DEMONSTRATIVE EXHIBITS
`OF PETITIONERS
`
`PGR2022-00014
`U.S. PATENT NO. 10,947,513
`
`Oral Argument Date: March 17, 2023 at 1:00 PM
`
`Petitioners’ Demonstratives
`Not Evidence
`
`1
`
`TRANSGENE/BIOINVENT − Ex. 1107
`Transgene et al. v. Replimune
`PGR2022-00014
`
`
`OF PETITIONERS
`
`PGR2022-00014
`U.S. PATENT NO. 10,947,513
`
`Oral Argument Date: March 17, 2023 at 1:00 PM
`
`Petitioners’ Demonstratives
`Not Evidence
`
`1
`
`TRANSGENE/BIOINVENT − Ex. 1107
`Transgene et al. v. Replimune
`PGR2022-00014
`
`
`
`ROADMAP OF DISCUSSION
`• Summary of claimed subject matter [Slides 3-5]
`• Discuss Grounds 4 & 6 still at issue in this PGR
`• Claims 1 & 11 were anticipated by Silvestre (Ground 3) [Slides 6-20]
`• Claims 1 & 11 would have been obvious over Du, Choi, and
`Zitvogel (Ground 6) [Slides 21-40]
`• Claim 13 would have been obvious over either Silvestre (Ground
`4) or Du, Choi, and Zitvogel (Ground 6) [Slides 41-53]
`• No unexpected results of Claim 13 [Slides 54-56]
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`2
`
`See Petition (Paper 1) at pp. 7-8, 41-43, 48, 52-55,
`62-69, 72-75; Petitioner's Reply to Patent Owner
`Response (Paper 24) at pp. 22-26
`
`
`
`CLAIM 1 HAS FOUR BASIC COMPONENTS
`
`Oncolytic
`virus
`
`Heterologous GM-CSF
`encoding gene
`
`Both heterologous genes
`inserted into viral genome
`
`Heterologous CTLA-4
`inhibitor encoding gene
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`3
`
`Ex. 1001 at 81:51-54; Paper 1 at pp. 64-66;
`Ex. 1007 at ¶¶ 263-278; Ex. 1106 at 85:14-20
`
`
`
`CLAIMS 11 AND 13 ADDITIONAL COMPONENTS
`
`Specifies insertion locus
`
`Specifies insertion strategy
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`4
`
`Ex. 1001 at 83:17-25; Paper 1 at pp.
`48, 54-55; Ex. 1106 at 88:11-20
`
`
`
`COMBINED ELEMENTS OF CLAIM 13
`Elements of Claim 13:
`1. Oncolytic (Claim 1) HSV (Claim 11)
`2. Heterologous GM-CSF encoding gene (Claim 1)
`3. Heterologous CTLA-4 inhibitor encoding gene (Claim 1)
`4. Both genes inserted into the viral genome (Claim 1) at the
`ICP34.5 locus (Claim 13)
`5. Genes inserted in back-to-back orientation under separate
`regulatory control (Claim 13)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`5
`
`Ex. 1001 at 81:51-54, 83:17-25; Paper 1 at pp. 48, 54-55, 64-
`66; Ex. 1007 at ¶¶ 263-278; Ex. 1106 at 85:14-20, 88:11-20
`
`
`
`SILVESTRE DISCLOSES EACH AND EVERY
`ELEMENT OF CLAIMS 1 AND 11
`Silvestre (Ex.1002)
`“The present invention concerns an oncolytic virus comprising inserted
`in its genome one or more nucleic acid molecule(s) encoding one or
`more immune checkpoint modulator(s).” Ex.1002, 3:23-26 (emphasis
`added); see also id., 3:31-32 (“In one embodiment, the oncolytic virus is a
`vaccinia virus.”).
`“In one embodiment, the oncolytic virus of this invention further
`expresses at least one therapeutic gene inserted in the viral genome.”
`Ex.1002, 10:8-10.
`
`Claim 1
`An oncolytic virus
`comprising
`
`(i) a heterologous
`GM-CSF-encoding
`gene; and
`
`“Advantageously, the oncolytic virus of the present invention carries a
`therapeutic gene selected from the group consisting of genes encoding
`suicide gene products and immunostimulatory proteins.” Id., 10:28-31.
`
`“Preferably, the immunostimulatory protein is an interleukin or a colony-
`stimulating factor, with a specific preference for GM-CSF.” Id., 12:7-9
`(emphasis added).
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`Ex. 1007 at ¶ ¶ 182-190;
`Paper 1 at pp. 42-43
`
`6
`
`
`
`SILVESTRE DISCLOSES EACH AND EVERY
`ELEMENT OF CLAIMS 1 AND 11
`Silvestre (Ex.1002)
`“In one embodiment, the encoded one or more immune checkpoint
`modulator(s) is an antagonist molecule that antagonizes the activity of PD-
`1, PD-L1 or CTLA4 with a specific preference for an anti PD-1 antibody
`and/or an anti CTLA4 antibody.” Ex.1002, 3:44-48 (emphasis added); see
`also id., 15:5-8.
`
`Claim 1
`(ii) a heterologous
`CTLA-4 inhibitor
`encoding gene,
`
`wherein both
`heterologous genes
`are inserted into the
`genome of the virus.
`
`“The present invention concerns an oncolytic virus comprising inserted
`in its genome one or more nucleic acid molecule(s) encoding one or
`more immune checkpoint modulator(s).” Ex.1002, 3:23-26 (emphasis
`added).
`
`“The nucleic acid molecule(s) encoding the immune checkpoint
`modulator(s) and eventually the therapeutic gene(s) can independently
`be inserted at any location of the viral genome, with a specific preference
`for a non-essential locus.” Id., 16:4-8.
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`7
`
`Ex. 1007 at ¶ ¶ 182-190;
`Paper 1 at pp. 42-43
`
`
`
`SILVESTRE DISCLOSES EACH AND EVERY
`ELEMENT OF CLAIMS 1 AND 11
`
`Claim
`
`Claim 11:
`
`The virus of claim 1,
`which is a herpes
`simplex virus (HSV).
`
`Silvestre (Ex.1002)
`“In one embodiment, the oncolytic virus of the present
`invention is obtained from a herpes virus. … Although the
`oncolytic herpes virus can be derived from different types of
`HSV, particularly preferred are HSV1 and HSV2.” Ex.1002,
`7:52-60 (emphasis added).
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`8
`
`Ex. 1007 at ¶ 210; Paper 1 at p. 48
`
`
`
`SILVESTRE DISCLOSES EACH AND EVERY
`ELEMENT OF CLAIMS 1 AND 11
`
`• Dr. Chiocca’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`9
`
`Ex. 1106 at 104:17-105:9; Paper 24 at p. 1
`
`
`
`SILVESTRE PROVIDES ONLY TWELVE
`REALISTIC OPTIONS, NOT “OVER 5,000”
`Dr. Chiocca’s Analysis:
`11 x 14 x 33 =
`5,000 possibilities
`
`11 options listed
`in Silvestre
`
`2-3 preferred
`options
`
`14 options listed
`in Silvestre
`
`2 preferred
`options
`
`Proper Objective Analysis:
`3 x 2 x 2 =
`12 combinations
`
`33 options listed
`in Silvestre
`
`2 preferred
`options
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`10
`
`Ex. 2009 at ¶ 29; Patent Owner Response
`(Paper 22) at pp. 14-17; Paper 24 at pp. 2-8
`
`
`
`SILVESTRE IDENTIFIES ONLY TWO OF
`THE ELEVEN AS PREFERRED VIRUSES
`
`• Patent Owner Response and Dr. Chiocca’s declaration (quoting Silvestre):
`
`Note: Vaccinia
`is a poxvirus
`(see, e.g., Ex.
`2009 at ¶ 27)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`11
`
`Paper 22 at p. 13; Ex. 2009 at
`¶ 28; Paper 24 at pp. 3-4
`
`
`
`SILVESTRE IDENTIFIES ONLY TWO OF
`THE ELEVEN AS PREFERRED VIRUSES
`• Dr. Chiocca’s deposition:
`• Silvestre’s disclosure:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`12
`
`Ex. 1002 at 7:58-60; Ex. 1106 at
`113:21-114:5; Paper 24 at pp. 3-4
`
`
`
`A POSITA WOULD HAVE IMMEDIATELY ENVISAGED
`ONLY THREE VIRUSES FROM SILVESTRE’S ELEVEN
`
`• Dr. Chiocca’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`13
`
`Ex. 1106 at 111:17-112:2, 122:19-
`123:4; Paper 24 at pp. 3-4
`
`
`
`THERE ARE THREE REALISTIC VIRUS OPTIONS ON
`WHICH A POSITA WOULD HAVE FOCUSED IN 2016
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`14
`
`Paper 24 at p. 4; Ex. 2009
`at ¶ 29; Paper 22 at p. 15
`
`
`
`SILVESTRE IDENTIFIES ONLY TWO PREFERRED
`IMMUNE CHECKPOINT MODULATORS
`
`• Silvestre’s disclosure:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`15
`
`Ex. 1002 at 3:44-48, 14:11-15, 15:5-8; Paper
`24 at p. 5; Ex. 1106 at 124:11-125:11
`
`
`
`SILVESTRE IDENTIFIES ONLY TWO PREFERRED
`IMMUNE CHECKPOINT MODULATORS
`
`• Dr. Chiocca’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`16
`
`Ex. 1106 at 124:11-125:11; Paper 24 at p. 5
`
`
`
`SILVESTRE IDENTIFIES ONLY TWO PREFERRED
`IMMUNE CHECKPOINT MODULATORS
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`17
`
`Paper 24 at p. 5; Ex. 2009
`at ¶ 29; Paper 22 at p. 15
`
`
`
`SILVESTRE IDENTIFIES ONLY TWO
`PREFERRED THERAPEUTIC GENES
`
`• Silvestre’s disclosure:
`
`• Silvestre’s claims:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`18
`
`Ex. 1002 at 11:33-35, 12:7-9, 38:41-
`42; 38:48-49; Paper 24 at p. 6
`
`
`
`SILVESTRE IDENTIFIES ONLY TWO
`PREFERRED THERAPEUTIC GENES
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`19
`
`Paper 24 at p. 6-7; Ex. 2009
`at ¶ 29; Paper 22 at p. 15
`
`
`
`SILVESTRE HIGHLIGHTS JUST
`TWELVE COMBINATIONS
`
`Proper Objective
`Analysis:
`
`3 preferred
`options (max)
`
`2 preferred
`options
`
`3 x 2 x 2 =
`12 combinations
`
`2 preferred
`options
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`20
`
`Paper 24 at pp. 2-8; Ex. 2009
`at ¶ 29; Paper 22 at p. 15
`
`
`
`CLAIMS 1 AND 11 WOULD HAVE BEEN
`OBVIOUS OVER DU, CHOI, AND ZITVOGEL
`
`Claim / Limitation
`
`1. An oncolytic virus comprising:
`(i) a heterologous GM-CSF encoding gene; and
`(ii) a heterologous CTLA-4 inhibitor encoding
`gene,
`wherein both heterologous genes are inserted into
`the genome of the virus.
`11. The virus of claim 1, which is a herpes simplex
`virus (HSV).
`
`Disclosed by:
`Choi
`Zitvogel
`Yes
`Yes
`Yes
`Yes
`
`Du
`Yes
`Yes
`Yes
`
`Yes
`
`Yes
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`21
`
`Ex. 1007 at ¶¶ 246-250, 263-282,
`316; Paper 1 at pp. 58-59, 64-68, 74
`
`
`
`DU’S TEACHINGS
`
`• Dr. Bell’s declaration:
`“Du explicitly teaches the creation of two separate engineered oncolytic viruses, one
`with [a heterologous GM-CSF-encoding gene] and one with [a heterologous CTLA-4
`inhibitor encoding gene], wherein the heterologous gene is inserted into the genome
`of the virus.” (Bell Declaration at ¶ 249)
`
`• Du’s disclosure:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`22
`
`Ex. 1007 at ¶ 249; Ex. 1003 at pp.
`340, 342; Paper 1 at pp. 58-59
`
`
`
`DU’S TEACHINGS
`
`• Du’s disclosure:
`
`• Dr. Bell’s declaration:
`“Du’s teaching that co-administering
`of viruses expressing each of GM-
`CSF and anti-CTLA-4 antibody
`proteins in combination provides an
`improved therapeutic result.” (Bell
`Declaration at ¶ 281)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`23
`
`Ex. 1007 at ¶ 281; Ex. 1003 at
`p. 347; Paper 1 at p. 67
`
`
`
`DU’S TEACHINGS
`
`• Dr. Chiocca’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`24
`
`Ex. 1106 at 154:17-155:4,
`165:2-10; Paper 24 at p. 14
`
`
`
`CHOI’S TEACHINGS
`
`• Dr. Bell’s declaration:
`“Choi discloses an oncolytic virus comprising two heterologous genes inserted into the viral
`genome, one of which encodes GM-CSF and the second of which encodes a gene that binds, and
`possibly inhibits, CTLA-4, as per Claim 1.” (Bell Declaration at ¶ 275)
`
`• Choi’s disclosure:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`25
`
`Ex. 1007 at ¶ 275; Ex. 1005 at
`p. 1011; Paper 1 at pp. 64-66
`
`
`
`CHOI’S TEACHINGS
`
`• Dr. Chiocca’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`26
`
`Ex. 1106 at 164:11-165:1;
`Paper 24 at pp. 14-15
`
`
`
`ZITVOGEL’S TEACHINGS
`
`• Dr. Bell’s declaration:
`“Zitvogel’s vaccinia virus expressing a GM-CSF
`immunostimulatory protein is an oncolytic virus
`comprising a heterologous GM-CSF-encoding
`gene within the viral genome, as per Claim 1.”
`(Bell Declaration at ¶ 269)
`
`• Dr. Bell’s declaration:
`“Zitvogel discloses the additional limitation
`of Claim 11 [herpes simplex virus (HSV)]”
`(Bell Declaration at ¶ 316)
`
`• Zitvogel’s disclosure:
`
`• Zitvogel’s disclosure:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`27
`
`Ex. 1007 at ¶¶ 269, 316, 317; Ex. 1004 at 7:49-53, 8:16-18, 12:28-
`30, 13:60-62; Paper 24 at p. 16; Paper 1 at pp. 64-66, 74
`
`
`
`ZITVOGEL’S TEACHINGS
`
`• Dr. Chiocca’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`28
`
`Ex. 1106 at 169:2-4, 170:6-17; Paper 24 at p. 14
`
`
`
`MOTIVATION TO COMBINE
`DU, CHOI, AND ZITVOGEL
`
`• Dr. Bell’s declaration:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`29
`
`Ex. 1007 at ¶ 280; Paper 1 at p. 67; Paper 24 at p. 14
`
`
`
`REASONABLE EXPECTATION OF SUCCESS
`IN MAKING THE COMBINATION
`
`• Dr. Bell’s declaration:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`30
`
`Ex. 1007 at ¶ 281; Paper 1 at pp. 67-68; Paper 24 at p. 14
`
`
`
`A POSITA NEED ONLY HAVE MADE A SIMPLE
`SUBSTITUTION OF ONE KNOWN ELEMENT FOR ANOTHER
`
`• Dr. Chiocca’s deposition: Teachings of Du and Choi
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`31
`
`Ex. 1106 at 166:2-22; Paper 24 at p. 15
`
`
`
`ONLY DISTINCTION BETWEEN ZITVOGEL AND CLAIM 11
`IS LACK OF HETEROLOGOUS ANTI-CTLA-4 GENE
`
`• Dr. Chiocca’s deposition: Teachings of Zitvogel
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`32
`
`Ex. 1106 at 173:8-16; 173:21-174:6;
`Paper 24 at p. 16
`
`
`
`WHAT ZITVOGEL SUPPOSEDLY LACKS,
`DU ALREADY TEACHES
`• Replimune’s argument: “Zitvogel is directed to the sequential
`administration of an immune checkpoint modulator and oncolytic
`virus”:
`• “Du, the primary reference in
`the combination, teaches the
`advantages of simultaneous
`administration of oncolytic
`viruses encoding anti-CTLA-4
`antibody and encoding GM-
`CSF” (Paper 24 at p. 18)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`33
`
`Paper 22 at pp. 28-31; Paper 24 at
`pp. 17-18; Ex. 1003 at p. 347
`
`
`
`WHAT ZITVOGEL SUPPOSEDLY LACKS,
`DU ALREADY TEACHES
`• Replimune’s argument: “Zitvogel Has No data on the Co-
`Administration of an Anti-CTLA-4 Antibody and Oncolytic Virus
`Encoding GM-CSF”:
`• “Du has [data on simultaneous
`administration] and teaches
`the enhanced therapeutic
`benefit of simultaneous
`administration of oncolytic
`viruses encoding anti-CTLA-4
`antibody and encoding GM-
`CSF.” (Paper 24 at p. 18)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`34
`
`Paper 22 at pp. 31-32; Paper 24 at
`pp. 17-18; Ex. 1003 at p. 347
`
`
`
`WHAT ZITVOGEL SUPPOSEDLY LACKS,
`DU ALREADY TEACHES
`• Replimune’s argument: “Viral-Based Expression Vectors [for anti-
`CTLA-4] of Zitvogel Are Not Oncolytic Viruses”:
`
`• “it is undisputed that Du teaches such use [of oncolytic virus as a
`vector for anti-CTLA-4]” (Paper 24 at p. 18)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`35
`
`Paper 22 at pp. 32-35; Paper 24 at
`pp. 17-18; Ex. 1003 at p. 340
`
`
`
`MOTIVATION TO USE GM-CSF AND
`ANTI-CTLA-4 TOGETHER COMES FROM DU
`• Replimune’s argument: “in the intervening ten-plus years [from Choi’s
`publication], no POSA was motivated by Choi … to make a single oncolytic
`virus comprising a GM-CSF-encoding gene and a CTLA-4 inhibitor-encoding
`gene.”
`
`• Dr. Bell’s
`declaration:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`36
`
`Paper 22 at pp. 35-37; Ex. 1007 at ¶ 280;
`Paper 24 at pp. 18-19; Paper 1 at pp. 63-68
`
`
`
`MOTIVATION TO COMBINE: DU TEACHES PRESENCE OF
`ANTI-CTLA-4 AND GM-CSF WITH ONCOLYTIC VIRUS
`PROVIDES THERAPEUTIC BENEFIT
`• Dr. Chiocca’s deposition: Teachings of Du
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`37
`
`Ex. 1106 at 156:6-14, 165:2-10; Paper
`1 at p. 67; Paper 24 at pp. 14-15
`
`
`
`MOTIVATION TO INSERT TWO GENES INTO A
`SINGLE ONCOLYTIC VIRUS COMES FROM CHOI
`
`• Dr. Chiocca’s deposition: Teachings of Choi
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`38
`
`Ex. 1106 at 164:18-165:1;
`Paper 24 at pp. 18-19
`
`
`
`ZITVOGEL DOES NOT TEACH AWAY
`
`• Zitvogel’s disclosure:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`39
`
`Ex. 1004 at 22:44-55, 25:33-36,
`26:51-56; Paper 24 at pp. 19-20
`
`
`
`ZITVOGEL DOES NOT TEACH AWAY
`
`• Dr. Chiocca’s
`deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`40
`
`Ex. 1106 at 172:12-173:2; Paper 24 at p. 21
`
`
`
`IT WOULD HAVE BEEN OBVIOUS TO A POSITA TO USE
`CLAIM 13’S INSERTION LOCUS AND STRATEGY
`Specifies insertion locus
`
`Specifies insertion strategy
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`41
`
`Ex. 1001 at 83:20-25; Paper 1 at
`pp. 54-55; Ex. 1106 at 88:11-20
`
`
`
`INSERTION LOCUS OF CLAIM 13
`WAS WELL KNOWN IN 2016
`• Dr. Bell’s declaration:
`• Ex. 1078:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`42
`
`Ex. 1007 at ¶ 319; Ex. 1078 at p. 5763;
`Paper 1 at pp. 54, 74-75; Paper 24 at p. 9
`
`
`
`ICP34.5 INSERTION LOCUS
`WAS PUBLISHED IN 2016
`• Dr. Chiocca’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`43
`
`Ex. 1106 at 97:3-19; Paper 24 at p. 9
`
`
`
`INSERTION STRATEGY OF CLAIM 13
`WAS WELL KNOWN IN 2016
`• Dr. Bell’s declaration:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`44
`
`Ex. 1007 at ¶ 230; Paper 1 at
`pp. 54-55; Paper 24 at p. 9
`
`
`
`INSERTION STRATEGY OF CLAIM 13
`WAS WELL KNOWN IN 2016
`• Dr. Bell’s deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`45
`
`Ex. 2021 at 41:13-42:8; Ex. 1007
`at ¶ 32; Paper 24 at pp. 9-11
`
`
`
`PUBLICATIONS DEMONSTRATE INSERTION OF TWO
`HETEROLOGOUS GENES INTO AN ONCOLYTIC VIRUS
`Dr. Bell’s deposition: (redirect)
`Ex. 1102 (2010)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`46
`
`Ex. 2021 at 57:20-58:1; 58:18-21;
`Ex. 1102; Paper 24 at p. 19
`
`
`
`PUBLICATIONS DEMONSTRATE INSERTION OF TWO
`HETEROLOGOUS GENES INTO AN ONCOLYTIC VIRUS
`Dr. Bell’s deposition: (redirect)
`
`Ex. 1103 (2011)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`47
`
`Ex. 2021 at 59:13-18, 61:6-8;
`Ex. 1103; Paper 24 at p. 19
`
`
`
`PUBLICATIONS DEMONSTRATE INSERTION OF TWO
`PUBLICATIONS DEMONSTRATE INSERTION OF TWO
`HETEROLOGOUS GENES INTO AN ONCOLYTIC VIRUS
`HETEROLOGOUS GENES INTO AN ONCOLYTIC VIRUS
`Ex. 1101 (2017):
`eoee COO
`;
`Dr. Bell’s deposition: (redirect)
`Dr. Bell’s deposition: (redirect)
`Rapid Generation of Multiple Loci-Engineered
`Marker-free Poxvirus and Characterization
`
`Ex. 1101; Paper 24 at p. 19
`
`O.
`Okay. And where in this document does
`it show construction of a virus with two genes
`
`inserted ina locus in back-to-back orientation?
`
`A.
`
`That would be in Figure lA.
`
`QO.
`
`And in that paper, are the two genes
`
`under the control of separate regulatory
`
`elements?
`
`A.
`
`Right.
`
`The first gene is under the
`
`of a Clinical-Grade Oncolytic Vaccinia Virus
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`
`—
`yipgpt
`
`Petitioners’ Demonstratives
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`Not Evidence (Exhibit 1107)
`
`48
`48
`
`Ex. 2021 at 55:7-10, 56:17-20;
`Ex. 2021 at 55:7-10, 56:17-20;
`Ex. 1101; Paper 24 at p. 19
`
`
`
`BACK-TO-BACK INSERTION WAS WELL KNOWN
`
`• Dr. Chiocca’s
`deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`49
`
`Ex. 1106 at 147:17-148:3;
`Paper 24 at p. 9
`
`
`
`INSERTING TWO GENES IN BACK-TO-BACK
`ORIENTATION INTO THE ICP34.5 LOCUS OF
`ONCOLYTIC HSV WAS KNOWN
`• “Ex. 1084 … describes ‘a herpes
`virus with an insertion into the
`ICP34.5 locus of a … fusion protein
`and a suicide gene that are put in
`back-to-back [with] two separate
`regulatory elements.” (Paper 24 at
`pp. 10-11)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`50
`
`Paper 24 at pp. 10-12; Ex. 1084
`
`
`
`INSERTING TWO GENES IN BACK-TO-BACK
`ORIENTATION INTO THE ICP34.5 LOCUS OF
`ONCOLYTIC HSV WAS KNOWN
`
`• Dr. Chiocca’s
`deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`51
`
`Ex. 1106 at 185:11-14, 187:16-20;
`Paper 24 at pp. 9, 12, 19
`
`
`
`WHEN ONE REPEATS AN EXPERIMENT FROM
`THE LITERATURE, THERE IS REASONABLE
`EXPECTATION OF SUCCESS
`
`• Dr. Chiocca’s
`deposition:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`52
`
`Ex. 1106 at 93:9-18, 190:10-19;
`Paper 24 at pp. 9, 12
`
`
`
`A POSITA WOULD HAVE HAD A REASONABLE
`EXPECTATION OF SUCCESS IN USING THE
`APPROACH SHOWN IN EX. 1084
`• Dr. Chiocca’s deposition: (referring to Ex. 1084)
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`53
`
`Ex. 1106 at 189:7-13, 190:10-19; Paper 24 at p. 12
`
`
`
`REPLIMUNE’S ALLEGED UNEXPECTED
`RESULTS WERE NOT UNEXPECTED
`
`• Du’s disclosure:
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`54
`
`Ex. 1003 at p. 347; Paper 24 at pp. 22-23
`
`
`
`REPLIMUNE’S ALLEGED UNEXPECTED
`RESULTS WERE NOT UNEXPECTED
`• Dr. Chiocca’s deposition:
`Discussing Du
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`55
`
`Ex. 1106 at 158:21-159:13;
`Paper 24 at pp. 22-24
`
`
`
`ANY UNEXPECTED RESULT RELATES TO THE
`SUBJECT MATTER OF CLAIM 1, NOT CLAIM 13
`
`• Dr. Chiocca’s deposition: Discussing results of ’513 Patent
`
`Petitioners’ Demonstratives
`Not Evidence (Exhibit 1107)
`
`56
`
`Ex. 1106 at 151:19-152:5, 152:18-
`153:9; Paper 24 at pp. 24-25
`
`
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