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`Paper No. ____
`Filed: June 21, 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 REPLY BRIEF ON REMAND
`PURSUANT TO PAPER NO. 108
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`
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`I.
`II.
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`TABLE OF CONTENTS
`PETITIONER ESTABLISHED REASONABLE EXPECTATION OF SUCCESS. .............. 1
`IT WOULD HAVE BEEN OBVIOUS TO EMPLOY THE PRETREATMENT
`REGIMEN. ......................................................................................................... 6
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`-i-
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`TABLE OF AUTHORITIES
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`Page
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`CASES
`Genzyme Corp. v. Dr. Reddy’s Labs., 716 Fed. App’x 1006 (Fed. Cir.
`Dec. 18, 2017) .............................................................................................. 2, 3
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd. 821 F.3d
`1359 (Fed. Cir. 2016)....................................................................................... 2
`Sanofi v. Watson Labs. Inc., 875 F.3d 636 (Fed. Cir. 2017) ..................................... 2
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`-ii-
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`The record is replete with evidence that a POSA would have had a
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`reasonable expectation of success in practicing the obvious method of the proposed
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`claims—evidence which Patent Owner (“PO”) mischaracterizes or ignores. In
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`doing so, PO also obfuscates the standard for reasonable expectation of success by
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`(1) not asserting that the claims require survival data, successful clinical trials, or
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`FDA approval; while, at the same time, (2) criticizing Petitioner’s evidence for not
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`including data from a successful phase III trial. PO’s obfuscation cannot avoid a
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`determination of unpatentability.
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`I.
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`Petitioner Established Reasonable Expectation of Success.
`Applying the Federal Circuit’s claim construction, both experts’ testimony
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`support reasonable expectation of success. As Dr. Seth testified, it would have
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`been obvious to treat docetaxel-resistant DRmCRPC patients by administering
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`cabazitaxel and prednisone “for the purpose of increasing patient survival.”
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`EX1002 ¶¶ 47, 84, 86, 90, 116, 120-22, 132, 163, 183; EX1043 ¶10. Dr. Seth sent
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`his patients to the TROPIC study before the critical date expecting them to benefit
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`from a better chance of living longer by controlling their disease if they received
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`cabazitaxel. EX2258, 26:9-37:25 (“most of [us] knew that anything would be
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`better than mitoxantrone”). Dr. Sartor conceded physicians may have intended to
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`increase survival of their patients. Paper 84, 3, 7-8; EX1098, 342:3-9, 355:17-21,
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`429:8-431:3. PO’s argument (at 14) that oncologists enrolled patients despite a
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`-1-
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`death at 30 mg/m2 shows the likelihood of success outweighed these risks.
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`Reasonable expectation of success in the context of this patent necessarily
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`means the intended tumor control and survival increase will not occur for most
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`patients. EX1001, 11:57; EX1002, ¶¶ 44, 47, 215; Paper 3, 20, 56-57; Paper 43,
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`14. PO argues physicians could only “hope” cabazitaxel would work, but for a
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`particular “patient in need” there is still today only a hope of success. EX1043 ¶38.
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`Relying on Sanofi v. Watson Labs. Inc., 875 F.3d 636 (Fed. Cir. 2017), PO
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`incorrectly argues the Federal Circuit “required” proof of a reasonable expectation
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`of actual results based on an intent element. Id. at 646-47 (court noting defendants
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`“accepted” framework, not holding it was required). Watson did not, and had no
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`occasion to, overrule Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd. 821
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`F.3d 1359, 1367-68 (Fed. Cir. 2016) (quantitative removal “of no moment” to
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`reasonable expectation because not a claim limitation). Because the claim element
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`is an intention, reasonable expectation of success must be proven for having an
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`intention, not for achieving the intended result.
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`PO relies on Watson and Genzyme Corp. v. Dr. Reddy’s Labs., 716 Fed.
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`App’x 1006, 1007 (Fed. Cir. Dec. 18, 2017) to argue there was no reasonable
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`expectation cabazitaxel would increase survival. But unlike those cases—in which
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`the prior art affirmatively taught the drug was unlikely to work (Watson) or where
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`neither the targeted receptor nor any receptor in its family had ever been shown to
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`-2-
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`work (Genzyme)—here, there was clear motivation and reasonable expectation of
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`success in the prior art and no teaching away. Docetaxel had already been shown to
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`increase survival through its anti-cancer activity. Clinical and preclinical studies
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`confirmed cabazitaxel retained docetaxel’s anti-cancer activity even against
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`DRmCRPC and breast cancer, and no prior art taught away. Paper 109, 7-15; Paper
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`42, 8-12, 14-16; Paper 43, 7-10; Settled Issues 5-6, 7-17.
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`PO’s arguments (at 5, 8) that “anti-cancer activity” does not “translate” into
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`increased “overall survival” clinical study results or that Pivot lacked a control arm
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`are irrelevant. The proposed claims do not require overall survival results or a
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`comparison to a control arm. Opp., 2-3 & n.1. PO also ignores the testimony of
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`both parties’ experts confirming that controlling mCRPC long enough increases
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`survival of that patient. Paper 84, 2-3, 9; EX1098, 400:5-401:24; Paper 93, 5
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`(“progression-free survival does not translate” means not synonym with “overall
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`survival” because includes death unrelated to disease); EX2258, 49:24-52:16.
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`The prior art confirmed that cabazitaxel, like docetaxel, could control
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`DRmCRPC long enough to increase survival. E.g., Paper 84, 2-3 (Mita/Attard
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`disclosed 6 months progression-free survival); Paper 43, 11; EX1043 ¶45; EX1008
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`(ongoing 22 months later); EX1009; EX1010, 1547 (12.3 months); EX1022, 161,
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`163. It is undisputed that docetaxel’s anti-cancer activity gave it the capacity to
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`increase survival in mCRPC patients, and the Board properly credited Petitioner’s
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`-3-
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`evidence that cabazitaxel retained that same anti-cancer activity, even among
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`docetaxel-resistant patients. FWD, 31, 37-38.
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`PO’s argument that four “failed studies” taught away from cabazitaxel’s
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`efficacy are red herrings for several reasons. First, PO ignores the Board’s settled
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`finding that there was no teaching away from cabazitaxel. Second, regulatory
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`“failure” does not undermine efficacy. FWD, 32-33. Dr. Seth’s testimony, “there’s
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`so many factors” (Opp., 14) referred to likelihood of regulatory success, a different
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`analysis than obviousness. Third, failing to achieve a primary endpoint does not
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`mean the drugs failed to increase survival for patients. Indeed, three of the studies
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`either prolonged survival or simply failed to demonstrate superiority of these other
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`drugs to docetaxel. Paper 42, 11-12; EX1043 ¶¶20-22; EX1022, 162-63
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`(satraplatin increased progression-free survival); EX2006, 669, 672; EX1053, 14-
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`15, n.30 (DN-101 better than low-dose docetaxel); EX2027, 1 (GVAX not superior
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`over docetaxel). With little in common with cabazitaxel, a POSA “would attribute
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`little weight” to PO’s examples. EX1043 ¶23. Instead, the prior art taught
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`cabazitaxel had docetaxel-like efficacy, even among docetaxel-resistant patients.
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`FWD, 31, 37-38.
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`PO’s argument that the Board failed to give FDA fast-track approval
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`substantial weight “because survival was not a limitation of the claims at issue”
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`glaringly misstates the Board’s finding. The Board concluded that the fast-track
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`-4-
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`results were entitled to little weight, inter alia, because “statistically significant”
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`survival results were not an element of the claims. FWD, 49. They still are not.
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`The Board also concluded the survival results were not probative of non-
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`obviousness because the prior art disclosed the critical elements of the method.
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`Settled Issues 1-4, 20-23; FWD, 45, 47, 49; Paper 3, 56. Dr. Sartor failed to
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`compare the patent’s survival data to the closest prior art because he thought that
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`Winquist and the TROPIC Listing were “irrelevant.” EX1041, 322:18-323:8. Dr.
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`Sartor’s latest testimony confirms he improperly disregarded the prior art.
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`The Board already correctly concluded it was obvious to reduce dosage to
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`20 mg/m2 based in part on Pivot’s teachings for addressing emergent side effects.
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`Settled Issues 24-28; Paper 3, 43-47; Paper 43, 11. PO’s argument that Pivot’s
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`teachings are insufficient to establish reasonable expectation of success in men
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`ignores the results reported in Mita and Attard, which included men, and that Pivot
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`was based on Mita’s success in men against prostate cancer (at doses as low as 15
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`mg/m2) and its identification of 20 mg/m2 as a recommended dose. EX1012, 723,
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`727; Paper 42, 16; EX1002, ¶¶94-99, 155-58, 165-70; EX1043 ¶30.
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`PO admitted that Example 1 “used cabazitaxel on 25 [mg/m2].” EX2177,
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`72:17-18. PO never argued during trial that Example 1 provides survival data for
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`the 20 mg/m2 dose. The Board correctly determined that it does not. Settled Issue
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`26. Even if Examples 1 and 2 of the patent could be read together based on a non-
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`-5-
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`prior art reference (deBono) this would not provide data specifically for the 20
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`mg/m2 dose. Dr. Seth’s testimony merely establishes that Example 1 discloses less
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`about the 20 mg/m2 dose than was disclosed in the totality of the prior art.
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`II.
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`It Would Have Been Obvious to Employ the Pretreatment Regimen.
`PO argues that it would be “irrational” to add premedications if HSRs were
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`“rare” and unless the HSR rate was higher than docetaxel’s. Opp., 18-22. But Dr.
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`Sartor confirmed the importance of saving even one life. EX1041, 218:10-12 (“I
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`had a guy nearly die.”); Paper 43, 12, 17. It would be irrational to preclude
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`physicians from giving these life-saving premedications. EX1041, 218:2-219:5.
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`PO’s argument that Dr. Sartor was surprised three pretreatments were used
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`in the TROPIC Study (Opp., 22) is meaningless because his private surprise is
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`irrelevant. PO also conflates whether the label requires all three premedications
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`with whether it would have been obvious to a POSA to administer them. Petitioner
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`need not prove that all physicians would always administer all three premed-
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`ications for it to be obvious to use these known tools for their known functions.
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`PO’s argument (Opp., 23) that “no physician” would prescribe an H2 blocker
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`“unless it was required” is groundless. Aventis EX2227 confirms that many
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`doctors used H2 blockers for docetaxel pretreatment in 2008 despite not being
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`required to do so by the label. See also EX1046-1048. H2 blockers are safe drugs
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`(such as Zantac®). EX1043 ¶¶76-77. Dr. Sartor confirmed POSAs in 2009 would
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`-6-
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`not have thought their use was contraindicated. Paper 84, 7; EX1098, 524:11-18.
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`PO repeatedly mischaracterizes Dr. Seth’s testimony. Opp., 18, 24-25. Dr.
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`Seth said there is “no guarantee” you will always get HSRs, and said a POSA
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`would give “premedications”—plural— identifying dexamethasone as one.
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`EX2177, 113:2-15; 118:13-119:5. PO waited to ask Dr. Seth to list the other
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`“premedications” used with docetaxel until his next deposition. EX2258, 113:13-
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`117:1 (listing Zantac, Benadryl, others), 128:8-129:7 (“It was taught to me [by]...
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`people who I studied with.”). Dr. Seth’s later testimony does not contradict his
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`earlier testimony. EX2258, 129:8-14 (doubt any POSA would just give steroids).
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`PO argues a POSA could not be motivated to use the claimed pretreatment
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`regimen because cabazitaxel had an “improved safety profile” over docetaxel.
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`Opp., 21. But cabazitaxel’s safety profile was positive in part because its side
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`effects were easily addressable by known means. Settled Issues 27-28; FWD, 55,
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`75-80. Moreover, Pivot showed Mita did not teach away from pretreatments and
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`that reducing the risk of HSRs was well worth any administrative “inconvenience,”
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`even if the HSR rate may have been lower. FWD, 75, 78-79; EX1043 ¶ 68;
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`EX1041, 255:15-16. PO argues HSRs were not an issue because cabazitaxel was
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`administered to post-docetaxel patients, but this unsupported attorney argument is
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`contradicted by Pivot’s demonstration that life-threatening HSRs could result even
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`among post-docetaxel and -paclitaxel patients. FWD, 75; EX1010, 1547-49.
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`-7-
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`Dated: June 21, 2019
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`Respectfully submitted,
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`/ Steven W. Parmelee /
`Steven W. Parmelee, Lead Counsel
`Reg. No. 31,990
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`-8-
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`CERTIFICATE OF SERVICE
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`Pursuant to 37 C.F.R. § 42.6(e), this is to certify that I caused to be served
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`true and correct copies of the foregoing Petitioner’s Reply Brief on Remand, by
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`electronic service, on this 21st day of June 2019, on the Patent Owner at the
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`correspondence address of the Patent Owner as follows:
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`Daniel J. Minion
`Dominick A. Conde
`William E. Solander
`Joshua I. Rothman
`Whitney L. Meier
`VENABLE LLP
`1290 Avenue of the Americas
`New York, NY 1014-3800
`Email:DMinion@venable.com
`Email : DConde@Venable.com
`Email: WSolander@Venable.com
`Email: JRothman@Venable.com
`Email: WMeier@Venable.com
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`Respectfully submitted,
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`Dated: June 21, 2019
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`/ Steven W. Parmelee /
`Steven W. Parmelee, Lead Counsel
`Reg. No. 31,990
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`-9-
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