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 Sur-Reply
`
`
`___________
`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 Sur-Reply
`
`
`
`TABLE OF CONTENTS
`
`PGR2022-00014
`Patent No. 10,947,513
`
` Page(s)
`
`2.
`
`3.
`
`I.
`
`II.
`III.
`
`CLAIM 13 IS NOT OBVIOUS OVER SILVESTRE .................................... 1
`Silvestre Does Not Anticipate Claims 1 and 11 ................................... 2
`1.
`Petitioners’ Narrowed List of Viruses Is Based on
`Hindsight .................................................................................... 4
`Silvestre Identifies More Than Two Preferred
`Therapeutic Genes...................................................................... 9
`Silvestre Identifies More Than Two Preferred Immune
`Checkpoint Modulators ............................................................ 13
`Claim 13 Is Not Obvious Over Silvestre ............................................ 15
`CLAIM 13 IS NOT OBVIOUS OVER DU, CHOI, AND ZITVOGEL...... 20
`PATENT OWNER’S UNEXPECTED RESULTS STAND
`UNREBUTTED ............................................................................................ 23
`IV. CONCLUSION ............................................................................................. 27
`
`i
`
`
`
`TABLE OF AUTHORITIES
`
`PGR2022-00014
`Patent No. 10,947,513
`
` Page(s)
`
`Cases
`Arctic Cat Inc. v. Bombardier Rec. Prods. Inc.,
`876 F.3d 1350 (Fed. Cir. 2017) .......................................................................... 21
`Arctic Cat Inc. v. Polaris Indus.,
`795 Fed. Appx. 827 (Fed. Cir. 2019) .................................................................. 22
`Argentum, Pharms. LLC v. Cipla Ltd.,
`IPR2017-00807, Paper 19 (PTAB Oct. 30, 2017) ................................................ 5
`Beable Educ., Inc. v. Achieve3000, Inc.,
`IPR2021-01169, Paper 34 (PTAB Jan. 3, 2023) ................................................ 17
`Belden Inc. v. Berk–Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) .......................................................................... 16
`Broad Ocean Tech., LLC v. Nidec Motor Corp.,
`IPR2015-01617, Paper 70 (PTAB April 25, 2019) .............................................. 1
`Chemours Co. FC, LLC v. Daikin Industries, LTD.,
`4 F.4th 1370 (Fed. Cir. 2021) ............................................................................. 26
`Henny Penny Corp. v. Frymaster LLC,
`938 F.3d 1324 (Fed. Cir. 2019) .......................................................................... 22
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 19
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ............................................................................ 1
`Iron Grip Barbell Co. v. USA Sports, Inc.,
`392 F.3d 1317 (Fed. Cir. 2004) .......................................................................... 25
`Janssen Pharms., Inc. v. Watson Labs., Inc.,
`2012 WL 3990221 (D.N.J. Sept. 11, 2012) .......................................................... 9
`
`ii
`
`
`
`PGR2022-00014
`Patent No. 10,947,513
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015) ...................................................................passim
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 26
`
`Los Angeles Biomedical Rsch. Inst. at Harbor-UCLA Med. Ctr. v. Eli
`Lilly & Co.,
`849 F.3d 1049 (Fed. Cir. 2017) .......................................................................... 17
`MEHL/Biophile Int’l Corp. v. Milgraum,
`192 F.3d 1362, 1365 (Fed. Cir. 1999) .................................................................. 8
`Motorola, Inc. v. Interdigital Tech. Corp.,
`121 F.3d 1461, 1473 (Fed Cir. 1997) .................................................................. 9
`Mylan Pharms. Inc. v. Merck Sharp & Dohme Corp.,
`50 F.4th 147 (Fed. Cir. 2022) ............................................................................. 14
`Mylan Pharms. Inc. v. Merck Sharp & Dohme Corp.,
`IPR2020-00040, Paper 91 (PTAB May 7, 2021) ............................................... 15
`In re Ruschig,
`343 F.2d 965 (CCPA 1965) .............................................................................. 4, 5
`Sanofi-Aventis U.S. LLC v. Genentech, Inc.,
`IPR2015-01624, Paper 15 (PTAB Feb. 5, 2016) .................................................. 9
`Wasica Fin. GmbH v. Cont’l Auto. Sys.,
`853 F.3d 1272 (Fed. Cir. 2017) ........................................................................ 1, 8
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 27
`
`iii
`
`
`
`PGR2022-00014
`Patent No. 10,947,513
`
`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`2007
`2008
`2009
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`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
`
`
`
`PGR2022-00014
`Patent No. 10,947,513
`
`Exhibit
`2017
`
`2018
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`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.
`
`v
`
`
`
`PGR2022-00014
`Patent No. 10,947,513
`
`The Petition requested PGR of claims 1-8 and 10-26. Patent Owner
`
`disclaimed claims 1-8, 10-12, and 14-26. Thus, only claim 13 remains at issue,
`
`which Petitioners allege is obvious over Silvestre (Ground 4), and obvious over Du,
`
`Choi and Zitvogel (Ground 6). The record is clear. Petitioners have not shown that
`
`either Ground 4 or 6 renders claim 13 obvious.
`
`I.
`
`CLAIM 13 IS NOT OBVIOUS OVER SILVESTRE
`
`Claim 13 depends from claim 11, which depends from claim 1. As explained
`
`previously (POR, 11), Petitioners’ argument for why claim 13 is purportedly obvious
`
`depends on their argument that Silvestre anticipates claims 1 and 11. Petitioners,
`
`however, failed to make a prima facie case of anticipation of claims 1 and 11 in the
`
`Petition. Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1369
`
`(Fed. Cir. 2016) (“It is of the utmost importance” that the invalidity challenge be
`
`identified “with particularity” in the petition). Petitioners now scramble to backfill
`
`their arguments using Kennemetal (as so many before them have tried to do, and
`
`failed). But the Board need not even consider Petitioners’ new Kennametal
`
`argument because Petitioners did not raise that theory of anticipation in the
`
`Petition—and this new argument raised for the first time in reply is far too little, far
`
`too late. See Broad Ocean Tech., LLC v. Nidec Motor Corp., IPR2015-01617, Paper
`
`70, 23 (PTAB April 25, 2019) (“Petitioner’s reliance on the reasoning of Kennametal
`
`is improper because it was not raised in the Petition.”); Wasica Fin. GmbH v. Cont’l
`1
`
`
`
`PGR2022-00014
`Patent No. 10,947,513
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`Auto. Sys., 853 F.3d 1272, 1285-86 (Fed. Cir. 2017) (anticipation challenge was
`
`“insufficiently precise and underdeveloped” because the “petition failed to set forth
`
`the necessary ‘factual component[s]’ needed to advance this [Kennametal] theory”).
`
`More fundamentally though, even if the Board considers Petitioners’ new
`
`argument, your honors will see that Petitioners misapply Kennametal, while making
`
`dozens of inaccurate statements, including that no facts are in dispute, (which is not
`
`true), and that Patent Owner’s expert made certain admissions (which he clearly did
`
`not do). Patent Owner dispatches each of these inaccuracies below.
`
`Silvestre Does Not Anticipate Claims 1 and 11
`
`Silvestre includes no embodiment of an oncolytic virus that encodes GM-
`
`CSF and CTLA-4 inhibitor. POR, 12-15. Yet, Petitioners argued, in the Petition,
`
`that Silvestre anticipates claims 1 and 11 because it separately “discloses each
`
`element of these claims.” Petition, 42. Petitioners’ argument, however, requires that
`
`a POSA pick and choose from Silvestre’s lists of viruses, immune checkpoint
`
`modulators (“ICM”) and therapeutic genes, resulting in over 5,000 possible
`
`combinations. POR, 14-15. The sheer number of possible combinations in
`
`Silvestre does not provide a POSA any meaningful way to “at once envisage” the
`
`exact combination recited in claims 1 and 11. Id., 15-16.
`
`In reply, Petitioners concoct a complex new argument that Silvestre discloses
`
`“but twelve realistic options.” Reply, 3. To arrive at this purported “small,
`
`2
`
`
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`PGR2022-00014
`Patent No. 10,947,513
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`recognizable class of twelve options” (id.), Petitioners weave a tortuous path through
`
`Silvestre’s disclosure, adopting certain “preferences” while disregarding others.
`
`According to Petitioners, a POSA would have focused only upon: “(1) the three
`
`viruses a POSITA would have chosen (herpes, pox, and adeno); (2) the two [ICMs]
`
`preferred by Silvestre (anti-PD-1 and anti-CTLA4); and (3) the two therapeutic
`
`genes preferred by Silvestre (a suicide gene with CDase and UPRTase activity and
`
`GM-CSF as an immunostimulatory gene),” creating “just twelve combinations.”
`
`Reply, 7 (emphasis original).1 Petitioners then argue that “the twelve combinations
`
`from Silvestre immediately envisaged by a POSITA … align with the anticipation
`
`finding in Kennametal.” Id., 8.
`
`Petitioners’ reliance on Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780
`
`F.3d 1376 (Fed. Cir. 2015), however, is misplaced. In Kennametal, the challenged
`
`claims required a ruthenium binding agent and a PVD coating to be used together.
`
`The prior art patent claimed only five binding agents (one of which was ruthenium)
`
`and disclosed only three coating techniques (one of which was PVD). The Federal
`
`Circuit found that the reference effectively taught fifteen combinations, which was
`
`a small enough set to anticipate the claims. Id., 1382-83.
`
`1 Emphasis added unless noted otherwise.
`
`3
`
`
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`PGR2022-00014
`Patent No. 10,947,513
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`Silvestre, in contrast, discloses over 5,000 combinations. Only using
`
`impermissible hindsight guided by the instant claims do Petitioners dissect and
`
`recombine the thousands of permutations to create twelve combinations. This defies
`
`the law of anticipation. In re Ruschig, 343 F.2d 965, 974-75 (CCPA 1965)
`
`(forbidding “the mechanistic dissection and recombination” of the prior art “to create
`
`hindsight anticipations with the guidance of an applicant’s disclosures”).
`
`Notwithstanding Petitioners’ highly selective hindsight reasoning, the Board
`
`in Kennametal had expressly rejected the argument that options characterized as
`
`“preferred” somehow negated the description of other options. Kennametal, 780
`
`F.3d at 1380 (“The Board found that the description of coating by PVD was not
`
`negated by the fact that CVD and MTCVD were ‘characterized by Grab as
`
`preferred.’”). Yet, this is precisely the approach taken by Petitioners. Reply, 3-7.
`
`The Board should reject Petitioners’ narrowing effort outright. But even taken at
`
`face value, Petitioners’ new anticipation theory fails, as shown below.
`
`1. Petitioners’ Narrowed List of Viruses Is Based on Hindsight
`
`Silvestre discloses eleven types of viruses from which the oncolytic virus “can
`
`be obtained.” EX1002, 7:11-30; Reply, 3. Yet, Petitioners argue “that, for insertion
`
`of multiple heterologous genes back in 2016 … a POSITA probably would have
`
`chosen” “herpesvirus, poxvirus and adenovirus [because they] were the only three
`
`types from the list of 11 viruses that were commonly used in the art.” Reply, 4. But
`
`4
`
`
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`PGR2022-00014
`Patent No. 10,947,513
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`there is simply no reason for the POSA to limit Silvestre’s list of viruses to only
`
`those that were purportedly commonly used to express multiple heterologous genes,
`
`as Silvestre discloses embodiments where the virus encodes a single heterologous
`
`gene. EX1002, 3:23-26 (“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).”)2
`
`Of course, the only logical explanation for Petitioners’ narrowing approach is
`
`that they started with the claims of the ’513 patent (which require two heterologous
`
`genes) and worked backwards—precisely the type of “mechanistic dissection and
`
`recombination” of the prior art to create “hindsight anticipations with the guidance
`
`of an applicant’s disclosures” that the law prohibits. Ruschig, 343 F.2d at 974;
`
`Argentum, IPR2017-00807, Paper 19, 4-9 (petition failed to meet “envision”
`
`standard because “preferences” were “hindsight”).
`
`2 Given that Silvestre consistently describes the oncolytic virus as comprising “one
`
`or more [ICMs]” (EX1002, 1:20-22, 3:22-26, 4:3-6, 4:14-16, 12:11-15), the number
`
`of potential combinations could actually be in the millions. Argentum, Pharms. LLC
`
`v. Cipla Ltd., IPR2017-00807, Paper 19, 6 (PTAB Oct. 30, 2017) (“disclosed nasal
`
`compositions as comprising an anti-inflammatory agent and ‘at least one’ additional
`
`therapeutic agent … could result in more than 800 million possible compositions.”).
`
`5
`
`
`
`Petitioners are also wrong in stating that “HSV” is one of only two virus types
`
`“preferred by Silvestre.” Reply, 4.3 Silvestre states:
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`PGR2022-00014
`Patent No. 10,947,513
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`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.
`
`EX1002, 7:52-60. A POSA would have understood Silvestre’s statement that
`
`“particularly preferred are HSV1 and HSV2” to mean that these two HSV subtypes
`
`are preferred within the herpesvirus embodiment—not that herpesvirus, as a class,
`
`is “particularly preferred” over the other disclosed virus types. As Dr. Chiocca
`
`testified:
`
`When -- can I go back? When you look at the HSV, when
`you look at that paragraph, it has the same structure as your
`other ones, “one embodiment.” But when it talks about
`the “particularly preferred,” what they’re saying is that
`because there’s multiple strains of HSV, the particularly
`
`3 Petitioners also never made that argument in the Petition. See Petition, 44
`
`(“Silvestre discloses preparing modified oncolytic virus using other virus types,
`
`including HSV.”).
`
`6
`
`
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`PGR2022-00014
`Patent No. 10,947,513
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`preferred ones are HSV-1 and 2. It doesn’t say that HSV
`is a preferred virus.
`
`EX1106, 116:12-20; id., 117:11-17 (“[A]gain, herpes virus is one embodiment just
`
`like everybody else, amongst that embodiment, HSV-1 and 2 are preferred. It’s not
`
`that they’re preferred, they’re preferred within that embodiment.”).
`
`The Reply also suggests that Dr. Chiocca admitted that a POSA in 2016 would
`
`have envisaged only herpesvirus, poxvirus, and adenovirus. Reply, 4. Not true.
`
`When asked to confirm whether “herpes virus, poxvirus, and adenovirus were
`
`commonly use[d] for insertion of heterologous genes” in 2016, Dr. Chiocca
`
`answered, “Correct. And I question whether measles, retro, and influenza, I
`
`would have to look that up.” EX1106, 111:2-9; id., 71:21-72:11 (same for sind bis
`
`virus); id., 80:18-81:6 (VSV); id., 81:7-13 (NDV). Therefore, far from confirming
`
`that a POSA “would have envisaged” only herpesvirus, poxvirus, and adenovirus,
`
`Dr. Chiocca questioned whether six additional viruses had been used—he just
`
`“would have to look that up.”
`
`Moreover, although not expressly stated in the Reply, Petitioners’ rationale
`
`for narrowing Silvestre’s list of viruses is based on “packaging capacity.” EX1106,
`
`67:1-11; Reply, 4 (citing EX1007 ¶¶61-72, 104-107). While Petitioners presented
`
`this concept in the Petition, they did so only in support of non-enablement (Ground
`
`1). See Petition, 12-16, 22-38. If Petitioners wanted to rely on this concept in
`
`7
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`Patent No. 10,947,513
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`support of anticipation, they should have done so in the Petition. The Reply is not
`
`the time to do so. Wasica, 853 F.3d, 1286-87 (“Shifting arguments in this fashion is
`
`foreclosed by statute, [Federal Circuit] precedent, and Board guidelines.”)4
`
`Additionally, as Dr. Chiocca confirmed, “packaging capacity is sort of the
`
`limit on the maximum amount of additional nucleic acid that you can put into a
`
`viral genome without disrupting its ability to be an oncolytic virus.” EX1106,
`
`67:22-68:5; id., 67:19-21 (Q. Because when you have an oncolytic virus, it still has
`
`to replicate? A. Correct.). Here, Silvestre never shows that oncolytic activity is
`
`maintained when an ICM-encoding gene and a therapeutic gene are inserted into the
`
`genome of any of the viruses disclosed in Silvestre. See EX1002, 30:57-58
`
`(“expression of the different anti mPD-1 molecules did not affect the oncolytic
`
`activity of the vaccinia virus.”). Petitioners simply assume that it would be—but
`
`that is insufficient for anticipation. MEHL/Biophile Int’l Corp. v. Milgraum, 192
`
`F.3d 1362, 1365 (Fed. Cir. 1999) (inherent disclosure requires that “the prior art
`
`necessarily functions in accordance with, or includes, the claimed limitations.”).
`
`4 To illustrate Petitioners’ shifting positions, Petitioners argued, in the Petition, that
`
`“[n]o guidance is provided on selecting a suitable virus” (Petition, 33)—yet
`
`Petitioners argue in reply that a POSA’s common knowledge would have allowed
`
`them to select only “herpesvirus, poxvirus, and adenovirus.” Reply, 3-4.
`
`8
`
`
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`Finally, Patent Owner is not aware of any authority, nor have Petitioners cited
`
`any, that would allow Petitioners to narrow Silvestre’s list of viruses based on the
`
`common “knowledge in the art.” Reply, 3-4. Sanofi-Aventis U.S. LLC v.
`
`Genentech, Inc., IPR2015-01624, Paper 15, 15-16 (PTAB Feb. 5, 2016) (rejecting
`
`anticipation argument that “required [a POSA] to selectively apply the general
`
`teachings of [a prior art reference] to the specific production of immunoglobulins
`
`and, in doing so, would have made choices based on inferences gleaned from outside
`
`the reference” explaining that an analysis “based on ‘common knowledge’ … falls
`
`within the purview of obviousness, not anticipation”); Motorola, Inc. v.
`
`Interdigital Tech. Corp., 121 F.3d 1461, 1473 (Fed. Cir. 1997) (“presumed
`
`knowledge [of a POSA] does not grant a license to read into the prior art reference
`
`teachings that are not there”); see also Janssen Pharms., Inc. v. Watson Labs., Inc.,
`
`2012 WL 3990221, *7-*9 (D.N.J. Sept. 11, 2012) (rejecting anticipation argument
`
`that “a challenger may reduce the size of the genus by asking which species would
`
`have ‘stood out’ to the skilled artisan”).
`
`2. Silvestre Identifies More Than Two Preferred Therapeutic
`Genes
`
`Petitioners suggest that Dr. Chiocca “admitted” that Silvestre “teaches GM-
`
`CSF as the preferred immunostimulatory gene.” Reply, 6-7. Again, not true. All
`
`Dr. Chiocca “admitted” was that Silvestre contains the statement that “[p]referably,
`
`9
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`
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`Patent No. 10,947,513
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`the immunostimulatory protein is an interleukin or a colony-stimulating factor, with
`
`a specific preference for GM-CSF.” Reply, 6. For context, that statement appears
`
`at the end of the following paragraph:
`
`Examples of suitable immunostimulatory proteins in the
`context of the invention include without limitation
`cytokines, with a specific preference for interleukins
`(e.g. IL-2, IL-6, IL-12, IL-15, IL-24), chemokines (e.g.
`CXCL1O, CXCL9, CXCL11), interferons (e.g. IFNg,
`(TNF), colony-
`IFNalpha),
`tumor necrosis
`factor
`stimulating factors (e.g. GM-CSF, C-CSF, M-CSF …),
`APC (for Antigen Presenting Cell)-exposed proteins (e.g.
`B7.1, B7.2 and the like), growth factors (Transforming
`Growth Factor TGF, Fibroblast Growth Factor FGF,
`Vascular Endothelial Growth Factors VEGF, and the like),
`MHC antigens of class I or II, apoptosis inducers or
`inhibitors (e.g. Bax, Bcl2, BclX …), cytostatic agents
`(p21, p16, 5 Rb …),
`immunotoxins, antigenic
`polypeptides (antigenic polypeptides, epitopes, and the
`like) and markers (betagalactosidase, luciferase …).
`Preferably, the immunostimulatory protein is an
`interleukin or a colony-stimulating factor, with a
`specific preference for GM-CSF.
`
`10
`
`
`
`EX1002, 11:53-12:9.5 When questioned about this paragraph during his deposition,
`
`Dr. Chiocca testified:
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`PGR2022-00014
`Patent No. 10,947,513
`
`But, again, before that – that’s at the end of your sentence.
`But before that he says there’s a vast number, and amongst
`suitable
`all
`that
`vast
`number,
`he
`says
`immunostimulatory
`proteins with
`a
`specific
`preference, IL-2, IL-6, IL-12, IL-15, IL-24, CXCL10,
`CXCL9, CXCL11, interferons, interferonNalpha, tumor
`necrosis factor …
`
`EX1106, 127:3-10. Dr. Chiocca further testified that he did not agree that GM-CSF
`
`is the only preferred immunostimulatory gene: “I think GM-CSF is one of the
`
`preferreds. It seems like to me when I read that sentence, there’s lots of preferreds
`
`in that sentence.” Id., 129:2-8. Petitioners do not explain why a POSA “would
`
`have focused” only on GM-CSF while ignoring all of the other “preferred”
`
`immunostimulatory proteins.6
`
`5 As a matter of syntax, “specific preference for GM-CSF” relates back to “colony-
`
`stimulating factor,” meaning that GM-CSF is a preferred “colony-stimulating
`
`factor,” not that GM-CSF is Silvestre’s only preferred immunostimulatory protein.
`
`6 Petitioners’ Reply cites testimony falsely suggesting that “GM-CSF is what
`
`[Silvestre] actually … use in their example.” Reply, 6 (citing EX1106, 129:9-12).
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`11
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`Patent No. 10,947,513
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`Petitioners’ reliance on Silvestre’s claim 12 (Reply, 6) fairs no better. Claim
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`12 recites: “[t]he method of claim 11, wherein said colony-stimulating factor is
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`therapeutic human GM-CSF.” EX1002, 38:48-49. Claim 11 recites: “[t]he method
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`of claim 7, wherein said immunostimulatory protein is an interleukin or a colony-
`
`stimulating factor.” Id., 38:45-50. Thus, by reciting that “said colony-stimulating
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`factor is therapeutic human GM-CSF,” claim 12 simply limits the “colony-
`
`stimulating factor” alternative of claim 11 to GM-CSF, leaving all of the disclosed
`
`interleukins as possible options. EX1106, 130:3-6 (Q. Okay. But it’s what they have
`
`in the claim? A. That’s what they have in the claim 12. And in the claim above that
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`they have all the other interleukins, cytokines.)7
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`But as Dr. Chiocca quickly clarified, “this virus does not have GM-CSF. This is
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`the vaccinia virus that has the deletion, but does not actually express GM-CSF.”
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`EX1106, 129:19-130:2.
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`7 Following Petitioners’ logic, Silvestre expresses a preference for at least one
`
`suicide gene, at least one colony-stimulating factor (GM-CSF), and various
`
`interleukins, including IL-2, IL-6, IL-12, IL-15, IL-24, for a total of at least seven
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`“preferred” therapeutic genes.
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`12
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`PGR2022-00014
`Patent No. 10,947,513
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`3. Silvestre Identifies More Than Two Preferred Immune
`Checkpoint Modulators
`
`Petitioners state that “it is undisputed that Silvestre indicates a ‘specific
`
`preference’ for only two [ICMs]: anti-PD-1 and anti-CTLA4.” Reply, 5. This,
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`again, is not true. As disclosed in Silvestre:
`
`immune checkpoint
`the one or more
`Desirably,
`modulator(s) encoded by the oncolytic virus of the present
`invention antagonize(s) at least partially (e.g. more than
`50%) the activity of inhibitory immune checkpoint(s), in
`particular those mediated by any of the following PD-1,
`PD-L1, PD-L2, LAG3, Tim3, BTLA and CTLA4, with
`a specific preference for a monoclonal antibody that
`specifically binds to any of such target proteins. …
`Alternatively,
`the encoded one or more
`immune
`checkpoint modulator(s) exert(s) an agonist function in the
`sense that it is capable of stimulating or reinforcing
`stimulatory signals, in particular those mediated by CD28
`with a specific preference for any of ICOS, CD137 (4-
`1BB), OX40, CD27, CD4O, GITR
`immune
`checkpoints.
`
`EX1002, 13:45-14:1. Therefore, Silvestre indicates a “specific preference for” many
`
`ICMs. Moreover, Silvestre’s statement that “[i]n 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
`13
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`
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`PGR2022-00014
`Patent No. 10,947,513
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`an anti PD-1 antibody and/or an anti CTLA4 antibody” (Reply, 5) simply means that
`
`within that one embodiment of antagonist molecules, anti-PD-1 and anti-CTLA-4
`
`are preferred. It does not mean that those two antibodies are the only preferred
`
`ICMs.8
`
`*
`
`*
`
`*
`
`There is simply nothing in Silvestre that would have led a POSA to focus only
`
`upon three viruses, two ICMs, and two therapeutic genes. Indeed, a POSA might
`
`very well have focused on: the three viruses a POSA “probably would have chosen”
`
`and the six viruses Dr. Chiocca “questioned” could have been used; the seven
`
`therapeutic genes and eight ICMs identified as “preferred” by Silvestre. This still
`
`leads to over 500 combinations, which is significantly more than Kennametal’s
`
`“limited class” of fifteen. Mylan Pharms. Inc. v. Merck Sharp & Dohme Corp., 50
`
`F.4th 147, 154 (Fed. Cir. 2022) (“We cannot provide a specific number defining a
`
`‘limited class’ … [b]ut we agree with Merck and hold that the Board did not err in
`
`finding that a class of 957 predicted salts that may result from the 33 disclosed
`
`8 Following Petitioners’ logic, Silvestre expresses a preference for at least two
`
`immune checkpoint antagonists, (anti-PD1 and anti-CTLA-4 antibody) and at least
`
`six immune checkpoint agonists (ICOS, CD137, OX40, CD27, CD4O, GITR), for a
`
`total of at least eight “preferred” ICMs.
`
`14
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`PGR2022-00014
`Patent No. 10,947,513
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`compounds and eight preferred acids, some of which may not even form under
`
`experimental conditions, is insufficient to meet the ‘at once envisage’ standard.”)
`
`Claim 13 Is Not Obvious Over Silvestre
`
`Petitioners have not shown that claims 1 and 11 are anticipated by Silvestre.
`
`For this reason alone, Ground 4 fails. Mylan Pharmaceuticals Inc. v. Merck Sharp
`
`& Dohme Corp., IPR2020-00040, Paper 91, 54 (PTAB May 7, 2021) (“The
`
`challenge to claim 3 as obvious over WO ’498 alone fails because it is based on
`
`Petitioner’s ‘predicate’ anticipation challenge to claim 1.”) Ground 4 also fails
`
`because Petitioners have not shown that the additional limitations of claim 13 would
`
`have been obvious over Silvestre.
`
`As explained (POR, 18), Petitioners’ only argument for why a POSA would
`
`have been motivated to use the insertion strategy of claim 13 was that the “simplest
`
`and most common method to insert two genes to a locus is in a back-to-back
`
`orientation.” But as Petitioners’ expert Dr. Bell testified, and Petitioners now
`
`recognize, it was “perhaps an over-statement [to] say it’s the simplest and most
`
`common.” Reply, 9-10.
`
`Petitioners’ only argument is now that a POSA would have been motivated to
`
`use the back-to-back insertion strategy of claim 13 because it was known. Reply,
`
`10-11. But the mere assertion that it was “known” is not enough to show that a
`
`POSA would have been motivated to use it. POR, 23. “[O]bviousness concerns
`
`15
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`Patent No. 10,947,513
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`whether a skilled artisan not only could have made but would have been motivated
`
`to make the combinations or modifications of prior art to arrive at the claimed
`
`invention.” Belden Inc. v. Berk–Tek LLC, 805 F.3d 1064, 1073 (Fed. Cir. 2015)
`
`(emphasis in original).
`
`Additionally, Dr. Chiocca testified that the ICP34.5 locus “was not a
`
`preferred site.” EX1106, 97:6-7; id., 99:16 (“It was not a commonly known
`
`strategy.”). Dr. Chiocca explained that:
`
`In general I think the ICP 34.5 locus is a very difficult
`locus to put genes into it, and it has a high degree of
`recombination. It’s a very GC, rich region of the virus. So
`there are a lot of problems with that locus. … And
`inserting two heterologous genes into that site I think
`creates even more problems.
`
`Id., 101:10-18; id., 188:21-189:2 (“I think that inserting into this locus of the virus
`
`is very difficult, and there are easier places to do it.”); id., 102:8-9 (“And a lot of
`
`other labs don’t [use that strategy] either that I can tell.”) Neither Petitioners nor Dr.
`
`Bell have provided any explanation why, other than the mere fact that the insertion
`
`strategy was known, a POSA would have been motivated to insert two heterologous
`
`genes at the ICP34.5 locus in a back-to-back orientation as claimed.
`
`Petitioners also argue that the Board should disregard the three post-filing
`
`publications cited by Patent Owner showing how Dr. Bell and Petitioners have used
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`16
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`
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`Patent No. 10,947,513
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`insertion strategies other than back-to-back. Reply, 11. But the Board is free to rely
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`on post-filing publications for their proper supporting roles, e.g., to indicate the
`
`knowledge, motivations, and expectations of a POSA. See Beable Educ., Inc. v.
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`Achieve3000, Inc., IPR2021-01169, Paper 34, 89 (PTAB Jan. 3, 2023). And here,
`
`Patent Owner is using these references to contradict Petitioners’ assertion that “the
`
`simplest and most common method to insert two genes to a locus is in a back-to-
`
`back orientation.” POR, 18-22.
`
`As to a POSA’s reasonable expectation of success, Petitioners argue that
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`“Replimune and Dr. Chiocca conducted the wrong analysis by focusing not on
`
`whether a POSITA could make the virus of Claim 13 from Silvestre, but instead on
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`how the created virus would function.” Reply, 12-13. According to Petitioners
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`“[u]nclaimed features are irrelevant to the reasonable expectation of success
`
`analysis.” Id., 13. But claim 13 explicitly requires an “oncolytic virus,” which
`
`according to Petitioners, is a virus that “infects and replicates in tumor cells, such
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`that the tumor cells are killed.” Petition, 6.9 As the Federal Circuit has explained,
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`the “question of a reasonable expectation o
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