Trials@uspto.gov
`571-272-7822
`
` Paper 18
`
`Entered: February 17, 2023
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.
`Petitioner
`v.
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner
`
`____________
`
`IPR2022-00853
`Patent 9,464,140 B2
`____________
`
`Before ULRIKE W. JENKS, SUSAN L. C. MITCHELL, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge
`
`
`DECISION
`Denying Petitioner’s Request for Rehearing
`of Decision Denying Institution of Inter Partes Review
`37 C.F.R. § 42.71(d)
`
`
`
`
`
`571-272-7822
`
` Paper 18
`
`Entered: February 17, 2023
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.
`Petitioner
`v.
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner
`
`____________
`
`IPR2022-00853
`Patent 9,464,140 B2
`____________
`
`Before ULRIKE W. JENKS, SUSAN L. C. MITCHELL, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge
`
`
`DECISION
`Denying Petitioner’s Request for Rehearing
`of Decision Denying Institution of Inter Partes Review
`37 C.F.R. § 42.71(d)
`
`
`
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`INTRODUCTION
`I.
`Miltenyi Biomedicine GmbH and Miltenyi Biotec Inc. (collectively,
`“Petitioner”) requests rehearing of our decision (Paper 11, “Decision” or
`“Dec.”) denying institution of inter partes review of claims 1–19 and 21–28
`of U.S. Patent No. 9,464,140 B2 (“the ’140 Patent,” Ex. 1001). Paper 12
`(“Request” or “Req.”). With our authorization, Patent Owner filed a
`Response to the Request (Paper 15, “Response” or “Resp.”), Petitioner filed
`a Reply in support of its Request (Paper 16, “Reply”), and Patent Owner
`filed a Sur-reply (Paper 17, “Sur-reply”).
`We deny the Request for the reasons explained below.
`
` STANDARD OF REVIEW
`II.
`In response to a request for rehearing, the panel reviews a decision
`whether to institute trial for an abuse of discretion. 37 C.F.R. § 42.71(c). An
`abuse of discretion may be found if there was an erroneous interpretation of
`law, a factual finding not supported by substantial evidence, or an
`unreasonable judgment in weighing relevant factors. 37 C.F.R. § 42.71(c);
`Star Fruits S.N.C. v. U.S., 393 F.3d 1277, 1281 (Fed. Cir. 2005); The Arnold
`Partnership v. Dudas, 362 F.3d 1338, 1340 (Fed. Cir. 2004); In re Gartside,
`203 F.3d 1305, 1315–16 (Fed. Cir. 2000). “The burden of showing a
`decision should be modified lies with the party challenging the decision.”
`37 C.F.R. § 42.71(d). The rehearing request “must specifically identify all
`matters the [requesting] party believes the Board misapprehended or
`overlooked, and the place where each matter was previously addressed in a
`motion, an opposition, or a reply.” Id.
`
`2
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
` OVERVIEW OF PETITIONER’S REQUEST
`III.
`Our Decision addressed the four Grounds challenging claims of the
`’140 patent. Dec. 4. Petitioner challenges our analysis of Grounds I and II as
`based on an erroneous “interpretation of the law governing reasonable
`expectation of success.” Req. 1. With respect to Ground III, Petitioner
`contends that we incorrectly interpreted the prosecution record resulting in
`an unreasonable weighing of the relevant Advanced Bionics factors. See id.
`at 3. Petitioner does not challenge our analysis of Ground IV.
`
`IV. GROUNDS I and II
`In denying institution, we determined that Petitioner did not establish
`sufficiently that a one of ordinary skill in the art would have been motivated
`to practice the challenged method claims with a reasonable expectation of
`success, “[c]onsidering the inherent unpredictability of the field and the
`history of failure of similar technology.” Dec. 41. We noted in our Decision
`that “[t]he claims at issue in OSI Pharms., were structurally similar to those
`at issue here and directed to a method of treating non-small cell lung cancer
`(“NSCLC”) in a mammal using a therapeutically effective amount of
`erlotinib, which had previously been shown to inhibit the epidermal growth
`factor receptor (“EGFR”) in vitro.” Dec. 40 (citing OSI Pharms., LLC v.
`Apotex Inc., 939 F.3d 1375, 1378–79 (Fed. Cir. 2019)). We also noted the
`OSI court’s reasoning that:
`Cancer treatment is highly unpredictable. Even though the
`EGFR was identified in some cancers as a drug target, the in
`vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the
`EGFR turned out to be a poor proxy for how effective that drug
`actually was in treating cancer in vivo (i.e., in the body).
`3
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`Numerous EGFR inhibitors that showed promising in vitro
`activity failed for a variety of reasons.
`Id. (quoting 939 F.3d at 1377). We further noted the OSI court’s description
`of high failure rates for NSCLC treatments, and its finding that
`the asserted references do not disclose any data or other
`information about erlotinib’s efficacy in treating NSCLC. The
`record does not contain any clinical (human) data or preclinical
`(animal) data. It does not even include in vitro (test tube) data
`regarding erlotinib’s effect on NSCLC.
`Id. (quoting 939 F.3d at 1384).
`Petitioner now argues that we misapprehended the facts underlying
`the court’s decision in OSI, and abused our discretion in analogizing the
`facts of the present case to OSI rather than to Genzyme Therapeutic Prods. v.
`Biomarin Pharm., 825 F.3d 1360 (Fed. Cir. 2016). Req. 4–9. Petitioner
`asserts that “the OSI facts are . . . diametrically opposed to the facts here,”
`and contends that we
`misunderstood the OSI decision as finding that “erlotinib [] had
`previously been shown to inhibit the epidermal growth factor
`receptor (‘EGFR’) in vitro.” Id. In fact, just the opposite was
`true: the prior art did “not even include in vitro (test tube) data
`regarding erlotinib’s effect on NSCLC.”
`Req. 8–9 (quoting OSI, 939 F.3d at 1383); see Reply 2.
`We did not misunderstand the facts underlying OSI; rather, Petitioner
`suggests a false equivalency between erlotinib’s in vitro inhibition of EGFR
`and in vitro data regarding erlotinib’s effect on NSCLC that is not reflected
`in our Decision. Consistent with our description, the OSI court explained
`that “erlotinib inhibits the EGFR and has good anticancer activity in some
`cancers,” but that the art did not encompass “in vitro . . . data regarding
`
`4
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`erlotinib’s effect on NSCLC,” nor teach “efficacy in treating NSCLC.” See
`OSI at 1383, 1384; Dec. 40. Although we found that in vitro data of record
`placed Petitioner in a “somewhat better” position than that described in OSI,
`we weighed Petitioner’s evidence against Patent Owner’s evidence of “the
`inherent unpredictability of the field and the history of failures of similar
`technology,” and the lack of “clinical (human) data or preclinical (animal)
`data” highlighted in OSI. Id. at 40–41 (citations omitted).
`
`In addressing unpredictability of the field and the history of failures,
`the OSI court stated that “[t]he lack of erlotinib-NSCLC efficacy data or
`other indication of success here is significant because of the highly
`unpredictable nature of treating NSCLC, which is illustrated by the over
`99.5% failure rate of drugs entering Phase II.” OSI at 1384. Petitioner,
`however, argues that OSI is distinguishable, because “[i]n the field of CD19-
`directed CAR T-cell therapy before 2010, there were nine other trials aside
`from the one described by CART-19 ClinicalTrials.gov.” Req. 8 (citing
`Ex. 2037, 1036). According to Petitioner, the record “provided evidence of
`positive results in three of them.” Id. at 8–9 (citing Pet., 36; Ex. 1002
`¶¶ 178-84). In describing the latter three trials, Petitioner asserts that “[a]
`POSA would have also known that several other anti-CD19 CAR T cells in
`the art had been used successfully in cancer patients, indicating that at a
`minimum, there would be a decrease in the number of tumor cells.” Pet. 36.
`But we also considered Patent Owner’s evidence that “[t]he literature
`was so riddled with failed CAR-T cell therapy experiments that
`“[i]nfluential scientists [at the National Institutes of Health] didn’t think
`engineered T cells could ever work.” Prelim. Resp. at 3 (citing Ex. 2001 at
`5
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`9) (brackets added by Patent Owner). Patent Owner pointed, for example, to
`evidence that “of twenty-five CAR-T cell clinical trials” in the prior art,
`“only four had shown any ‘CAR-mediated antitumor effect’ or mere
`‘reduction in biological markers of tumor activity.’” Id. at 25–26 (citing
`Ex. 2037 at 1036). According to Patent Owner, “[u]nder even the most
`charitable view, that is an 84% failure rate.” Id.; see also id. at 26
`(challenging Petitioner’s definition of “success” given the limited positive
`results in only a few patients, alternative interpretation of the data, and short-
`term CAR-T cell persistence); see also id. at 26–27 (discussing patient trials
`considered “complete failures”).
`Petitioner also points to Campana’s statement that its in vitro studies
`“provide[d] compelling justification for clinical trials using T cells
`expressing anti-CD19-BB-ζ.” See Pet. 16; Ex. 1003 ¶ 118. While Campana’s
`in vitro results may have provided sufficient justification to begin clinical
`testing, on the record before us, this does not equate to a reasonable
`expectation that such trials will be successful. 1 Moreover, despite
`Campana’s suggestion to conduct clinical trials, which was published in
`2005, a 2012 review summarizing the state of the art reported that, “despite
`
`
`1 Petitioner’s passing reference to “KSR’s obvious-to-try doctrine” presents
`an impermissible new argument. Req. 7 (citing KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 421 (2007)). As this argument has not previously been
`presented, it could not have been “misapprehended or overlooked.”
`37 C.F.R. § 42.71(d). As Patent Owner points out, moreover, Petitioner
`provides no support for its “suggestion that making CAR-Ts to treat cancer
`was an art composed of ‘finite’ and “predictable” solutions in 2011.”
`Response 8 (citing Ex. 2007, 1).
`
`6
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`promising preclinical results, the majority of . . . initial CAR T cell trials
`showed little evidence of anti-tumor activity with limited activation,
`persistence, and homing to tumor sites being the main barriers.” Ex. 2035 at
`956.
`
`In view of the above, we neither misapprehended the facts of OSI, nor
`abused our discretion in applying OSI to the present facts. We turn now to
`Petitioner’s argument that the Federal Circuit’s Genzyme decision should
`control.
`The subject of the Genzyme decision, Pompe’s disease, is described as
`“a genetic condition associated with a deficiency or absence of the
`lysosomal enzyme acid a-glucosidase (“GAA”),” that results in damaging
`accumulation of glycogen in skeletal and heart muscle. Genzyme, 825 F.3d
`at 1364. Early efforts at treating Pompe’s disease with enzyme replacement
`therapy had failed, “because the injected enzyme was predominantly taken
`up by the patient’s liver, reducing glycogen levels there but not in the
`skeletal or heart muscles where the excess glycogen does the most harm.”
`Id. at 1363. The Federal Circuit in Genzyme affirmed as obvious “method[s]
`of treating . . . Pompe’s disease” by administering “a therapeutically
`effective amount of human . . . [GAA].” Genzyme at 1363, 1369.
`Petitioner argues that, “like here, the prior art [in Genzyme] disclosed
`the claimed composition, provided successful in vitro data, and suggested
`initiating clinical trials.” Req. 2 (citing Genzyme at 1364). Importantly,
`however, the Federal Circuit found “substantial evidence” supporting “a
`reasonable expectation of success in arresting or reducing the accumulation
`
`7
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`of glycogen” using a GAA enzyme modified with a muscle-specific M–6–P
`targeting signal. 2 According to the Federal Circuit,
`the prior art disclosed that GAA modified to include M–6–P
`was effectively taken up by muscle cells and that it reduced the
`concentration of glycogen in those cases. And the dosage
`experience with Gaucher disease, in conjunction with the
`known half-life of GAA in the body, provided a sound basis for
`belief that a dosage interval of one to two weeks would be
`effective.
`825 F.3d 1360 at 1373. Considering the state of the prior art, the court
`reasoned that “there was little left to do but to confirm that the strategy
`suggested by the various prior art references would work.” Id.
`The facts supporting a reasonable expectation of success in Genzyme,
`thus, bear little resemblance to the present case. Petitioner has not, for
`example, shown that prior testing distinguished T cells expressing anti-
`CD19-BB-ζ over the prior art such that one of ordinary skill in the art would
`have reasonably expected success. Nor was there any history of failures
`using the M–6–P modified enzyme in Genzyme. Here, in contrast,
`considering the evidence that CAR-T therapy had a history of failures with
`few, at best marginal, successes, Petitioner’s arguments are unpersuasive. 3
`
`
`2 Genzyme left undisturbed the Board’s underlying findings that the field
`“had matured to the point that it was recognized that GAA had to be
`translationally modified with M–6–P; in vivo studies had been performed in
`which GAA containing M–6–P had been intravenously administered to mice
`and Japanese Quail; [and] it was known that human GAA containing M–6–P
`could be produced in the milk of transgenic animals.” Genzyme at 1365.
`3 In a footnote, Petitioner appears to invite us, for the first time, to consider
`Milone in the context of Grounds 1 and 2. See Req. 6, n.2. This is not a
`proper basis for reconsideration. 37 C.F.R. § 42.71(d).
`8
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`See, e.g., Ex. 2035 at 956 (“despite promising preclinical results, the
`majority of . . . initial CAR T cell trials showed little evidence of anti-tumor
`activity with limited activation, and homing to tumor sites being the main
`barriers”).
`Petitioner also appears to argue that we abused our discretion in
`instituting on claims directed to certain human CAR T cells in IPR2022-
`00855, while declining to institute on claims directed to a method of treating
`cancer by administering those cells in IPR2022-00853. Req. 10–13.
`Petitioner fails to persuade us that there is any inconsistency in finding
`sufficient expectation of success in “making the pharmaceutical
`composition,” but not in using that composition for “treating a human
`cancer.” See IPR2022-00855, Paper 10, 26–27; Dec. 41.
`As we understand Petitioner’s argument, because “inherency may
`supply a missing claim limitation in an obviousness analysis,” we should
`have recognized that “the amounts [of those CAR-T cells] recited in the
`prior art (e.g., 2.5×107 to 6.1×108 cells per kg) would necessarily be ‘anti-
`tumor effective’” and, thus, inherently satisfy the efficacy limitation of the
`method claims. See id. at 11–13 (quoting Persion Pharms. v. Alvogen Malta
`Operations, 945 F.3d 1184, 1190 (Fed. Cir. 2019) (emphasis added); Reply
`3–4. Although this logic might be supported where a reasonable expectation
`of success is assured, as in Genzyme where “there was little left to do but to
`confirm that the strategy suggested by the prior art would work,” we are not
`persuaded by Petitioner’s attempt to use a supposed inherent property of a
`product as a substitute for showing reasonable expectation of success in
`performing the claimed method of treatment. See Genzyme at 1373.
`9
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`Proving a reasonable expectation of success is a required part of any
`obviousness challenge. See, e.g., Teva Pharms. USA, Inc. v. Corcept
`Therapeutics, Inc., 18 F.4th 1377, 1381,1383 (Fed. Cir. 2021) (“Teva was
`required to prove a reasonable expectation of success in achieving the
`specific invention claimed. . . . without showing a reasonable expectation of
`success, Teva did not prove obviousness”). To assume otherwise would
`imply that a method claim is never patentable over the inherent
`characteristics of a known product used to perform the method, and
`preclude, for example, the patenting of any new use for an existing
`compound. This is not the law. See, e.g., Novartis Pharms. Corp. v. W.-
`Ward Pharms. Int’l Ltd., 923 F.3d 1051, 1060 (Fed. Cir. 2019) (finding
`method claim patentable where a person of ordinary skill would not have
`had a reasonable expectation of success in using a known compound to treat
`advanced renal cell carcinoma).
`
`V. GROUND III
`For Ground III, Petitioner sought to supplement its reasonable
`expectation of success argument for Grounds I and II by the addition of
`Milone. See Dec. 41. In our Decision, we stated: “But because the Examiner
`extensively discussed Milone in the context of claims similar to those at
`issue here, we first consider[ed] Patent Owner’s argument that we should
`exercise our discretion to deny institution under § 325(d).” Id. Part 2 of the
`Advanced Bionics Framework requires that we consider “whether the
`petitioner has demonstrated that the Office erred in a manner material to the
`patentability of [the] challenged claims.” Advanced Bionics at 8. Finding
`that Part Two the Advanced Bionics Framework was not satisfied with
`10
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`respect to this Ground, we exercised our discretion under 35 U.S.C § 325(d)
`and declined to institute inter partes review. Id. at 48.
`Petitioner argues that we misapplied Part 2 of the Advanced Bionics
`Framework. Req. 13–15; Reply 4–5. Petitioner contends that we erred in
`“fail[ing] to acknowledge that the distinguishing claim limitation directed to
`the amino acid sequence of CD3 zeta (SEQ ID NO: 24) is notably absent
`from the independent claim of the ’140 patent . . . . [and] the Examiner
`considered Milone in the context of claims that were limited in a way the
`challenged claim is not.” Req. 14–15. Petitioner further argues that we
`“erred by putting weight on the Examiner’s assumed knowledge of Milone”
`in subsequent prosecution of the application that issued as the ’140 patent.
`Req. 15. We do not find Petitioner’s argument persuasive.
`On pages 2–3 of our Decision, we review the relevant chain of
`priority, including that the ’140 patent challenged here “issued from
`application No. US 14/996,953, which is a continuation of application
`No. 13/992,622 (“the ’622 parent application”),” and that “the ’622 parent
`application issued as U.S. Patent No. 9,499,629 B2 (“the ’629 patent).” On
`pages 9–12 of our Decision, we review the prosecution history of the ’622
`parent application, including the extensive discussions of Milone and the
`Examiner’s Reasons for Allowance indicating that “SEQ ID NO: 24
`provides novelty to the instant claims.” On page 12 of the Decision, we
`reproduce claim 1 of the resulting ’629 patent, which recites “a CD3 Zeta
`signaling domain . . . comprising the amino acid sequence of SEQ ID NO:
`24.”
`
`11
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`With respect to the challenged claims of the ’140 patent, claim 1
`recites “a CD3-zeta signaling domain,” and claim 12 more specifically
`recites that “the CD3 Zeta signaling domain comprises the amino acid
`sequence of SEQ ID NO: 24.” Ex. 1001, 91:10–21, 92:10–12. Thus, taken as
`a whole, the challenged claims of the ’140 patent encompass the identical
`limitation that Petitioner contends was “notably absent” from challenged
`claim 1. Considering just “the CD3 Zeta signaling domain” limitation of
`claim 1, we find doubtful Petitioner’s contention that “the Examiner
`considered Milone in the context of claims that were limited in a way the
`challenged claim [1] is not.” As applied to claim 12, also before the
`Examiner, such a contention lacks any support.
`For the additional reasons set forth in Section IV of Patent Owner’s
`Response and Section III of its Sur-reply, both of which we adopt in full, we
`agree with Patent Owner that “it defies credulity to argue that the Examiner
`never considered’ Milone just because he did not address it in an office
`action” of the particular application that issued as the ’140 patent. See Resp.
`14; see also Dec. 46–47 (determining that the Examiner was well aware of
`Milone when allowing the ’140 patent).
`Institution of inter partes review is discretionary. Harmonic Inc. v.
`Avid Tech., Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016) (explaining that “the
`PTO is permitted, but never compelled, to institute an IPR proceeding”).
`Considering the above, the panel did not misapprehend or overlook anything
`regarding the examination that would warrant reconsideration of our
`decision not to institute trial.
`
`12
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`VI. CONCLUSION
`For the reasons above, we conclude that Petitioner has not shown that
`we abused our discretion in denying institution under 35 U.S.C. § 325(d).
`Accordingly, we deny Petitioner’s Request.
`
`VII. ORDER
`In consideration of the foregoing, it is hereby:
`ORDERED that Petitioner’s Request for Rehearing is denied.
`
`
`
`
`
`
`13
`
`
`
`IPR2022-00853
`Patent 9,464,140 B2
`
`FOR PETITIONER:
`
`Yite Jon Lu
`Gary Frischling
`MILBANK LLP
`ptabdocketl2y7@orrick.com
`ptabdocketg2f1@orrick.com
`
`
`FOR PATENT OWNER:
`Brian R. Landry
`Kathryn Doyle
`Alireza Behrooz
`SAUL EWING ARNSTEIN & LEHR LLP
`blandry@saul.com
`kathryn.doyle@saul.com
`alireza.behrooz@saul.com
`
`Thomas S. Fletcher
`Jessamyn S. Bernike
`David M. Krinsky
`WILLIAMS & CONNOLLY LLP
`tfletcher@wc.com
`jberniker@wc.com
`dkrinsky@wc.com
`
`
`
`14
`
`
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