Paper No. 110
`Date Filed: June 7, 2019
`
`Filed on behalf of: Sanofi Mature IP
`
`By:
`
`Daniel J. Minion
`dminion@venable.com
`(212) 218-2100
`
`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
`U.S. Patent No. 8,927,592
`________________
`
`PATENT OWNER’S RESPONSIVE BRIEF ON THE EFFECT OF
`THE CAFC DECISION ON PATENT OWNER’S MOTION TO AMEND
`
`
`Date Filed: June 7, 2019
`
`Filed on behalf of: Sanofi Mature IP
`
`By:
`
`Daniel J. Minion
`dminion@venable.com
`(212) 218-2100
`
`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
`U.S. Patent No. 8,927,592
`________________
`
`PATENT OWNER’S RESPONSIVE BRIEF ON THE EFFECT OF
`THE CAFC DECISION ON PATENT OWNER’S MOTION TO AMEND
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`Petitioner Must Prove That a POSA Would Have Had a
`Motivation to Practice the Claimed Invention with a
`Reasonable Expectation of Increased Survival ............................................... 2
`
`III.
`
`The Prior Art Did Not Provide a Reasonable Expectation of
`Success ............................................................................................................. 5
`
`A.
`
`B.
`
`C.
`
`D.
`
`Anti-cancer Activity Does Not Provide a Reasonable
`Expectation of Success of Increasing Survival ..................................... 6
`
`The Results of TROPIC Were Unexpected .......................................... 9
`
`It Was Not Obvious to Practice the Methods of the
`Proposed Claims with the Intended Purpose of Increasing
`Survival................................................................................................ 11
`
`Petitioner Has Not Presented Evidence That a POSA
`Would Have Been Motivated to Administer a 20 mg/m2
`Dose of Cabazitaxel with the Intent of Increasing
`Survival................................................................................................ 15
`
`IV. A POSA Would Not Have Been Motivated to Use the Claimed
`Premedication Regimen with Cabazitaxel ..................................................... 17
`
`V.
`
`The Proposed Claims Are Patentable Subject Matter ................................... 25
`
`VI. Conclusion ..................................................................................................... 25
`
`i
`
`
`
`TABLE OF AUTHORITIES
`
`Cases
`Genzyme Corp. v. Dr. Reddy’s Labs., Ltd.,
`No. 13-1506-(GMS), 2016 U.S. Dist. LEXIS 62056 (D.
`Del. May 11, 2016) ........................................................................................12
`
`Genzyme Corp. v. Dr. Reddy’s Labs., Ltd.,
`Nos. 2016-2206, 2016-2207, 2017 U.S. App. LEXIS
`25454 (Fed. Cir. Dec. 18, 2017) ....................................................................13
`
`PersonalWeb Techs., LLC v. Apple Inc.,
`848 F.3d 987 (Fed. Cir. 2017) .......................................................................20
`
`Sanofi v. Glenmark Pharms. Inc.,
`204 F. Supp. 3d 665 (D. Del. 2016) ..............................................................12
`
`Sanofi v. Glenmark Pharms. Inc.,
`C.A. No. 14-264, 2015 U.S. Dist. LEXIS 114406 (D.
`Del. Aug. 28, 2015) ......................................................................................... 3
`
`Sanofi v. Watson Labs. Inc.,
`875 F.3d 636 (Fed. Cir. 2017) .....................................................................3, 4
`
`Vanda Pharms., Inc. v. West-Ward Pharms. Int’l Ltd.,
`887 F.3d 1117 (Fed. Cir. 2018) .....................................................................25
`
`ii
`
`
`
`I.
`
`Introduction
`
`Under the proper claim construction and burden of persuasion, there can be
`
`little dispute that the proposed claims were not obvious. Petitioner’s expert Dr. Seth
`
`admitted that the TROPIC study was performed to determine ultimately whether
`
`cabazitaxel and prednisone increased survival over the standard of care and that a
`
`person of ordinary skill in the art (“POSA”) would have merely “hoped” at the time
`
`that the TROPIC study would be successful. The mere fact that the TROPIC study
`
`was ongoing would not have provided a reasonable expectation that the cabazitaxel
`
`therapy would increase survival in patients with docetaxel-resistant mCRPC
`
`(“DRmCRPC”), particularly in light of the minimal data regarding cabazitaxel (none
`
`regarding survival) and the numerous failures of other prostate cancer therapies,
`
`which despite having anti-cancer activity, did not increase survival in patients with
`
`mCRPC. As to proposed Claim 34, Petitioner’s expert testified that a POSA at the
`
`time would not have even thought of administering a dose of 20 mg/m2 to a patient
`
`with DRmCRPC. Thus a POSA could not have had a reasonable expectation that
`
`such a dose would prolong patients’ lives.
`
`Petitioner’s argument that the premedication limitations of the proposed
`
`claims were obvious rests largely on Petitioner’s mischaracterizations of expert
`
`testimony, unsupported conclusions about the prior art, and incorrect legal theories.
`
`Petitioner fails to credibly explain why a POSA would have been motivated to
`
`1
`
`
`
`employ a more complicated premedication regimen for cabazitaxel (three drugs) as
`
`compared to docetaxel (dexamethasone alone), and thereby forego the “significant
`
`administration and convenience advantages” of avoiding it. In fact, both parties’
`
`experts testified that when it comes to hypersensitivity reactions (“HSRs”) they “err
`
`on the side of caution,” yet would still not have been motivated to use the claimed
`
`three-component premedication regimen prior to knowing the results and full
`
`protocol of the TROPIC study. Because the evidence shows that the same would be
`
`true for a POSA, the proposed method claims would not have been obvious.
`
`II.
`
`Petitioner Must Prove That a POSA Would Have Had a Motivation to
`Practice the Claimed Invention with a Reasonable Expectation of
`Increased Survival
`
`Contrary to the Federal Circuit’s holding that the preamble of Claim 31 is
`
`limiting (C.A. No. 18-1203, D.I. 63 (“Slip Op.”) at 8), Petitioner continues to assert
`
`that it need not establish that a POSA would have reasonably expected increased
`
`survival with the claimed methods. In doing so, Petitioner reverts to its strawman
`
`argument that the proposed claims “do not require survival data, a successful trial,
`
`or FDA approval” (Paper 109 (“Br.”) at 18), a standard that Patent Owner has never
`
`2
`
`
`
`advocated for. See, e.g., Paper 98, 32:19-24.1 But, the Federal Circuit explicitly
`
`rejected Petitioner’s argument that “the claims do not require the administered doses
`
`to have any effect on the patient,” by finding that “the proposed claims would now
`
`clearly require ‘increasing survival.’” Slip Op. at 11. Consequently, the obviousness
`
`analysis requires consideration of that element.
`
`Sanofi v. Glenmark is particularly instructive because the preamble
`
`“decreasing a risk of cardiovascular hospitalization [or hospitalization for atrial
`
`fibrillation]” was found limiting and certain claims were interpreted to have an intent
`
`requirement under the Jansen case like the claims at issue here. Sanofi v. Glenmark
`
`Pharms. Inc., C.A. No. 14-264, 2015 U.S. Dist. LEXIS 114406, at *6-7, *14-16 (D.
`
`Del. Aug. 28, 2015), aff’d sub nom. Sanofi v. Watson Labs. Inc., 875 F.3d 636 (Fed.
`
`Cir. 2017). Defendants there were required to prove a reasonable expectation that
`
`the drug in question would reduce the risk of cardiovascular hospitalization or
`
`hospitalization for atrial fibrillation. Sanofi v. Watson Labs. Inc., 875 F.3d at 647.
`
`Thus, here, as in Sanofi, the reasonable expectation of success analysis includes the
`
`preamble, and the obviousness analysis must require a higher standard for a
`
`1 Contrary to Petitioner’s implications, Patent Owner has never wavered from this
`
`position. See Paper 22 at 10-18; Paper 53 at 4-5; C.A. No. 18-1203, D.I. 20
`
`(“Appellate Opening Brief”) at 42-47; D.I. 29 (“Appellate Reply Brief”) at 16-19.
`
`3
`
`
`
`reasonable expectation of success, i.e., increasing survival, than the original claims,
`
`for which the Board required merely a reasonable expectation of anti-cancer activity.
`
`Paper 99 (“FWD”) at 30. The mere existence of a clinical trial to determine whether
`
`the method in fact produced the result, which was also known in the prior art in
`
`Sanofi, is insufficient to provide an expectation that the method produces that result.
`
`Sanofi v. Watson Labs. Inc., 875 F.3d at 641-42, 648.
`
`Petitioner’s assertion (Br. at 17) that “Patent Owner had no choice but to
`
`disclaim any result or data element from the scope of the proposed claims because
`
`the patent itself provides no survival data for the 20 mg/m2 dose” is wrong. First,
`
`Petitioner has not advanced any basis for its apparent legal proposition that Patent
`
`Owner could not claim a method of increasing survival with a 20 mg/m2 cabazitaxel
`
`dose in the absence of any specific survival data on that dose in the ’592
`
`specification. Second, in the TROPIC study patients started at a dose of 25 mg/m2,
`
`and a dose reduction was permitted to 20 mg/m2. Ex. 1041 at 97:5-98:23. Example
`
`2 of the ’592 patent describes this dose reduction. Ex. 1001 at col. 17, ll. 36-55.
`
`Data concerning this dose reduction are also provided elsewhere in the ’592 patent.
`
`For example, the ’592 patent notes that 9.8% of the courses of cabazitaxel in the
`
`TROPIC study were dose-reduced to 20 mg/m2. Ex. 1001 at col. 16, ll. 49-50, col.
`
`17, Table 5. Therefore, the survival benefit reported in Table 1 of the ’592
`
`4
`
`
`
`specification includes the results from those patients who received the 20 mg/m2
`
`dose.
`
`III. The Prior Art Did Not Provide a Reasonable Expectation of Success
`
`Aside from making a legally flawed inherency argument in its opposition brief
`
`(Paper 43), Petitioner essentially conceded that there was no evidence in the prior
`
`art that cabazitaxel would increase survival in patients with DRmCRPC. In the
`
`absence of evidence, Petitioner now resorts to asserting that the issues on remand
`
`are already settled by the Board. For example, Petitioner states (Br. at 8) that “[t]he
`
`Board explained at length why a POSA would administer cabazitaxel with an
`
`intention of increasing survival” citing to several “Settled Issues” in Section II.C of
`
`its brief. However, none of the “Settled Issues” enumerated therein go to the
`
`question of whether a POSA would have reasonably expected that cabazitaxel would
`
`increase survival prior to the results of TROPIC. Rather, each correlate to passages
`
`from the Board’s decision which at most found that a POSA would have expected
`
`20-25 mg/m2 of cabazitaxel to have “anti-cancer activity” in patients with
`
`DRmCRPC, which both sides’ experts agreed does not translate into increased
`
`survival. Ex. 2177 at 94:7-16 (Dr. Seth agreeing that there were no surrogates for
`
`overall survival); Ex. 2258 at 52:14-16 (Dr. Seth admitting that “tumor response
`
`rates do not translate into overall survival”).
`
`5
`
`
`
`Petitioner also wrongly asserts (Br. at 9) that the Board relied on Dr. Seth’s
`
`testimony that a POSA would have reasonably concluded that the “TROPIC
`
`protocol” would produce an increase in survival. Petitioner does not cite to any
`
`actual finding from the Board that increased survival was expected with cabazitaxel
`
`in patients with DRmCRPC. At pages 31-32 of the FWD, the Board is merely setting
`
`forth Petitioner’s arguments and Dr. Seth’s testimony and does not indicate in any
`
`way that they agree with or adopt this aspect of Dr. Seth’s testimony. The naked,
`
`unsupported testimony of Dr. Seth from his original declaration cannot be sufficient
`
`for Petitioner to meet its burden when measured against the weight of the real-world
`
`evidence that a POSA would not have expected increased survival in TROPIC.
`
`A.
`
`Anti-cancer Activity Does Not Provide a Reasonable Expectation
`of Success of Increasing Survival
`
`The disconnect between anti-cancer activity and increased survival is
`
`reflected in the literature and multitude of therapies that were reported to reduce
`
`tumor size and/or PSA levels in clinical studies but nonetheless failed to prolong
`
`overall survival in mCRPC patients in subsequent phase III studies. Paper 22 at 14-
`
`15; Ex. 2030 at 303, 307 (lack of proven surrogates for survival make intermediate
`
`endpoints problematic); Ex. 2176 at ¶¶ 80-101 (Dr. Sartor discussing general art and
`
`suramin (Ex. 2020), satraplatin (Ex. 2110; Ex. 1022), atrasentan (Ex. 2190; Ex.
`
`2191; Ex. 2010), GVAX (Ex. 2034; Ex. 2018; Ex. 2027), and DN-101 (with
`
`docetaxel) (Ex. 2006; Ex. 2043; Ex. 2127)). Knowledge of these failed studies
`
`6
`
`
`
`would have confirmed the POSA’s belief that the anti-cancer activity reported in
`
`Mita and Pivot would not have provided a reasonable expectation that cabazitaxel
`
`therapy would increase survival of patients with DRmCRPC.
`
`Petitioner’s attempts to minimize these failures (Br. at 14) are unavailing.
`
`First, these cited study reports are all prior art. Second, while Petitioner is correct
`
`that these drugs did show anti-cancer efficacy, Petitioner is incorrect that they later
`
`showed increased survival. That is precisely the point. Although many of these
`
`studies had more patients with tumor or PSA responses than were reported in the
`
`prior art for cabazitaxel in prostate cancer,2 none of those therapies increases survival
`
`in patients with mCRPC. Petitioner’s final criticism that the cited studies were
`
`conducted in men with prostate cancer that had not yet developed taxane resistance
`
`is incredible given Petitioner’s position that results in breast cancer would be
`
`expected to translate in prostate cancer. Moreover, prolonging the lives of patients
`
`that failed docetaxel with another taxane is indisputably more difficult than treating
`
`taxane-naïve patients. Ex. 2176 at ¶¶ 49, 69. Indeed, the failures of many
`
`sophisticated pharmaceutical companies to develop a new drug that could prolong
`
`2 The only prior art data for cabazitaxel in patients with DRmCRPC is in Mita,
`
`wherein a single patient with DRmCRPC received 25 mg/m2 cabazitaxel and
`
`experienced a partial tumor response and a PSA reduction. Ex. 2176 at ¶ 70.
`
`7
`
`
`
`the life of patients with mCRPC despite showing anti-cancer activity underscores
`
`the difficulty of developing a drug that would increase survival in those patients after
`
`their cancer progressed even further following docetaxel therapy. Ex. 2176 at ¶ 168.
`
`As Dr. Seth agreed, even today, mCRPC is “a very difficult disease to treat.” Ex.
`
`2177 at 17:17-24.
`
`Petitioner’s argument (Br. at 9-10) that Pivot provided evidence of increased
`
`survival in the studied women with breast cancer is unsupported by any expert
`
`testimony.3 Pivot was an “uncontrolled study,” meaning cabazitaxel was not
`
`compared to a placebo or another therapy, and therefore contained no comparative
`
`survival data. Ex. 1010 at 1547-48. Thus, while Pivot reports a response median
`
`duration of 7.6 months, the authors do not conclude that cabazitaxel had a positive
`
`impact on patient survival compared to other therapies, nor could they have without
`
`a comparative arm. Ex. 1010 at 1550-51. Similarly, the 14% tumor response rate
`
`in Pivot provides little information as to whether the studied treatment improved
`
`survival. In fact, a 2005 analysis calculated there to be only a 25% chance that a
`
`drug that demonstrates a tumor response rate over 10% in a breast cancer study will
`
`3 In the cited testimony, Dr. Seth was explaining how he can tell today that a patient
`
`is living longer on cabazitaxel therapy with the benefit of having the knowledge of
`
`the TROPIC study results. Ex. 2177 at 68:9-69:12.
`
`8
`
`
`
`subsequently be shown to increase survival in those patients. Ex. 2145 at 5661,
`
`Table 1; Ex. 2177 at 84:6-18, 87:10-18; Ex. 2176 at ¶ 132. Significantly, these three-
`
`to-one odds of failure for the same tumor type (breast) undermines any assertion
`
`that success would have been predictable for a different tumor type (prostate).
`
`B.
`
`The Results of TROPIC Were Unexpected
`
`Petitioner’s assertion (Br. at 12) that “[e]xpert testimony from both sides also
`
`unanimously recognized that taxane therapies were expected to prolong patient life”
`
`is false. Dr. Sartor testified that he is able to tell his patients that cabazitaxel has
`
`“the potential to extend their life” only because he now has the benefit of the
`
`TROPIC results. Ex. 1041 at 115:12-116:2 (Q: “. . . when you’re administering
`
`cabazitaxel to someone today . . . .”) (emphasis added). In response to a follow-up
`
`question about whether he intended that cabazitaxel would extend the life of patients
`
`prior to knowing the results of TROPIC, Dr. Sartor responded in the negative and
`
`testified that he was “surprised, delighted, maybe a little shocked when the actual
`
`results [of TROPIC] came in.” Id. at 115:12-116:21.
`
`Petitioner asks the Board to discount Dr. Sartor’s opinions that the prior art as
`
`a whole did not provide the POSA with a reasonable expectation of success by again
`
`misstating Dr. Sartor’s analysis of Winquist and the TROPIC Listing. Br. at 8.
`
`Although Dr. Sartor repeatedly noted during questioning that he did not understand
`
`the legal term “prior art,” including telling counsel for Petitioner “I’m worried we’re
`
`9
`
`
`
`using prior art in a very legalistic manner,” counsel for Petitioner continued to pursue
`
`the same line of tortured questioning regarding several references over pages of
`
`testimony. Ex. 1041 at 39:8-53:6. A quick review of this back and forth makes clear
`
`that Dr. Sartor understood the term “prior art” to mean not that it was publicly
`
`available to a POSA prior to the critical date, but rather that it was relevant to what
`
`he believed to be the central issue in the proceeding, i.e., whether a POSA would
`
`have expected the claimed methods to increase survival in patients with DRmCRPC
`
`prior to the results of TROPIC.
`
`Regardless, there is no question that Dr. Sartor considered those references
`
`when forming his opinions as evidenced by pages of testimony regarding these
`
`references in his expert declarations and his clear testimony on redirect; he just
`
`simply did not find them to be particularly important or informative.4 Ex. 1041 at
`
`322:18-323:8; Ex. 2176 at ¶ 156 et seq. That Dr. Sartor did not find Winquist or the
`
`TROPIC listing informative to his opinion on an expectation of increasing survival
`
`is unremarkable. As a principal investigator on TROPIC, Dr. Sartor experienced
`
`difficulties initiating that study because there was so little data on the use, let alone
`
`the efficacy, of cabazitaxel in prostate cancer. Ex. 2176 at ¶¶ 93, 187. Thus, the
`
`4 Petitioner did not bring this testimony to the Board’s attention when it made its
`
`assertions as to Dr. Sartor’s testimony in Petitioner’s Reply.
`
`10
`
`
`
`mere listing of the study as ongoing—without reporting any data—did not provide
`
`either him or a POSA with any evidence that the results of TROPIC would be
`
`positive. This is consistent with Dr. Sartor’s testimony that when he presented the
`
`results publicly that “[p]ractitioners who had been aware of the existence of the study
`
`were surprised by the results.” Ex. 2176 at ¶¶ 185-187. Petitioner presents no
`
`evidence to the contrary.
`
`Indeed, the Board found that “the results of the TROPIC Study were
`
`unexpected enough to result in FDA fast-track approval of the first therapy for
`
`docetaxel-refractory mCRPC patients.” FWD at 49 (emphasis added). It ultimately
`
`gave this evidence little weight because survival was not a limitation of the claims
`
`at issue. Now, however, that the proposed claims have been construed to include
`
`such a limitation, the unexpected results of increased overall survival in TROPIC
`
`should be given substantial weight. The Board similarly gave Dr. Sartor’s opinions
`
`of non-obviousness little weight due to his “incorrect standard for ‘success’” (in
`
`addition to his confused testimony regarding the term “prior art”). FWD at 32-35.
`
`Now that Dr. Sartor’s standard of success, i.e., increasing survival, is correct as
`
`applied to the proposed claims, his unrebutted testimony should be credited.
`
`C.
`
`It Was Not Obvious to Practice the Methods of the Proposed
`Claims with the Intended Purpose of Increasing Survival
`
`Petitioner wrongly asserts that “[t]he Board concluded that a POSA would
`
`have known that the primary objective of the TROPIC study . . . was to increase
`
`11
`
`
`
`overall survival.” Br. at 8. But cited “Settled Issues” 1-4, 11, and 22 merely state
`
`the primary endpoint of the study was to measure overall survival. The purpose of
`
`conducting TROPIC, however, was not to prolong the lives of any of the patients in
`
`the study, but rather to determine “ultimately what is better [as between cabazitaxel
`
`and mitoxantrone]” (Ex. 2177 at 186:7-187:4), because at the time the answer to that
`
`question was unknown.
`
`Dr. Seth’s testimony that “he always intends to increase survival when treating
`
`patients with cabazitaxel” is irrelevant since his use of cabazitaxel has exclusively
`
`been after the results of TROPIC and subsequent FDA approval. Ex. 2258 at 31:3-
`
`8. Dr. Seth’s “hope[] to obtain a clinical benefit for the patients he sent to the
`
`TROPIC study” (Br. at 10) falls far short of a reasonable expectation of success and
`
`cannot support obviousness of a claimed invention. Sanofi v. Glenmark Pharms.
`
`Inc., 204 F. Supp. 3d 665, 691-92 (D. Del. 2016) (hypothesis that dronedarone would
`
`reduce cardiovascular hospitalizations versus placebo in an ongoing phase III trial
`
`did not give rise to a reasonable expectation that the claimed methods of
`
`administering dronedarone would actually reduce such hospitalizations), aff’d sub
`
`nom., Sanofi v. Watson Labs. Inc., 875 F.3d 636; see also Genzyme Corp. v. Dr.
`
`Reddy’s Labs., Ltd., No. 13-1506-(GMS), 2016 U.S. Dist. LEXIS 62056, at *38 (D.
`
`Del. May 11, 2016) (no reasonable expectation of success where inventor explained
`
`he had a “‘hope,’ but not an expectation” that a clinical trial would succeed in light
`
`12
`
`
`
`of the history of failure in the field), aff’d, Nos. 2016-2206, 2016-2207, 2017 U.S.
`
`App. LEXIS 25454 (Fed. Cir. Dec. 18, 2017).
`
`Dr. Seth’s testimony that “clinicians send patients to clinical studies to live,
`
`not die” (Br. at 10) similarly misses the point. First, the subjective intent of the
`
`physician in sending a patient to participate in any clinical trial, as opposed to the
`
`intent of the study clinicians who are actually treating the patients, is irrelevant here.
`
`Second, clinical studies on new, unapproved drugs such as TROPIC are necessary
`
`to determine whether the drug is safe and effective. Patients participate in clinical
`
`studies because they benefit by receiving additional regular and careful attention
`
`from the clinicians involved in the studies and because of their understanding that
`
`the results of clinical studies, positive or negative, provide a general benefit to the
`
`patient population as a whole. Ex. 2176 at ¶¶ 46-47. This is true despite the fact
`
`that patients understand that they may not personally benefit from their participation.
`
`Id. The fact that a patient in a randomized trial such as TROPIC may (or may not)
`
`get the experimental drug and may (or may not) benefit from it does not mean that
`
`the intent of the clinicians is to prolong the life of any particular study participant
`
`entering into the clinical study, especially given that each patient has a fifty percent
`
`chance of receiving treatment with mitoxantrone and prednisone, which was known
`
`at the time to provide no survival benefit. Ex. 2176 at ¶¶ 36, 192.
`
`13
`
`
`
`Indeed, the clinician would have well understood that their patient could
`
`actually be harmed by—or perhaps even die from—participating in a clinical study
`
`like TROPIC. See, e.g., Ex. 2147 at 4580S (reporting patient death from septic shock
`
`following cabazitaxel administration); Ex. 1012 at 726 (reporting sustained, life-
`
`threatening neutropenia in two patients following cabazitaxel administration); Ex.
`
`1010 at 1550 (reporting patient death due to shock with respiratory failure deemed
`
`possibly related to cabazitaxel administration). In fact, Dr. Seth conceded that for
`
`the patients in TROPIC who “win the coin flip” and were randomized to receive
`
`cabazitaxel therapy, there was at most only a “hope,” not an expectation, that
`
`cabazitaxel would work. Ex. 2258 at 32:1-16, 112:21-25 (“I have a Phase III trial.
`
`I’m hoping that trial is going to work. That is always the gut feeling you have when
`
`you have a Phase III trial. Will it work or not? I do not know because there’s so
`
`many factors that go into that success.”), 41:8-42:6 (“I think a POSA in 2008 or 9
`
`would just hope that cabazitaxel . . . would give them an overall benefit in controlling
`
`their disease which would increase their overall survival.”). Third, Dr. Seth ignores
`
`the fact that patients having DRmCRPC are in need not only of therapies to extend
`
`their lives, but also of therapies to improve quality of life. Indeed, physicians often
`
`administer chemotherapies with the intent of alleviating symptoms (e.g., pain) or
`
`shrinking tumor size without any intention of actually prolonging the patient’s life.
`
`Ex. 2083 at 300, 308; Ex. 2176 at ¶ 36; Ex. 2210 at 76-77; Ex. 1027 at 556-57.
`
`14
`
`
`
`D.
`
`Petitioner Has Not Presented Evidence That a POSA Would Have
`Been Motivated to Administer a 20 mg/m2 Dose of Cabazitaxel
`with the Intent of Increasing Survival
`
`Petitioner offers no basis why a POSA would have had a reasonable
`
`expectation that a 20 mg/m2 cabazitaxel dose would increase survival in patients
`
`with DRmCRPC, given the total absence of prior art data showing the effect of this
`
`dose in those patients, and in light of its expert’s belief that even after the TROPIC
`
`results were available, a POSA “most likely would not be able to think of giving a
`
`dose of 20 [mg/m2],” and “I don’t think most oncologists would think 20 milligrams
`
`would work.” Ex. 2177 at 72:17-73:2, 73:14-23. In Paper 93 at pages 4-5, Petitioner
`
`wrongly suggests that Dr. Seth testified that a POSA would have expected 20 mg/m2
`
`to increase survival. In the first cited testimony, Dr. Seth said only that a POSA
`
`would “hope” that 20 mg/m2 would provide an undefined “benefit” to the patient.
`
`Ex. 2258 at 40:20-42:6. In the second and third excerpts, Dr. Seth testified that
`
`cabazitaxel “was felt to be working” but was unsure whether it would also benefit
`
`patients at doses lower than 25 mg/m2, concluding only that cabazitaxel “could
`
`work” at the 20 mg/m2 dose. Ex. 2258 at 43:17-20, 44:22-45:20. Importantly,
`
`neither Winquist nor the TROPIC listing discloses the dose reduction to 20 mg/m2
`
`of cabazitaxel. Petitioner has not provided an explanation as to why a POSA would
`
`15
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`
`
`have been motivated to use such a lower dose,5 let alone to do so with the intent to
`
`increase survival.6 Petitioner’s assertion that the 20 mg/m2 dose was “active and
`
`well-tolerated” in women with breast cancer is insufficient evidence to establish a
`
`reasonable expectation of increased survival in men with DRmCRPC.7 Supra
`
`Section III.A.
`
`In light of the lack of survival data reported for cabazitaxel, the fact that a
`
`POSA would not consider anti-cancer activity to be evidence that a therapy increases
`
`5 Dr. Seth testified briefly about giving a patients the lower dose of 20 mg/m2 and
`
`“hoping to control their disease” at that dose, but this was only after the results of
`
`TROPIC were known and FDA approval. Ex. 2258 at 48:15-49:23.
`
`6 Patent Owner appealed and specifically disputed the underlying factual findings
`
`regarding Claim 34 even under the incorrect claim construction. Appellate Opening
`
`Brief at 47-48. Given the improper burden and preamble claim construction, it was
`
`not necessary for the Federal Circuit to consider this issue at the time they rendered
`
`their decision.
`
`7 As discussed above, Petitioner’s incorrect assertions about the lack of survival data
`
`on the 20 mg/m2 dose in the ’592 patent—even if they were taken as true—do not
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`support Petitioner’s obviousness challenge.
`
`16
`
`
`
`survival of patients with DRmCRPC, and the numerous failures of other therapies
`
`to provide a survival benefit despite anti-cancer activity, a POSA would not have
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`reasonably expected the methods of the proposed claims to prolong the lives of
`
`patients with DRmCRPC.8
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`IV. A POSA Would Not Have Been Motivated to Use the Claimed
`Premedication Regimen with Cabazitaxel
`
`Petitioner suggests that the Board has already made factual findings sufficient
`
`to find the proposed claims obvious under the proper allocation of the burden of
`
`persuasion. However, any such findings in the now-vacated decision were arrived
`
`at from a different legal analysis than the one that should now be undertaken on
`
`remand. In the FWD the Board considered “Patent Owner’s nonobviousness
`
`argument,” weighed Patent Owner’s expert’s testimony, and considered whether
`
`Mita would have taught away from using the claimed pretreatment regimen with
`
`cabazitaxel. FWD at 78-79 (“we are persuaded Mita does not teach away”), 80 (“Dr.
`
`Sartor’s testimony weighs against Patent Owner’s teaching away argument”). The
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`analysis with the burden of persuasion on Petitioner, however, is different because
`
`8 The proposed claims would still be patentable even if the claims did not require a
`
`specific finding of a reasonable expectation of increased survival in the prior art
`
`since a POSA cannot intend to increase survival without sufficient evidence that it
`
`is reasonably expected to do so. Ex. 2259 at ¶¶ 11-12.
`
`17
`
`
`
`it centers around whether there was a motivation in the prior art to use the claimed
`
`premedication with cabazitaxel therapy and must consider the admissions of
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`Petitioner’s expert Dr. Seth. Here Petitioner’s evidence fails.
`
`
`
`Although the Board found that Dr. Sartor’s testimony “weighs against Patent
`
`Owner’s teaching away argument,” namely that “when we administer an agent
`
`known to be associated with [HSRs], if there’s a method to help control those, then
`
`we use that,” that testimony does not bridge the evidentiary gap to the claimed
`
`regimen. FWD at 80. In particular, Petitioner does not explain why a POSA would
`
`have considered the single-component FDA-approved docetaxel premedication
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`inadequate, particularly given that the risk of HSRs was undisputedly lower for
`
`cabazitaxel than for docetaxel. Ex. 2176 at ¶¶ 252-256; Ex. 2177 at 115:11-19. In
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`fact, Dr. Seth unequivocally stated that it was still an open question in 2009 as to
`
`whether the administration of cabazitaxel would result in HSRs and that a POSA
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`“err[ing] on the side of preventing a hypersensitivity reaction” as a result of
`
`cabazitaxel administration would use dexamethasone alone, not the claimed three-
`
`component regimen:
`
`Q. Okay. The -- so the -- you would expect a
`POSA in 2009 would have expected the administration of
`cabazitaxel to result in hypersensitivity reactions?
`
`A. I would expect the POSA to be prepared in case
`a hypersensitivity reaction happens. I do not know if they
`
`18
`
`
`
`were always anticipating -- there’s no guarantee that
`you’re going to get hypersensitivity reaction with every
`drug you gave but I think any POSA would err on the
`side of preventing a hypersensitivity reaction.
`
`Q. And err on the side how?
`
`A. By giving premedications.
`
`Q. Specifically what premedications?
`
`A. The specific premedication we use for the
`docetaxel chemotherapy is dexamethasone.
`
`Ex. 2177 at 113:2-15; see also 118:13-119:5 (Dr. Seth: “POSAs would use the same
`
`premedication [dexamethasone] on docetaxel in cabazitaxel before TROPIC came
`
`out . . . .”).
`
`Dr. Seth’s testimony makes perfect sense. The claimed methods are directed
`
`to patients whose prostate cancer “has progressed during or after treatment with
`
`docetaxel” and thus has become docetaxel-resistant. Ex. 1002 at ¶ 117. Therefore
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`by definition, these patients were recently on docetaxel therapy, receiving
`
`dexamethasone alone as premedication. See FWD at 22. Docetaxel is
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`contraindicated in patients having a history of severe HSRs either to docetaxel or to
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`other drugs formulated with polysorbate because of the increased risk of subsequent
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`HSRs. Ex. 2176 at ¶ 255; Ex. 1024 at 1, 10. Therefore, a POSA would have
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`understood that the patients described in the proposed claims tolerated docetaxel
`19
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`
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`administration (having received enough do
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