Paper No. ___
`Filed: May 15, 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
`MOTION FOR OBSERVATIONS REGARDING THE CROSS-
`EXAMINATION OF DR. ALTON OLIVER SARTOR
`
`
`Filed: May 15, 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
`MOTION FOR OBSERVATIONS REGARDING THE CROSS-
`EXAMINATION OF DR. ALTON OLIVER SARTOR
`
`
`
`Case IPR2016-00712
`Patent 8,927,592
`
`In accordance with: (i) The Trial Practice Guide, and (ii) the Scheduling
`
`Order (Paper 10) as modified by the parties (Paper 49), Petitioner hereby submits
`
`the instant Motion for Observations Regarding the Cross- Examination Testimony
`
`of Dr. Alton Oliver Sartor, taken on May 8, 2017, after Petitioner filed its last
`
`substantive paper. The transcript of this testimony has been filed as EX1098.
`
`1.
`
`
`
`In EX1098 at 357:25-358:22, Dr. Sartor agreed that, with respect to
`
`post-docetaxel mCRPC patients treated with cabazitaxel according to claims 31-
`
`34, “the difference between 2007 and 2017 is knowledge that you have in your
`
`head”—specifically, the knowledge “that cabazitaxel is an effective drug.” This
`
`supports Petitioner’s argument that Aventis’s claim construction renders claims 31-
`
`34 unpatentable under 35 U.S.C. §101 because the alleged “inventive step” is
`
`knowledge that the prior art method works (Paper 44 (“Opp.”) at 6), as well as to
`
`Petitioner’s argument that Aventis’s claim construction merely recites knowledge
`
`of an inherent property that cannot distinguish over the prior art (id. at 8-10).
`
`2.
`
`
`
`In EX1098 at 377:12-24, Dr. Sartor agreed that his interpretation of
`
`the claims implied that “knowledge … of TROPIC data is necessary in order to
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`have the intention of increasing survival for Claims 31, 32, 33, and 34” in both
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`2007 and 2017. This contradicts Aventis’s position that “Aventis does not assert
`
`that the claims require FDA approval or a phase III study.” Paper 52 (“PO Reply”)
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`at 1 n.1; see also Opp. at 1-2 (arguing that Aventis’s construction requires
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`
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`Case IPR2016-00712
`Patent 8,927,592
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`“knowledge of statistical population data” from, e.g., a phase III study). It also
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`supports Petitioner’s 101 and inherency arguments described in obs. 1 above.
`
`3.
`
`
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`In EX1098 at 360:11-363:14, Dr. Sartor stated that under his
`
`interpretation of claim 31, an IV technician or a nurse who carried out each step of
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`claim 31 would nonetheless not be capable of practicing the claim, because they
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`would lack the knowledge that he contends is required to have an intention to
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`increase survival. This supports Petitioner’s arguments that Aventis’s claim
`
`construction renders claims 31-34 indefinite under 35 U.S.C. §112 and
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`unpatentable under 35 U.S.C. §101 because the metes and bounds of the claims are
`
`not clear, and the claims are directed to a mental state per se. See Opp. at 2-3, 5-6.
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`4.
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`
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`In EX1098 at 400:22-401:24, Dr. Sartor stated that if a post-docetaxel
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`patient treated with cabazitaxel lived for 9 months, he would “attribute cabazitaxel
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`to have treated with success,” that death within 5 months would only be “a little
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`grayer.” This supports Petitioner’s arguments that the observed successes of
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`cabazitaxel in Mita (see Pet. at 54-55, EX1002 at ¶¶103, 225 (citing EX1012 at
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`727, describing an objective response to 25 mg/m2 cabazitaxel in a post-docetaxel
`
`mCRPC patient whose disease did not progress until the eighth 3-week cycle—i.e.,
`
`6 months of progression-free survival)) and Pivot (see Pet. at 49, citing EX1010 at
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`1547 (reporting median overall survival of 12.3 months in taxane-resistant
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`metastatic breast cancer patients receiving cabazitaxel); see also Mot. to Amd. at
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`-2-
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`Case IPR2016-00712
`Patent 8,927,592
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`12 (admitting Pivot showed 12.3 month overall survival in taxane-resistant
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`metastatic breast cancer patients)), as reported in Attard and Beardsley, would lead
`
`a person of ordinary skill to have a reasonable expectation that cabazitaxel
`
`treatment would increase the survival of at least some patients with mCRPC that
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`had progressed during or after treatment with docetaxel. See Opp. at 11; see also
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`EX1043 at ¶45; Pet. at 33-34, 49, 54; EX1002 at ¶¶69-70, 103, 133, 183-84.
`
`5.
`
`
`
`In EX1098 at 429:8-431:3, Dr. Sartor stated, “I believe it is entirely
`
`possible that some physicians believed, in a subjective manner, that they could
`
`have benefit from participating in the [TROPIC study].” Dr. Sartor further clarified
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`that “it is possible that the study could have enrolled patients because physicians
`
`wanted the patients to receive cabazitaxel.” Id. This testimony supports
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`Petitioner’s argument that “physicians were enrolling their patients in a phase III
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`trial of the taxane cabazitaxel with an intention … of prolonging the life of at least
`
`some patients.” Opp. at 10.
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`6.
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`
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`In EX1098 at 348:23-349:3, Dr. Sartor testified that the phrase
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`“administering to a patient in need thereof” simply means that the patient is “a
`
`patient who needs to have their survival prolonged.” In EX1098 at 431:4-17.
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`Sartor testified that “virtually all” patients with mCRPC that has progressed during
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`or after treatment with docetaxel are in need of a method of increasing survival.
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`This testimony supports Petitioner’s claim construction that the preamble “at most
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`Patent 8,927,592
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`gives a more generic description of the patient” and that any post-docetaxel
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`mCRPC patient receiving treatment in 2008 had a recognized need for increased
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`survival. Opp. at 3.
`
`7.
`
`
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`In EX1098 at 447:6-448:17, Dr. Sartor testified that a physician could
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`only have the intent to increase survival alleged by Aventis to be required by claim
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`31 if the physician had taken additional steps not recited in claim 31 to determine
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`that the patient met the inclusion criteria of the TROPIC study. This testimony
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`demonstrates that Aventis’s construction of claim 31 would render the claim
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`unpatentable under 35 U.S.C. § 112 paragraphs 1 and 2. See Opp. at 5-6.
`
`8.
`
`
`
`In EX1098 at 451:13-452:14, 453:9-455:14, Dr. Sartor testified that a
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`physician in 2017 could not form the intent allegedly required to practice claim 31
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`in a post-docetaxel mCRPC patient if the patient had also been treated with any of
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`a number of drugs, including Zytiga, Xofigo, mitoxantrone, and Xtandi. This
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`testimony demonstrates that Aventis’s construction of claim 31 would render the
`
`claim unpatentable under 35 U.S.C. § 112 paragraphs 1 and 2. See Opp. at 5-6.
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`Additionally, this testimony is relevant to the question of commercial success (see
`
`Mot. to Amd. at 25; Opp. at 25; see also EX2149, ¶¶21-22, 27-30; EX1044, ¶¶23,
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`34-51, 68-69) because it indicates that, under Aventis’s claim construction, most
`
`uses of Jevtana® in post-docetaxel mCRPC patients do not fall within the scope of
`
`the claims because they occur subsequent to treatment with Zytiga, Xofigo, or
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`-4-
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`Case IPR2016-00712
`Patent 8,927,592
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`Xtandi. See EX1044, ¶48 (Jevtana pushed back to fourth-line treatment),
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`Attachments 5 & 7 (showing a large fraction of first- and second- line mCRPC
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`patients given Zytiga or Xtandi).
`
`9.
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`
`
`In EX1098 at 504:20-506:2, Dr. Sartor stated that, as far as he knew,
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`docetaxel was always formulated with polysorbate 80, not Cremophor. This
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`statement is relevant because Aventis has asserted that certain prior art references
`
`describing clinical studies in docetaxel using the same premedication regimen as
`
`was recommended in the Taxol label were “outdated,” and that the premedication
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`regimen was allegedly used with Taxol only due to the presence of Cremophor. PO
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`Reply at 6. Dr. Sartor’s testimony clarifies that the premedication regimen of claim
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`31 was used with docetaxel in these studies, even though docetaxel was formulated
`
`with polysorbate 80, not Cremophor.
`
`10.
`
`
`
`In EX1098 at 506:17-507:8, Dr. Sartor agreed that the dose of
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`docetaxel in Takenaka was close to the dose of cabazitaxel in the prior art, and that
`
`accordingly the amount of polysorbate 80 used in Takenaka would have been close
`
`to that used for cabazitaxel. This supports Petitioner’s argument that the close
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`match in the doses of Takenaka (30 mg/m2) and Winquist (25 mg/m2) means that a
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`25 mg/m2 dosage of cabazitaxel, as recited in the claims and as disclosed in
`
`Winquist, would not contraindicate use of the taxane premedication regimen used
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`-5-
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`Case IPR2016-00712
`Patent 8,927,592
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`in the Taxol Label, Hudis, Trudeau, and Takenaka: an antihistamine, a corticoid,
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`and an H2 antagonist. Opp. at 15-16.
`
`11.
`
`
`
`In EX1098 at 509:6-510:5, Dr. Sartor agreed that the 4% rate of
`
`severe (grade 3-4) hypersensitivity reactions (“HSRs”) reported for cabazitaxel in
`
`Pivot with antihistamine premedication was comparable to the rate of severe HSRs
`
`reported in the Taxol label for paclitaxel formulated with Cremophor even after
`
`premedication. In EX1098 at 547:1-13, Dr. Sartor agreed that the rate of severe
`
`HSRs for cabazitaxel in Pivot was larger than the 0.6% rate for prostate cancer
`
`patients reported by the Taxotere label for docetaxel with dexamethasone
`
`premedication, and this was also larger than the 2.2% HSR rate Dr. Sartor
`
`identified for breast cancer patients (EX1098 at 547:11-12). This supports
`
`Petitioner’s argument that “a 4% rate of grade 3 or higher HSRs would have been
`
`serious enough to merit the use of preventative premedications,” which quoted Dr.
`
`Sartor as saying “4 percent of people with a bad hypersensitivity is a crazy high
`
`number, scares the hell out of me.” Opp. at 17 (quoting EX1041 at 216:15-19).
`
`12.
`
`
`
`In EX1098 at 512:17-514:22, 517:23-518:4, Dr. Sartor testified that a
`
`physician today cannot form the intention allegedly required to practice claim 31
`
`for patients of ethnic groups including Japanese and African-Americans because
`
`the TROPIC study data were not specific to these ethnic groups. Dr. Sartor then
`
`reversed course, stating that even though the intent is not possible, physicians
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`Patent 8,927,592
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`nonetheless have “included the African Americans in the subset of beneficiaries”
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`for cabazitaxel treatment. Id. at 518:5-16. This testimony demonstrates that
`
`Aventis’s construction of claim 31 would render the claim unpatentable under 35
`
`U.S.C. § 112 paragraphs 1 and 2 (see Opp. at 5-6), and that the “intent” that Dr.
`
`Sartor alleges is an element of claim 31 is different from the criterion used by a
`
`person of ordinary skill to treat patients.
`
`13.
`
`
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`In EX1098 at 524:11-18, Dr. Sartor stated that a person of ordinary
`
`skill in 2009 would not have thought the use of H2 antagonists with cabazitaxel
`
`was contraindicated. This undermines his and Aventis’s assertions that the prior art
`
`taught away from use of H2 antagonists. Mot. to Amd. at 23-24;EX2259 at ¶49;
`
`EX2176 at ¶¶258-62. Dr. Sartor’s testimony confirms his prior admission that H2
`
`antagonists are not “extremely risky medications.” See EX1041 at 217:20-219:5
`
`(stating that H2 antagonists, Benadryl, and dexamethasone are not “extremely
`
`risky medications,” and that “I’ve never had any real harm done”); see also Opp.
`
`at 18, 24.
`
`14.
`
`
`
`In EX1098 at 342:3-9, Dr. Sartor testified that “‘intent’ is a word I
`
`suppose that could have different interpretations to different people.” In EX1098 at
`
`355:17-21, Dr. Sartor testified that he “had a hope” of increasing the survival of
`
`his patients that he enrolled in the TROPIC study, and agreed that this may qualify
`
`as “an intent to increase their overall survival” depending on “what the word
`
`-7-
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`Case IPR2016-00712
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`‘intent’ means.” In EX1098 at 409:23-410:8, Dr. Sartor testified with regard to his
`
`practice of administering mitoxantrone to post-docetaxel patients that his
`
`“intentions” are better conveyed as a “hope.” This testimony supports Petitioner’s
`
`argument that an intention to increase survival requires at most that increased
`
`survival is “desired or appreciated.” Opp. at 2-5.
`
`15.
`
`
`
`In EX1098 at 411:21-412:4, Dr. Sartor testified that he “actually used
`
`a fair amount of mitoxantrone” to treat mCRPC patients at the time of the TROPIC
`
`study. In EX1098 at 356:13-19, Dr. Sartor testified that he was “very comfortable
`
`with mitoxantrone,” and “knew what to expect of it.” In EX1098 at 407:24-408:3,
`
`Dr. Sartor testified that “mitoxantrone was approved in an era where there was no
`
`docetaxel, so the post-docetaxel patient is not proven to have benefit for
`
`mitoxantrone.” In EX1098 at 406:10-21, Dr. Sartor testified that he and the group
`
`at Sanofi selected mitoxantrone for the TROPIC study because “at least there was
`
`a hope that these patients would be randomized to something that would have
`
`palliative—well, an intention that they would have a palliative effect. Because it
`
`wasn’t a hope at the time. We—actually, it gets very confusing because we didn’t
`
`have data in the post-docetaxel space. So we were hoping more than intending with
`
`mitoxantrone, but that gets to be a nuance.” This testimony supports Petitioner’s
`
`argument that the prior art can disclose a method of increasing survival even
`
`without disclosing the results of the TROPIC study. See Opp. at 9-10, 11.
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`-8-
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`16.
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`
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`In EX1098 at 383:10-24, Dr. Sartor agreed that “a method of
`
`increasing survival means administration of cabazitaxel with the intention of
`
`increasing survival of the patient, regardless of whether the intended survival
`
`actually results.” In EX1098 at 394:9-17 and 395:9-396:3, Dr. Sartor agreed that,
`
`even today, administering cabaztixel as claimed or under proposed claim 31 may
`
`not result in the individual patient experiencing an increase in survival. In EX1098
`
`at 394:22-395:14, Dr. Sartor agreed that not every patient in the TROPIC study
`
`who received cabazitaxel experienced an increase in survival, that some patients
`
`“died very shortly after the drug was administered,” and that some patients “died
`
`as a consequence of the drug.” This supports Petitioner’s arguments that even if
`
`the proposed claim did require someone to “intend” to increase survival of the
`
`patient, this element would be satisfied by the prior art disclosure that increasing
`
`survival was desirable for a patient with mCRPC that has progressed during or
`
`after treatment with docetaxel. Opp. at 10.
`
`17.
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`
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`In EX1098 at 432:20-22, Dr. Sartor testified that “[t]he FDA doesn’t
`
`determine if a drug is effective or not. That’s a regulatory decision.” This
`
`testimony undermines Aventis’s arguments that the failure of unrelated drugs to
`
`obtain FDA approval would have prevented a person of ordinary skill in the art
`
`from having a reasonable expectation of success in combining the cited prior art
`
`references to arrive at the methods of claims 31-34. See Mot. to Amd. at 16.
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`18.
`
`
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`In EX1098 at 494:11-14, Dr. Sartor agreed that Mita discloses that
`
`“treatment for hypersensitivity reactions or emesis were provided if clinically
`
`indicated.” This testimony contradicts Aventis’s arguments that Mita taught away
`
`from premedication (PO Reply at 5-6) and confirms Petitioner’s argument that
`
`Mita expressly allowed premedication (Opp. at 22-23).
`
`19.
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`
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`In EX1098 at 508:1-509:15, Dr. Sartor agreed that the Pivot
`
`pretreatment regimen included an antihistamine to prevent or reduce HSRs despite
`
`that fact that Mita had no pretreatment regimen. This testimony supports
`
`Petitioner’s argument that Mita would not dissuade a person of skill in the art from
`
`using the claimed premedication regimen. Opp. at 17.
`
`20.
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`
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`In EX1098 at 520:3-5, Dr. Sartor testified that “prostate cancer is
`
`across the board quite similar.” This undermines Patent Owner’s argument that a
`
`person of ordinary skill in the art could not have formed a reasonable expectation
`
`of success with regard to the prior art cabazitaxel treatment protocol because of the
`
`heterogeneity of the disease and the complexity of resistance mechanisms. See,
`
`e.g., PO Response at 5; EX2176, ¶¶77, 79, 110, 134. 184; Mot. to Amd. at 24.
`
`
`
`
`
`Date: May 15, 2017
`
`
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
`Steven W. Parmelee
`Reg. No. 31,990
`
`
`
`
`
`
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`-10-
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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 Motion for Observations, on
`
`this 15th 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
`
`Respectfully submitted,
`
`/ Steven W. Parmelee /
` Steven W. Parmelee, Lead Counsel
` Reg. No. 31,990
`
`
`
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`
`
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`Dated: May 15, 2017
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`
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`
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`-11-
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