`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`TRANSGENE AND BIOINVENT INTERNATIONAL AB
`
`Petitioners,
`
`v.
`
`REPLIMUNE LIMITED
`
`Patent Owner.
`
`Case No. PGR2022-00014
`
`Patent No. 10,947,513
`
`
`
`Patent Owner Response
`
`
`
`

`

`
`TABLE OF CONTENTS
`
`PGR2022-00014
`Patent No. 10,947,513
`
`Page
`
`
`INTRODUCTION .......................................................................................... 1
`I.
`THE CHALLENGED CLAIM ....................................................................... 4
`II.
`III. PERSON OF ORDINARY SKILL IN THE ART ......................................... 5
`IV. CLAIM CONSTRUCTION ........................................................................... 5
`V. DISCLAIMER ................................................................................................ 5
`VI. THE BOARD IMPERMISSIBLY INSTITUTED ON GROUNDS
`NOT PRESENTED IN THE PETITION ....................................................... 7
`VII. GROUND 4: CLAIM 13 IS NOT OBVIOUS OVER SILVESTRE ........... 11
`A.
`Silvestre Does Not Anticipate Claims 1 and 11 Because It Does
`Not Disclose the Limitations as Arranged in the Claims ................... 11
`Silvestre Does Not Render Claim 13 Obvious ................................... 17
`B.
`VIII. GROUND 6: CLAIM 13 IS NOT OBVIOUS OVER DU, CHOI AND
`ZITVOGEL ................................................................................................... 27
`A.
`Zitvogel Would Not Have Motivated a POSA to Modify Du’s
`Teachings ............................................................................................ 28
`1.
`Zitvogel Teaches Away from Making an Oncolytic Virus
`Encoding an Anti-CTLA-4 Antibody ...................................... 28
`Zitvogel Has No Data on the Co-Administration of an
`Anti-CTLA-4 Antibody and Oncolytic Virus Encoding
`GM-CSF ................................................................................... 31
`The Viral-Based Expression Vectors of Zitvogel Are Not
`Oncolytic Viruses ..................................................................... 32
`Choi Would Not Have Motivated a POSA to Modify Du’s
`Teachings ............................................................................................ 35
`Petitioners Have Not Shown that “Back-to-Back” Insertion
`Strategy Was the “Simplest” or “Most Common” ............................. 37
`
`2.
`
`3.
`
`B.
`
`C.
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`
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`-i-
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`TABLE OF CONTENTS
`(continued)
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`PGR2022-00014
`Patent No. 10,947,513
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`Page
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`D. A POSA Would Not Have Had a Reasonable Expectation of
`Success in Creating a Single Oncolytic Virus Encoding GM-
`CSF and a CTLA-4 Inhibitor ............................................................. 38
`IX. THE OBJECTIVE INDICIA SUPPORT A FINDING OF NON-
`OBVIOUSNESS ........................................................................................... 41
`CONCLUSION ............................................................................................. 48
`
`
`
`X.
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`
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`-ii-
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`
`
`TABLE OF AUTHORITIES
`
`PGR2022-00014
`Patent No. 10,947,513
`
` Page(s)
`
`Cases
`Akzo N.V. v. United States ITC,
`808 F.2d 1471 (Fed. Cir. 1986) .......................................................................... 16
`In re Arkley,
`455 F.2d 586 (C.C.P.A. 1972) .............................................................................. 2
`Belden Inc. v. Berk–Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) .......................................................................... 23
`Chamberlain Grp., Inc. v. Techtronic Indus. Co.,
`935 F.3d 1341 (Fed. Cir. 2019) .......................................................................... 15
`Chemours Co. FC, LLC v. Daikin Indus., Ltd.,
`4 F.4th 1370 (Fed. Cir. 2021) ............................................................................. 30
`DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 30
`Endo Pharm., Inc. v. Depomed, Inc.,
`IPR2014-00651, Paper No. 12 (PTAB Sept. 29, 2014) ...................................... 16
`Eton Pharm., Inc. v. Exela Pharma Sciences, LLC,
`PGR2020-00086, Paper 13 (PTAB July 21, 2021) ............................................ 37
`Finisar Corp. v. DirecTV Grp., Inc.,
`523 F.3d 1323 (Fed. Cir. 2008) .......................................................................... 12
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .............................................................................. 30
`Hartness Int’l Inc. v. Simplimatic Eng’g Co.,
`819 F.2d 1100 (Fed. Cir. 1987) .......................................................................... 18
`
`
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`
`PGR2022-00014
`Patent No. 10,947,513
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`Page(s)
`
`Henny Penny Corp. v. Frymaster LLC,
`938 F.3d 1324 (Fed. Cir. 2019) .......................................................................... 17
`Intel Corporation v. PACT XPP Schweiz AG,
`IPR2020-00518, Paper 34 (PTAB Aug. 9, 2021) ................................................. 6
`Koninklijke Philips N.V. v. Google LLC,
`948 F.3d 1330 (Fed. Cir. 2020) ...................................................................... 9, 10
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................................... 36, 37
`Medtronic, Inc. v. Teleflex Innovs. S.A.R.L.,
`IPR2020-01341, Paper 93 (PTAB Feb. 7, 2022) ................................................ 17
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 41
`Otonomy, Inc. v. Auris Med., AG,
`743 F. App’x 430 (Fed. Cir. 2018) ..................................................................... 16
`Provepharm Inc. v. Wista Labs. Ltd.,
`IPR2018-00323, Paper 49 (PTAB July 2, 2019) .......................................... 25, 26
`Raytheon Techs. Corp. v. Gen. Elec. Co.,
`993 F.3d 1374 (Fed. Cir. 2021) ............................................................................ 6
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) .......................................................................... 12
`SAS Inst. Inc. v. Iancu,
`138 S. Ct. 1348 (2018) .................................................................................... 9, 10
`SHDS v. Truinject,
`IPR2020-00937, Paper 28 (PTAB Nov. 15, 2021) ............................................. 17
`Sirona Dental Sys. GmbH v. Institut Straumann AG,
`892 F.3d 1349 (Fed. Cir. 2018) .......................................................................... 10
`
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`Page(s)
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`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 41
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 41
`
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`-iii-
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`PGR2022-00014
`Patent No. 10,947,513
`
`EXHIBIT LIST
`Description
`U.S. Patent No. 10,947,513 (“’513 Patent”) Prosecution History
`Excerpt – March 15, 2022 Statutory Disclaimer
`’513 Patent Prosecution History Excerpt – January 13, 2021
`Examiner Interview Summary
`’513 Patent Prosecution History Excerpt – January 29, 2021
`Applicant Interview Summary
`’513 Patent Prosecution History Excerpt – February 1, 2021 Notice
`of allowance
`’513 Patent Prosecution History Excerpt – Third Party
`Observations
`Rough Transcript of 6 April 2022 Conference Call with the Board
`Email dated 19 April 2022 from Board to A. Stein
`U.S. Patent Publication No. 2022/0056480
`Declaration of E. Antonio Chiocca, M.D., Ph.D.
`https://www.transgene.fr/wp-content/uploads/SITC2021-
`poster_Transgene-BioInvent-BT-001.pdf
`Semmrich, Monika, et al. Vectorized Treg-depleting αCTLA-4
`elicits antigen cross-presentation and CD8+ T cell immunity to
`reject ‘cold’ tumors. Journal for immunotherapy of cancer 10.1
`(2022).
`U.S. Patent No. 10,765,710 (“Zitvogel”) Prosecution History
`Excerpts
`Thomas et al. Development of a new fusion-enhanced oncolytic
`immunotherapy platform based on herpes simplex virus type 1.
`Journal for immunotherapy of cancer 7.1 (2019): 1-17.
`Kaufman et al. Oncolytic viruses: a new class of immunotherapy
`drugs. Nature reviews Drug discovery 14.9 (2015): 642-662.
`U.S. Patent No. 10,555,981 (“Silvestre”) Prosecution History
`Excerpts
`’513 Patent Prosecution History Excerpt – April 30, 2020 Response
`
`iv
`
`
`
`
`
`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`2007
`2008
`2009
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`

`

`PGR2022-00014
`Patent No. 10,947,513
`
`Description
`Rojas et al. Defining Effective Combinations of Immune Checkpoint
`Blockade and Oncolytic VirotherapyOncolytic Virus Combination
`with Checkpoint Inhibitors. Clinical Cancer Research 21.24 (2015):
`5543-5551.
`Reserved
`Yang et al. Development of optimal bicistronic lentiviral vectors
`facilitates high-level TCR gene expression and robust tumor cell
`recognition. Gene therapy 15.21 (2008): 1411-1423.
`Kleinpeter et al. Vectorization in an oncolytic vaccinia virus of an
`antibody, a Fab and a scFv against programmed cell death-1 (PD-
`1) allows their intratumoral delivery and an improved tumor-
`growth inhibition. Oncoimmunology 5.10 (2016).
`Deposition Transcript of September 23, 2022 Deposition of Dr.
`John C. Bell
`Lun et al. Efficacy of systemically administered oncolytic vaccinia
`virotherapy for malignant gliomas is enhanced by combination
`therapy with rapamycin or cyclophosphamide. Clinical Cancer
`Research 15.8 (2009): 2777-2788.
`Curriculum vitae of E. Antoni o Chiocca, M.D., Ph.D.
`
`
`
`Exhibit
`2017
`
`2018
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`
`
`v
`
`

`

`
`I.
`
`INTRODUCTION
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`PGR2022-00014
`Patent No. 10,947,513
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`Replimune Limited (“Replimune” or “Patent Owner”) files this Response to
`
`Transgene and Bioinvent International AB (collectively, “Petitioners”)’s Petition for
`
`post grant review (“PGR”) of U.S. Patent No. 10,947,513 (“the ’513 Patent”). This
`
`response, which is accompanied by the expert declaration of E. Antonio Chiocca,
`
`M.D., Ph.D. (EX2009), is timely under the Board’s June 16, 2022 Scheduling Order
`
`(Paper 17) and the parties’ July 14, 2022 Notice of Joint Stipulation to Modify the
`
`Schedule (Paper 20).
`
` The Petition requested PGR of claims 1-8 and 10-26 of the ’513 Patent.
`
`Patent Owner has disclaimed claims 1-8, 10-12, and 14-26 by way of a Statutory
`
`Disclaimer filed on March 15, 2022. EX2001. Thus, only claim 13 remains at issue
`
`in this proceeding, which Petitioners allege is obvious in view of Silvestre (EX1002)
`
`(Ground 4), and obvious in view of the combination of Du (EX1003), Choi
`
`(EX1005), Zitvogel (EX1004) (Ground 6).
`
`Claim 13 is dependent on claim 11 which in turn is dependent on claim 1. The
`
`Petition’s Ground 4 did not allege that now disclaimed claims 1 and 11 were obvious
`
`over Silvestre. In its Institution Decision, the Board therefore considered
`
`Petitioners’ anticipation argument in non-instituted Ground 3, determining that
`
`“Silvestre teaches the limitations of claims 1 and 11.” Id. at 10 and 12. But merely
`
`teaching the limitations of claims 1 and 11 is not enough for anticipation.
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`
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`

`

`
`Anticipation requires that a reference “clearly and unequivocally disclose the
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`PGR2022-00014
`Patent No. 10,947,513
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`claimed [invention] or direct [POSAs] to [it] without any need for picking, choosing,
`
`and combining various disclosures not directly related to each other by the teachings
`
`of the cited reference.” In re Arkley, 455 F.2d 586, 587 (C.C.P.A. 1972) (original
`
`emphasis).
`
`Ground 4 fails because the disparate disclosures of Silvestre do not
`
`unequivocally disclose an oncolytic HSV encoding GM-CSF and CTLA-4 inhibitor
`
`as claimed. To the contrary, Silvestre is directed to making and characterizing an
`
`oncolytic vaccinia virus encoding an anti-PD1 antibody. Silvestre lacks any data or
`
`guidance regarding an oncolytic virus encoding any other heterologous gene, let
`
`alone two genes, such as GM-CSF and a CTLA-4 inhibitor.
`
`Additionally, Ground 4 fails because Petitioners have not shown that a POSA
`
`would have been motivated to pursue the “back-to-back” gene insertion strategy
`
`recited in claim 13 with a reasonable expectation of success. For this limitation,
`
`Petitioners solely rely on their expert Dr. Bell’s assertion that the “simplest and most
`
`common way” to insert two genes into a locus is in a “back-to-back orientation under
`
`the control of separate regulatory elements.” EX1007 ¶ 230. But at his deposition,
`
`Dr. Bell conceded that it was “perhaps an over-statement [to] say it’s the simplest
`
`and most common” (EX2021 at 43:3-4) and that “[t]here certainly are other
`
`
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`2
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`instances where people put genes in other vectors in series.” Id. at 42:16-17.1
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`Patent No. 10,947,513
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`And in fact, Dr. Bell and Petitioners are such people. EX2008 at Figure 38;
`
`EX2010 at Figure 5; EX2011 at Figure 1. This evidence belies Petitioners’
`
`hindsight-driven argument that a POSA necessarily would have used a back-to-back
`
`orientation insertion strategy as claimed.
`
`Petitioners’ Ground 6 based on Du, Choi and Zitvogel fares no better. Du and
`
`Choi are limited to oncolytic adenoviruses. Petitioners, therefore, rely on Zitvogel
`
`as providing the motivation to make an oncolytic HSV encoding GM-CSF and a
`
`CTLA-4 inhibitor. But not only does Zitvogel teach away from making an oncolytic
`
`virus that encodes an immune checkpoint inhibitor; it also lacks any data
`
`whatsoever regarding a combination of an anti-CTLA-4 antibody and oncolytic virus
`
`encoding GM-CSF, contrary to Petitioners’ and Dr. Bell’s assertion that Zitvogel
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`“teach[es] that the presence of anti-CTLA-4 and GM-CSF in combination with an
`
`oncolytic virus provides a synergistic effect and therapeutic benefit.” Petition at 67-
`
`68; EX2007 ¶¶ 280-81. As Dr. Bell conceded during his deposition, “[t]he figures
`
`as presented in Zitvogel do not have that scenario.” EX2021 at 23:16-17.
`
`Petitioners have also not shown that a POSA would have had a reasonable
`
`expectation of success in making the oncolytic HSV as claimed. In a highly
`
`
`1 Emphasis added throughout unless noted.
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`3
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`unpredictable field—according to Dr. Bell, “the field of virology, immunology, and
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`cancer biology is complex and unpredictable” (EX1007 ¶ 139)—a POSA would
`
`need more than the limited disclosures of Silvestre, Du, Choi and Zitvogel to have
`
`any degree of confidence that a POSA could arrive at the claimed invention. And
`
`this is confirmed by Transgene own prior statements to this Office during the
`
`prosecution of its own patents.
`
`For these reasons, and further reasons articulated below, Petitioners’
`
`challenges fail, and the Board should find that Petitioners failed to establish that
`
`claim 13 is unpatentable.
`
`II. THE CHALLENGED CLAIM
`Claim 13 is the only challenged claim remaining at issue in this proceeding.
`
`Claim 13 depends from claims 1 and 11. Re-written in independent format, claim
`
`13 recites:
`
`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 [(claim 1),]
`
`[wherein the virus] is a herpes simplex virus (HSV) [(claim 11),]
`
`wherein the GM-CSF-encoding gene and the CTLA-4 inhibitor
`encoding gene are inserted into the ICP34.5 encoding locus,
`either by insertion, or partial or complete deletion, in a back to
`4
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`Patent No. 10,947,513
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`back orientation in relation to each other, each under separate
`regulatory control [(claim 13)].
`
`III. PERSON OF ORDINARY SKILL IN THE ART
`In its Institution Decision, the Board adopted Petitioner’s definition of a
`
`POSA which is a person with “a Ph.D. in molecular biology, or a related field, with
`
`expertise in virology (including expertise growing, isolating, and rescuing viruses),
`
`immunology, and cancer biology with at least four years of post-Ph.D. experience
`
`in those areas.” Institution Decision at 8-9. For purposes of this proceeding only,
`
`Patent Owner does not dispute this definition.
`
`IV. CLAIM CONSTRUCTION
`Petitioners assert that “oncolytic virus” should be construed to mean “a virus
`
`that infects and replicates in tumor cells, such that the tumor cells are killed.”
`
`Petition at 6. Solely for purposes of this proceeding, Patent Owner does not dispute
`
`that an “oncolytic virus” is a “virus that infects and replicates in tumor cells, such
`
`that the tumor cells are killed.” Patent Owner, however, does dispute Petitioners’
`
`characterization of the term insofar as it encompasses “viral vectors” such as those
`
`disclosed in Zitvogel. See § VIII.A.3, infra.
`
`V. DISCLAIMER
`The Petition’s Grounds 3 and 6 alleged that now-disclaimed claims 1 and 11,
`
`from which claim 13 depends, are anticipated by Silvestre (Ground 3), or would
`
`
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`5
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`have been obvious over Du, Choi and Zitvogel (Ground 6). In its Institution
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`Decision, the Board stated that “Petitioner shows, and Patent Owner does not dispute
`
`(see Statutory Disclaimer), that Silvestre teaches the limitations of claims 1 and 11.”
`
`Institution Decision at 12; see also id. at 19 (“In view of Patent Owner’s disclaimer
`
`of claims 1 and 11, Petitioner shows, and Patent Owner does not dispute, that the
`
`combination of Du, Choi, and Zitvogel teaches or otherwise renders obvious the
`
`limitations of those claims.”)
`
`In reaching this conclusion, it appears that the Board relied on Patent Owner’s
`
`statutory disclaimer to find that the elements of claims 1 and 11 are disclosed in
`
`the prior art. Patent Owner respectfully submits that the Board erred in reaching this
`
`conclusion. The Federal Circuit and this Board has made clear that disclaimer “does
`
`not legally constitute ‘an admission that the subject of the disclaimer appears in the
`
`prior art.’” Raytheon Techs. Corp. v. Gen. Elec. Co., 993 F.3d 1374, 1379 n.4 (Fed.
`
`Cir. 2021); Intel Corporation v. PACT XPP Schweiz AG, IPR2020-00518, Paper 34
`
`at 2 (PTAB Aug. 9, 2021) (“We do not, as Petitioner urges, treat the disclaimer as
`
`Patent Owner ‘conceding the invalidity of claim 4.’” (emphasis original)—the Board
`
`ultimately finding that disclaimed claim 4 was not obvious, and therefore Intel had
`
`not proved that dependent claim 5 was obvious). For any avoidance of doubt, Patent
`
`Owner’s position remains that originally issued claims 1 and 11 are patentable over
`
`
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`6
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`

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`the cited art. Patent Owner disclaimed certain claims, including claims 1 and 11,
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`Patent No. 10,947,513
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`solely to narrow the issues in dispute.
`
`VI. THE BOARD IMPERMISSIBLY INSTITUTED ON GROUNDS NOT
`PRESENTED IN THE PETITION
`
`At institution, the Board recognized, in addressing the “back-to-back
`
`orientation” limitation of claim 13, that Dr. Bell does not cite a single prior art
`
`reference for his assertion that “[t]he simplest and most common method to insert
`
`two genes to a locus is in a back-to-back orientation under control of separate
`
`regulatory elements.” See Institution Decision at 14 (acknowledging that “Patent
`
`Owner is correct in stating that no sources are cited in paragraph 230” of the Bell
`
`Declaration addressing claim 13); see also EX2021 at 41:7-10, 44:2-5. And while
`
`it is true that Dr. Bell’s paragraph 230 “does cite back to paragraphs 73-81 and 87-
`
`88 of his own declaration” (Institution Decision at 14), none of those paragraphs
`
`addresses the “back-to-back orientation” limitation. Indeed, as the Board explained:
`
`In those paragraphs, Dr. Bell explains that the “deletion of
`endogenous nucleotides requires either pre-existing knowledge
`of the effect of disrupting the particular gene at the insertion site
`or requires a difficult and time-consuming trial-and-error process
`to gain such knowledge.” Id. ¶ 73 (citing Ex. 1035). Exhibit 1035
`is a review article entitled “Unconventional viral gene expression
`mechanisms as therapeutic targets.” See Ex. 1035. Dr. Bell
`points to Figure 1 of this article as showing that certain viral
`
`
`
`7
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`genomes include genes that are overlapping and/or that encode
`polyproteins, which can add to a further level of difficulty in
`identifying a suitable insertion locus. Ex. 1007 ¶ 74 (citing Ex.
`1035, 364, Fig. 1). Dr. Bell further explains that “inactivation of
`the neurovirulence factor ICP34.5 in HSV1 has been well-known
`to direct tumor-specific cell lysis, making HSV1 ICP34.5 knock-
`outs useful oncolytic virus vectors,” but also notes that “unless
`such a well-known insertion site is used, determining whether
`insertion of a heterologous gene at any particular site will be
`successful requires a difficult and time-consuming trial-and-
`error process.” Id. ¶ 77 (citing Ex. 1039, 292, Ex. 1040, 4–7, Ex.
`1041, 575).
`
`Institution Decision at 14-15. As is clear, the Board failed to make any mention of
`
`a “back-to-back orientation” in its discussion of Dr. Bell’s paragraphs 73-81 and 87-
`
`88. In short, neither the Petition nor Dr. Bell has provided any evidentiary support
`
`for the assertion that “[t]he simplest and most common method to insert two genes
`
`to a locus is in a back-to-back orientation”—because it is not—nor have they set
`
`forth a combination of references that even presents a prima facie case of
`
`obviousness.
`
`The Board nevertheless “determine[d] that Petitioner has provided sufficient
`
`evidence … to show that inserting the genes at issue in a back-to-back orientation
`
`would have been known in the art.” Institution Decision at 15-16. As support for
`
`
`
`8
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`this conclusion, the Board pointed to EX1084, in a footnote, as purportedly
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`PGR2022-00014
`Patent No. 10,947,513
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`“showing back-to-back insertion of two genes at ICP34.5 in HSV1 virus.” Id. at 16,
`
`n.7. But EX1084 was not relied upon in the Petition as disclosing that limitation.
`
`Rather, EX1084 was cited only against claim 5 for the proposition that “GALV-R-
`
`was a well-known fusogenic protein with known functionality when heterologously
`
`expressed in oncolytic viruses.” Petition at 70; see also id. at 53.
`
`The Petition guides the proceeding. See Koninklijke Philips N.V. v. Google
`
`LLC, 948 F.3d 1330, 1335–36 (Fed. Cir. 2020). The Federal Circuit has explained
`
`that “Congress chose to structure a process in which it's the petitioner ... who gets to
`
`define the contours of the proceeding,” and that “the statute envisions that a
`
`petitioner will seek an inter partes review of a particular kind—one guided by a
`
`petition describing ‘each claim challenged’ and ‘the grounds on which the
`
`challenge to each claim is based.’ ” Id. at 1335. “Although the Board is not limited
`
`by the exact language of the petition, ... the Board does not ‘enjoy[] a license to
`
`depart from the petition and institute a different inter partes review of his own
`
`design.’ ” Id. at 1336 (quoting SAS Inst. Inc. v. Iancu, 138 S. Ct. 1348, 1356 (2018)).
`
`Here, the Petition alleges that claim 13 would have been obvious over
`
`Silvestre (Ground 4) or the combination of Du, Choi, and Zitvogel (Ground 6). See
`
`Petition at 54-55; id. at 74-75. With all due respect, the Board departed from the
`
`Petition and improperly instituted trial based on two prior art combinations that adds
`
`
`
`9
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`EX1084 (to support Petitioners’ “simplest” and “most common” argument), neither
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`PGR2022-00014
`Patent No. 10,947,513
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`of which were advanced in the Petition, in violation of Supreme Court and Federal
`
`Circuit precedent. SAS, 138 S. Ct. at 1355 (“[T]he petitioner, not the Director, …
`
`define[s] the contours of the proceeding”), id. at 1356 (The Board does not “enjoy[]
`
`a license to depart from the petition and institute a different inter partes review.”);
`
`Koninklijke Philips, 948 F.3d at 1335 (“We hold that the Board erred by
`
`instituting inter partes review based on a combination of prior art references
`
`not advanced in [the] petition.”); Sirona Dental Sys. GmbH v. Institut Straumann
`
`AG, 892 F.3d 1349, 1356 (Fed. Cir. 2018) (“It would thus not be proper for the Board
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`to deviate from the grounds in the petition and raise its own obviousness theory …”).
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`Because it constitutes reversible error to invalidate claim 13 premised on prior art
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`combinations that Petitioners did not present in the Petition, Patent Owner
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`respectfully requests that the Board affirm the patentability of claim 13, as
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`Petitioners have not otherwise shown that claim 13 would have been obvious over
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`the originally presented combinations, as shown below.2
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`2 But even if EX1084 were to be considered, the fact that back-to-back could have
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`been used is not enough to show that a POSA would have been motivated to use
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`that strategy. See § VII.B, infra.
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`10
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`VII. GROUND 4: CLAIM 13 IS NOT OBVIOUS OVER SILVESTRE
`As noted above, claim 13 depends on claim 11, which itself depends on claim
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`1. Because Ground 4 did not assert that claims 1 and 11 were obvious over Silvestre,
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`the entirety of Petitioners’ argument for why claim 13 would have been obvious is
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`premised on the argument that Silvestre anticipates claims 1 and 11. See also
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`Institution Decision at 10 (“In our assessment of Petitioner’s obviousness argument
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`for claim 13, we have also considered Petitioner’s anticipation argument (Ground 3)
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`for disclaimed claims 1 and 11.”). However, as shown below, the Petition fails to
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`demonstrate that disclaimed claims 1 and 11 are anticipated by Silvestre. For this
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`reason alone, Ground 4 fails.
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`But even if the Board were to find that claims 1 and 11 are anticipated by
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`Silvestre, Petitioners have not shown that the additional limitations of claim 13
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`would have been obvious in view of Silvestre, as discussed below. Ground 4,
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`therefore, fails for this additional reason.
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`Silvestre Does Not Anticipate Claims 1 and 11 Because It Does Not
`Disclose the Limitations as Arranged in the Claims
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`As noted, Ground 4 challenges claim 13 based on obviousness over Silvestre.
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`Ground 4 did not include a separate obviousness analysis for claims 1 and 11, from
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`which claim 13 depends. In its Institution Decision, the Board therefore “considered
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`Petitioner’s anticipation argument (Ground 3) for disclaimed claims 1 and 11” (see
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`11
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`Institution Decision at 10) and found that “Silvestre teaches the limitations of claims
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`1 and 11.” Id. at 12. However, to anticipate, a reference “must not only disclose all
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`elements of the claim within the four corners of the document, but must also disclose
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`those elements arranged as in the claim.” Sanofi-Synthelabo v. Apotex, Inc., 550
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`F.3d 1075, 1083 (Fed. Cir. 2008). It is “not quite enough” if a reference discloses
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`elements without putting them together. Finisar Corp. v. DirecTV Grp., Inc., 523
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`F.3d 1323, 1334 (Fed. Cir. 2008).
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`Here, Petitioners do not show that Silvestre arranges the limitations as recited
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`in claims 1 and 11. That is because they cannot do so. EX2009 ¶¶ 27-28. As
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`Petitioners themselves concede, “the bulk of Silvestre’s disclosure, including the
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`working examples, is directed toward creating an oncolytic poxvirus.” Petition at
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`44. For example, Silvestre’s sole independent claim is directed to “an oncolytic
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`virus comprising inserted in its genome a nucleic acid molecule encoding one or
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`more immune checkpoint modulator(s) wherein said virus is a vaccinia virus [i.e.,
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`a poxvirus] defective for Ribonucleotide reductase (RR) activity … and defective
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`for thymidine kinase (TK) … wherein said one or more immune checkpoint
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`modulator(s) is an antibody that specifically binds to PD-1.” Id. at Claim 1.
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`Silvestre’s working examples are similarly limited to “a vaccinia virus (VV)
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`Western Reserve (WR) working strain defective for thymidine kinase (TK-) (locus
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`J2R) and RR- (locus I4L) rendering the virus non-replicative in healthy (non-
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`12
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`dividing) cells.” Id. at 27:10-16. The immune checkpoint inhibitor gene inserted
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`into the oncolytic virus in each of the examples is J43, a hamster antibody targeting
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`murine PD-1. Id. at 27:1-2.
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`Consistent with its working examples and claims, Silvestre states that:
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`In one embodiment, the oncolytic virus is a vaccinia virus. In a
`preferred embodiment, the vaccinia virus is engineered to lack
`thymidine kinase activity (e.g. the genome of said VV has an
`inactivating mutation in J2R gene to produce a defective TK
`phenotype). Alternatively or in combination, the vaccinia virus
`is engineered to lack RR activity (e.g. the genome of said VV has
`an inactivating mutation in I4L and/or F4L gene to produce a
`defective RR phenotype).
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`EX1001 at 3:30-44.
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`In a preferred embodiment, the oncolytic virus of this
`invention is a vaccinia virus defective for TK resulting from
`inactivating mutations in the J2R gene. In another preferred
`embodiment, the oncolytic virus of this invention is a vaccinia
`virus defective for both TK and RR activities resulting from
`inactivating mutations in both the J2R gene and the I4L and/or
`F4L gene(s) carried by the viral genome (e.g. as described in
`WO2009/065546 and Foloppe et al., 2008, Gene Ther., 15: 1361-
`71). In another preferred embodiment, the oncolytic virus of
`this invention is a vaccinia virus defective for dUTPase
`resulting from inactivating mutations in the F2L gene (e.g. as
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`13
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`described in WO2009/065547), eventually in combination with
`disruption of at least one of TK and RR activities or both …
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`Id. at 9:57 – 10:6.
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`In an alternative and also preferred embodiment, the oncolytic
`virus of the invention is a vaccinia virus (preferably from the
`Wyeth strain) defective for TK activity (resulting from
`inactivating mutations in the virus J2R gene) in the genome of
`which is inserted a nucleic acid molecule encoding an anti-PD1
`antibody. More preferably, said vaccinia virus is armed with an
`immunostimulatory therapeutic gene with a special preference
`for the human GM-CSF gene described herein.
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`Id. at 19:11-22.
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`Instead of disclosing the arrangement of the elements of claims 1 and 11,
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`Silvestre provides lists of possible viruses, immune checkpoint modulators, and
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`therapeutic genes from which a POSA would have to pick and choose in order to
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`make an oncolytic HSV that encodes GM-CSF and a CTLA-4 inhibitor as claimed:
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`14
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`EX1002 at 7:10 – 15:49 (listing 11 possible oncolytic viruses, 14 immune
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`checkpoint targets, and 33 therapeutic genes, resulting in over 5,000 different
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`possible combinations); EX2009 ¶ 29. When “a reference discloses elements in
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`different locations in the disclosure, the relevant question is whether the reference is
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`sufficiently clear in disclosing the combinability of those elements such that a skilled
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`artisan would ‘at once envisage’ the claimed combination.” Chamberlain Grp., Inc.
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`v. Techtronic Indus. Co., 935 F.3d 1341, 1350 (Fed. Cir. 2019).
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`Petitioners merely argue that Silvestre teaches all of claims 1 and 11’s
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`elements—not that Silvestre connects them or arranges them as recited in the
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`claims. See Petition at 42 (“Silvestre anticipates [claim 1 and 11] because Silvestre
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`15
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`discloses each element of these claims and Silvestre’s disclosure is enabling
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`describes the claimed invention sufficiently to have placed it in possession of a
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`POSITA”); id. (“Claim 1 is the sole independent claim, and Silvestre teaches all of
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`its elements.”); id. at 43 (“Silvestre also anticipates [claim 11] because Silvestre
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`teaches all the limitations of [this] claim[].”) Petitioners provide no reasoned
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`analysis or explanation as to how, based on the disclosure of Silvestre, a POSA
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`would at once envisage the specific oncolytic virus claimed in claims 1 and 11.
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`EX2009 ¶ 29. See also Otonomy, Inc. v. Auris Med., AG, 743 F. App’x 430, 438
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`(Fed. Cir. 2018) (affirming Board’s finding of no anticipation, where the prior art
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`“describe[d] that the ‘compositio