGCCATTCCAGAAGGG
`CAAGCTGGCCATTCCAGAAGGGA
`AAGCTGGCCATTCCAGAAGGGAA
`AGCTGGCCATTCCAGAAGGGAAG
`GCTGGCCATTCCAGAAGGGAAGC
`CTGGCCATTCCAGAAGGGAAGCA
`TGGCCATTCCAGAAGGGAAGCAG
`GGCCATTCCAGAAGGGAAGCAGG
`GCCATTCCAGAAGGGAAGCAGGT
`CCATTCCAGAAGGGAAGCAGGTT
`CATTCCAGAAGGGAAGCAGGTTT
`ATTCCAGAAGGGAAGCAGGTTTT
`TTCCAGAAGGGAAGCAGGTTTTC
`TCCAGAAGGGAAGCAGGTTTTCC
`CCAGAAGGGAAGCAGGTTTTCCT
`CAGAAGGGAAGCAGGTTTTCCTT
`AGAAGGGAAGCAGGTTTTCCTTT
`GAAGGGAAGCAGGTTTTCCTTTA
`AAGGGAAGCAGGTTTTCCTTTAC
`AGGGAAGCAGGTTTTCCTTTACC
`GGGAAGCAGGTTTTCCTTTACCC
`GGAAGCAGGTTTTCCTTTACCCG
`GAAGCAGGTTTTCCTTTACCCGG
`AAGCAGGTTTTCCTTTACCCGGA
`AGCAGGTTTTCCTTTACCCGGAG
`GCAGGTTTTCCTTTACCCGGAGA
`CAGGTTTTCCTTTACCCGGAGAA
`AGGTTTTCCTTTACCCGGAGAAA
`GGTTTTCCTTTACCCGGAGAAAG
`GTTTTCCTTTACCCGGAGAAAGA
`TTTTCCTTTACCCGGAGAAAGAT
`TTTCCTTTACCCGGAGAAAGATG
`TTCCTTTACCCGGAGAAAGATGA
`TCCTTTACCCGGAGAAAGATGAA
`CCTTTACCCGGAGAAAGATGAAC
`CTTTACCCGGAGAAAGATGAACC
`TTTACCCGGAGAAAGATGAACCT
`TTACCCGGAGAAAGATGAACCTA
`TACCCGGAGAAAGATGAACCTAC
`ACCCGGAGAAAGATGAACCTACT
`CCCGGAGAAAGATGAACCTACTT
`CCGGAGAAAGATGAACCTACTTA
`CGGAGAAAGATGAACCTACTTAC
`GGAGAAAGATGAACCTACTTACA
`GAGAAAGATGAACCTACTTACAT
`AGAAAGATGAACCTACTTACATC
`GAAAGATGAACCTACTTACATCC
`AAAGATGAACCTACTTACATCCT
`AAGATGAACCTACTTACATCCTG
`AGATGAACCTACTTACATCCTGA
`GATGAACCTACTTACATCCTGAA
`
`Moderna Ex 1003-p. 32
`Moderna v Protiva
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 32 of 236 US 2006/0134189 Al
`
`Position
`571-593
`572-594
`573-595
`574-596
`575-597
`576-598
`577-599
`578-600
`579-601
`580-602
`581-603
`582-604
`583-605
`584-606
`585-607
`586-608
`587-609
`588-610
`589-611
`590-612
`591-613
`592-614
`593-615
`594-616
`595-617
`596-618
`597-619
`598-620
`599-621
`600-622
`601-623
`602-624
`603-625
`604-626
`605-627
`606-628
`607-629
`608-630
`609-631
`610-632
`611-633
`612-634
`613-635
`614-636
`615-637
`616-638
`617-639
`618-640
`619-641
`620-642
`621-643
`622-644
`623-645
`624-646
`625-647
`626-648
`627-649
`628-650
`629-651
`630-652
`631-653
`632-654
`633-655
`634-656
`635-657
`636-658
`
`Sequence
`ATGAACCTACTTACATCCTGAAC
`TGAACCTACTTACATCCTGAACA
`GAACCTACTTACATCCTGAACAT
`AACCTACTTACATCCTGAACATC
`ACCTACTTACATCCTGAACATCA
`CCTACTTACATCCTGAACATCAA
`CTACTTACATCCTGAACATCAAG
`TACTTACATCCTGAACATCAAGA
`ACTTACATCCTGAACATCAAGAG
`CTTACATCCTGAACATCAAGAGG
`TTACATCCTGAACATCAAGAGGG
`TACATCCTGAACATCAAGAGGGG
`ACATCCTGAACATCAAGAGGGGC
`CATCCTGAACATCAAGAGGGGCA
`ATCCTGAACATCAAGAGGGGCAT
`TCCTGAACATCAAGAGGGGCATC
`CCTGAACATCAAGAGGGGCATCA
`CTGAACATCAAGAGGGGCATCAT
`TGAACATCAAGAGGGGCATCATT
`GAACATCAAGAGGGGCATCATTT
`AACATCAAGAGGGGCATCATTTC
`ACATCAAGAGGGGCATCATTTCT
`CATCAAGAGGGGCATCATTTCTG
`ATCAAGA