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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`––––––––––––––
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`GENOME & COMPANY,
`Petitioner,
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`v.
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`THE UNIVERSITY OF CHICAGO,
`Patent Owner
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`––––––––––––––
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`PGR2019-00002
`Patent 9,855,302 B2
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`––––––––––––––
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`PATENT OWNER SUR-REPLY
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`PGR2019-00002
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`Patent Owner Sur-Reply
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`TABLE OF CONTENTS
`INTRODUCTION: BURDEN OF PROOF ............................................. 1
`I.
`II. THE PERSON OF ORDINARY SKILL IS NOT AN
`AUTOMATON......................................................................................... 1
`III. ENABLEMENT – Ground 1 .................................................................... 3
`A. Cancer types .........................................................................................3
`B. Checkpoint inhibitors ...........................................................................5
`C. Bifidobacterium species and strains .....................................................8
`1. O’Mahony .......................................................................................9
`2. Lopez ............................................................................................ 10
`D. Routes of administration ................................................................... 11
`E. Routine testing ................................................................................... 12
`F. Conclusion ......................................................................................... 13
`IV. OBVIOUSNESS ..................................................................................... 13
`A. Korman/Singh/Dong – Grounds 2–4 ................................................. 13
`B. Korman/Kohwi – Grounds 5–8 ......................................................... 17
`C. Korman/Mohania/Prakash – Grounds 9–11 ...................................... 20
`V. CONCLUSION....................................................................................... 23
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`I. INTRODUCTION: BURDEN OF PROOF
`Patent Owner has shown that Petitioner’s evidence is insufficient to
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`prove the factual predicates required to reach the conclusions that the claims
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`are unpatentable for lack of enablement or for obviousness. Petitioner largely
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`sidesteps Patent Owner’s Response by inaccurately portraying it as a “proof
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`of enablement” (Reply 8) or “obviousness rebuttal” (id. at 2). It is not Patent
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`Owner’s burden to prove enablement or nonobviousness. Rather, Patent
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`Owner has presented evidence of gaps, unwarranted assumptions, and flat-out
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`inaccuracies in Petitioner’s case, defects that compel the conclusion, as a
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`matter of law, that Petitioner has not and cannot satisfy its burden to prove
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`unpatentability by a preponderance of the evidence under 35 U.S.C. § 326(e).
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`II. THE PERSON OF ORDINARY SKILL IS NOT AN AUTOMATON
` Petitioner argues that the person of ordinary skill in this case would
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`have “an advanced degree or its substantial equivalent” and “research
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`experience” in the biological sciences. Ex. 1002 ¶ 40. Petitioner also argues
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`that the level of skill is high, requiring specialized knowledge of several fields.
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`Pet. 37 (citing Ex. 1002 ¶ 132). Inherent in the concept of a person of ordinary
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`skill in the art holding an advanced degree, specialized knowledge, and
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`research experience, is the ability to review the scientific literature critically
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`and to evaluate it.
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`Yet at numerous points in its challenges, Petitioner argues that its
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`highly sophisticated POSA would have blindly accepted the conclusions of
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`research papers, despite demonstrated limitations in experimental design and
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`discrepancies in statistical analysis, because these papers were peer-reviewed
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`and cited by others. Reply 2, 3, 10, 18–20, 22, 23.
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`Mere publication of results does not make those results true, nor does
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`it constitute credible evidence of what one of ordinary skill would rely on per
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`se. Petitioner’s POSA would be a critical reviewer of the literature and not
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`credit conclusions backed by irreproducible data or speculation. E.g.,
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`Ex. 2007 ¶ 136 (Dr. Mani testifying that a POSA would have dismissed
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`Kohwi’s results due to their irreproducibility).
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`Petitioner has not contested Dr. Mani’s critiques of the statistical
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`shortcomings in several papers on which Petitioner’s case critically relies,
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`including Dong (PO Resp. 57; Ex. 2007 ¶¶ 118–121), Kohwi (PO Resp. 63–
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`65; Ex. 2007 ¶¶ 136–140), O’Mahony (PO Resp. 20–23; Ex. 2007 ¶¶ 57–66),
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`and Lopez (PO Resp. 24–36; Ex. 2007 ¶¶ 70–88). Nor has Petitioner
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`responded to the substance of Patent Owner’s argument that a POSA would
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`have questioned these papers given their dubious statistics. Petitioner instead
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`stands on its insistence that its highly trained, skilled, and experienced POSA
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`would simply accept statements from these papers as true without critical
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`analysis. But just as a POSA would bring to bear a complete knowledge of the
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`relevant prior art and an ordinary creativity in synthesizing that art, KSR Int’l
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`Co. v. Teleflex Inc., 550 U.S. 398, 420–21 (2007), so too would the POSA
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`recognize the limitations of the prior art and refuse to credit its conclusions on
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`insufficient evidence. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d
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`1540, 1550 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984) (each prior art
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`reference must be considered in its entirety).
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`III. ENABLEMENT – Ground 1
`Enablement is a question of law based upon underlying factual findings.
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`In re Vaeck, 947 F.2d 488, 495 (Fed. Cir. 1991). Petitioner’s allegations
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`therefore must be supported by sufficient and credible evidence to justify their
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`finding. Patent Owner has shown, however, that Petitioner’s evidence does
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`not support the factual allegations critical to Petitioner’s enablement
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`challenge. Patent Owner also has shown through evidence presented in its
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`Response that Petitioner’s assertions of uncertainty and unpredictability are
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`premised on unwarranted assumptions. For these reasons, Petitioner’s
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`enablement challenge should be rejected.
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`A. Cancer types
`Although Petitioner argues that cancer is a large class of widely varying
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`diseases (Pet. 21–26), Petitioner has not identified any type of cancer that was
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`reported as failing to respond to immune checkpoint inhibitor therapy.
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`Patent Owner has shown that immune checkpoint inhibitors treat cancer
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`types across a wide range of mutational burdens. PO Resp. 10–13. Because
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`the responsive cancer types are spread throughout the mutational burden
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`spectrum, a POSA at the time would have expected that the untested types
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`interspersed among them are responsive as well. Id.; Ex. 2007 ¶ 45. This
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`evidence demonstrates that cancers are not widely varying and heterogeneous
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`with respect to their susceptibility to checkpoint inhibitors. Petitioner merely
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`points out that not all cancer types have been tested; Petitioner does not
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`explain why the reported cancers, all of which are responsive, are not
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`representative of all cancer types in the context of checkpoint inhibitor
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`therapy.
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`Although Petitioner argues that there are many mechanisms aside from
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`immune checkpoints by which tumor cells evade the immune system (Reply
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`12–13), Petitioner offers no response to Patent Owner’s argument and
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`evidence that checkpoint inhibition “alters the balance of co-stimulatory and
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`co-inhibitor signals on T cells, and alters this balance in favor of T cell
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`activation” (Ex. 2007 ¶ 32), thereby lowering the threshold for the immune
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`system to act on a tumor. PO Resp. 5. This disinhibition acts to increase
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`immune system responsiveness regardless of how the tumor is evading
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`detection. It is precisely because this approach is cause-agnostic that persons
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`of ordinary skill had reason to expect it to work against all cancer types. Id.
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`B. Checkpoint inhibitors
`Although Petitioner argues that checkpoint inhibitors are a large class
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`of agents that are recited functionally in the claims, and that the ’302 patent
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`identifies no examples of checkpoint inhibitors in certain classes (such as
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`antibody fragments and interfering nucleic acids), Petitioner has not offered
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`any evidence that such agents do not exist, aside from its expert’s
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`ignorance. Reply 5 n.4 (citing Ex. 1043 ¶ 19). Petitioner also offers no
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`evidence that one of ordinary skill would not have recognized the emergence
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`of such agents as they are introduced in the art. The law of enablement
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`contemplates
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`claiming
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`broadly
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`to
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`cover
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`after-arising
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`embodi-
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`ments. “Enablement does not require the inventor to foresee every means of
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`implementing an invention at pains of losing his patent franchise.” Invitrogen
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`Corp. v. Clontech Laboratories, Inc., 429 F.3d 1052, 1070–71 (Fed. Cir.
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`2005) (rejecting enablement challenge where functionally-defined claim had
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`been asserted against an accused infringer practicing the invention in a manner
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`not described in the specification).
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`Patent Owner has shown that the low but consistent response rates of
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`many cancers to checkpoint inhibitors creates no uncertainty about whether
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`checkpoint inhibitors work for cancer patient populations. PO Resp. 13–16.
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`Petitioner offers no authority for its argument that enablement requires a
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`100% (or some other threshold) response rate.1 And Petitioner’s argument
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`that a low response rate indicates uncertainty is refuted by Patent Owner’s
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`evidence of how the field has viewed these response rates. The FDA’s
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`approval of nivolumab for lung cancer in March 2015 with a response rate of
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`15% (Ex. 2057 at 21) demonstrates that the field accepted low response rates
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`and considered a cancer treatment to work notwithstanding a low response
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`rate. PO Resp. 14–15; Ex. 2007 ¶ 47. Thus, for a population of patients with
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`a given cancer, the efficacy of a checkpoint inhibitor was sufficiently certain
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`(even when 85% of the trial population had not reported a response) that the
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`FDA was willing to approve it for all patients within the population. Id.
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`1 E.g., Pet. 27 (“[T]he same immune checkpoint inhibitor does not
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`successfully treat all patients with non-small cell lung carcinoma.”) (emphasis
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`in original).
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`Petitioner has not responded to this evidence of the field’s ready adoption of
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`checkpoint inhibitors.
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`The efficacy of checkpoint inhibitors is assessed at the level of patient
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`populations because that is how organizations charged with evaluating the
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`safety and efficacy of such therapies (e.g., the FDA) assess them. Id. But
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`even if individual patient responses are considered, Petitioner does not dispute
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`Patent Owner’s evidence as to how a treatment regimen is selected.
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`Petitioner’s expert acknowledged that the process of cancer treatment begins
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`with knowing the particular cancer the patient has (Ex. 2078, 13:17–20),
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`thereby eliminating the “many different kinds of cancers” (Pet. 22; Ex. 1002
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`¶ 95 (verbatim)) as an axis of uncertainty in cancer therapy. Patent Owner’s
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`uncontested evidence from Dr. Mani, a board-certified oncologist, shows that,
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`for a given patient, an oncologist often tries out several therapies, to find one
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`that provides the best possible result for that patient and treating oncologist,
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`through a routine and manageable process. Ex. 2007 ¶ 53; PO Resp. 16–17.
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`Petitioner has neither challenged this evidence nor contested that the process
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`Dr. Mani describes is anything other than routine. And despite being held out
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`as having “extensive experience in human cancer therapy” (Reply 15 n.10),
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`Petitioner’s expert acknowledged, in contrast, that he has never had primary
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`responsibility for a cancer patient’s care by, for example, prescribing an
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`immune checkpoint inhibitor or any other therapeutic agent (Ex. 2078, 8:5–9,
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`9:6–8). Nor has he ever served as the principal investigator of a clinical trial
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`(id. at 9:9–16).
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`C. Bifidobacterium species and strains
`Although Petitioner argues that Bifidobacterium species and strains
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`have heterogeneous effects on the immune system because papers have
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`reported nonuniform effects on expression levels of selected cytokines in
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`in vitro assays using PBMCs and DCs (Pet. 29–32; Reply 8–11), Petitioner
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`has not provided evidence that any purported differences among in vitro
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`cytokine expression levels result in different in vivo effects or differences in
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`treating cancer. PO Resp. 32–36. The reported differences may simply be
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`artifacts of the assay conditions employed, rather than reflect inherent
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`variation in effect with different Bifidobacterium strains. PO Resp. 21–22.
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`Petitioner offers no evidence that its references’ in vitro assays are
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`representative of in vivo effects.
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`Concerning
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`the
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`two references Petitioner relies on
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`to assert
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`heterogeneity among Bifidobacterium species, Patent Owner showed that both
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`lack statistical rigor or any functional readout to justify that reliance. PO
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`Resp. 19–36.
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`1. O’Mahony
`O’Mahony (Ex. 1017) provides no statistical analysis comparing
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`strains. PO Resp. 20–24; Ex. 2033, 87:5–8; 86:25–87:3; 87:15–88:6;
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`Ex. 2078, 22:16–29:24. O’Mahony therefore provides no meaningful basis
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`on which to evaluate any differences between them. Petitioner does not
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`explain why it is reasonable to dispense with statistical analysis here.
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`Petitioner also fails to answer Patent Owner’s evidence that O’Mahony used
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`an assay outside its reported dynamic range. PO Resp. 21; Ex. 2007 ¶ 58
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`(citing Ex. 2065). Furthermore, O’Mahony does not provide any information
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`about whether the observed in vitro differences in a few cytokines, even if
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`they were statistically significant, had any effects on the immune system.
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`Petitioner offers no evidence that in vitro PBMC tests are accepted proxies for
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`in vivo immune system function or for the in vivo effects of bacteria on
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`cancer. PO Resp. 24. Finally, Petitioner assumes the truth (i.e., the
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`correctness) of O’Mahony’s data without a declaration from a person having
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`first-hand knowledge of how the data was generated, a practice specifically
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`prohibited by 37 C.F.R. § 42.61(c). Paper 10, 13.
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`Petitioner asserts that Patent Owner “represented” during prosecution
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`that O’Mahony’s strain 1714 “was immunosuppressive” in order to obtain
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`allowance of the ’302 patent. Reply 9 (citing Ex. 1014, 132; id. at 64). Patent
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`Owner made no such representation. Rather, Patent Owner cited passages in
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`O’Mahony that describe immunosuppressive properties of strain 1714 and
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`argued that the conflicting disclosures in Sharon and O’Mahony would have
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`led one of ordinary skill in the art away from the combination. Patent Owner’s
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`critique of O’Mahony was limited to a discussion of O’Mahony’s disclosure
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`on its face. Patent Owner made no representations regarding whether
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`O’Mahony’s data or conclusions are correct. Petitioner’s continued confusion
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`about the difference between what a document discloses on its face versus the
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`correctness of its data or conclusions demonstrates a fundamentally flawed
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`understanding of the nature, weight, and effect of evidence.
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`Lopez
`2.
`Lopez uses rank-order statistics that cannot, as a matter of basic
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`statistical principles explained by Patent Owner’s expert, be used to compare
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`the magnitudes of cytokine expression among groups. PO Resp. 24–36;
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`Ex. 2007 ¶¶ 70–88. They can be used only to determine whether the cytokines
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`are expressed in similar or different rank orders. PO Resp. 27–29; Ex. 2007 ¶
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`77. Furthermore, Petitioner ignores the functional data Lopez provides, such
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`as data reporting similar PBMC proliferation and DC maturation effects of the
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`strains, which demonstrates, if anything, the uniformity of strain effects. PO
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`Resp. 30–33; Ex. 2007 ¶¶ 82, 83. Sanchez’s passing citation to Lopez as
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`evidence of Bifidobacterium heterogeneity (Ex. 1044, quoted at Reply 10–11)
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`does not establish Lopez’s conclusions as correct, because Patent Owner has
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`shown that it would have been unreasonable for a POSA to have relied on
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`Lopez as evidence of Bifidobacterium heterogeneity due to its insufficiently
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`powerful non-parametric statistics and its functional data suggestive of
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`uniform effects. As discussed above in section II, one of ordinary skill brings
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`critical judgment to the assessment of what the prior art discloses. A legal
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`holding of non-enablement must be predicated on facts, not on undetected
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`errors that have crept into the art, because persons of ordinary skill would not
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`rely on such errors.
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`D. Routes of administration
`Although Petitioner argues that various routes of administration for
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`checkpoint inhibitors and Bifidobacterium are “likely” inoperable (Pet. 46–
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`47; Reply 5), Petitioner presents no evidence concerning inoperable routes
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`other than the ignorance of its expert, a pathologist who has never
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`administered a checkpoint inhibitor to a human subject. Id.; Ex. 2078, 10:14–
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`17. Petitioner also presents no evidence that routes of administration are not
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`standard knowledge or routinely determined. Eli Lilly and Co. v. Actavis
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`Elizabeth LLC, 435 Fed. Appx. 917, 922–23 (Fed. Cir. July 29, 2011)
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`(affirming district court’s conclusion that a method-of-treatment claim,
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`unrestricted with respect to formulation and dosage form, was enabled, noting
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`the district court’s findings that “the various conceivable formulations are
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`standard” and are routinely determined, and that “they were not part of the
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`basis for the invention’s patentability”); Invitrogen, 429 F.3d at 1070–71
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`(discussed supra).
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`E. Routine testing
`Although Petitioner
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`argues
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`that
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`the
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`required
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`testing
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`is
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`“[u]nquestionably
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`. . . burdensome and undue” (Pet. 43; Reply 6–7),
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`Petitioner does not explain what that testing would involve beyond quantity,
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`or why it would be anything other than routine. PO Resp. 37–43. Petitioner
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`newly argues in Reply that the testing would be “challenging and expensive”
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`involving “in vitro and in vivo experiments” taking “years to complete”
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`(Reply 16–17) but cites no evidence to substantiate these claims aside from
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`its expert’s verbatim unsupported statement (Ex. 1043 ¶ 76). This new
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`argument is untimely because Petitioner does not explain why it could not
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`have presented it in its Petition, at a time when Patent Owner would have had
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`a meaningful opportunity to respond to it with expert testimony. It should be
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`disregarded for both its untimeliness and lack of credible evidentiary support.
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`F. Conclusion
`Patent Owner has demonstrated that the evidence of record is
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`insufficient to show the unpredictability on which Petitioner bases its case
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`with respect to (a) the susceptibility of all cancer types to immune checkpoint
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`inhibitor therapy; (b) efficacy of checkpoint inhibitor therapy in patient
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`populations with a given cancer; or (c) Bifidobacterium heterogeneity.
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`For these reasons, Petitioner has not made out a case for non-
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`enablement of the challenged claims.
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`IV. OBVIOUSNESS
`Throughout the portion of its Reply concerning the obviousness
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`challenges, Petitioner largely repeats its original arguments without
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`responding to the substance of Patent Owner’s evidence. Because Patent
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`Owner shows that Petitioner’s evidence does not support the factual
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`predicates underpinning Petitioner’s obviousness challenges, those challenges
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`should be rejected.
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`A. Korman/Singh/Dong – Grounds 2–4
`Petitioner
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`its
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`demonstrates
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`Bifidobacterium
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`Patent Owner Sur-Reply
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`longum has anti-tumor activity (Reply 18) without
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`responding to the substance of Patent Owner’s argument. Although Singh
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`does say its data suggest that B. longum “exerts strong antitumor properties”
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`(Abstr.), Singh consistently limits itself to the finding that B. longum inhibits
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`AOM from inducing colon carcinogenesis without attributing that finding to
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`any particular mechanism. PO Resp. 47–48; Ex. 2007 ¶ 99. Patent Owner
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`showed
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`that all of Singh’s supposed anti-tumor effects could be
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`anticarcinogen effects against AOM, a possibility Singh itself acknowledges
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`and Petitioner’s expert admitted. PO Resp. 47–48; Ex. 2033, 16:12–14 (“Q.
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`And Singh does not rule out any of these possible mechanisms, these
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`anticarcinogen properties. A. Correct.”). Petitioner does not respond to this
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`showing. Thus Petitioner still offers no justification for relying on Singh for
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`more than Singh is evidence of.
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`Petitioner deceptively misquotes Singh at Reply 19 to suggest that
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`Singh attributes B. longum’s mechanism to immunomodulation. But Singh
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`states that the bacteria “may proceed through diverse mechanisms,” not
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`“proceeded.” (Ex. 1004, 6, first full para.).2 Petitioner’s ellipses then delete
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`over 400 words of Singh’s text that raise well-documented anti-AOM
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`properties by which B. longum may have its effects.3 Patent Owner explained
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`in its Response how this very content undermines Petitioner’s reliance on
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`Singh. PO Resp. 46–47. Petitioner argues instead that Singh must be
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`accepted as true because it is cited favorably by other articles as evidence that
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`B. longum resulted in “suppression of colon tumor incidence, tumor
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`multiplicity and tumor volume.” Reply 18. But these references, like Singh,
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`do not attribute that “suppression” to activity by B. longum against the cancer.
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`They refer simply to “suppression,” which may just as well result from
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`B. longum’s documented ability to metabolize and sequester the carcinogen
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`2 Petitioner’s citations shift from exhibit page numbers in the Petition to
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`printed page numbers in the Reply. Exhibit page 6 of Singh corresponds to
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`printed page 838.
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`3 The beginning of Petitioner’s quotation occurs 11 lines up from the bottom
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`of the left column on page 838 (exhibit page 6). The end of it occurs over 40
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`lines later, or 12 lines up from the end of the continuation paragraph in the
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`right column.
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`AOM. PO Resp. 48; Ex. 2007 ¶¶ 99.
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`Petitioner does not respond to Patent Owner’s evidence that the art
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`specifically criticized and warned against using AOM-induced carcinogenesis
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`models in the way Singh did precisely because Singh’s methodology cannot
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`distinguish between anti-tumor and anti-carcinogen effects. PO Resp. 48
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`(citing Ex. 2007 ¶ 99; Ex. 2069, 9–10).
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`Petitioner particularly calls out Lee (Ex. 1011)’s description of Singh
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`as evidence that “Bifidobacterium spp. . . . stimulate immune function and
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`anti-tumor effects.” Reply 19–20 (quoting Ex. 1011, 6). But as discussed
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`above, a statement is not true simply because it is printed in a research paper,
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`even a peer-reviewed one. One of ordinary skill would have recognized that
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`Singh speculates about B. longum’s mechanism of action but reaches no
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`conclusion. PO Resp. 46–47; Ex. 2007 ¶ 95. Singh’s speculations do not
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`become facts simply because Lee repackages them that way.
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`Petitioner’s rationale for combination is predicated on a POSA’s
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`knowledge that B. longum is immunostimulatory. Pet. 50–51. But Singh’s
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`speculations about mechanism do not rise to the level of a clear disclosure that
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`B. longum is immunostimulatory. Thus Singh did not supply the POSA with
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`knowledge that B. longum is immunostimulatory. Subsequent authors’
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`citations to Singh do not ameliorate this basic failure of proof.
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`Petitioner also provides no analysis or discussion in its Reply of Patent
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`Owner’s critique of Dong, the other reference Petitioner relies on as evidence
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`that B. longum is immunostimulatory. Petitioner instead attempts to
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`incorporate its expert analysis at Reply 10 n. 7 with no explanation. This
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`unexplained incorporation violates the rule against incorporation by reference
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`and also circumvents the type volume limit. Paper 25, 4.
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`For these reasons, Petitioner’s obviousness challenge based on
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`Korman, Singh, and Dong should be rejected.
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`Concerning claim 9, Petitioner’s analysis rests entirely on an
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`unexplained and unsubstantiated statement by Dr. Braun that separating two
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`administrations of bacterial formulation by at least one week “would have
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`been considered routine optimization.” Ex. 1002 ¶ 179 (claim chart at page
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`79/186). As Patent Owner explained in the Response, Petitioner may not rely
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`on expert testimony as a substitute for disclosure in a prior-art reference. PO
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`Resp. 60–61.
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`B. Korman/Kohwi – Grounds 5–8
`Petitioner leaves Patent Owner’s detailed showing of Kohwi’s
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`irreproducibility entirely unrebutted.
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`Patent 9,855,302 B2
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`Patent Owner Sur-Reply
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`Patent Owner showed that Kohwi conducted essentially the same
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`experiment twice: inoculating mice with 100×103 tumor cells and one day
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`later with either 109 B. infantis cell injections or saline. PO Resp. 63–65;
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`Ex. 2007 ¶¶ 136–138. The experimental conditions were identical, according
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`to Kohwi. PO Resp. 64; Ex. 2007 ¶ 137.
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`Yet one run of the experiment produced a significant difference
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`between B. infantis and saline, while the other did not. PO Resp. 64–65;
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`Ex. 2007 ¶¶ 139–140. Thus the experimental result was not reproducible.
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`Because it was not reproducible, Dr. Mani concluded that Kohwi’s results
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`were not reliable, because reproducibility is the bedrock of scientific inquiry,
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`and a non-reproducible result must be the product of either random chance or
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`uncontrolled experimental conditions. PO Resp. 65; Ex. 2007 ¶ 139.
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`Petitioner has not attempted to show that any part of Patent Owner’s
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`assessment of Kohwi’s irreproducibility is in error. Petitioner’s only response
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`is to argue that a POSA would have been blind to Kohwi’s statistical
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`discrepancies because other peer-reviewed papers cite Kohwi as evidence that
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`Bifidobacterium have anti-tumor and immunomodulatory properties. Reply
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`22. Petitioner simply ignores Dr. Mani’s testimony that the person of ordinary
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`skill would have lacked confidence in Kohwi’s study and would have
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`Patent Owner Sur-Reply
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`concluded that Kohwi was not evidence of antitumor or immunostimulatory
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`effects of Bifidobacterium, because Kohwi was unable to reproduce its results.
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`Ex. 2007 ¶ 136.
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`Furthermore, Kohwi’s discussion of its results is speculative, as
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`Petitioner acknowledges in quoting Kohwi as stating that Bifidobacterium
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`“may” have effects on the immune response. Reply 23, last para. But
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`Petitioner relied on Kohwi as hard fact of the immunostimulatory nature of
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`Bifidobacterium to support both its rationale for combination and reasonable
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`expectation of success. Pet. 60–62. Petitioner’s alternative rationale, that a
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`POSA would have known that checkpoint inhibitors and Bifidobacterium both
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`had antitumor properties (Reply 24), is not supported by evidence, because
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`Kohwi’s statistical discrepancies would have prevented the POSA from
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`drawing that conclusion about Bifidobacterium. Ex. 2007 ¶ 136. Regardless
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`of which rationale Petitioner relies on, Petitioner does not explain how
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`Kohwi’s speculations about possible mechanisms for B. infantis would have
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`been interpreted by a POSA as concrete fact. Patent Owner raised this issue
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`in detail in its Response and showed that Kohwi hypothesized several
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`alternative explanations for its results. PO Resp. 65–69. Petitioner does not
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`respond to this argument and instead continues to rely on Kohwi’s
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`Patent Owner Sur-Reply
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`speculations as fact. Reply 23. Petitioner even mischaracterizes as fact Patent
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`Owner’s discussion of Kohwi’s speculations. Id. (omitting from its quotation
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`from PO Resp. 68 the phrase “Kohwi speculates that”).
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`Thus, because Kohwi’s data is irreproducible and its conclusions are
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`speculative, a POSA would not have relied on Kohwi as a teaching that
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`B. infantis has anti-tumor effects or is immunostimulatory. Petitioner’s
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`rationale for combination and reasonable expectation of success theory both
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`depend critically on these assertions, however, and therefore lack basis in
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`evidence. Petitioner’s challenge based on Korman and Kohwi should be
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`rejected for this reason.
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`Regarding claims 5, 6, 9, 10, 11, 23, 24, and 26: Petitioner does not
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`respond to the substance of Patent Owner’s arguments. In particular, for
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`claims 5, 6, 23, and 24, rather than respond to Patent Owner’s arguments,
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`Petitioner propounds a new theory with new evidence in its Reply. Reply 24.
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`Petitioner thereby deprives Patent Owner of a meaningful opportunity to
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`present its own expert testimony. This new argument and evidence should be
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`discarded for that reason.
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`C. Korman/Mohania/Prakash – Grounds 9–11
`Petitioner does not respond to Patent Owner’s argument that Mohania’s
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`DMH-induced cancer model, like Singh’s AOM-induced model, cannot
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`distinguish between anti-tumor and anti-carcinogen effects. See Ex. 2069, 9–
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`10. Further, Petitioner acknowledges that Mohania speculates on a number
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`of possible mechanisms without ruling any of them in or out. Reply 25–26
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`(quoting Mohania).
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`Petitioner then argues that Mohania does not definitively show that
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`anticarcinogen effects account for Mohania’s findings. Reply 26, second full
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`para. But Petitioner here has the burden of proof exactly backwards. It is not
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`for Patent Owner to prove that Mohania rules in anticarcinogen effects as the
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`exclusive mechanism. Rather, it was for Petitioner to rule it out. Petitioner
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`thus has not satisfied its burden of proof under 36 U.S.C. § 326(e).
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`Finally, Petitioner attempts to salvage its argument based on Mohania
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`by advancing new evidence. But this new evidence— Dr. Braun’s
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`interpretation of Mohania Figure 2— contradicts his earlier testimony.
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`Petitioner now argues that “Inspection of [Mohania] Fig. 2 reveals that in
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`parallel with epithelial cells, more PD-1 stained lymphocytes are observed in
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`DMH-treated tissue.” Reply 27 (citing Ex. 1043 ¶ 97). This argument is
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`inconsistent with Dr. Braun’s testimony at deposition that Mohania does not
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`show that T-infiltrating lymphocytes express PD-1 (Ex. 2033, 44:17–19) and
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`Patent Owner Sur-Reply
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`that his interpretation of Mohania is that it “doesn’t detail the question” of
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`whether increased expression of PD-1 reported is by activated T cells (id.
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`44:20–45:3).
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`Dr. Braun’s new testimony should be discarded because it is untimely
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`and unexplained. Petitioner does not explain why it could not have presented
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`this evidence in its Petition, at a time when Patent Owner would have had a
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`meaningful opportunity to respond to it with expert testimony. Nor does
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`Dr. Braun explain how he conducted his analysis of Mohania Figure 2.
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`Dr. Braun does not explain, or provide an annotated version of Figure 2 to
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`illustrate, how he distinguished epithelial cells from T cells or what he
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`considered the threshold to be to consider a cell stained. Dr. Braun also does
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`not explain why, even if a POSA would
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