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`Paper No. ____
`Filed: May 10, 2019
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MYLAN LABORATORIES LIMITED.,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA S.A.,
`Patent Owner.
`_____________________________
`
`Case IPR2016-00712
`Patent No. 8,927,592
`_____________________________
`
`
`PETITIONER MYLAN’S BRIEF ADDRESSING THE EFFECT OF CAFC
`DECISION ON PATENT OWNER’S MOTION TO AMEND
`PURSUANT TO PAPER NO. 108
`
`
`
`
`
`I.
`II.
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`TABLE OF CONTENTS
`INTRODUCTION ................................................................................................. 1
`DECIDED ISSUES SUPPORTING THE BOARD’S ORIGINAL
`UNPATENTABILITY DETERMINATION ARE NOW PRECLUSIVE AND
`SUPPORT DENIAL OF THE MOTION. ................................................................... 1
`A.
`Settled Issues 1-4: The Example 1 Protocol Is In the Prior Art ............ 2
`B.
`Settled Issues 5-6: No Teaching Away ................................................. 3
`C.
`Settled Issues 7-17: Obvious to Intend Increasing Survival ................. 3
`D.
`Settled Issues 18-23: No Nexus to Secondary Considerations. ............ 5
`Settled Issues 24-28: Prior Art Renders 20 mg/m2 Obvious. ................ 6
`E.
`IT WOULD HAVE BEEN OBVIOUS TO PRACTICE THE TREATMENT
`REGIMEN WITH THE INTENDED PURPOSE OF INCREASING SURVIVAL. .............. 7
`IV. UNDER THE FEDERAL CIRCUIT’S CLAIM CONSTRUCTION, THE PROPOSED
`CLAIMS REQUIRE AN INTENTION, NOT A RESULT. .......................................... 15
`IT WOULD HAVE BEEN OBVIOUS TO A POSA TO EMPLOY THE
`PREMEDICATION REGIMEN WITH THE CABAZITAXEL TREATMENT
`REGIMEN. ....................................................................................................... 18
`VI. THE PROPOSED CLAIMS ARE UNPATENTABLE UNDER §101. .......................... 25
`VII. CONCLUSION ................................................................................................... 25
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`
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`III.
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`V.
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`-i-
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`TABLE OF AUTHORITIES
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`Page
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`CASES
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`Engel Indus., Inc. v. Lockformer Co., 166 F.3d 1379 (Fed. Cir. 1999) ..................... 1
`Intelligent Bio-Systems Inc. v. Illumina Cambridge Ltd., 821 F.3d
`1359 (Fed. Cir. 2016)..................................................................................... 15
`KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) ............................................... 20
`Mayo v. Prometheus. 132 S. Ct. 1289, 1294, 1297-98 (2012) ............................... 25
`Tronzo v. Biomet, Inc., 236 F.3d 1342 (Fed. Cir. 2001) ............................................ 1
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`-ii-
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`I.
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`Introduction
`In its February 5, 2019 opinion, the Federal Circuit vacated the Board’s
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`denial of Patent Owner’s motion to amend in light of Aqua Products and the
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`Board’s construction of the proposed claims, instructing the Board on remand to
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`treat the preamble as an additional limitation of proposed claim 31. However, the
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`Federal Circuit left undisturbed the Board’s conclusion that claims 1-5 and 7-30 of
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`the ’592 patent (the “original claims”) are all unpatentable. As a result, the
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`underlying issues the Board decided in reaching its unpatentability conclusion are
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`now settled and preclusive. Further, the evidentiary record—identical to that
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`which was before the Board when it entered its final written decision (“FWD,”
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`Paper 99)—establishes that the proposed claims are unpatentable even in light of
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`Aqua Products and applying the Federal Circuit’s claim construction.
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`II. Decided Issues Supporting the Board’s Original Unpatentability
`Determination Are Now Preclusive and Support Denial of the Motion.
`Issues decided in a trial proceeding and thus “within the scope of the
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`judgment appealed from” are only open to reconsideration on remand if “explicitly
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`reserved or remanded by the [appellate] court,” all other issues “are foreclosed
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`from further consideration.” Engel Indus., Inc. v. Lockformer Co., 166 F.3d 1379,
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`1383 (Fed. Cir. 1999); see also Tronzo v. Biomet, Inc., 236 F.3d 1342, 1349 (Fed.
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`Cir. 2001) (“Because Biomet failed to [appeal punitive damages], clearly
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`implicated in the initial decision of the district court, our mandate in Tronzo I acted
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`-1-
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`to prevent Biomet from raising this issue on remand or in any future proceedings in
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`this litigation.”). This doctrine is part of the mandate rule. As a result of this
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`doctrine, the Board’s conclusion that claims 1-5 and 7-30 are unpatentable and
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`every issue the Board decided in reaching that conclusion are final and preclusive.
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`In deciding that the original claims were unpatentable, the Board decided
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`issues of fact and law that support a finding that the proposed claims are likewise
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`unpatentable. In light of the Federal Circuit’s mandate, the Board should consider
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`them to be conclusively settled. The settled issues of fact and law include the
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`following:
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`A.
`Settled Issues 1-4: The Example 1 Protocol Is In the Prior Art
`As of the priority date1, the prior art references Winquist and the TROPIC
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`1.
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`Listing together disclosed the same treatment protocol being used in the same
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`clinical trial for treating the same patient population as that described in Example 1
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`of the ’592 patent. FWD, 16-19, 42.
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`2.
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`In 2008, a POSA would have known that Winquist and the TROPIC Listing
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`disclosed the same treatment regimen being used in the same ongoing phase III
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`trial—the TROPIC Study—and would have read them together. FWD, 23-24.
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`
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`1 The priority date asserted by Patent Owner for the proposed claims is January
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`11, 2010. Paper 22 at 2.
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`-2-
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`3.
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`The method steps of claims 1 and 27 were disclosed in the prior art in the
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`same combination claimed and exemplified in the ’592 patent. FWD, 43.
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`4.
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`The 25 mg/m2 dose of cabazitaxel, which Patent Owner’s expert
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`characterized as “critical,” was disclosed in Winquist. FWD, 45.
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`B.
`Settled Issues 5-6: No Teaching Away
`There is no evidence of a teaching away from the combination of Winquist
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`5.
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`and the TROPIC Listing. FWD, 27.
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`6.
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`A reference does not teach away if it expresses a general preference for an
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`alternative approach from among known options, particularly if the reference does
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`not criticize, discredit, or otherwise discourage the solution claimed. FWD, 59.
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`C.
`Settled Issues 7-17: Obvious to Intend Increasing Survival
`In 2008, a POSA would have known of cabazitaxel’s anti-cancer activity
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`7.
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`because Mita and Attard reported an objective response in a docetaxel refractory
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`mCRPC patient treated with 25 mg/m2 cabazitaxel. FWD, 19, 31.
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`8.
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`In 2008, a POSA would have known that cabazitaxel targeted the same
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`tubulin binding site as docetaxel, shown to be effective in breast and prostate
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`cancers. FWD, 31.
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`9.
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`By 2008, Attard disclosed cabazitaxel showed improvement over paclitaxel
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`and docetaxel with a higher therapeutic index and activity against taxane-resistant
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`tumors. FWD, 20, 31.
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`-3-
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`10.
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`In 2008, a POSA would have known that cabazitaxel’s 14% objective
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`response rate in docetaxel-refractory metastatic breast cancer patients motivated
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`the phase III clinical trial (the TROPIC Study) in post-docetaxel mCRPC patients.
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`FWD, 20, 31.
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`11.
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`In 2008, a POSA would have known that assessing overall survival was the
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`primary endpoint of the TROPIC Study reported in the prior art. FWD, 31.
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`12.
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`In 2008, a POSA would have known that cabazitaxel was designed to retain
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`the tubulin-binding activity known to make docetaxel lethal to cancer cells while
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`also reducing its affinity for the P-gp pump. A POSA also would have been aware
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`of P-gp affinity as a major mechanism of docetaxel resistance. FWD, 37.
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`13.
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`In 2008, a POSA would have believed that, like docetaxel, cabazitaxel was
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`active against breast and prostate cancers. FWD, 37-38.
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`14. The prior art disclosed that preclinical and clinical studies confirmed
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`cabazitaxel was active against docetaxel-resistant breast and prostate cancers.
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`FWD, 38; id. at 19-20, 6-7 n.7-8, 10, 12.
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`15. The prior art disclosed the claimed treatment method and its utility as having
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`anti-cancer activity in docetaxel-resistant mCRPC and breast cancer patients.
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`FWD, 36-37.
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`16. Patent Owner’s expert incorrectly concluded that Winquist and the TROPIC
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`Listing are not prior art. His analysis was undermined by his apparent dismissal of
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`-4-
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`highly relevant clinical trial listings as prior art, and his opinion that a POSA
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`would not have had a reasonable expectation of a successful treatment in a phase
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`III clinical trial from reading Winquist and the TROPIC Listing in view of Attard
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`(reporting on the Mita study) and Beardsley (reporting on the Pivot study) is
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`entitled to little weight. FWD, 34-35.
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`17. Neutropenia and other side effects of cabazitaxel were not so high as to
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`require a proven survival benefit as a treatment prerequisite. FWD, 36.
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`D.
`Settled Issues 18-23: No Nexus to Secondary Considerations.
`18. Petitioner’s evidence rebutted the presumption of nexus and negated any
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`weight to be given Patent Owner’s evidence of non-obviousness. FWD, 41.
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`19. The presumed nexus between Jevtana®’s commercial success and the ’592
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`patent claims is undercut by Patent Owner’s failure to acknowledge or address the
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`seven prior art Orange Book-listed patents for Jevtana®. FWD, 44.
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`20. The evidence of unexpected results is neutral. A statistically significant
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`increase in overall survival of a patient population is not a claim limitation. The
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`claimed method was disclosed in the prior art, and Attard and Beardsley note
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`cabazitaxel’s anticancer activity in docetaxel-refractory phase I (mCRPC) and
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`phase II (metastatic breast cancer) patients. FWD, 49.
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`21. Beardsley expressly notes that the results of administering cabazitaxel in
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`docetaxel-refractory cancer patients were sufficient to permit moving directly to
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`-5-
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`the phase III TROPIC Study, which undermines the argument that the TROPIC
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`Study results were unexpected given the absence of a phase II trial in mCRPC
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`patients. FWD, 49-50.
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`22. A POSA would have had a reasonable expectation that the TROPIC Study
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`protocol disclosed in Winquist and the TROPIC Listing would result in anticancer
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`activity. Winquist and the TROPIC Listing note that prolonging patient survival
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`(“overall survival”) was the primary endpoint of the study, which, by October
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`2008, had been ongoing since 2006. FWD, 31, 50.
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`23. The weight to be given long-felt need, failure of others, and praise is
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`tempered by evidence that the TROPIC Study treatment protocol was disclosed in
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`the prior art along with evidence of anti-cancer activity in docetaxel-refractory
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`mCRPC and metastatic breast cancer patients. FWD, 47-48, 51.
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`E.
`Settled Issues 24-28: Prior Art Renders 20 mg/m2 Obvious.
`24. Winquist, the TROPIC Listing, and Pivot disclose the elements recited in
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`dependent claims 2, 5, 12, 15-26, and 28-30. FWD, 52-53.
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`25. Pivot discloses the active and well-tolerated use of both 20 and 25 mg/m2
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`doses of cabazitaxel in docetaxel-refractory metastatic breast cancer patients.
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`FWD, 53-54.
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`26. The ’592 patent does not describe any clinical trial result for a 20 mg/m2
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`dose of cabazitaxel, even though dependent claims 15, 21, 26, and 30 recite a 20
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`-6-
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`mg/m2 dose. This fact tends to undercut Patent Owner’s argument that clinical trial
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`results are necessary to support a reasonable expectation of success. FWD, 55.
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`27. Pivot’s 20 and 25 mg/m2 doses, which were used in the phase II study, were
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`consistent with the phase I data regarding safe doses reported in Mita, as well as
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`the phase III doses reported in Winquist and the TROPIC Listing. FWD, 56.
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`28. Winquist and Pivot disclose administration of cabazitaxel doses of 20 and 25
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`mg/m2, and Pivot describes how an experienced oncologist would manage
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`emergent side effects with dose control, antihistamines, and antiemetics. FWD, 55.
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`III.
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`It Would Have Been Obvious to Practice the Treatment Regimen With
`the Intended Purpose of Increasing Survival.
`In its February 5, 2019 opinion, the Federal Circuit left all of these Settled
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`Issues undisturbed, and they are not altered by either the Federal Circuit’s ruling
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`regarding Aqua Products or the Federal Circuit’s claim construction holding. With
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`respect to claim construction, the Federal Circuit held that the “patient in need
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`thereof” from proposed claim 31 relies on the preamble for antecedent basis and
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`thus that “the preamble expresses the intentional purpose—increasing survival—
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`for which the method must be performed.” Slip Op. at 9-10; see also id. at 11 n.5
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`(noting that the claim requirement regarding “increasing survival” is a “purpose
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`limitation”). The court instructed that “[o]n remand, the Board should therefore
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`treat the preamble as an additional limitation of proposed claim 31.” Slip Op. at 12.
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`As discussed in detail below, and treating the preamble as a limitation, the prior art
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`-7-
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`establishes that a POSA would have been motivated to practice the prior art
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`TROPIC protocol in combination with the proposed premedication regimen for the
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`intended purpose of increasing survival and would have had a reasonable
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`expectation of success of achieving what is claimed as a whole.
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`The Board’s settled findings help resolve that it would have been obvious
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`for a POSA to use the prior art TROPIC protocol disclosed in Winquist and the
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`TROPIC Listing for the purpose of increasing survival. For example, the Board
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`concluded that a POSA would have known that the primary objective of the
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`TROPIC Study, which began in 2006, was to increase overall survival and that the
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`study remained ongoing through October 2008. Settled Issues 1-4, 11, 22; Ex.
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`1008 at 1; Ex. 1009 at 3948. The Board concluded there is no evidence of a
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`teaching away from the solution disclosed in Winquist and the TROPIC Listing.
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`Settled Issues 5-6. The Board also concluded that Dr. Sartor’s argument that a
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`POSA would not have had a reasonable expectation of successful treatment in the
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`TROPIC Study was incurably tainted by his failure to consider Winquist and the
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`TROPIC Listing, both of which were highly relevant prior art. Settled Issue 16.
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`The Board explained at length why a POSA would administer cabazitaxel
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`with an intention of increasing survival. It concluded that a POSA would have
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`believed cabazitaxel, like docetaxel, was active against both breast and prostate
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`cancer because it was designed to retain docetaxel’s cancer-fighting activity while
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`-8-
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`simultaneously reducing its affinity for the P-gp pump, known to be a major
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`mechanism of docetaxel resistance. Settled Issues 12-14. The Board thus relied on
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`Dr. Seth’s testimony that a POSA would have reasonably concluded the prior art
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`TROPIC protocol would produce an increase in survival. Settled Issues 7-10, 12-
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`15; FWD 31-32 (“Dr. Seth concludes that, based on the available knowledge
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`regarding administration of cabazitaxel in docetaxel-resistant prostate and breast
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`cancer patients described above,” a POSA “would have reasonably concluded that
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`the treatment method disclosed in Winquist and the TROPIC Listing ‘would yield
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`intrinsic anti-cancer activity, and would produce therapeutic or other medical
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`benefits similar to those for which docetaxel had been previously administered—
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`for example, an increase in overall survival.”), 37-38 (“As explained by Dr. Seth, a
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`POSA would have believed cabazitaxel was (like docetaxel) active against both
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`breast and prostate cancer. Moreover, preclinical and clinical studies confirmed
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`that cabazitaxel was active against docetaxel-resistant prostate and breast cancer.”).
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`In finding a POSA would have believed cabazitaxel would share the life-
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`prolonging anti-cancer activity of paclitaxel and docetaxel—but in docetaxel-
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`resistant patients—the Board also relied on preclinical and clinical studies that
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`“confirmed that cabazitaxel was active against docetaxel-resistant prostate and
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`breast cancer.” Settled Issue 14. Among other things, this evidence demonstrated
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`the 20-25 mg/m2 dose of cabazitaxel had the capacity to control docetaxel-resistant
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`-9-
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`cancer for months, providing increased survival to the individuals whose cancer
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`was controlled. Ex. 1022, 163 (complete response median duration of 7.6 months);
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`Ex. 1010 at 1550; Ex. 1002 ¶¶ 97 (“no detectable tumor remained), 165-168 (these
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`doses “had been previously validated by clinical research”), 66-69, 122 (reasonable
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`expectation of success in TROPIC Study because “docetaxel-resistant mCRPC had
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`been successfully treated using cabazitaxel in the past”); Ex. 2177 at 68:9-23 (“I
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`am hoping that their prostate cancer is under control and that control would lead
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`them to have a longer survival”), 68:24-69:12 (“safe to say” patient on cabazitaxel
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`after five 3-week cycles “is living longer”); Paper 53 at 3. As Dr. Seth testified, it
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`would have been obvious to treat docetaxel-resistant mCRPC patients by
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`administering cabazitaxel and prednisone “for the purpose of increasing patient
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`survival.” Ex. 1002 ¶¶ 47, 84, 86, 90, 116, 120-22, 132, 163, 183; FWD, 31.
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`Statistically significant population data was simply not a “prerequisite”; nor is it an
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`element of the claims. FWD, 36-37; Settled Issues 15, 17.
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`Dr. Seth explained that he hoped to obtain a clinical benefit for the patients
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`he sent to the TROPIC study, that clinicians send patients to clinical studies to live,
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`not die, and that he always intends to increase survival when treating patients with
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`cabazitaxel. Ex. 2258 at 38:4-9, 37:9-15, 31:13-22, 21:22-22:19; Ex. 2258 at 5:19-
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`20 (oncologists “are always trying to give patients overall survival.”). Knowing
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`that patients in phase III clinical trials for mCRPC generally “intend to ‘live longer
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`-10-
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`and better’ as a result of the trial,” practitioners enrolling patients in such trials
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`would reasonably intend to extend patient life. Ex. 1043 ¶¶ 39-40. That is why the
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`trial remained ongoing in October 2008 nearly two years after it started. Id. ¶¶ 23;
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`Ex. 1002 ¶¶ 122.172.
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`Dr. Sartor confirmed patients and doctors knew which patients in the open
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`label TROPIC Study were receiving the life-prolonging taxane (cabazitaxel) rather
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`than the palliative mitoxantrone treatment. Id. at 232:12-25. They thus appreciated
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`not only that the patient was in need of survival, but also that the individual was
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`being administered a taxane with the potential to control the cancer and thereby
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`prolong survival. Although Dr. Sartor may have been personally delighted or even
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`privately surprised when the statistically significant population results indicated
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`regulatory approval would be forthcoming, he agreed he had no reason to believe a
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`POSA would find the published dose was not credible. Id. at 96:17-22.
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`There is no dispute that one of the primary purposes of treating an mCRPC
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`patient is to prolong survival. Ex. 1043 ¶ 10; Ex. 2176 ¶¶ 35 (because mCRPC was
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`incurable “the goals of therapy were to...attempt prolongation of life.”), 161-62
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`(“the desired outcome” of phase III studies in prostate cancer was “an increase in
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`overall survival”); Ex. 1041 at 29:10-12 (“I try to make people live longer, live
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`better.”), 83:10-20 (“Our goal is to help patients live longer, live better, and what
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`my steady goals are for everybody.”), 113:17-23 (“[O]verall survival was the
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`-11-
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`primary endpoint. And so I'm going to say exactly what I've said earlier...we want
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`to help people live longer, live better. Those are my steady goals.”); Settled Issues
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`11, 22 (primary endpoint was overall survival). It is thus settled that the prior art
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`disclosed the diagnosis of the patients and their need for increased survival, and
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`that the desired outcome of the method was, in fact, increased survival.
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`Indeed, cabazitaxel’s promising potential for increasing survival of
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`docetaxel-resistant mCRPC patients was known and appreciated. Expert testimony
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`from both sides also unanimously recognized that taxane therapies were expected
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`to prolong patient life. Both Drs. Sartor and Seth testified that when a POSA
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`administers taxane therapy to a patient, the POSA intends to prolong survival. Dr.
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`Sartor noted that with taxane therapies “because [they are] life-prolonging
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`therapies, I have a hope of prolonging survival.” Ex. 1041 at 114:3-115:11 (“What
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`you've just described is all true today; correct? A. It was true then, too.”); id. at
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`56:11-14 (“You cannot have the cabazitaxel patent without understanding first the
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`efficacy of docetaxel.”), 56:15-25 (Tannock “laid the foundation for docetaxel to
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`prolong survival”; relevant to cabazitaxel). Dr. Sartor even noted that when
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`administering docetaxel and cabazitaxel therapies, he is able to tell patients that
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`these treatments have “the potential to extend their life.” Ex. 1041 at 115:12-116:2.
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`In contrast, where Dr. Sartor has no intention of increasing survival, such as when
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`he prescribes “pain medications without the hope that survival will be prolonged,”
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`-12-
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`he does so merely because they “can help improve quality of life.” Id. at 283:2-17.
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`As evidenced by the prior art, improving quality of life without increasing survival
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`was never the exclusive intention of cabazitaxel treatment. E.g., Ex. 2258 at 18:18-
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`23 (“one of the purposes of administering a taxane such as docetaxel or
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`cabazitaxel” in 2008 “is to prolong the survival of the patient”).
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`To the extent that Patent Owner maintains the argument that it previously
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`advanced—that Dr. Seth’s use of the term “hope” in discussions of increasing
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`survival somehow indicates that a POSA cannot reasonably possess an expectation
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`to intend to increase survival—this issue has already been finally resolved by the
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`Board. FWD at 36-37 (“Patent Owner’s criticisms of Dr. Seth’s testimony” in its
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`Observations on Cross-Examination (Paper 80) are entitled to “little weight” and
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`“are effectively rebutted by Petitioner” in Paper 93). As Dr. Seth explained, “hope”
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`is the term that an oncologist would use when deciding to give a drug to a patient.
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`Paper 93 at 1-4; Ex. 2258 at 30:13-31:2. Dr. Sartor’s testimony supports this view.
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`Ex. 1041 at 115:12-116:9. Dr. Seth’s use of the word hope does not reflect an
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`absence of reasonable expectation of success, but rather the terminology used by
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`oncologists both before and after the results of the TROPIC Study became known.
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`Moreover, Dr. Seth clarified the degree of confidence behind the “hope” of
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`using cabazitaxel, stating “we expected it to get FDA approval and it would
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`increase overall survival.” EX2258 at 80:12-81:12; see also id. at 45:18-20 (20 to
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`25 mg/m2, they would feel like it would work), 43:17-20 (“the drug was known
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`and was felt to be working” at 20 or 25 mg/m2). When pressed as to the percentage
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`chance, he stated: “I thought we definitely would see a survival benefit,” and when
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`asked whether the odds of success were greater than 50 percent, replied “[y]ou can
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`say 50. I mean we would see a definite benefit versus mitoxantrone.” Id. at 80:12-
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`81:12.
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`Patent Owner has argued that a POSA would not have intended to increase
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`survival before DeBono because a number of different drugs for various
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`indications had not received FDA approval. Among the drugs that did not receive
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`FDA approval, Patent Owner cited to drugs for treating conditions other than
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`docetaxel-resistant mCRPC, drugs for which results were published only after the
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`priority date, and drugs for which efficacy (including survival comparable to other
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`FDA-approved drugs) was shown. E.g., Paper 42 at 11-12; Ex. 1043, ¶¶ 16-23, 24-
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`25, 28-30. None of these arguments undermines the reasonable likelihood of
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`success of cabazitaxel. Id. Further, Dr. Sartor’s testimony about clinical trial
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`success rates is not relevant because he has a different understanding regarding
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`clinical trials than a POSA. Ex. 1041 at 134:9-15.
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`Of course, adding the taxane pretreatment to the method of claims 27-30 to
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`prevent hypersensitivity reactions (“HSRs”) does not undermine the intended
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`purpose of increasing survival. As discussed in Section V below, HSRs were a
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`known and potentially fatal complication of cabazitaxel. Using the proposed
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`pretreatment would naturally follow the known intention to increase survival using
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`the prior art method of Winquist and the TROPIC Listing.
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`IV. Under the Federal Circuit’s Claim Construction, the Proposed Claims
`Require an Intention, Not a Result.
`Patent Owner would require that, in order to establish the obviousness of the
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`proposed claims, Petitioner must prove that a POSA would have had a reasonable
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`expectation of actually increasing survival, of demonstrating a statistically
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`significant increase in overall survival in a phase III trial, or even of obtaining
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`FDA approval. But this requirement impermissibly engrafts increased survival
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`results onto the scope of claims that merely require an intended purpose, not
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`results. Obviousness does not require proof that the prior art combination would
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`work “as intended” by the prior art, but only “a motivation to combine
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`accompanied by a reasonable expectation of achieving what is claimed in the
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`patent-at-issue.” Intelligent Bio-Systems Inc. v. Illumina Cambridge Ltd., 821 F.3d
`
`1359, 1367-68 (Fed. Cir. 2016); see also FWD, 29 (“it would be inappropriate to
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`engraft an efficacy or FDA approval requirement onto the obviousness analysis”).
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`There is no claim element requiring the actual result of survival or proof of
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`survival, as opposed to merely having an intended purpose of increasing survival—
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`even under the Federal Circuit’s claim construction holding the preamble is a
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`limitation. It would therefore be error to require Petitioner to prove a reasonable
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`-15-
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`
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`expectation of actually increasing survival or of obtaining statistically significant
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`phase III clinical trial results. See Settled Issues 17, 20-23.
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`The proposed claims have no claim element requiring the result of survival
`
`or proof of survival. Indeed, Patent Owner argued throughout the appeal that the
`
`intended purpose limitation does not engraft any survival result, whether
`
`individually or “in a population of patients,” onto the scope of the claims. In its
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`appellate briefing in this case, for example, Patent Owner clearly disclaimed any
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`population survival results limitation in the claims:
`
`The Phrase “to a patient in need thereof” Adds an Intent Limitation to
`the Proposed Substitute Claims[.] ¶ The Board overstates Patent
`Owner’s position, describing Patent Owner’s purported “implicit
`proposal that the preamble imposes a claim requirement that the
`method must result in an increase in ‘overall survival’ in a population
`of patients.” Appx71. But that is not Patent Owner’s position. Rather,
`Patent Owner asserts that the claims are limited to administering the
`claimed premedication and chemotherapy with the intent of
`prolonging the life of the patient.
`PO’s Appellate Opening Brief at 38 (emphasis added). In its Appellate Reply
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`Brief, Patent Owner further confirmed that the “intent” limitation does not engraft
`
`any individual results limitation onto the scope of the claims:
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`Mylan focuses on whether a POSA could determine prospectively
`whether a particular patient would in fact live longer after receiving
`cabazitaxel. Id. But Patent Owner’s construction simply requires
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`-16-
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`
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`
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`administering the cabazitaxel regimen with the intent to prolong life
`and does not require knowledge of whether the life of any particular
`patient will be prolonged.
`PO’s Appellate Reply Brief at 12. Furthermore, Patent Owner confirmed that
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`increasing survival need not be the exclusive intention of performing the method:
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`Further, when construed in accordance with the controlling Jansen
`line of cases, the claim 31 preamble directly impacts how the method
`steps are performed. That is, a physician administering cabazitaxel,
`premedication, and prednisone according to claim 31 to shrink a
`tumor, stabilize disease, or to reduce pain, but without the intention of
`prolonging life, is not practicing the claimed method.
`PO’s Appellate Reply Brief at 6.
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`Likewise, Dr. Sartor confirmed that intending to increase survival does not
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`require that survival result from the method. E.g., Ex. 1041, 309:12-25 (“method of
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`increasing their survival even though it didn’t turn out the way that I intended”).
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`Like the original claims, the proposed claims require no survival result.
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`Of course, Patent Owner had no choice but to disclaim any result or data
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`element from the scope of the proposed claims because the patent itself provides
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`no survival data for the 20 mg/m2 dose. E.g., Settled Issue Nos. 1-4, 26; Ex. 1041
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`at 150:25-151:6 (25 mg/m2 dose “is critical”), 152:22-153:53 (“patient population
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`is the key element”), 206:7-10 (’592 patent used dose of 25 mg/m2). As the Federal
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`Circuit noted on appeal, the patent’s survival data appears in Example 1. Slip Op.
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`-17-
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`
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`at 10-11. Notably, Example 1 does not disclose administering a 20 mg/m2 dose or
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`using the pretreatment regimen. Settled Issue 26; Ex. 1001, 10:30-17:32. Proposed
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`claims 32 and 34 demonstrate that the same intention to increase survival from the
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`preamble can be practiced in the patent regardless of whether one administers (i)
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`the 25 mg/m2 dose (for which the patent states clinical trial data demonstrated an
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`increase in overall survival) or (ii) whether one administers the 20 mg/m2 dose (for
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`which the patent makes no such statement). The claimed “intended purpose” thus
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`does not require survival data, a successful trial, or FDA approval. Settled Issue 26.
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`V.
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`It Would Have Been Obvious to a POSA to Employ the Premedication
`Regimen with the Cabazitaxel Treatment Regimen.
`The Board made factual findings underlying its denial of the motion to
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`amend where it found that Petitioner’s arguments and evidence established various
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`facts. These findings did not turn on placing any burden of proof on Patent Owner
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`or on the issue of whether the preamble was a limitation. The evidence in this case
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`has not changed, nor has the persuasiveness of Petitioner’s evidence. The Board’s
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`prior findings that Petitioner established specific factual points, though located in
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`the vacated portion of the FWD addressing the proposed substitute claims, are still
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`correct today. These findings—and the evidence that underlies them—support the
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`conclusion that employing the pretreatment regimen with the chemotherapy
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`regimen disclosed in Winquist and the TROPIC Listing would have been obvious.
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`The Board previously found that “Petitioner persuasively establishes that the
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`-18-
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`recited premedication regimen—administration of an antihistamine, a corticoid,
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`and an H2 antagonist—was well known as a prophylactic treatment” for HSRs in
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`taxane therapies. FWD, 75. The Board “agree[d] with Petitioner” that a POSA
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`“would have been motivated to use the same prior art taxane premedication
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`regimen to decrease the risk of HSRs associated with cabazitaxel treatment.” Id.
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`In reaching these conclusions, the Board relied on its findings that multiple
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`prior art references disclosed the use of the proposed pretreatment regimen to
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`avoid the occurrence of severe HSRs. FWD, 75-77; Ex. 2093, 23-24, 39; Ex. 1046
`
`at 106; Ex. 1047, 422, 424; Ex. 1048, 58-59, 62-63. The Board noted that Dr.
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`Sartor agreed this same regimen “had been kicked around by 2008 for use in
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`taxane therapy.” FWD, 76; Ex. 1041 at 211:22-23. The Board also found that Dr.
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`Seth’s testimony “confirms” that this taxane pretreatment regimen was known and
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`a POSA would have been motivated to use the same three premedication drugs in
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`cabazitaxel treatment of mCRPC to reduce HSRs. FWD, 75-76; Ex. 1043 ¶¶ 52-55,
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`64-68.2
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`The Board ultimately concluded that combining the proposed pretreatment
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`regimen with the chemotherapy regimen disclosed in Winquist and the TROPIC
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`
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`2 Dr. Seth was instructed to use the pretreatment regimen with docetaxel during
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`his fellowship and beyond. Ex. 2258 at 128:8-130:11, 131:2-11 Ex. 1003, 1.
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`-19-
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`Listing was obvious because doing so merely used a known and avai
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