1111111111111111 IIIIII IIIII 11111 1111111111 1111111111 111111111111111 11111 1111111111 11111111
`US 20060134189A 1
`
`110) United States
`(12) Patent Application Publication
`MacLachlan et al.
`
`(10) Pub. No.: US 2006/0134189 Al
`.Jun. 22, 2006
`(43) Pub. Date:
`
`154) SIRNA SILENCll\G m APOLIPOPROTEll\ B
`
`Related U.S. Application Data
`
`(75)
`
`Inventors: Ian \faclachlau, Vam:omer (CA):
`Lloyd R. Jeffs. Delt1 (C\); .\dam
`Judge. Vancuuver (CA); Amy C.II.
`Lee, Surrey (CA); Lorne R. Palmer.
`Vancuuwr (CA): Yandana Sood.
`Vc111COllVCf (CA)
`
`Correspondence Address:
`TOWNSE!',D Al',D TOW!',SEND . \ND CREW,
`LLP
`TWO El\,IBARC\DERO CEl\rnR
`EIGHTH l'LOOR
`S.\N FRAI\CTSCO, C.\ 94111-3834 (llS)
`
`I Tl) Assignee: Protiva Biotherapeutics, Inc. Hurm1hy
`(C.\J
`
`(21)
`
`.'\ppl. No.:
`
`11/28.1,550
`
`(22) Filed:
`
`No,. 17, 2005
`
`((lO) Provisiunal application Nu. G0/703,22G, filed on Jul.
`27, 2005. Prnvision:1! application No. 60/62t),808,
`filed un Nov. 17, 2004.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`(200G.0l)
`A61K 48/00
`lf6JK 91127
`(2006.01)
`Cl2N 15/88
`(2006.01)
`CfJ7H 21/02
`(2006.01)
`(52) U.S. Cl. ............................ 424/450: 435/458: 514/44:
`536/23.1
`
`(57)
`
`ABSTRA<:T
`
`Thi.: presmt invenliun provides nucleic a,id-lipid particle,
`comprising siRNA molecules that silence .\poH expression
`am! methuds uf usiug ,w:h nuclei, add-lipid particles lo
`silence .\poH expression.
`
`Moderna Ex 1004-p. 1
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`

`Figure 1
`. Plasma IFN-alpha Concentrations
`
`70,000 . . - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ,
`Apo-8 siRNA
`
`60,000
`
`50,000
`
`-0
`
`C e: ;:;· = --· 0 ::
`
`20,000
`
`10,000
`
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`I
`
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`
`Lipid
`
`A
`
`C
`
`D
`
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`
`F
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`
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`
`Neg
`Pos
`siRNA siRNA
`
`--I
`
`E
`0)
`.3: 40,000
`('O
`.t;;
`a.
`
`ro z !:!:: 30,000
`
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`

`Patent Application Publication Jun. 22, 2006 Sheet 2 of 236
`
`US 2006/0134189 Al
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`cnz
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`Moderna Ex 1004-p. 3
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`

`

`Patent Application Publication Jun. 22, 2006 Sheet 3 of 236
`
`US 2006/0134189 Al
`
`0)
`C
`(.)
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`(J)
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`
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`
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`
`Moderna Ex 1004-p. 4
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`

`Figure 4
`In Vivo Apo B Silencing
`
`54%
`
`P < 1e-6
`•------------ ------...
`
`Anti-ApoB siRNA
`
`Control siRNA
`
`80%
`
`C
`0
`"ii,
`tJ)
`,._
`Q)
`Q.. 60%
`X w
`co
`0
`0..
`<(
`(l.)
`>
`~
`a3 a:::
`
`40%
`
`20%
`
`Moderna Ex 1004-p. 5
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`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 5 of 236
`
`US 2006/0134189 AJ
`
`120%
`
`100%
`
`100%
`
`114%
`
`80%
`
`C:
`
`g
`0 u 60%
`en co
`Q.
`"' >
`
`40%
`
`20%
`
`0%
`
`76%
`
`63%
`
`18%
`
`12%
`
`r
`
`Figure 5
`
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`

`Patent Application Publication Jun. 22, 2006 Sheet 6 of 236
`
`US 2006/0134189 Al
`
`160%
`
`140%
`
`120%
`
`~
`
`-II- mismatch SNALP
`..,... empty partides
`-+-apob-1 SNALP
`
`/
`
`v
`
`.. C 10D%
`e
`
`0
`0
`<II
`ii
`:i:
`<II >
`Cl)
`al
`a.
`0
`~
`"
`
`80%
`
`60%
`
`40%
`
`20%
`
`• + •
`
`0%-\---,---,---.---r---.-------.-,----,----,-,---,--,---,---,----,----,---.--,--,---.--,-~----
`-2
`6
`8
`10
`4
`20
`2
`12
`14
`22
`-4
`18
`0
`16
`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
`c:: 60%
`8
`co a.
`!JI >
`
`(/)
`
`40%
`
`56%
`
`20%
`
`0%
`
`22%
`
`15%
`
`1%
`
`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
`
`Moderna Ex 1004-p. 8
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`

`Patent Application Publication Jun. 22, 2006 Sheet 8 of 236
`
`US 2006/0134189 Al
`
`100%
`
`100%
`
`100%
`
`92%
`
`:g
`
`C
`0
`l)
`CJ)
`Ill
`Cl.
`§Z
`
`80%
`
`60%
`
`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
`DLenDMA
`
`mismatch 2:30:20
`DLenDMA
`
`Moderna Ex 1004-p. 9
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`

`Patent Ap11Iication Publication Jun. 22, 2006 Sheet 9 of 236
`
`US 2006/0134189 Al
`
`100%
`
`100%
`
`80%
`
`,::
`
`g 60%
`8
`U)
`co
`0. .,
`>
`
`40%
`
`20%
`
`0%
`
`65%
`
`13%
`
`10%
`
`6%
`
`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
`
`Moderna Ex 1004-p. 10
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`

`Patent Application Publication Jun. 22, 2006 Sheet 10 of 236 US 2006/0134189 Al
`
`120%
`
`100%
`
`105%
`
`87%
`
`72%
`
`51%
`
`16%
`
`0%
`
`PBS
`vehicle
`
`apob-1
`SNALP
`Day1
`
`apob-1
`SNALP
`Day3
`
`apob-1
`SNALP
`Day7
`
`apob-1 mismatch mismatch mismatch mismatch
`SNALP
`SNALP
`SNALP
`SNALP
`SNALP
`Day10
`Day7
`Day1
`Day3
`Day1O
`
`Figure 10
`
`Moderna Ex 1004-p. 11
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`

`Patent Ap11lication Publication Jun. 22, 2006 Sheet 11 of 236
`
`US 2006/0134189 A1
`
`120%
`
`100%
`
`80%
`
`60%
`
`40%
`
`20%
`
`e c
`
`0
`0
`(/)
`CD
`0.
`Ill >
`
`/
`
`~ - - - 4 - - - - -(cid:157)
`
`+
`
`1
`
`-....apob-1 Sl'.A.LP
`-<>- mismatctl SNALP
`
`0% +----~---~--~---~--~---~-----~
`96
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`Hours After SNALP Administration
`Figure 11
`
`84
`
`108
`
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`

`Patent Ap11Iication Publication Jun. 22, 2006 Sheet 12 of 236
`
`US 2006/0134189 Al
`
`180
`
`160
`
`140
`
`120
`
`100 ·
`
`I
`80 Ci).. .. ---
`
`1
`
`······· .............. ··(1)···••'
`
`60
`
`40
`
`20
`
`·-0 Normal Diet+ mismatch SNALP
`
`.... High Fat Diet+ mismatch SNALP
`
`··O· Normal Diet + apob-1 SNALP
`
`.... High Fat _Diet+ apob-1 SNALP
`
`i
`0+----..------,----.----~---...-----~----.---~
`20
`25
`40
`10
`30
`15
`0
`35
`5
`Study Day
`Figure 12
`
`Moderna Ex 1004-p. 13
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`

`Patent Application Publication Jun. 22, 2006 Sheet 13 of 236
`
`US 2006/0134189 Al
`
`100%
`
`100%
`
`99%
`
`~ C
`
`0
`(,)
`Cl)
`co
`c..
`~.
`
`80%
`
`60%
`
`40%
`
`20%
`
`0%
`
`14%
`
`PBS Vehicle
`
`2:40:10 apob-1
`Figure 13
`
`2:40:10 mismatch
`
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`

`Patent Ap11lication Publication Jun. 22, 2006 Sheet 14 of 236
`
`US 2006/0134189 A1
`
`160%
`
`120%
`
`e ..,
`
`C
`0
`0
`(/)
`CD
`0.
`!I) >
`
`80%
`
`40%
`
`0%
`
`l!IPBS
`D apob-1 SNALP
`~ mismatch SNALP
`
`126%
`
`100%
`
`150%
`
`38%
`
`43%
`
`livermRNA
`
`plasma protein
`
`Figure 14
`
`Moderna Ex 1004-p. 15
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`

`Patent Application Publication Jun. 22, 2006 Sheet 15 of 236 US 2006/0134189 Al
`
`128%
`
`115%
`
`100%
`
`66%
`
`51%
`
`120%
`
`-100%
`
`e so%
`~
`~ 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
`
`Moderna Ex 1004-p. 16
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`

`Patent Application Publication Jun. 22, 2006 Sheet 16 of 236 US 2006/0134189 Al
`
`160%
`
`140%
`
`120%
`
`100%
`
`£100% ...
`
`" 8 80%
`~
`"' > 60%
`
`40%
`
`20%
`
`0%
`
`87%
`
`106%
`
`104%
`··93%· .. ·····-·--·····-·-----t--+-+-
`
`. ...
`
`82%
`
`56%
`
`38%
`
`34%
`
`20%
`
`PBS
`Vehlele
`
`apob-1
`
`apob-1 no- apob-1 U-
`P
`mod-sense
`
`Protlva
`apob-1
`
`· al)Ob-1•
`Protlva
`apot>-1 no- mismatch
`p
`
`apoS-1514 apoS-2600 apob-10851 apot>-12192 apot>-13397
`
`Figure 16
`
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`

`Patent Ap11lication Publication Jun. 22, 2006 Sheet 17 of 236
`
`US 2006/0134189 A1
`
`160%
`
`140%
`
`120%
`
`a.
`
`e 100%
`"' U)
`~ 80%
`0
`if!.
`
`60%
`
`100%
`
`151%
`
`136%
`
`125%
`
`105%
`
`89%
`
`65%
`
`40%
`
`20%
`
`0%
`
`PBS
`
`apob-1
`
`apol>-1 no apot>-1 U-
`phosphate mod-$ense
`
`Prouva
`apob-1
`
`apoo-1-
`ProUva
`apol>-1 no mismatch
`phoophale
`
`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 Al
`
`5.000
`
`4,000
`
`1,000
`
`Predicted lmmunostimulatory activity by sequence motifs:
`
`1514=Hlgh
`2690=Low
`10851=Medium
`12192=Medium
`13397=Hlgh
`
`PBS
`
`ap,t,-1
`
`ap,»-1 no _ . , U-.-od- ProtN• apot,-1 Prowa ap,b-1
`pt,ospl,ala
`.. ,,..
`nophcsphote
`
`ap,b-1-
`ml.s!rotcll
`
`apoB-1514
`
`ap,B-21300
`
`apoB-10851
`
`apoB-1"92
`
`ap,B-13397
`
`Figure 18
`
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`

`Patent Application Publication Jun. 22, 2006 Sheet 19 of 236
`
`US 2006/0134189 Al
`
`D100nM20:1 ....,_
`D100nM70:1 -
`
`180%
`
`le0%
`
`140%
`
`1211%
`
`161'11
`
`:. 14a'II
`. ;
`;·,J
`''
`
`128'11
`, 121'11
`
`Figure 19
`
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`

`Patent Application Publication Jun. 22, 2006 Sheet 20 of 236
`
`US 2006/0134189 Al
`
`Figure 20
`Table 5
`
`SiRNA target sequence
`TGCGACCCGATTCAAGCACCTCC
`TGCCACCAGGATCAACTGCAAGG
`ACCTACTTACATCCTGAACATCA
`CTCCACTCACTTTACCGTCAAGA
`CATCAGCCCACTTGCTCTCATCA
`GAAGATGGGCCTCGCATTTGAGA
`GGGGATGAAGATTACACCTATIT
`CTCTACAAATCTGTITCTCTTCC
`AATAACTACCTICCTAAAGAAAG
`CTGGATTACAGTTGCAAATATCT
`GGGCATCATCATTCCGGACTTCG
`CTGGAGGCTCATGTTGCCCTAAA
`AGGCAACACATTACATTTGGTCT
`GGCCACCTAAGTTGTGACACAAA
`ATCAAGGGTGTTATTTCCATACC
`TGCCAAACTGCTTCTCCAAATGG
`AGGCACCAATGTAGATACCAAAA
`CTCCAGAGATCTAAAGATGTTAG
`CTCCACGAATGTCTACAGCAACT
`GTTGACCTGCTTICCTACAATGT
`TATCAGGCTGATTACGAGTCATT
`AGACAGGCACCTGGAAACTCAAG
`CAAGACCCAATTTAACAACAATG
`CCTGAAGCACATCAATATTGATC
`AAGCACATCAATATTGATCAATT
`GATGAGCACTATCATATCCGTGT
`CAGCACCTAGCTGGAAAGTTAAA
`GCTAAGCAATGTCCTACAACAAG
`AAGCAATGTCCTACAACAAGTT A
`TAGCACACTTGTCACCTACATTT
`GAGCAATATICTATCCAAGATTG
`TACAATTGACTTTGTCGAAATGA
`GAGAATCACCCTGCCAGACTICC
`CCAGACTICCGTTTACCAGAAAT
`ATGCACAACTCTCAAACCCTAAG
`GCGCAACGAGATCAAGACACTGT
`GAAGATAGACTICCTGAATAACT
`CTOAATAACTATGCACTGTITCT
`AOCAAGCAAGTTGGCAAGTAAGT
`CACCATAOAGATGTCGGCATTCG
`AACCAGTCAGATATTGTTGCTCA
`GTGGAGGGTAGTCATAACAGTAC
`OACCACAAGCTTAGCTIGGAAAG
`AITGAGTCATCTACCAAAOGAGA
`GCTAACCTCTCTGAAAGACMCO
`GTCCATAATOGTT.CAOAAATACT
`OTATAGGGAACTGTTGAAAOATT
`CTCAAGTCAAGTTGAGCAATITC
`CAGGAATATCTIAGCATCCTTAC
`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
`93.76
`9917
`10200
`10344
`10560
`10602
`12326
`12831
`12932
`13436
`13.473
`13602
`
`Immunostimulatorv 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
`Hillh
`
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`Patent Ap11lication Publication Jun. 22, 2006 Sheet 21 of 236
`
`US 2006/0134189 A1
`
`Figure 21
`Table 6
`
`Immunostimulatory activity
`Position SiRNAtargetsequence
`GCGGACGCCGTTACTGCTGCTGT Med
`24
`CCGAAAGTACGTGTACAACTATG High
`174
`ACCAACCAGTGTACCCTTAAAGA High
`307
`CATGACACGTGTTACACAGAAAC High
`861
`TITGAAGACCCTTCAAGAACTGA Med
`1002
`AGCCACAGTGCTATACTCACATC Med
`1187
`Low
`TGTCACCTACCTGATGGCTCTGA
`1257
`AGCCACGCAGTTAACAGCTATIT
`Low
`1363
`GGGAAGAACCATGGAACAAGTAA High
`1512
`GAAGAACTGTATGTCCAAGATCT Med
`1837
`CTGGAGAATTCTCAATTTCCAAC Med
`1882
`AAGCAGTTATCTTCCCAGAGAAA Med
`2016
`TITGAGATTGGTTTAGAAGGAAA High
`2089
`GTGGACCACTTTGGCTATACTAC Med
`2230
`GTGCACAAACTTTGCAGGGAATC Med
`2432
`Low
`GGGCATCATCATCCCAGACTTCG
`·2688
`AAAGAGGCCAGTCAAGCTGITCA Med
`2814
`CAGCAACACACTGCATCTGGTCT High
`2841
`CAGGAGCTTACTCCAACGCCAGC Med
`2960
`GTGGAGCAGTATTCTGCCACTGC
`Low
`3058
`GTGCAGCAGTCTGAAGCTACTGT Med
`3151
`Low
`GATCACCTCAATAGCCTCTCAGA
`3784
`1TCCACAAATGTCTACAGCAAIT Med
`4101
`TGTGAGAGAGATGITACAACTGG High
`4540
`AAGAACACAGCTTCCTTGAAATA High
`4693
`TCTCACTGGACTTCTTCTCAAAA
`Low
`5312
`AGCTACAGCCCTAITCTTTCATA
`Low
`5387
`CTACAGCCCTATTCTITCATAAC
`Low
`5389
`GGGCAGCTATATAGTAAGTITCT Med
`5803
`CAAGACCAAACTGAATGACAAAG High
`5979
`GCCTACAACACTAAAGACAAAAT High
`6022
`TTAGAGGTAAATGATGCTGTTGA High
`6142
`High
`CACCATCAACCTCCCAITCITCA
`6225
`TTGGAGAGAAATCGAAGAGGAAT Low
`6265
`Low
`CCTCAGCAGATTCATCATTATCT
`6379
`GAACAGTATCATATCCGTGTAAA Med
`6664
`ATTGACTGACATGTTGGTGAAGA High
`7278
`TGACATGTTGGTGAAGAAGTTGA High
`7284
`ATGAAAGACCATITCCAAGATAC Med
`7531
`GCAGAGCAATATTCCATCCAAAA Med
`7702
`TITGAGGTCAGTCTCCGTGCTCT Med
`7807
`ATTCACTCTTCTCAACACCTTCC
`High
`7956
`TACAATTGACTTGCTGGAAATAA Med
`7992
`CATTAOAACTATCGACCAAATIT Med
`8025
`TGGTATGACTGTCAAAGTAAACA Hiih
`8622
`GCATACATTCGTCCCAAATTAGC Med
`8828
`GAGTACCAGATTCAATCAGTACA Med
`9276
`AAGAAACAOOCTIOAAAOAATIT Med
`9470
`CACCATTAGTITAACCAAOAAAA High
`10248
`GCCAACCTCCATGCTCCCATATT
`·Med
`10297
`
`Moderna Ex 1004-p. 22
`Moderna v Arbutus
`
`

`

`Patent Ap11lication Publication Jun. 22, 2006 Sheet 22 of 236
`
`US 2006/0134189 A1
`
`Figure 22
`Table 7
`A B .RNA
`.po
`sequences
`SI
`Sequence
`Position
`1-23
`ATTCCCACCGGGACCTGCGGGGC
`2-24
`TTCCCACCGGGACCTGCGGGGCT
`3-25
`TCCCACCGGGACCTGCGGGGCTG
`4-26
`CCCACCGGGACCTGCGGGGCTGA
`CCACCGGGACCTGCGGGGCTGAG
`5-27
`CACCGGGACCTGCGGGGCTGAGT
`6-28
`ACCGGGACCTGCGGGGCTGAGTG
`7-29
`CCGGGACCTGCGGGGCTGAGTGC
`8-30
`CGGGACCTGCGGGGCTGAGTGCC
`9-31
`GGGACCTGCGGGGCTGAGTGCCC
`10-32
`GGACCTGCGGGGCTGAGTGCCCT
`11-33
`GACCTGCGGGGCTGAGTGCCCTT
`12-34
`ACCTGCGGGGCTGAGTGCCCTTC
`13-35
`CCTGCGGGGCTGAGTGCCCTTCT
`14-36
`CTGCGGGGCTGAGTGCCCTTCTC
`15-37
`TGCGGGGCTGAGTGCCCTTCTCG
`16-38
`GCGGGGCTGAGTGCCCTTCTCGG
`17-39
`CGGGGCTGAGTGCCCTTCTCGGT
`18-40
`19-41
`GGGGCTGAGTGCCCTTCTCGGTT
`GGGCTGAGTGCCCTTCTCGGTTG
`20-42
`GGCTGAGTGCCCTTCTCGGTTGC
`21-43
`GCTGAGTGCCCTTCTCGGTTGCT
`7.2-44
`CTGAGTGCCCTTCTCGGTTGCTG
`23-45
`24-46
`TGAGTGCCCTTCTCGGTTGCTGC
`GAGTGCCCTTCTCGGTTGCTGCC
`25-47
`AGTGCCCTTCTCGGTTGCTGCCG
`7.6-48
`GTGCCCTTCTCGGTTGCTGCCGC
`27-49
`TGCCCTTCTCGGTTGCTGCCGCT
`28-50
`GCCCTTCTCGGTTGCTGCCGCTG
`?9-51
`CCCTTCTCGGTTGCTGCCGCTGA
`30-52
`CCTTCTCGGTTGCTGCCGCTGAG
`31-53
`CTTCTCGGTTGCTGCCGCTGAGG
`32-54
`TTCTCGGTTGCTGCCGCTGAGGA
`33-'.15
`TCTCGGTTGCTGCCGCTGAGGAG
`34-56
`C'l'CGG'l'TGCTGCCGCTGAGGAGC
`35-57
`TCGGTTGCTGCCGCTGAGGAGCC
`36-58
`CGGTTGCTGCCGCTGAGGAGCCC
`37-59
`GGTTGCTGCCGCTGAGGAGCCCG
`38-60
`GTTGCTGCCGCTGAGGAGCCCGC
`39 61
`TTGCTGCCGCTGAGGAGCCCGCC
`40-62
`TGCTGCCGCTGAGGAGCCCGCCC
`11-63
`GCTGCCGCTGAGGAGCCCGCCCA
`42-64
`CTGCCGCTGAGGAGCCCGCCCAG
`43-65
`TGCCGCTGAGGAGCCCGCCCAGC
`44-66
`GCCGCTGAGGAGCCCGCCCAGCC
`45-67
`46-68
`CCGCTGAGGAGCCCGCCCAGCCA
`CGCTGAGGAGCCCGCCCAGCCAG
`47-69
`GCTGAGGAGCCCGCCCAGCCAGC
`48-70
`49-71
`CTGAGGAGCCCGCCCAGCCAGCC
`TGAGGAGCCCGCCCAGCCAGCCA
`50-72
`51-73
`GAGGAGCCCGCCCAGCCAGCCAG
`AGGAGCCCGCCCAGCCAGCCAGG
`52-74
`GGAGCCCGCCCAGCCAGCCAGGG
`53-75
`GAGCCCGCCCAGCCAGCCAGGGC
`54-76
`AGCCCGCCCAGCCAGCCAGGGCC
`55-77
`GCCCGCCCAGCCAGCCAGGGCCG
`56-78
`CCCGCCCAGCCAGCCAGGGCCGC
`57-79
`CCGCCCAGCCAGCCAGGGCCGCG
`58-80
`CGCCCAGCCAGCCAGGGCCGCGA
`59-81
`GCCCAGCCAGCCAGGGCCGCGAG
`60-82
`CCCAGCCAGCCAGGGCCGCGAGG
`61-83
`CCAGCCAGCCAGGGCCGCGAGGC
`62-84
`
`Moderna Ex 1004-p. 23
`Moderna v Arbutus
`
`

`

`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
`~ed
`CTCCATCACTTTOACCAGGAAGT Med
`TTTOAOOCAACTATACCTGAAAT Med
`TCTOAATAAGTTGGCCAACATGA High
`GGCCAACATGATTOCCOATGTTG Him.
`OCCMCATGAT'.fOCCGATGTTGA Him
`CTTCAACACTGTGACITCAATGT
`High
`GTGGAGTATAATOAAGATGGTCT Med
`ACTOACTGACITTCATCTGTACT
`Low
`CTGGAATACGTITCTTCAGMCT Med
`TGCCAGAAGGATGGTTGATGAAA High
`GAAGAGGGTGTTAGACAGTATAG Med
`GGCCAACAGGATATCAAGTTTAC Med
`AATGACTTTCTTCAATCCATACT Med
`AGAGAGTATCTTAGCATGCTTAC
`Low
`TCTTAGCATGCTI'ACTGATATAA
`Low
`OACCAACTCTCTAGCTACTATGA Med
`GTCCACAAGATTGATTGACCTGT High
`TCTCAGATACATCACCGAGTTAC Med
`CATCACCGAGTTACTGAGAAAGC Low
`GTAGACTACTATAAAGACCATCC Med
`TGCAACCAAGCTGGCATAA,GAAC Hi!dt
`
`Moderna Ex 1004-p. 24
`Moderna v Arbutus
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 24 of 236
`
`US 2006/0134189 Al
`
`13638
`13935
`
`GACCAACTCTCTGATTACTATGA
`AGGCAGTAGACTATAAGCAGAAG
`
`Med
`Low
`
`Moderna Ex 1004-p. 25
`Moderna v Arbutus
`
`

`

`Patent Ap11Iication 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 1004-p. 26
`Moderna v Arbutus
`
`

`

`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
`C'I'GCGCTGC'l'GCTGCTGC'!'GCTG
`TGCGCTGCTGCTGCTGCTGCTGG
`GCGCTGCTGCTGCTGCTGCTGGC
`CGCTGCTGCTGCTGCTGCTGGCG
`GCTGCTGCTGCTGCTGCTGGCGG
`CTGCTGCTGCTGCTGCTGGCGGG
`TGCTGCTGCTGCTGCTGGCGGGC
`GCTGCTGCTGCTGCTGGCGGGCG
`CTGCTGCTGCTGCTGGCGGGCGC
`TGCTGCTGCTGCTGGCGGGCGCC
`GGCGGGCGCCAGGGCCGAAGAGG
`GCGGGCGCCAGGGCCGAAGAGGA
`CGGGCGCCAGGGCCGAAGAGGAA
`GGGCGCCAGGGCCGAAGAGGAAA
`GGCGCCAGGGCCGAAGAGGAAAT
`GCGCCAGGGCCGAAGAGGAAATG
`CGCCAGGGCCGAAGAGGAAATGC
`GCCAGGGCCGAAGAGGAAATGCT
`CCAGGGCCGAAGAGGAAATGCTG
`CAGGGCCGAAGAGGAAATGCTGG
`AGGGCCGAAGAGGAAATGCTGGA
`GGGCCGAAGAGGAAATGCTGGAA
`GGCCGAAGAGGAAATGCTGGAAA
`GCCGAAGAGGAAATGCTGGAAAA
`CCGAAGAGGAA.ATGCTGGAAAAT
`CGAAGAGGAAATGCTGGAAAATG
`GAAGAGGAAATGCTGGAAAATG'l'
`AAGAGGAMTGCTGGAAAATGTC
`AGAGGAAATGCTGGAAAA'l'G'I'CA - -
`GAGGAAATGCTGGAAAATGTCAG
`AGGAAATGCTGGAAAA'l'G1'CAGC
`GGAAATGCTGGAAAATGTCAGCC
`GAAA1'GCTGGAAAATGTCAGCCT
`AAATGCTGGAAAATGTCAGCCTG
`AATGCTGGAAAATGTCAGCCTGG
`A'l'GCTGGAAAATGTCAGCCTGGT
`TGCTGGAAAATGTCAGCCTGGTC
`GCTGGAAAATGTCAGCCTGGTCT
`CTGGAAAATGTCAGCCTGG'l'CTG
`TGGAAAATGTCAGCCTGGTCTGT
`GGAAAATGTCAGCCTGGTCTGTC
`GAAAATGTCAGCCTGGTCTGTCC
`AAAATGTCAGCCTGGTCTGTCCA
`AAATGTCAGCCTGGTCTGTCCAA
`AATGTCAGCCTGGTCTGTCC~
`ATGTCAGCCTGGTCTGTCCAAAA
`TGTCAGCCTGGTCTGTCCAAAAG
`GTCAGCCTGGTCTGTCCAAAAGA
`TCAGCCTGGTCTGTCCAAAAGAT
`CAGCCTGGTCTGTCCAAAAGATG
`AGCCTGGTCTGTCCAAAAGATGC
`GCCTGGTCTGTCCAAAAGATGCG
`CCTGGTCTGTCCAAAAGATGCGA
`CTGGTCTGTCCAAAAGATGCGAC
`TGGTCTGTCCAAAAGATGCGACC
`GGTCTGTCCAAAAGATGCGACCC
`GTCTGTCCAAAAGATGCGACCCG
`
`Moderna Ex 1004-p. 27
`Moderna v Arbutus
`
`

`

`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
`TCTGTCCAAMGATGCGACCCGA
`CTGTCCAAAAGATGCGACCCGAT
`TGTCCA.AAAGATGCGACCCGATT
`GTCCAAAAGATGCGACCCGATTC
`TCCAAAAGATGCGACCCGATTCA
`CCAAAAGATGCGACCCGATTCM
`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
`CTCCGGAAGTACACA'l'ACAACTA
`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 1004-p. 28
`Moderna v Arbutus
`
`

`

`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
`3.32-354
`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
`CTGGGAC'l'GCTGATTCAAGAAGT
`TGGGACTGCTGATTCAAGAAGTG
`GGGACTGCTGATTCAAGAAGTGC
`GGACTGCTGATTCAAGAAGTGCC
`GACTGCTGATTCAAGAAGTGCCA
`ACTGCTGATTCAAGAAGTGCCAC
`CTGCTGAT'I'CAAGAAGTGCCACC
`TGCTGATTCAAGAAGTGCCACCA
`GCTGATTCAAGAAGTGCCACCAG
`CTGATTCAAGAAGTGCCACCAGG
`TGATTCAAGAAGTGCCACCAGGA
`GA'l'TCAAGAAGTGCCACCAGGAT
`ATTCAAGAAGTGCCACCAGGATC
`TTCAAGAAGTGCCACCAGGATCA
`TCAAGAAGTGCCACCAGGATCAA
`CAAGAAGTGCCACCAGGATCAAC
`AAGAAGTGCCACCAGGATCAACT
`AGAAGTGCCACCAGGATCAACTG
`GAAGTGCCACCAGGATCAACTGC
`AAGTGCCACCAGGATCAACTGCA
`AGTGCCACCAGGATCAACTGCAA
`GTGCCACCll.GGATCAACTGCAAG
`TGCCACCAGGATCAACTGCAAGG
`GCCACCAGGATCAACTGCAAGGT
`CCACCAGGATCAACTGCAAGGTT
`CACCAGGATCAACTGCAAGGTTG
`ACCAGGATCAACTGCAAGGTTGA
`CCAGGATCAACTGCAAGGTTGAG
`CAGGATCAACTGCAAGGTTGAGC
`AGGATCAACTGCAAGGTTGAGCT
`GGATCAACTGCAAGGTTGAGCTG
`GATCAACTGCAAGGTTGAGCTGG
`ATCAACTGCAAGGTTGAGCTGGA
`TCAACTGCAAGGTTGAGCTGGAG
`CAACTGCAAGGTTGAGCTGGAGG
`AACTGCAAGGTTGAGCTGGAGGT
`ACTGCAAGGTTGAGCTGGAGGTT
`CTGCAAGGTTGAGCTGGAGGTTC
`TGCAAGGTTGAGCTGGAGGTTCC
`GCAAGGTTGAGCTGGAGGTTCCC
`CAAGGTTGAGCTGGAGGTTCCCC
`AAGGTTGAGCTGGAGGTTCCCCA
`A~GTTGAGCTGGAGGTTCCCCAG
`.GGTTGAGCTGGAGGTTCCCCAGC
`GTTGAGCTGGAGGTTCCCCAGCT
`TTGAGCTGGAGGTTCCCCAGCTC
`TGAGCTGGAGGTTCCCCAGCTCT
`GAGCTGGAGGTTCCCCAGCTCTG
`AGCTGGAGGTTCCCCAGCTCTGC
`GCTGGAGGTTCCCCAGCTCTGCA
`CTGGAGGTTCCCCAGCTCTGCAG
`
`Moderna Ex 1004-p. 29
`Moderna v Arbutus
`
`

`

`Patent Ap11Iication 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
`408-130
`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
`TTCCCCAGCTC'l'GCAGC'l''l'CATC
`TCCCCAGCTCTGCAGCTTCATCC
`CCCCAGCTCTGCAGCTTCATCCT
`CCCAGCTCTGCAGCTTCATCCTG
`CCAGCTCTGCAGCTTCATCCTGA
`CAGCTCTGCAGCTTCA'l'CCTGAA
`AGCTCTGCAGCTTCATCCTGAAG
`GCTCTGCAGCTTCATCCTGAAGA
`CTCTGCAGCTTCATCCTGAAGAC
`TCTGCAGCTTCATCCTGAAGACC
`CTGCAGCTTCATCCTGAAGACCA
`TGCAGCTTCATCCTGAAGACCAG
`GCAGCTTCATCCTGAAGACCAGC
`CAGCTTCATCCTGAAGACCAGCC
`AGCT'I'CATCCTGAAGACCAGCCA
`GCTTCATCCTGAAGACCAGCCAG
`C'l"I'CATCCTGAAGACCAGCCAGT
`TTCATCCTGAAGACCAGCCAGTG
`TCATCCTGAAGACCAGCCAGTGC
`CATCCTGAAGACCAGCCAGTGCA
`ATCCTGMGACCAGCCAGTGCAC
`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
`AAGAGGTGTATGGCTTCA.ACCCT
`AGAGGTGTATGGCTTCAACCCTG
`GAGGTGTATGGCTTCAACCCTGA
`AGGTGTATGGCTTCAACCCTGAG
`GGTGTATGGCTTCAACCCTGAGG
`GTGTATGGCTTCAACCCTGAGGG
`TGTATGGCTTCAACCCTGAGGGC
`GTATGGCTTCAACCCTGAGGGCA
`TATGGCTTCAACCCTGAGGGCM
`ATGGCTTCAACCCTGAGGGCAAA
`TGGCTTCAACCCTGAGGGCAAAG
`GGCTTCAACCCTGAGGGCAAAGC
`
`Moderna Ex 1004-p. 30
`Moderna v Arbutus
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 30 of 236 US 2006/0134189 Al
`
`Position
`439-461
`440-462
`441-463
`442-4 64
`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
`468-490
`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
`CMCCCTGAGGGCAAAGCCTTGC
`AACCCTGAGGGCAAAGCCTTGCT
`ACCCTGAGGGCAAAGCCTTGCTG
`CCCTGAGGGCMAGCCTTGCTGA
`CCTGAGGGCAAAGCCTTGCTGAA
`CTGAGGGCAAAGCCTTGCTGAAG
`TGAGGGCAAAGCCTTGCTGAAGA
`GAGGGCAAAGCCTTGCTGAAGAA
`AGGGCAAAGCCTTGCTGAAGAAA
`GGGCAAAGCCTTGCTGAAGAAAA
`GGCAAAGCCTTGCTGAAGAAAAC
`GCAAAGCCTTGCTGAAGAAAACC
`CAAAGCCTTGCTGMGAAAACCA
`AAAGCCTTGCTGAAGAAMCCAA
`AAGCCTTGCTGAAGAAAACCAAG
`AGC C TTGCTGA.AGAAAAC CAAGA
`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
`AGGAGTT'l'GCTGCAGCCATGTCC
`GGAGTTTGCTGCAGCCATGTCCA
`GAGTTTGCTGCAGCCATGTCCAG
`AGTTTGCTGCAGCCATGTCCAGG
`GTTTGCTGCAGCCATGTCCAGGT
`TTTGCTGCAGCCATGTCCAGGTA
`TTGCTGCAGCCATGTCCAGGTAT
`TGCTGCAGCCATGTCCAGGTATG
`GCTGCAGCCATGTCCAGGTATGA
`CTGCAGCCATGTCCAGGTATGAG
`TGCAGCCATGTCCAGGTATGAGC
`GCAGCCATGTCCAGGTATGAGCT
`CAGCCATGTCCAGGTATGAGCTC
`AGCCATGTCCAGGTATGAGCTCA
`GCCATGTCCAGGTATGAGCTCAA
`CCATGTCCAGGTATGAGCTCAAG
`CATGTCCAGGTATGAGCTCAAGC
`.,ATGTCCAGGTATGAGCTCAAGCT
`
`Moderna Ex 1004-p. 31
`Moderna v Arbutus
`
`

`

`Patent Application Publication Jun. 22, 2006 Sheet 31 of 236 US 2006/0134189 Al
`
`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
`560-5B2
`561-583
`562-584
`563-585
`564-586
`565-587
`566-588
`567-589
`568-590
`569-591
`570-592
`
`Sequence
`'l'G'rCCAGGT ATGAGCTCAAGC TG
`GTCCAGGTATGAGCTCAAGCTGG
`TCCAGGTATGAGCTCAAGCTGGC
`CCAGGTATGAGCTCAAGCTGGCC
`CAGGTATGAGCTCAAGCTGGCCA
`AGGTATGAGCTCAAGCTGGCCAT
`GGTATGAGCTCAAGCTGGCCATT
`GTATGAGCTCAAGCTGGCCAT'l'C
`TATGAGCTCAAGCTGGCCATTCC
`ATGAGCTCAAGCTGGCCA'l'TCCA
`TGAGCTCAAGCTGGCCATTCCAG
`GAGCTCAAGCTGGCCATTCCAGA
`AGCTCAAGCTGGCCATTCCAGAA
`GCTCAAGCTGGCCATTCCAGAAG
`CTCAAGCTGGCCATTCCAGAAGG
`TCAAGCTGGCCATTCCAGAAGGG
`CAAGCTGGCCATTCCAGAAGGGA
`AAGCTGGCCATTCCAGAAGGGAA
`AGCTGGCCATTCCAGAAGGGAAG
`GCTGGCCATTCCAGAAGGGAAGC
`CTGGCCATTCCAGAAGGGAAGCA
`TGGCCATTCCAGAAGGGAAGCAG
`GGCCATTCCAGAAGGGAAGCAGG
`GCCATTCCAGAAGGGAAGCAGGT
`CCATTCCAGAAGGGAAGCAGGTT
`CATTCCAGAAGGGAAGCAGGTTT
`ATTCCAGAAGGGAAGCAGGTTTT
`TTCCAGAAGGGAAGCAGGTTTTC
`TCCAGAAGGGA.AGCAGGTTTTCC
`CCAGAAGGGAAGCAGGTTTTCCT
`CAGAAGGGAAGCAGGTTTTCCTT
`AGAAGGGAAGCAGGTTTTCCTTT
`GAAGGGAAGCAGGTTTTCCTTTA
`AAGGGAAGCAGGTTTTCCTTTAC
`AGGGAAGCAGGTTTTCCTTTACC
`GGGAAGCAGGTTTTCCTTTACCC
`GGAAGCAGGTTTTCCTTTACCCG
`GAAGCAGGTTTTCCT'l'TACCCGG
`AAGCAGGTTTTCCTTTACCCGGA
`AGCAGG'l'1"l'TCCTTTACCCGGAG
`GCAGGTTTTCCTTTACCCGGAGA
`CAGG1'TTTCCTTTACCCGGAGAA
`AGGTTT'rCC1'TTACCCGGAGAAA
`GGTTTTCCTTTACCCGGAGAAAG
`GTT'l"J'CCTTTACCCGGAGAAAGA
`TTTTCCTTTACCCGGAGAAAGAT
`'l''l'TCCTTTACCCGGAGAAAGATG
`TTCCTTTACCCGGAGAAAGATGA
`TCCTTTACCCGGAGAAAGATGAA
`CCTTTACCCGGAGAAAGATGAAC
`CTTTACCCGGAGAAAGATGAACC
`TTTACCCGGAGAAAGATGAACCT
`TTACCCGGAGAAAGATGAACCTA
`TACCCGGAGAA