Paper No. ___
`Filed: May 22, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`
`MYLAN LABORATIORIES, LTD.,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA S.A.,
`Patent Owner.
`
`_____________________________
`
`Case IPR2016-00712
`Patent 8,927,592
`_____________________________
`
`PETITIONER MYLAN LABORATORIES LIMITED’S
`
`RESPONSE TO PATENT OWNER’S MOTION FOR OBSERVATIONS ON
`
`THE CROSS-EXAMINATION OF DR. RAHUL SETH
`
`
`Filed: May 22, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`
`MYLAN LABORATIORIES, LTD.,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA S.A.,
`Patent Owner.
`
`_____________________________
`
`Case IPR2016-00712
`Patent 8,927,592
`_____________________________
`
`PETITIONER MYLAN LABORATORIES LIMITED’S
`
`RESPONSE TO PATENT OWNER’S MOTION FOR OBSERVATIONS ON
`
`THE CROSS-EXAMINATION OF DR. RAHUL SETH
`
`
`
`Case IPR2016-00712
`Patent 8,927,592
`
`Petitioner submits this Response to Patent Owner Aventis’s Motion for
`
`Observations on the Cross-Examination of Dr. Rahul Seth (“Observations”)
`
`pursuant to the Scheduling Order (Paper 10) as modified by the parties (Paper 49).
`
`
`
`1.
`
`Observation 1 omits relevant testimony and mischaracterizes the cited
`
`testimony. Dr. Seth explained that the dosage of cabazitaxel was disclosed
`
`(EX2258 at 28:6-9, 142:25-143:9), and that it was only the doses of mitoxantrone
`
`and prednisone that were not expressly disclosed in Winquist and TROPIC (id. at
`
`143:6-9); accordingly, the control arm of the TROPIC study could not be perfectly
`
`replicated solely based on Winquist and TROPIC. No claim of the ’592 patent
`
`recites mitoxantrone, and only dependent Claims 14-16 require a dose of
`
`prednisone. As Dr. Seth has previously explained, those claims are obvious over
`
`Winquist, TROPIC, and Tannock. See, e.g., EX1002, ¶¶152-54, 160; Pet. at 42-45.
`
`
`
`2.
`
`Regarding Observation 2, Dr. Seth explained that “hope” is the
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`equivalent term that an oncologist would use when deciding to give a drug to a
`
`patient. EX2258 at 30:17-31:2. Furthermore, as Dr. Seth pointed out (id.),
`
`Aventis’s questions misapplied a legal term (“expectation of success”) to whether
`
`the outcome of cabazitaxel treatment could be predicted for every patient. The
`
`relevant legal question is whether a POSA would have “reasonable expectation of
`
`success” that the prior art references could be combined to arrive at the claimed
`
`invention; “reasonable expectation of success” does not depend on whether a prior
`
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`Case IPR2016-00712
`Patent 8,927,592
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`art method is efficacious in every patient or is likely to receive FDA approval. See
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`Pet. at 53; see also id. at 20-21, 28, 33, 52; EX1002, ¶¶89, 112, 120-21, 133.
`
`Indeed, as explained by Dr. Seth, in 2009 and today “it is impossible to know on an
`
`individual basis whether such a method will work (before treatment),” and
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`physicians routinely administer chemotherapy drugs such as cabazitaxel without
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`such guarantees. EX1043, ¶¶38-39 (citing EX1041 at 115:19-23); see also
`
`EX1002, ¶220 (cancer drugs working in only 10% of patients considered
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`effective). Furthermore, Dr. Seth clarified the degree of confidence behind the
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`“hope” of cabazitaxel, stating that “when we were thinking about cabazitaxel in
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`2009, we expected it to get FDA approval and it would increase overall survival.
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`… We felt cabazitaxel was a drug worthwhile to give patients a clinical benefit.”
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`EX2258 at 80:12-81:12. When pressed as to the percentage chance, he stated that
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`“I could not say what percentage we would see but I thought we definitely would
`
`see a survival benefit,” and when asked whether the odds of success were greater
`
`than 50 percent, replied “You can say 50. I mean, we would see a definite benefit
`
`versus mitoxantrone.” Id.
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`
`
`3.
`
`Observation 3 repeats the same mischaracterizations explained above
`
`for response 2, presuming that the use of the term “hope” precludes a “reasonable
`
`expectation,” even though Dr. Seth explained that he uses the term “hope” as
`
`equivalent to “expectation” when describing a decision to treat a patient. EX2258
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`Case IPR2016-00712
`Patent 8,927,592
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`at 30:17-31:2. As also described in response 2, Aventis misapplies the concept of
`
`“reasonable expectation of success” to a question of whether a POSA would
`
`recognize inherent properties of a prior art method of treatment.
`
`
`
`4.
`
`Regarding Observation 4, Dr. Seth’s quoted statement was in response
`
`to a question regarding the results of future research with no specified time
`
`horizon: “There's always a hope we're going to cure prostate cancer?” EX2258 at
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`32:17-18 (emphasis added); see also id. at 32:21-33:11 (explaining that he was
`
`predicting future research progress in the field). Aventis’s observations equivocate
`
`between “hope” with regard to unknown future research and “hope” with regard to
`
`administering a treatment with known anti-cancer activity to a particular patient,
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`and is at any rate not relevant to a reasonable expectation of success. See Reply at
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`2; Pet. at 34.
`
`
`
`5.
`
`Regarding Observation 5, Dr. Seth explained that he cannot speak as a
`
`patient because he never personally had prostate cancer, nor did his family
`
`members. EX2258 at 36:24-37:6, 38:4-9. Dr. Seth explained that he hoped to
`
`obtain a clinical benefit for the patients he sent to the TROPIC study, that
`
`clinicians send patients to clinical studies to live, not die, and that he always
`
`intends to increase survival when treating patients with cabazitaxel. Id. at 38:4-9,
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`37:9-15, 31:13-22, 21:22-22:19.
`
`
`
`6.
`
`Observation 6 misquotes Dr. Seth as saying a POSA “would try to
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`Case IPR2016-00712
`Patent 8,927,592
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`hope that [dose of] cabazitaxel would work,” whereas in fact Dr. Seth stated a
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`POSA would conclude cabazitaxel could work at 20 or 25 mg/m2. EX2258 at 45:1-
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`20. In particular, Dr. Seth stated with regard to 15 mg/m2 dose that “I can't really
`
`say what a POSA would feel [on that], but 20 to 25 milligrams per meter squared,
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`I feel we would feel that [would] work.” Id. Mita’s example of efficacy at 15
`
`mg/m2 in mCRPC and 25 mg/m2 in post-docetaxel mCRPC supports a conclusion
`
`that cabazitaxel would likewise be effective at 20 or 25 mg/m2 in post-docetaxel
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`mCRPC, regardless of whether a dose of 15 mg/m2 would be equally effective. See
`
`EX1043, ¶30; EX1002, ¶103, 225; Reply at 9; Pet. at 22, 27, 54. The observation
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`also mischaracterizes the testimony regarding “hope” vs. “expect,” as discussed
`
`above.
`
`
`
`7.
`
`As discussed above in Responses 2-4 and 6, Aventis mischaracterizes
`
`the testimony regarding an oncologist’s “hope” when treating an individual and a
`
`POSA’s reasonable expectation of success when combining prior art methods. As
`
`Dr. Seth has previously pointed out, the ’592 patent’s data does not specifically
`
`prove a survival benefit with the 20 mg/m2 dose, nor does DeBono. Reply at 16;
`
`EX2177 at 72:17-73:23. Despite this lack of data, Dr. Seth explained that based on
`
`the prior art “a POSA would think 20 milligrams would probably work close to 25
`
`milligrams per meter squared in giving a patient a benefit.” EX2258 at 41:3-7; see
`
`also id. at 43:17-20 (“the drug was known and was felt to be working” at 20 or 25
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`Case IPR2016-00712
`Patent 8,927,592
`mg/m2), 45:18-20 (“20 to 25 milligrams per meter squared, I feel we would feel
`
`that work would”), 48:15-49:23 (dose reductions common).
`
`
`
`8.
`
`Observation 8 mischaracterizes Dr. Seth’s testimony. In EX2258 at
`
`52:4-16, Dr. Seth was asked whether progression-free survival was “the same” as
`
`overall survival. He replied that one does not translate into the other—that is, the
`
`two terms are not synonyms. Similarly, he answered that overall survival is not
`
`synonymous with tumor response rate (one does not “translate into” the other).
`
`Similarly, at 50:10-19, Dr. Seth observed that “overall survival” includes patients
`
`who died for reasons unrelated to treatment, so it is a measurement that only
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`partially represents the control of the patient’s disease due to the efficacy of the
`
`drug. See also id. at 50:22-51:20 (oncologists try to control patients’ cancer,
`
`increasing progression-free survival, which leads to overall survival, albeit not
`
`with an “absolute one-on-one correlation”), 5:12-12:9 (palliation arises from
`
`control of disease and goes hand-in-hand with increased survival).
`
`
`
`9.
`
`Regarding Observation 9, Dr. Seth never contended that Mita was a
`
`two-arm study, nor that a study had been performed comparing cabazitaxel without
`
`prednisone to mitoxantrone with prednisone. Rather, as explained by Dr. Seth,
`
`prednisone served a primarily palliative role in the treatment of prostate cancer
`
`(EX1002 ¶153), so Mita’s objective responses in mCRPC patients treated with
`
`cabazitaxel would be reasonably predictive of cabazitaxel’s efficacy in treating
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`Patent 8,927,592
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`mCRPC (E.g., id. at ¶¶67, 69, 225).
`
`10.
`
` The present-day preferences of Dr. Seth discussed in observation 10
`
`are not relevant to any alleged concerns a POSA would have had in 2008 regarding
`
`cabazitaxel. Insofar as the cited statements are relevant, they are consistent with
`
`the conclusion that cabazitaxel is not a commercial success. For example, doctors
`
`today prescribe less cabazitaxel because other drugs such as Zytiga and Xtandi
`
`provide greater efficacy and fewer side effects. EX1034, ¶34. This does not
`
`indicate a judgment that the cabazitaxel’s side effects outweigh its benefits, but
`
`merely that the other drugs provide better tradeoffs. Furthermore, Dr. Seth testified
`
`that it was known how to manage the various known side effects of cabazitaxel.
`
`EX2258 at 61:24-62:5 (known tools to alleviate neutropenia), 126:24-130:11
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`(common practice in 2009 to prevent side effects such as HSR and emesis in
`
`docetaxel using premedication with antihistamine, corticoid, and H2 blockers).
`
`11.
`
` Observation 11 draws a false conclusion from Dr. Seth’s testimony.
`
`Dr. Seth has never suggested that a clinical study comparing cabazitaxel to Zytiga
`
`or Xtandi would be required to conclude which is better. The judgment of
`
`individual doctors treating mCRPC indicates which is felt to be better: cabazitaxel
`
`consistently falls far behind its competitors. EX1034, ¶34; EX1044, ¶¶48, 51.
`
`12.
`
` Observation 12 misrepresents Dr. Seth’s testimony and Petitioner’s
`
`arguments. Dr. Seth has explained that cabazitaxel was known to be similar in
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`Patent 8,927,592
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`activity and mechanism of action to docetaxel, but that it overcame docetaxel
`
`resistance. EX1002, ¶¶73, 77, 121, 133. Accordingly, Dr. Seth concluded that a
`
`POSA would expect cabazitaxel to have a similar effect in post-docetaxel patients
`
`as docetaxel had in non-resistant patients. Id., ¶214; see also Pet. at 33-34, Reply at
`
`20-21. As explained in the petition, the most appropriate comparison is with the
`
`closest prior art—that is, with the administration of cabazitaxel as disclosed by
`
`Winquist and TROPIC. Pet. at 56. The similar efficacy of cabazitaxel to docetaxel
`
`provides additional evidence that there were no unexpected results. Id.
`
`13.
`
` Observation 13 omits relevant testimony and mischaracterizes the
`
`cited testimony. At 82:18-25, counsel pointed Dr. Seth to Claim 27 and asked a
`
`question about its obviousness. Dr. Seth replied by starting to read the claim before
`
`being cut off by counsel with a question about Claim 31: “The survival. 27 says:
`
`Method of increasing survival of a patient with [mCRPC] during or after treating
`
`with docetaxel. Q. What about [claim 31] …” Aventis’s characterization of Dr.
`
`Seth’s answer also takes it out of context. Dr. Seth was asked a series of questions
`
`relating to paragraph 45 of his reply declaration, which refers to the discussion of
`
`Claims 27-30 in his original declaration. EX2258 at 81:13-82:24. As explained
`
`therein, a POSA would have reasonably administered cabazitaxel to an mCRPC
`
`patient as recited in Claim 27 based on Winquist and TROPIC with the purpose of
`
`increasing survival (EX1002, ¶132), and even if an expectation of increase in
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`Case IPR2016-00712
`Patent 8,927,592
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`survival were necessary, a POSA would have had that expectation as well (id.,
`
`¶133). Read in full, Dr. Seth’s testimony indicates that Claim 27 would have been
`
`obvious even if an expectation of increased survival were needed, even though it is
`
`not required by the claim. To the extent Aventis seeks to reinterpret Dr. Seth’s
`
`testimony as a legal conclusion, such reinterpretation is improper.
`
`14.
`
` Dr. Seth did not state that he was not aware of “the success rates in
`
`Phase III oncology studies prior to 2009,” as alleged in Observation 14. Dr. Seth
`
`stated “I cannot recall knowing the exact data for Phase III trials in 2009 for
`
`prostate cancer that met its objective responses.” EX2258 at 90:25-91:2. Dr. Seth
`
`never stated that he was unaware of oncology success rates in general; indeed, he
`
`cited in his original declaration to a publication by Booth (upon which Dr. Sartor
`
`has also relied), which indicated a 60% success rate for phase III oncology trials.
`
`EX1002 at ¶221-23. No statistical analysis has been presented to indicate that this
`
`general rate of success at phase III was inaccurate, or that prostate cancer trials
`
`were known to differ from the overall oncology rate of success to a statistically
`
`significant degree, and Dr. Seth’s remaining cited testimony is consistent with this.
`
`15.
`
` Observation 15 mischaracterizes the cited testimony. The observation
`
`quotes Dr. Seth as stating that he cannot “recall a cytotoxic agent that is used for
`
`prostate cancer that did not go on for a Phase II,” and suggests that this implies that
`
`cabazitaxel was extraordinary in this regard. However, cabazitaxel did undergo a
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`Case IPR2016-00712
`Patent 8,927,592
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`phase II trial in breast cancer, as Dr. Seth pointed out (EX2258 at 93:5), and the
`
`breast cancer phase II trial was known in the art to have justified the phase III trial
`
`in prostate cancer. EX1002, ¶70 (discussing Beardsley, EX1022).
`
`16.
`
` Observation 16 mischaracterizes the cited testimony. First, Dr. Seth
`
`distinguished larotaxel as having had “lower single-arm survival in breast cancer”
`
`EX2258 at 100:10-11. Second, Dr. Seth correctly noted that whereas cabazitaxel
`
`was known to be used in both breast and prostate cancer, with successful results in
`
`both, the cited prior art did not suggest using larotaxel to treat prostate cancer.
`
`EX2258, 98:20-99:2; EX1043, ¶¶17, 23.
`
`17.
`
` Observation 17 omits relevant testimony and draws a false analogy.
`
`Dr. Seth pointed out that, whereas the use of cabazitaxel for mCRPC was known in
`
`the prior art, the prior art only suggested the use of larotaxel in breast cancer, and
`
`in that indication, it had lower survivability in phase II than cabazitaxel, yet
`
`nonetheless showed survival benefits equivalent to capecitabine in phase III. Id.
`
`18.
`
` Observation 18 mischaracterizes Dr. Seth’s testimony. Dr. Seth did
`
`not state that differences in prostate cancer cause difficulties in treatment; on the
`
`contrary, the differing responses of patients to drugs means that, even if only a
`
`small number of patients benefit from a drug, the drug can still be considered
`
`successful because it benefits those patients. See, e.g., EX1002 ¶¶98, 220.
`
`19.
`
` Regarding Observation 19, Dr. Seth’s testimony indicates that certain
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`Patent 8,927,592
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`drugs that Dr. Sartor presumed to be failures because the FDA had not approved
`
`them, such as GVAX, were in fact useful drugs that successfully increased the
`
`survival of at least some prostate cancer patients. This testimony is corroborated by
`
`Dr. Sartor’s testimony, in which he indicated that he routinely administers drugs
`
`that had not received FDA approval to prostate cancer patients. See EX1041 at
`
`181:8-12, 182:16-184:4, 215:22-25. Dr. Seth further explained that patients are
`
`routinely treated with unapproved drugs, and that phase III trials such as GVAX’s
`
`may fail due to faulty study design, even when the drug is useful for treatment, but
`
`that trials are designed with the expectation that they will not fail. EX2258 at
`
`111:15-113:2.
`
`20.
`
` Observation 20 mischaracterizes the cited testimony. Dr. Seth’s
`
`testimony indicates that when physicians conduct a phase III trial, they do so
`
`because they expect there to be a reasonable probability that the trial will succeed.
`
`See Reply at 14 (“relevant decision-makers consider a 25%
`
`likelihood…reasonable”). Whether they can know with certainty is immaterial, as
`
`absolute predictability is not required, merely reasonable probability. Pet. at 28-29.
`
`
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`
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`Date: May 22, 2017
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
`Steven W. Parmelee
`Reg. No. 31,990
`
`
`
`
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`Case IPR2016-00712
`Patent 8,927,592
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`CERTIFICATE OF SERVICE
`
`This is to certify that I caused to be served a true and correct copy of the
`
`foregoing Petitioner Mylan Laboratories Limited’s Response to Patent Owner’s
`
`Motion for Observations on the Cross-Examination of Dr. Rahul Seth, on this 22nd
`
`day of May, 2017, on the Patent Owner at the correspondence address of the Patent
`
`Owner as follows:
`
`Dominick A. Conde
`William E. Solander
`Jason A. Leonard
`Whitney L. Meier
`Daniel J. Minion
`Joshua I. Rothman
`FITZPATRICK, CELLA, HARPER & SCINTO
`1290 Avenue of the Americas
`New York, NY 1014-3800
`Email: dconde@fchs.com
`Email: wsolander@fchs.com
`Email: jleonard@fchs.com
`Email: wmeier@fchs.com
`Email: dminion@fchs.com
`Email: jrothman@fchs.com
`
`
`
`Dated: May 22, 2017
`
`
`
`
`
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
`
`
`
`
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`-11-
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