Trials@uspto.gov
`571-272-7822
`
`Paper 16
`Date: June 16, 2022
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TRANSGENE and BIOINVENT INTERNATIONAL AB,
`Petitioner,
`
`v.
`
`REPLIMUNE LIMITED,
`Patent Owner.
`
`PGR2022-00014
`Patent 10,947,513 B2
`
`
`
`
`
`
`
`
`
`Before CHRISTOPHER G. PAULRAJ, RYAN H. FLAX, and
`JAMIE T. WISZ, Administrative Patent Judges.
`
`PAULRAJ, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Post-Grant Review
`35 U.S.C. § 324
`
`
`
`
`
`
`
`

`

`PGR2022-00014
`Patent 10,947,513 B2
`
`I.
`
`INTRODUCTION
`
`Transgene and BioInvent International AB (collectively, “Petitioner”),
`
`filed a Petition requesting post-grant review of claims 1–8 and 10–26 of U.S.
`
`Patent No. 10,947,513 B2 (Ex. 1001, “the ’513 patent”). Paper 1 (“Pet.”).
`
`Replimune Limited (“Patent Owner”) filed a Preliminary Response to the
`
`Petition. Paper 8 (“Prelim. Resp.”). As part of its Preliminary Response,
`
`Patent Owner included a Statutory Disclaimer of claims 1–8, 10–12, and 14–
`
`26 of the ’513 patent, leaving claim 13 as the sole remaining challenged
`
`claim in this proceeding. Prelim. Resp. 1; Ex. 2001. Pursuant to our
`
`authorization, Petitioner filed a Preliminary Reply addressing Patent
`
`Owner’s arguments for discretionary denial under 35 U.S.C. § 325(d). Paper
`
`12 (“Prelim. Reply”).
`
`In view of Patent Owner’s Statutory Disclaimer, we treat claims 1–8,
`
`10–12, and 14–26 as having never been part of the ’513 patent, such that
`
`Petitioner cannot seek post-grant review of those claims. See Vectra Fitness,
`
`Inc. v. TNWK Corp., 162 F.3d 1379, 1383 (Fed. Cir. 1998) (“This court has
`
`interpreted the term ‘considered as part of the original patent’ in section 253
`
`to mean that the patent is treated as though the disclaimed claims never
`
`existed.”) (citing Guinn v. Kopf, 96 F.3d 1419, 1422 (Fed. Cir. 1996));
`
`37 C.F.R. § 42.107(e) (“No inter partes review will be instituted based on
`
`disclaimed claims.”). Grounds 1, 2, 3, and 5 set forth in the Petition (see,
`
`e.g., Pet. 3–4), which are directed to the disclaimed claims, are also hereby
`
`deemed moot. And, because no post-grant review will be instituted based on
`
`disclaimed claims, we do not consider claims 1–8, 10–12, and 14–26 to be
`
`within the scope of this proceeding. Cf. General Elec. Co. v. United Techs.
`
`Corp., IPR2017-00491, Paper 9 (PTAB July 6, 2017) (precedential)
`
`(denying institution of inter partes review in view of a statutory disclaimer
`
`2
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`

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`PGR2022-00014
`Patent 10,947,513 B2
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`of all challenged claims). We base our decision to institute on the only
`
`remaining challenged claim (claim 13, which depends from independent
`
`claim 1 and intervening claim 11) that has not been disclaimed.
`
`To institute a post-grant review, we must determine whether the
`
`information presented in the Petition, “if such information is not rebutted,
`
`would demonstrate that it is more likely than not that at least 1 of the claims
`
`challenged in the petition is unpatentable.” 35 U.S.C. § 324(a). Upon
`
`consideration of the Petition and the Preliminary Response, for the reasons
`
`set forth below, we determine that the evidence and arguments presented in
`
`the Petition are sufficient to satisfy the “more likely than not” standard
`
`regarding the asserted unpatentability of claim 13 in the ’513 patent.
`
`Therefore, we authorize a post-grant review to be instituted as to claim 13.
`
`Our determinations at this stage of the proceeding are based on the
`
`evidentiary record developed thus far, and do not constitute a final decision
`
`as to patentability of claims for which post-grant review is instituted. Our
`
`final decision will be based on the full record developed during trial.
`
`A. Real Parties-in-Interest
`
`Petitioner identifies Transgene and BioInvent International AB as the
`
`real parties-in-interest (“RPI”). Pet. 1. Patent Owner identifies only itself as
`
`the RPI. Paper 6, 1. There is no dispute over RPIs in this proceeding.
`
`B. Related Matters
`
`The parties do not identify any related matters. See Pet. 2; Paper 6, 1.
`
`C. The ’513 Patent (Ex. 1001)
`
`The ’513 patent is titled “Engineered Virus.” Ex. 1001, code (54).
`
`The ’513 patent issued from application 16/068,830, filed January 9, 2017,
`
`but claims earliest priority to three Great Britain applications filed January 8,
`
`3
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`Patent 10,947,513 B2
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`2016. Id. at codes (21), (22), (30) (discussed in detail below in Section II.A.
`
`as to post-grant eligibility).
`
`The Specification explains that a number of viruses are known for the
`
`oncolytic treatment of cancer. Id. at 2:9–11. Viruses may treat cancer by
`
`directly infecting tumor cells, and by generating an immune response against
`
`tumor cells not infected with the virus. See id. at 1:22–46. The
`
`Specification refers to such viruses as oncolytic viruses, meaning “a virus
`
`that infects and replicates in tumor cells, such that the tumor cells are
`
`killed.” Id. at 9:10–12. Notably, oncolytic viruses should be disabled so
`
`that they are no longer pathogenic. See id. at 2:11–14.
`
`The Specification explains that herpes simplex virus (HSV) was a
`
`known oncolytic virus. See id. at 2:9–11. “A number of disabling mutations
`
`to HSV, including disruption of the genes encoding ICP34.5, . . . have been
`
`identified which do not prevent the virus from replicating in culture or in
`
`tumor tissue in vivo, but which prevent significant replication in normal
`
`tissue.” Id. at 2:14–19. The specification further describes HSV oncolytic
`
`viruses that deliver a therapeutic gene for treating cancer. Id. at 2:25–27.
`
`For example, the Specification describes clinical trials that tested an HSV
`
`virus encoding a heterologous gene for granulocyte macrophage colony-
`
`stimulating factor (“GM-CSF”) in place of the gene for infected cell protein-
`
`34.5 (“ICP34.5”). Id. at 2:27–31. Finally, the Specification describes
`
`combining such oncolytic immunotherapy with immune checkpoint
`
`blockers, such as agents targeting anti-cytotoxic T lymphocyte-associated
`
`antigen-4 (“CTLA-4”), programmed cell death protein-1 (“PD-1”), or
`
`programmed cell death protein ligand-1 (“PD-L1”). See id. at 2:49–3:11.
`
`In view of this background, the ’513 patent discloses “oncolytic
`
`viruses expressing GM-CSF and at least one molecule targeting an immune
`
`4
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`

`

`PGR2022-00014
`Patent 10,947,513 B2
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`co-stimulatory pathway.” Id. at 4:3–5. The immune co-stimulatory pathway
`
`activating molecule may include “a protein capable of blocking signaling
`
`through CTLA-4,” for example a CTLA-4 binding antibody. Id. at 4:65–67.
`
`“The virus is preferably a herpes simplex virus (HSV), such as HSV1” that
`
`“does not express functional ICP34.5.” Id. at 5:9–11.
`
`The ’513 patent discloses examples of viruses expressing GM-CSF
`
`and CTLA-4. See id. at 30:43–31:14. Specifically, the Specification
`
`describes fusogenic viruses expressing mGM-CSF, gibbon ape leukemia
`
`virus (“GALV”), and anti-mouse and anti-human CTLA-4. See id. The
`
`GM-CSF and CTLA-4 expressing viruses are Virus 27 and Virus 31,
`
`illustrated in Figures 5 and 13, reproduced below. Id.
`
`
`
`
`
`Figures 5B and 5D “depict structures of HSV1 viruses modified by the
`
`deletion of ICP34.5 and ICP47 such that the US11 gene is under control of
`
`the ICP457 immediate early promoter and containing heterologous genes in
`
`the ICP34.5 locus.” Id. at 6:10–15. Figure 5B illustrates Virus 27. See id.
`
`at Fig. 5B. Figure 5D illustrates Virus 31. See id. at Fig. 5D.
`
`5
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`

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`PGR2022-00014
`Patent 10,947,513 B2
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`Figure 13 of the ’513 patent is reproduced below:
`
`Figure 13 “shows the structure of ICP34.5 and ICP47 deleted viruses
`
`expressing [] GM-CSF and codon optimized anti-mouse or anti-human
`
`CTLA-4 antibody constructs,” and the resulting structure of the CTLA-4
`
`
`
`antibody. Id. at 7:9–17.
`
`D. Illustrative Claims
`
`Petitioner challenges claim 13 of the ’513 patent, which depends on
`
`claim 11, which in turn depends on independent claim 1.1 We reproduce
`
`claims 1, 11, and 13 below:
`
`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).
`
`
`1 Claim 13 is treated as independent by virtue of its dependency from, and its
`incorporation of the limitations of disclaimed independent claim 1 and
`intervening dependent claim 11.
`
`6
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`

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`PGR2022-00014
`Patent 10,947,513 B2
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`13. The virus of 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 back orientation in relation to
`each other, each under separate regulatory control.
`
`Ex. 1001, 81:51–54; 83:17–18, 20–25.
`
`E. Prior Art and Asserted Grounds
`
`Petitioner asserts that claim 13 would have been unpatentable on the
`
`following grounds:
`
`Claim(s) Challenged
`13
`13
`
`35 U.S.C. §
`103
`103
`
`Reference(s)/Basis
`Silvestre2
`Du3, Choi4, Zitvogel5
`
`Petitioner relies on the declaration of John C. Bell, Ph.D. (Ex. 1007).
`
`A. Post-Grant Eligibility
`
`II. ANALYSIS
`
`Post-grant reviews are available only for patents “described in section
`
`3(n)(1)” of the Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125
`
`Stat. 284 (2011) (“AIA”). AIA § 6(f)(2)(A); see Arkema Inc. v. Honeywell
`
`Int’l Inc., PGR2016-00011, Paper 13 at 15 (PTAB Sept. 2, 2016). These
`
`patents issue from applications “that contain[] or contained at any time . . . a
`
`claim to a claimed invention that has an effective filing date as defined in
`
`section 100(i) of title 35, United States Code, that is on or after” “the
`
`
`2 Silvestre et al., US 10,555,981 B2, issued Feb. 11, 2020 (Ex. 1002).
`3 T. Du et al., Tumor-specific oncolytic adenoviruses expressing granulocyte
`macrophage colony-stimulating factor or anti-CTLA4 antibody
`for the treatment of cancers, 21 CANCER GENE THERAPY 340–348 (2014)
`(Ex. 1003).
`4 Zitvogel et al., US 10,765,710 B2, issued Sept. 8, 2020 (Ex. 1004).
`5 K-J Choi et al., Concurrent delivery of GM-CSF and B7-1 using an
`oncolytic adenovirus elicits potent antitumor effect, 13 GENE THERAPY
`1010–1020 (2006) (Ex. 1005).
`
`7
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`PGR2022-00014
`Patent 10,947,513 B2
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`expiration of the 18-month period beginning on the date of the enactment
`
`of” the AIA. AIA § 3(n)(1). Because the AIA was enacted on September
`
`16, 2011, post-grant reviews are available only for patents that issue from
`
`applications that at one point contained at least one claim with an effective
`
`filing date of March 16, 2013, or later. See also 37 C.F.R. § 42.204(a)
`
`(requiring that “petitioner . . . certify that the patent for which review is
`
`sought is available for post-grant review”).
`
`The ’513 patent issued on March 16, 2021, from U.S. Application No.
`
`16/068,830 (“the ’830 application”), filed on January 9, 2017 as
`
`PCT/GB2017/050038. Ex. 1001, codes (21), (22), (45), (86). The ’830
`
`application further claims benefit of priority to three GB patent applications
`
`filed on January 8, 2016. Id. at code (30). Accordingly, the ’513 patent
`
`issued from applications having a filing date of March 16, 2013 or later.
`
`Petitioner filed the request for post-grant review on December 15, 2021,
`
`which is within nine months of the grant of the ’513 patent. 35 U.S.C.
`
`§ 321(c). See Pet. 3.
`
`Patent Owner does not challenge the eligibility of the ’513 patent for
`
`post-grant review. We determine that the ’513 patent is eligible for post-
`
`grant review.
`
`B. Level of Ordinary Skill in the Art
`
`Petitioner proposes that a person of ordinary skill in the art (“POSA”)
`
`“would have had 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.” Pet. 6 (citing Ex. 1007 ¶¶ 35, 96). Patent
`
`Owner does not argue otherwise. See Prelim. Resp. 16–17.
`
`8
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`Patent 10,947,513 B2
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`At this stage of the proceeding and for purposes of our analysis in this
`
`Decision, we adopt Petitioner’s uncontested definition as that definition is
`
`consistent with the level of skill in the art reflected by the prior art. See
`
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that
`
`specific findings regarding ordinary skill level are not required “where the
`
`prior art itself reflects an appropriate level and a need for testimony is not
`
`shown” (quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755
`
`F.2d 158, 163 (Fed. Cir. 1985))). It is from the perspective of such a person
`
`of ordinary skill that we consider the claims and prior art.
`
`C. Claim Construction
`
`We interpret a claim “using the same claim construction standard that
`
`would be used to construe the claim in a civil action under 35 U.S.C.
`
`282(b).” 37 C.F.R. § 42.200(b) (2019). This standard requires that we
`
`construe claims “in accordance with the ordinary and customary meaning of
`
`such claim[s] as understood by one of ordinary skill in the art and the
`
`prosecution history pertaining to the patent.” Id.
`
`Petitioner contends that the Specification defines the term “‘oncolytic
`
`virus’ as ‘a virus that infects and replicates in tumor cells, such that the
`
`tumor cells are killed.’” Pet. 6 (citing Ex. 1001, 9:10–12). Petitioner argues
`
`that the Specification “distinguishes this broader definition from the
`
`allegedly narrower subcategory of ‘selectively replication competent’
`
`viruses that ‘replicate[] more effectively in tumor tissue than in non-tumor
`
`tissue.’” Id. (citing Ex. 1001, 9:12–17).
`
`Patent Owner does not dispute Petitioner’s construction of “oncolytic
`
`virus.” See Prelim. Resp. 17.
`
`We do not perceive a need to construe any claim terms of the ’513
`
`patent for purposes of determining whether to institute trial. See Vivid
`
`9
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`Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 295, 803 (Fed. Cir. 1999)
`
`(holding that “only those terms need [to] be construed that are in
`
`controversy, and only to the extent necessary to resolve the controversy”);
`
`see also Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d
`
`1013, 1017 (Fed. Cir. 2017) (applying Vivid Techs. in the context of an inter
`
`partes review).
`
`D. Obviousness over Silvestre
`
`Petitioner asserts that claim 13 would have been obvious over
`
`Silvestre. Pet. 54–55 (Ground 4). In our assessment of Petitioner’s
`
`obviousness argument for claim 13, we have also considered Petitioner’s
`
`anticipation argument (Ground 3) for disclaimed claims 1 and 11. See id. at
`
`42–44, 48.
`
`1. Overview of Silvestre (Ex. 1002)
`
`Silvestre is a U.S. patent that issued on February 11, 2020 from
`
`Application No. 15/325,562, that was filed as PCT/EP2015/066263 on July
`
`16, 2015. Ex. 1002, codes (21), (22), (45), (86). Thus, on its face, Silvestre
`
`qualifies as prior art under 35 U.S.C. § 102(a)(2).
`
`Silvestre is directed to an oncolytic virus including a nucleotide
`
`sequence that encodes an immune checkpoint modulator. Id. at 3:23–26.
`
`The oncolytic virus is preferably selected from a group that includes HSV.
`
`Id. at 3:27–31. The immune checkpoint modulator preferably includes an
`
`antagonist molecule that antagonizes the activity of CTLA-4, “with a
`
`specific preference for an anti PD-1 antibody and/or an anti CTLA4
`
`antibody.” Id. at 3:41–48; see also id. at 15:5–12, 45–48.
`
`Silvestre discloses further embodiments of oncolytic viruses. For
`
`example, the oncolytic virus may include a herpes virus derived from HSV1.
`
`Id. at 7:52–60. “The herpes virus may be genetically modified so as to
`
`10
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`PGR2022-00014
`Patent 10,947,513 B2
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`restrict viral replication in tumors or reduce its cytotoxicity in non-dividing
`
`cells.” Id. at 7:60–63. For example, the virus may include “defects in the
`
`function of genes encoding virulence factors such as the ICP34.5 gene.” Id.
`
`at 8:1–3.
`
`Silvestre discloses oncolytic viruses including immunostimulatory
`
`proteins. Id. at 11:55–57. “A vast number of proteins are known in the art
`
`for their ability to exert an immunostimulatory effect.” Id. at 11:57–59.
`
`Silvestre describes a “specific preference for GM-CSF” as an
`
`immunostimulatory protein. Id. at 12:7–9. Silvestre further describes a
`
`known “oncolytic herpes simplex 1 (T-VEC) [] genetically engineered to
`
`attenuate the virus virulence, increase selectivity for cancer cells and
`
`enhance antitumor immune response (through GM-CSF expression).” Id. at
`
`2:32–30.6
`
`Silvestre discloses that “[t]he 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. at 16:4–8.
`
`2. Analysis of Claim 13
`
`Petitioner contends that Silvestre discloses all of the features recited in
`
`disclaimed claims 1 and 11, from which claim 13 depends. Pet. 42–43, 48.
`
`As to claim 1, Petitioner contends that Silvestre discloses an oncolytic virus
`
`including heterologous genes inserted into the genome of the virus. Id. at
`
`42–43 (citing Ex. 1002, 3:23–26, 31–32, 16:4–8; Ex. 1007 ¶¶ 183–190).
`
`
`6 Citing Neil N. Senzer et al., Phase II Clinical Trial of a Granulocyte-
`Macrophage Colony-Stimulating Factor–Encoding, Second-Generation
`Oncolytic Herpesvirus in Patients With Unresectable Metastatic Melanoma,
`27(34) J. CLIN. ONCOLOGY 5763–71 (2009) (Ex. 1078).
`
`11
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`Additionally, Petitioner contends that Silvestre discloses the heterologous
`
`genes include at least one therapeutic gene, preferably encoding GM-CSF,
`
`and at least one immune checkpoint modulator gene, preferably encoding an
`
`anti-CTLA-4 antibody. Id. (citing Ex. 1002, 10:8–10, 28–31, 12:7–9, 3:44–
`
`48, 15:5–8; Ex. 1007 ¶¶ 183–190). As to claim 11, Petitioner contends that
`
`Silvestre describes HSV1 as a particularly preferred virus. Id. at 48 (citing
`
`Ex. 1002, 7:52–60).
`
`In view of the above, Petitioner shows, and Patent Owner does not
`
`dispute (see Statutory Disclaimer), that Silvestre teaches the limitations of
`
`claims 1 and 11.
`
`As to claim 13, Petitioner contends that Silvestre discloses using T-
`
`VEC as an engineered virus. Id. at 54 (citing Ex. 1002, 2:33–36). Petitioner
`
`contends that “T-VEC was well known to a POSITA to be an oncolytic HSV
`
`with a heterologous GM-CSF gene inserted into the ICP34.5 encoding locus
`
`via a complete deletion and replacement of the ICP34.5 gene with a GM-
`
`CSF encoding gene.” Id. (citing Ex. 1007 ¶ 229; Ex. 1078, 5763).
`
`Petitioner contends that claim 13’s requirement of inserting the GM-CSF
`
`gene and the CTLA-4 inhibitor encoding gene in a back-to-back orientation
`
`in relation to each other, each under separate regulatory control, would have
`
`been “[t]he simplest and most common method” of inserting the genes. Id.
`
`at 54–55 (citing Ex. 1007 ¶ 230). Petitioner contends that one of ordinary
`
`skill in the art would have been motivated to do so, with a reasonable
`
`expectation of success, “because insertion into the ICP34.5 locus had
`
`already been successfully demonstrated in the T-VEC oncolytic HSV1
`
`virus.” Id. at 55 (citing Ex. 1007 ¶ 230). Petitioner contends that one of
`
`ordinary skill in the art would have followed a proven insertion strategy to
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`avoid a trial-and-error process of identifying a new gene insertion site. Id.
`
`(citing Ex. 1007 ¶¶ 73–81, 87–88, 230–231).
`
`In response, Patent Owner first argues that Petitioner improperly relies
`
`on “common knowledge” to supply claim limitations that are not taught or
`
`suggested by Silvestre. See Prelim. Resp. 18–22 (citing Arendi S.A.R.L. v.
`
`Apple Inc., 832 F.3d 1355, 1361 (Fed. Cir. 2016) (“[C]ommon sense is
`
`typically invoked to provide a known motivation to combine, not to supply a
`
`missing claim limitation.”)). Specifically, Patent Owner argues that
`
`Petitioner relies improperly on common knowledge to supply the limitation
`
`of “back-to-back orientation of a GM-CSF-encoding gene and a CTLA-4
`
`inhibitor-encoding gene each under separate regulatory control.” Id. at 20–
`
`21 (citing Pet. 54–55). Patent Owner argues that Petitioner does not provide
`
`evidentiary support to explain why one of ordinary skill in the art would use
`
`a back-to-back orientation under control of separate regulatory requirements.
`
`Id. at 21. Patent Owner further argues that Petitioner’s expert declaration
`
`merely repeats the argument without evidentiary support. Id. at 22 (citing
`
`Ex. 1007 ¶¶ 230, 319). Patent Owner argues that the limitation cannot be
`
`shown by common knowledge because the “claimed technology is difficult
`
`and that there is a high level of unpredictability in the relevant art.” See id.
`
`at 20–21 (citing Pet. 20, 22–23; see also Arendi, 832 F.3d at 1361).
`
`Second, Patent Owner argues that Petitioner did not articulate a
`
`motivation to combine Silvestre with the alleged common knowledge with a
`
`reasonable expectation of success. Prelim. Resp. 23–26. Patent Owner
`
`argues that Petitioner’s proffered motivation to select the known ICP34.5
`
`encoding locus to avoid a trial-and-error process “says nothing about
`
`inserting two genes in combination into the same locus.” Id. at 23 (citing
`
`Pet. 55). Patent Owner further argues that Petitioner fails to identify why
`
`13
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`one of ordinary skill “would have been motivated to use a back-to-back
`
`orientation under control of separate regulatory elements.” Id. at 23–24
`
`(citing Pet. 54–55). Finally, Patent Owner argues that Petitioner does not
`
`show a reasonable expectation of success for inserting two genes as claimed,
`
`given the difficult technology and the high level of unpredictability in the
`
`art. Id. at 25 (citing Pet. 55, 20, 22–23, 30).
`
`Based on the present record, we find that Petitioner has shown that it
`
`is more likely than not that inserting the GM-CSF gene and the CTLA-4
`
`inhibitor encoding gene in a back-to-back orientation in relation to each
`
`other would have been known to a person of ordinary skill in the art.
`
`Petitioner’s expert Dr. Bell states that “[w]hen inserting two genes into a
`
`given locus, the simplest and most common way to do so is to insert them in
`
`a back-to-back orientation under control of separate regulatory elements.”
`
`Ex. 1007 ¶ 230. While Patent Owner is correct in stating that no sources are
`
`cited in paragraph 230, Dr. Bell does cite back to paragraphs 73–81 and 87–
`
`88 of his own declaration. See id.
`
`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
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`certain viral genomes include genes that are overlapping and/or that encode
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`polyproteins, which can add to a further level of difficulty in identifying a
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`suitable insertion locus. Ex. 1007 ¶ 74 (citing Ex. 1035, 364, Fig. 1).
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`Dr. Bell further explains that “inactivation of the neurovirulence factor
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`ICP34.5 in HSV1 has been well-known to direct tumor-specific cell lysis,
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`making HSV1 ICP34.5 knock-outs useful oncolytic virus vectors,” but also
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`notes that “unless such a well-known insertion site is used, determining
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`whether insertion of a heterologous gene at any particular site will be
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`successful requires a difficult and time-consuming trial-and-error process.”
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`Id. ¶ 77 (citing Ex. 1039, 292, Ex. 1040, 4–7, Ex. 1041, 575). Accordingly,
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`within paragraphs 73–81 and 87–88, Dr. Bell provides evidentiary support
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`for his conclusions in paragraph 230. See Ex. 1007 ¶¶ 73-81, 87-88.
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`We are not persuaded by Patent Owner’s reliance upon the Arendi
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`case to argue that Petitioner improperly relies upon common sense to supply
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`a missing limitation. In Arendi, the court noted that “the Board’s
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`presumption that adding a search for phone numbers to [the prior art
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`refence] would be ‘common sense’ was conclusory and unsupported by
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`substantial evidence, the missing limitation is not a ‘peripheral’ one, and
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`there [was] nothing in the record to support the Board’s conclusion that
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`supplying the missing limitation would be obvious to one of skill in the art.”
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`832 F.3d at 1366–67. But here, as noted above, Dr. Bell cites to several
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`references in support of his rationale that one of ordinary skill in the art
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`seeking to insert both the genes would have started with the known ICP34.5
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`locus rather than undertaking a rigorous trial-and-error process to find an
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`altogether new insertion locus. We do not find the concern stated in Arendi
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`about using common sense “as a wholesale substitute for reasoned analysis
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`and evidentiary support” to be present in this case. See id. at 1362. Here,
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`the “common sense” challenged by Patent Owner refers to the “common
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`knowledge” of the ordinarily skilled artisan as of the invention referenced in
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`the Petition and by Dr. Bell, and it is from such a person’s perspective that
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`we must read Silvestre. Thus, based on the current record, we determine
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`that Petitioner has provided sufficient evidence beyond merely a conclusory
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`assertion of “common sense” to show that inserting the genes at issue in a
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`back-to-back orientation would have been known in the art.7
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`Accordingly, for the reasons above, we are persuaded that Petitioner
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`shows that it is more likely than not that it will prevail in establishing
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`unpatentability with regard to claim 13.
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`E. Obviousness over Du, Choi, and Zitvogel
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`Petitioner asserts that claim 13 would have been obvious over the
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`combination of Du, Choi, and Zitvogel. Pet. 74 (Ground 6). Petitioner’s
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`obviousness argument as to claim 13 also refers to Petitioner’s obviousness
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`argument for disclaimed claims 1 and 11 in view of Du, Choi, and Zitvogel.
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`See id. at 64–68, 74.
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`1. Overview of Du (Ex. 1003)
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`Du is a journal article that bears a publication date of 2014. Ex. 1003,
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`340. Petitioner contends that Du was published and accessible to the public
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`no later than July 18, 2014. Pet. 5 (citing Ex. 1011 ¶¶ 47–55). Thus, on its
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`face, Du qualifies as prior art under 35 U.S.C. § 102(a)(1). Id.
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`
`7 We recognize that Petitioner in its Preliminary Reply also cites to Exhibit
`1084, Fig. 1 as “showing back-to-back insertion of two genes at ICP34.5 in
`HSV1 virus.” Prelim. Reply 5. Patent Owner contends that this is improper
`as it goes beyond the scope of our authorization to file a Preliminary Reply
`limited to the § 325(d) issue. Paper 13, 1; Paper 9, 2. We are not persuaded
`that Petitioner’s reliance on Exhibit 1084 is improper as it further
`demonstrates material error under the Advanced Bionics framework
`(discussed infra). In any event, Patent Owner has been put on notice that
`Exhibit 1084 may indeed be relied upon to support Petitioner’s contentions
`regarding the obviousness of the back-to-back insertion limitation of claim
`13. The parties are invited to further develop the record with regard to this
`exhibit at trial.
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`Du discloses oncolytic adenoviruses expressing either GM-CSF or
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`anti-CTLA4 antibody for the treatment of cancers. Ex. 1003, 340. Du
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`discloses two viruses, SKL001 and SKL002. Id. at 341. SKL001 encodes
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`the heavy and light chains of anti-CTL4A monoclonal antibody (“mAb”).
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`Id. SKL002 replaces the coding region of anti-CTLA4 with the cDNA of
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`GM-CSF. Id. at 341. Du discloses that administering both viruses in
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`combination, was “significantly more effective” in treating tumors than
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`administering each virus alone. Id. at 345–346.
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`2. Overview of Choi (Ex. 1005)
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`Choi is a journal article that bears a publication date of 2006.
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`Ex. 1005, 1010. Petitioner contends that Choi was published and accessible
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`to the public no later than March 9, 2006. Pet. 5 (citing Ex. 1011 ¶¶ 38–46).
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`Thus, on its face, Choi qualifies as prior art under 35 U.S.C. § 102(a)(1). Id.
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`Choi discloses an oncolytic adenovirus that expresses both GM-CSF
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`and B7-1, an immune-stimulatory membrane molecule. Id. at 1010. Choi
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`discloses preparing the adenovirus by placing two independent expression
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`cassettes, each separately expressing murine GM-CSF and murine B7-1, in
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`the E1 and E3 region of a replication-incompetent adenovirus. Id. at 1011.
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`3. Overview of Zitvogel (Ex. 1004)
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`Zitvogel is a U.S. patent that issued on September 8, 2020 from
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`Application No. 15/325,576, that was filed as PCT/EP2015/066353 on July
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`16, 2015. Ex. 1004, codes (21), (22), (45), (86). Thus, on its face, Zitvogel
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`qualifies as prior art under 35 U.S.C. § 102(a)(2).
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`Zitvogel discloses cancer therapy including a combination of an
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`oncolytic virus with an immune checkpoint modulator. Id. at 3:30–33. The
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`oncolytic virus is preferably selected from the group including vaccinia virus
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`and HSV. Id. at 3:33–38. Zitvogel discloses an embodiment in which the
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`oncolytic virus is an HSV mutant with defects in the ICP34.5 gene,
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`including T-VEC as a representative example. See id. at 8:10–35.
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`Zitvogel discloses that the immune checkpoint modulator may
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`preferably be an anti CTLA-4 antibody. Id. at 3:51–53. Zitvogel discloses
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`that the immune checkpoint modulator “may be delivered to the subject in
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`the form of a vector expressing the one or more immune checkpoint
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`modulator.” Id. at 22:37–43.
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`Zitvogel discloses an embodiment where the oncolytic virus expresses
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`at least one therapeutic gene encoding an immunostimulatory protein. Id. at
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`3:48–50. “Preferably, the [immunostimulatory] protein is an interleukin or a
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`colony-30 stimulating factor, with a specific preference for GM-CSF.” Id. at
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`12:28–30. Zitvogel discloses that the therapeutic gene is preferably inserted
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`in a non-essential locus of the viral genome. Id. at 13:60–63.
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`4. Analysis of Claim 13
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`Petitioner contends that the combination of Du, Choi, and Zitvogel
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`teaches all of the features recited in disclaimed claims 1 and 11, from which
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`claim 13 depends. Pet. 58–59, 64–66, 74. As to claim 1, Petitioner contends
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`that Du discloses co-administering two oncolytic viruses, a first virus
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`including a heterologous GM-CSF encoding gene and a second virus
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`including a heterologous CTLA-4 inhibitor encoding gene. Pet. 58–59
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`(citing Ex. 1003, 340). Petitioner argues that one of ordinary skill in the art
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`would have been motivated to “modify Du’s teachings to create a single
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`virus with both claimed heterologous genes” by Du alone, and in
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`combination with Choi and Zitvogel. Id. at 66.
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`First, Petitioner argues that “Du provides express motivation” to
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`create a single virus by teaching that co-administering the two viruses
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`provides a synergistic antitumor effect. Id. at 59–60 (citing Ex. 1006, 340,
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`346; Ex. 1007 ¶¶ 247–250). Petitioner contends that one of ordinary skill in
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`the art would have had a reasonable expectation of success in creating a
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`single virus with both heterologous genes inserted, “because it was well
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`known in the art that administering a single oncolytic virus with multiple
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`inserted genes had been done, was preferred, and provided distinct
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`advantages over administering multiple viruses each with different inserted
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`genes, including improved ease of administration.” Id. at 61 (citing
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`Ex. 1007 ¶¶ 251–252). Dr. Bell declares that “administering a single virus
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`containing the two heterologous genes would ensure that an infected host
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`cell would receive copies of both heterologous genes