`
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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 8,927,592
`_____________________________
`
`
`
`PETITIONER’S REPLY
`37 C.F.R. §42.24(c)
`
`

`

`IV. 
`
`TABLE OF CONTENTS
`I. 
`Introduction ...................................................................................................... 1 
`II.  Mylan Has Established Motivation to Combine and Reasonable Expectation
`of Success ........................................................................................................ 2 
`A.  Aventis’s Erroneous Legal Standard ..................................................... 2 
`B. 
`Ground 1: Winquist and TROPIC Listing Discloses Claims 1-2,
`5, 12-13, 17-20, 22-25, and 27-29 ......................................................... 4 
`Aventis’s Prednisone Arguments Ignore the Prior Art .......................... 5 
`C. 
`III.  Dr. Sartor’s Analysis Is Improperly excludes Clinical Trial Listings as Prior
`Art .................................................................................................................... 5 
`A.  Dr. Sartor’s Erroneous Legal Analysis Originated With Aventis .......... 6 
`Aventis’s “Surprise” Evidence Is Irrelevant ......................................... 8 
`B. 
`Prior Art Cabazitaxel Demonstrated Anti-Cancer Activity in Docetaxel-
`Resistant Cancer .............................................................................................. 8 
`A.  Uncertain Treatment Outcomes Do Not Render the Claims
`Patentable ............................................................................................ 10 
`Alleged “Failures” Do Not Undermine Cabazitaxel’s Known
`Anti-Cancer Activity ........................................................................... 11 
`Aventis’s “Risk of Cabazitaxel”Argument Is Incorrect ...................... 13 
`C. 
`Phase III and FDA Success Are Not Determinative ...................................... 14 
`V. 
`20 mg/m2 Dose was Obvious ......................................................................... 16 
`VI. 
`VII.  Ground 2 ........................................................................................................ 16 
`VIII.  Grounds 3-6 ................................................................................................... 17 
`IX.  Secondary Considerations ............................................................................. 17 
`A. 
`Lack of Nexus ..................................................................................... 17 
`B. 
`Alleged Filling of Long-Felt, Unmet Need ......................................... 18 
`C. 
`Alleged Failure of Others .................................................................... 19 
`D.  Alleged Unexpected Properties ........................................................... 20 
`E. 
`Alleged Praise ...................................................................................... 21 
`F. 
`Alleged Commercial Success .............................................................. 21 
`G.  Alleged Copying .................................................................................. 23 
`
`B. 
`
`-i-
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`Conclusion ..................................................................................................... 23 
`X. 
`Certificate of Compliance ........................................................................................ 24 
`Certificate of Service ............................................................................................... 25 
`
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`-ii-
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`I. INTRODUCTION
`Patent Owner (“Aventis”) filed a response (Paper 21, “POR”) attacking
`
`reasonable expectation of success and arguing secondary considerations. Aventis
`
`does not challenge the Board’s correct claim construction that the claim preambles
`
`are not limiting and agrees that the parties’ definitions of the POSA should not
`
`affect the outcome of this IPR. POR, 14. Moreover, Aventis does not contest
`
`motivation to combine the references (except Didier in Ground 2), or that Winquist
`
`and TROPIC Listing each describe a single cabazitaxel administration regimen.
`
`POR, i-iii, 47-49, 53; Pet., 26.
`
`Instead, Aventis relies on the “surprising results” that the phase III TROPIC
`
`study succeeded in its stated aim. POR, 1-2. Aventis also contends that “no life-
`
`extending treatments were available” for post-docetaxel mCRPC patients until
`
`cabazitaxel “changed that.” POR, 1. However, each of Aventis’s objective
`
`evidence arguments fails to account for the fact that cabazitaxel is the prior art, not
`the claimed invention. Aventis does not identify any novel element of the claims
`
`or objective evidence that is attributable to such. In short, Aventis attempts to
`
`patent the results of a prior art method.
`
`Aventis’s reasonable expectation of success arguments similarly miss the
`
`mark. The ’592 patent claims do not include any requirement that the method have
`
`FDA approval, a successful phase III trial, or actually increase survival of the
`
`individual patient. Indeed, the ’592 patent defines the “patient” to include non-
`
`clinical uses. Pet., 20. Even if some utility in human mCRPC patients is required,
`
`cabazitaxel’s anti-cancer utility was not in doubt in 2009. Because Winquist and
`
`-1-
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`

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`TROPIC Listing describe a single administration regimen, there can be no dispute
`
`that the POSA would be motivated to combine their teachings regarding that
`
`regimen, thereby successfully meeting each of the actual limitations of the claims.
`II. MYLAN HAS ESTABLISHED MOTIVATION TO COMBINE AND
`REASONABLE EXPECTATION OF SUCCESS
`A. Aventis’s Erroneous Legal Standard
`Aventis argues that obviousness requires a successful phase III study or
`
`FDA approval because it requires “not only [] the expectation that the prior art
`
`elements are capable of being physically combined, but also that the combination
`
`would have worked for its intended purpose.” POR, 14-15, 20 (citing DePuy Spine,
`
`Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009)).
`
`However, obviousness does not require proof that the prior art combination would
`
`work “as intended” by the prior art, but only “a motivation to combine
`
`accompanied by a reasonable expectation of achieving what is claimed in the
`
`patent-at-issue.” Intelligent Bio-Systems Inc. v. Illumina Cambridge Ltd., 821 F.3d
`
`1359, 1367-68 (Fed. Cir. 2016). DePuy involved a teaching away in the asserted
`
`prior art reference from the very combination motive asserted by the patent
`
`challenger because it taught that the combination would “render[] the device
`
`inoperative for its intended purpose.” 567 F.3d, 1326-27. Here, there is a
`
`motivation to combine Winquist and TROPIC Listing because they describe the
`
`very same cabazitaxel administration regimen. Pet., 26; infra II.B. Aventis’s own
`
`expert, Dr. Sartor, confirmed that they describe the same regimen actually being
`
`used in the TROPIC Study and that the POSA would read the two references
`
`-2-
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`

`

`together. EX1041, 57:2-8, 94:14-95:4, 97:7-100:4. Motivation to combine these
`
`references is undisputed.
`
`Furthermore, Aventis identifies no prior art teaching that combining the
`
`disclosures of Winquist and TROPIC Listing would render them “inoperable.”
`Indeed, Dr. Sartor testified that the POSA would not consider the 25 mg/m2 dose in
`Winquist to be uncredible. EX1041, 96:17-22. Because there is no alleged teaching
`
`away from the combination of the prior art references, DePuy is inapplicable.
`
`Aventis’s speculations that the TROPIC study might fail to reach its primary
`
`endpoint, provide clinical benefits that outweigh side effects, or achieve FDA
`
`approval, are each irrelevant because none of these things are elements of the
`
`claims. See In re Montgomery, 677 F.3d, 1375, 1380 (Fed. Cir. 2012) (method of
`
`treating claims do not create “an efficacy requirement”); Intelligent Bio-Systems,
`
`1367-68 (quantitative removal irrelevant to reasonable expectation because not a
`
`claim requirement); see also Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1292
`
`(Fed. Cir. 2013); Biomarin Pharmaceutical Inc. v. Genzyme Therapeutic Products
`
`Lmt. P’ship, IPR2013-00537, Paper 79, 4-7, 12-13, 18 n.18.
`
`Because the claims of the ’592 patent are evaluated under the BRI standard
`
`and do not recite a required result regarding efficacy or safety, Petitioner need not
`
`establish a reasonable likelihood of a successful phase III trial or FDA approval to
`
`demonstrate obviousness.
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`-3-
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`B. Ground 1: Winquist and TROPIC Listing Discloses
`Claims 1-2, 5, 12-13, 17-20, 22-25, and 27-29
`Petitioner has demonstrated the POSA would have been motivated to
`
`combine the teachings of these two disclosures and would have had a reasonable
`
`likelihood of thereby successfully obtaining the claimed invention because each
`
`claims element is disclosed therein as part of a single regimen.
`
`Dr. Sartor testified that Winquist and TROPIC Listing expressly taught
`administration of the critical 25 mg/m2 dose of cabazitaxel as a new cycle every
`three weeks in combination with prednisone. EX1041, 62:8-18, 96:17-22, 73:10-
`
`15, 150:6-152:6; see also Pet., 5-6. He also testified that these references taught the
`
`patients had mCRPC that had progressed during or after treatment with docetaxel.
`
`EX1041, 65:2-18, 67:23-68:6, 93:9-17, 59:7-20, 83:10-15, 87:13-88:4. Even
`
`Aventis has implicitly conceded that there is no patentable distinction between the
`
`claim language about progression and the disclosures of Winquist and TROPIC
`
`Listing. POR, 3, 20, 41, 54 (discussing obviousness in terms of patients previously
`
`treated with docetaxel).
`
`It is also undisputed that the POSA would have known from Winquist and
`
`TROPIC Listing that the cabazitaxel regimen was not merely a proposed treatment
`
`regimen, but was actually being administered. EX1041, 97:7-100:4, 71:16-25.
`
`Indeed, TROPIC Listing confirms that the claimed method is fully enabled by
`
`expressly stating that administration of the “treatment” was ongoing in 2008 and
`
`began in 2006. EX1008, 1-2. The primary objective was overall survival. Id.;
`
`EX1041, 114:3-25; EX1043, ¶10.
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`-4-
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`Because the claimed method was in the public domain, whatever benefits
`
`may flow from it, even if they were unexpected (they are not) or remained to
`
`definitively proven, cannot remove the prior art method from the possession of the
`
`public. Pet., 52-53. This principle has been reinforced repeatedly by the Federal
`
`Circuit. See Montgomery, 677 F.3d at 1381 (“efficacy is inherent in carrying out
`
`the claim steps”); see also Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354;
`
`In re Kao, 639 F.3d 1057, 1070, 1072-73 (Fed. Cir. 2011); King Pharmaceuticals,
`
`Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1275-76 (Fed. Cir. 2010); PharmaStem
`
`Therapeutics Inc. v. Viacell Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007).
`C. Aventis’s Prednisone Arguments Ignore the Prior Art
`As discussed in Section II.B, co-administration of cabazitaxel and
`
`prednisone is expressly disclosed in the prior art. Aventis’s prednisone arguments
`
`(POR, 45-46) are also contradicted by the routine prior art administration of
`
`prednisone in post-docetaxel mCRPC patients. EX1043, ¶¶11-13, EX2176, ¶¶36,
`
`38-39, 97; EX2111, 1, 9-12, 14-17, 27, 31; EX1041, 235:2-236:4; POR, 52-53 (“de
`
`facto standard therapy” post-docetaxel); EX2177, 46:22-47:9:19; EX2083, 307;
`
`EX1010, 1551 (XRP6258 safety “very favorable”). Moreover, the possibility of
`
`additional obvious options does not render non-obvious this expressly-disclosed
`
`combination. EX1043, ¶14; EX1013, 1502; EX2111, 9.
`III. DR. SARTOR’S ANALYSIS IS IMPROPERLY EXCLUDES
`CLINICAL TRIAL LISTINGS AS PRIOR ART
`At deposition, Dr. Sartor admitted that he incorrectly concluded that
`
`Winquist and TROPIC Listing are not prior art. EX1040, 45:12-17; 43:18-44:4
`
`(admitting that he “didn’t think it was prior art when you just put it in a listing. It’s
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`-5-
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`not relevant to me to put it in a listing. So I didn’t—I honestly don’t think that’s
`
`part of the prior art when you list a clinical trial.”); 44:19-45:6 (“I don’t think
`
`[TROPIC Listing] is [prior art]. I think it’s just a listing.”). Dr. Sartor’s analysis
`
`was incurably tainted by his erroneous exclusion clinical trial listings as prior art.
`
`See Montgomery, 677 F.3d at 1378-80 (published protocol for ongoing phase III
`
`study anticipated claims).
`A. Dr. Sartor’s Erroneous Legal Analysis Originated
`With Aventis
`Relying on Coal. For Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-
`
`01136, Paper 23, 9-10. Aventis contends that Winquist and TROPIC Listing
`
`cannot render unpatentable the claims of the ’592 patent because “disclosure of a
`
`protocol for testing a hypothesis without any evidence of efficacy or safety is
`
`insufficient to show that the method itself is useful for the claimed patients.” POR,
`
`37. As discussed above, that is simply not correct.
`
`Moreover, Aventis misconstrues Biogen, in which the Board unequivocally
`
`disavowed the idea that proving obviousness requires proof that the active agent
`
`“as a drug is effective,” safe, or likely to obtain FDA approval:
`We wish to make clear that we are not engrafting into the § 103(a)
`obviousness evaluation whether DMF as a drug is effective. In re
`Anthony, 414 F.2d 1383 (CCPA 1969) (FDA, not USPTO, is
`responsible for safety of drugs which are sought to be patented); In re
`Watson, 517 F.2d 465 (CCPA 1975) (Congress has given
`responsibility to FDA, not USPTO, to determine in the first instance
`whether drugs are safe); Purdue Pharma L.P. v. Endo
`Pharmaceuticals Inc., 438 F.3d 1123, 1134 (Fed. Cir. 2006) (quantum
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`-6-
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`of proof necessary for FDA approval is significantly higher than the
`proof required in the USPTO).
`Id., 11. Governing precedents similarly declare that proving obviousness is a lower
`
`standard than proving sufficient efficacy and safety to warrant FDA approval. E.g.,
`
`Allergan, 726 F.3d at 1292 (“Motivation to combine…cannot be limited to those
`
`reasons the FDA sees fit to consider in approving drug applications.”); Astrazeneca
`
`LP v. Apotex, Inc., 633 F.3d 1042, 1064-65 (Fed. Cir. 2010) (lacking FDA
`
`approval does not demonstrate lack of drug utility).
`
`Biogen is also distinguishable because it concerns the failure of the prior art
`
`to disclose the “therapeutically effective amount” limitation that was an express
`
`limitation of the claims. Biogen, IPR2015-01136, 6-7. Moreover, “the target site
`
`of action and the exact mechanism of action of DMF [were] unknown,” and thus
`
`the prior art merely proposed a phase II “proof of concept study” for this novel
`
`mechanisms of treating MS. Id., 12-13. In contrast, this IPR deals with claims that
`
`do not include a therapeutic efficacy limitation and that are directed to a known
`
`target site and mechanism of action that had previously been shown to be active in
`
`both breast and prostate cancer in cabazitaxel and in its close analogue docetaxel.
`
`See Pet., 21-24, 33-34, 46-47, 54; Section IV.
`
`Furthermore, unlike in Biogen, the ongoing phase III study described in
`
`TROPIC Listing is not merely a proposed trial to “determine” efficacy and safety
`
`(EX1052, 1-2), but is instead an ongoing trial “comparing the safety and efficacy”
`
`of cabazitaxel to the community standard treatment. Biogen, at 9-11; EX1008.
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`-7-
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`B. Aventis’s “Surprise” Evidence Is Irrelevant
`Aventis contends that “all grounds fail” because Dr. Sartor reported some
`
`private difficulty enrolling patients at one institution and was personally “surprised”
`
`to succeed. POR, 16, 43. However, Dr. Sartor confirmed that the skilled artisan
`
`“would have no clue” about such “difficulties” and that this was just “private
`
`knowledge” that was not in the mind of the POSA. EX1041, 293:13-294:12. He
`
`also confirmed that he successfully enrolled patients at least as early as January
`
`2008 and may have enrolled patients in Boston as well. Id., 138:8-18.
`
`Aventis also relies on Dr. Sartor’s statement that some practitioners “were
`
`surprised by the results.” POR, 16. However, alleged surprise by Dr. Sartor or his
`
`unnamed colleagues is insufficient to remove the prior art method from the public
`
`domain. See Section II.
`IV. PRIOR ART CABAZITAXEL DEMONSTRATED ANTI-
`CANCER ACTIVITY IN DOCETAXEL-RESISTANT CANCER
`Aventis contends that it is contradictory to argue that cabazitaxel’s
`
`similarities with docetaxel disposed it to have “activity against prostate cancer”
`
`and breast cancer but that its differences with docetaxel allowed it to overcome at
`
`least some mechanisms of docetaxel resistance. POR, 21-23, 29-33. However,
`
`cabazitaxel was designed to retain the tubulin-stabilizing activity that was known
`
`to make docetaxel lethal to cancer cells while simultaneously reducing its affinity
`
`for the PGP pump, which was taught to be a major mechanism of docetaxel
`
`resistance. Pet., 8, 22-23; EX1002, ¶¶60, 66-69, 77; EX1021, 75; see also Section
`
`III.A supra (shared mechanism of action). Moreover, as explained by Dr. Seth,
`
`Aventis’s assertion that paclitaxel was only efficacious against breast cancer, and
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`-8-
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`the POSA would thus not believe that cabazitaxel was (like docetaxel) active
`
`against both breast and prostate cancer, is simply incorrect. EX1043, ¶25; see also
`
`EX1022, 163; EX2083, 303; EX1050, 354.
`
`Moreover, preclinical and clinical studies confirmed that cabazitaxel was
`
`active against docetaxel-resistant prostate and breast cancer. EX1010, 1551;
`
`EX1022, 163; EX1041, 51:10-16. Mita expressly teaches that the responses
`
`observed in these prostate cancer patients in the phase I trial provided “Evidence of
`
`anticancer activity due to XRP6258,” through partial responses in two patients,
`
`including 66-89% reduction in PSA and a “reduction in his target lesion” at each of
`the 15 mg/m2 and 25 mg/m2 doses. EX1012, 727. Pienta taught that the “use of the
`PSA endpoint” has become the “standard method to screen for activity in Phase II
`
`trials.” EX2083, 303. Dr. Seth explained that the RECIST guidelines define a
`
`partial response as a reduction of the largest diameter of the lesion by at least 30%.
`
`EX1002, ¶¶27, 69; EX1043, ¶15; EX1051, 983-84.
`
`Aventis contends that the Petition relies “too heavily” on the phase I study.
`
`But the Petition also relied on the prior art teaching that the claimed administration
`
`regimen was, in fact, being administered to the claimed patient population based at
`
`least in part on the activity in docetaxel-resistant prostate and breast cancer
`
`observed in the phase I-II trials. Pet., 23, 47. Aventis’s argument that this data was
`
`insufficient is contradicted by its own prior actions before the FDA. EX1022, 163;
`
`EX1054, SA_JEV_2146392-93, SA_JEV_2146418.
`
`Testimony that a POSA would have been looking for a larger study to
`
`characterize the benefit versus the risks of cabazitaxel (POR, 27) merely confirms
`
`-9-
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`that the POSA would have proceeded to administer the regimen to patients in the
`
`phase III trial. Aventis concedes that Beardsley disclosed that such administration
`
`had, in fact, begun based on “[cabazitaxel’s] activity in the docetaxel refractory
`
`setting [in breast cancer].” POR, 36 (citing EX1022, 163).
`A. Uncertain Treatment Outcomes Do Not Render the
`Claims Patentable
`Aventis’s argues cancer and resistance heterogeneity preclude reasonable
`
`expectation of success for prior art cancer therapies. POR, 24-27, 34. But neither
`
`the TROPIC Study nor the ’592 patent provide a cure for tumor heterogeneity or
`
`resistance. Indeed, cabazitaxel has not made a dramatic impact on patient outcome
`
`in the sense that mCRPC still inevitably results in death. EX1041, 200:9-21
`
`(“[Y]ou’re going to die from this disease. So we’re kicking the can down the
`
`road.”). Dr. Sartor testified both today and in 2008, that even with FDA-approved
`
`“life-prolonging therapies” such as docetaxel and cabazitaxel he still only has “a
`
`hope of prolonging survival” when he prescribes them. EX1041, 114:3-115:11.
`
`Dr. Sartor also testified that he continues today to prescribe non-FDA-
`
`approved therapies to his mCRPC patients in the clinical setting. EX1041:183:23-
`
`185:7. He also agreed: “in the context where you've run out of FDA-approved
`
`options to increase overall survival, [] it’s not unreasonable for a practicing
`
`oncologist to prescribe a medication that they merely hope will benefit the patient
`
`even if they have expectation that it may not.” EX1041, 186:4-12. Thus, Attard did
`
`not teach away from cabazitaxel, but merely confirmed that cabazitaxel was
`
`expected to work similarly to docetaxel except with greater activity in post-
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`docetaxel patients. Moreover, even if increased survival was unexpected,
`
`unexpected properties do not negate motivations based on expected properties. See
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 976 (Fed. Cir.
`
`2014).
`
`B. Alleged “Failures” Do Not Undermine Cabazitaxel’s
`Known Anti-Cancer Activity
`Aventis contends that the POSA would not have expected cabazitaxel to
`
`
`
`have efficacy because phase III trials of some other drugs did not result in FDA
`
`approval. However, Aventis points to no evidence explaining why cabazitaxel
`
`would be less likely to have efficacy simply because a different compound
`
`“failed.” As Dr. Sartor testified, “it’s not true” that clinical trials are “all the same.”
`
`EX1041, 241:3-12.
`
`Furthermore, as Dr. Seth explains, Aventis deemed trials failures that
`
`demonstrated clinical efficacy, including prolonged survival comparable to another
`
`widely-used and FDA-approved life-prolonging treatment, clinically significant
`
`pain benefits, and progression free survival benefits. EX1043, ¶¶19-23; EX1041,
`
`240:10-248:15 (larotaxel comparable survival to capecitabine); EX2003, 3 (same);
`
`see also EX2020, 210 (suramin palliative advantages over placebo); EX1041,
`
`239:8-17, 285:18-286:5, 287:3-25 (therapeutic palliative benefit); EX2074, 1312 (
`
`“clinical benefit” of pain reduction); EX2010, 1960; EX2190, 2176; EX1041,
`
`283:2-17 (survival not sole consideration for mCRPC treatment); EX1022, 162-63
`
`(satraplatin increased progression free survival with “significant clinical benefits”
`
`for HRPC); EX2006, 669, 672; EX1053, 14-15, n.30 (DN-101 increased survival
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`-11-
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`over weekly low-dose docetaxel but not over high-dose docetaxel); EX2027, 1
`
`(“[We] raised the bar too high in these phase 3 trials when we put GVAX up
`
`against an active chemotherapy drug [docetaxel]”). Dr. Sartor agreed that a trial
`
`finding comparable survival to a widely-used, FDA-approved treatment shown to
`
`prolong survival was not a failure. EX1041, 175:5-25 (“[M]aybe I have a pride of
`
`authorship. But I don’t feel like [FIRSTANA] was a failed trial. It just didn’t meet
`
`the primary endpoint.”), 171:6-14, 176:13-17, 266:23-267:2.
`
` Aventis also relied on other compounds failing to even enter clinical trials
`
`or reach phase III trials. POR, 23, 31-35. But any such compounds merely confirm
`
`that the POSA would have viewed cabazitaxel as a cut above. EX1043, ¶18;
`
`EX1041, 248:16-250:19 (milataxel and epothilone D never entered phase III
`
`trials); EX1022, 163 (ixabepilone, capecitabine, trastuzumab, and pertuzumab
`
`studies relied upon by Aventis were only phase II trials).
`
`Aventis also relies on studies (including for larotaxel) that published years
`
`after the critical date. However, none of these publications could have influenced
`
`whether the POSA would have been motivated to combine the asserted prior art
`
`references with a reasonable expectation of success. See Teva, 752 F.3d at 976.
`
`Notably, Aventis also fails to mention that Antonarakis disclosed FDA approval of
`
`four agents for increasing survival of mCRPC patents during this time period.
`
`EX2004, 1709. As Dr. Sartor agreed, “If you’re going to consider the failure of
`
`non-cabazitaxel clinical trials…after the filing date of the ’592 patent” it “also
`
`would be fair to consider the successes.” EX1041, 274:18-24.
`
`-12-
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`C. Aventis’s “Risk of Cabazitaxel”Argument Is Incorrect
`Aventis contends that a POSA would not administer cabazitaxel to post-
`
`docetaxel prostate cancer patients without phase III “clinical evidence” that its
`
`effiacy outweighed its risks, and thus would only administer it if there were a
`
`proven survival benefit to outweigh the risk of toxicity. However, Dr. Sartor
`
`testified that he continues to prescribe drugs to mCRPC patients even today when
`
`he is treating patients in a clinical setting even though the drugs are not approved
`
`by the FDA for the treatment of mCRPC. EX1041, 180:22-182:15, 185:8-22. He
`
`testified that he treats patients with “non-FDA-approved therapies” when “they’re
`
`not in a clinical trial,” that he does so without the benefit of any phase III clinical
`
`data establishing efficacy, and that he thinks “that’s probably typical of other
`
`oncologists” as well. Id., 182:16-183:10, 183:23-185:7. In short, Dr. Sartor agreed
`
`“in the context where you’ve run out of FDA-approved options to increase overall
`
`survival, that it’s not unreasonable for a practicing oncologist to prescribe a
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`medication that they merely hope will benefit the patient even if they have
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`expectation that it may not.” Id., 186:4-12.
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`Aventis also argues that administering cabazitaxel was of particular concern
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`after docetaxel because it is “a second chemotherapy agent in the same class of
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`cytotoxic drugs as docetaxel.” POR, 17. However, Dr. Sartor concedes that the
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`POSA in 2009 was not so limited. EX2176, ¶39 (docetaxel retreatment); EX2001,
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`¶36 (mitoxantrone); EX1043, ¶26 (mitoxantrone used post-docetaxel despite side
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`effects); EX2111, 1, 15, 28-29, Tables 7-8. As explained by Dr. Seth, the reported
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`incidences of neutropenia and other side effects of cabazitaxel were not so high to
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`require a proven survival benefit as a treatment prerequisite. EX1043, ¶26;
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`EX1012, 726 (Table 3); EX1010, 1550-51.
`V. PHASE III AND FDA SUCCESS ARE NOT DETERMINATIVE
`Aventis’s contention that obviousness requires predictable success of the
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`phase III results is wrong. As discussed in Section II.B, proof of obviousness does
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`not require FDA approval, evidence of FDA-approvable safety and efficacy ratios,
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`or a successful phase III trial. Dr. Sartor agreed that the POSA could be outside the
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`USA and not limited by FDA regulatory jurisdiction. EX1041, 141:4-142:4.
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`Aventis’s focus on FDA approval improperly confuses regulatory and business
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`decisions with technical failures because a drug “may not be developed further in
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`that disease because of business concerns.” EX2145, 5661.
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`Moreover, Dr. Seth explained that Aventis’s focus on a 25% likelihood of
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`FDA approval in breast cancer ignores El-Maraghi’s teaching of a higher phase III
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`success rate and its statement that the FDA approval rate is similar for targeted and
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`non-targeted drugs. EX1043, ¶29; EX1023, 1351. Aventis contends that an FDA
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`approval rate lower than 50% is “antithetical to a reasonable expectation of
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`success.” POR, 31. But even if generalizable to cabazitaxel, these “success rates”
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`merely confirm that the relevant decision-makers consider a 25% likelihood of
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`FDA approval to be reasonable under the circumstances.
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`Aventis does not dispute that Booth reported that phase III oncology studies
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`are more likely to succeed than to fail, instead asserting that “the phase II failure
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`rate is more relevant here” and that only 40% of oncology drugs that entered phase
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`I trials survived both phase I and II trials. POR, 39. But this 40% success rate
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`understates the success of phase II trials because it includes compounds failing at
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`phase I, which it concedes more likely to fail than phase II trials. EX1043, ¶24;
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`POR, 25 (8% of drugs entering clinical development get approved).
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`Aventis suggests the FDA required Sanofi to select overall survival as the
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`primary endpoint of the TROPIC Study. POR, 40. However, Dr. Sartor testified
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`that Sanofi could have instead performed a blinded study and used “pain and
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`subjective endpoints” instead of overall survival. EX1041, 232:12-20, 237:12-23,
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`239:8-17; EX1043, ¶26; EX2211, 11-12.
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`Aventis contends that the TROPIC study was a “relatively risky endeavor,”
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`and that Dr. Sartor privately experienced some “skepticism.” POR, 39-40; EX1041,
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`293:13-294:12 (POSA would not know private struggles). However, Dr. Sartor
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`confirmed that he successfully enrolled patients. EX1041, 138:8-18. As Dr. Seth
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`explained, physicians knew the TROPIC study was ongoing and would not have
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`enrolled their own patients in they viewed the study as marginal. EX1043, ¶39. Dr.
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`Sartor confirmed that the study design was not marginal, that the POSA knew the
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`FDA was a “tough taskmaster” and Sanofi could not “pull any wool over their
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`eyes,” and that the remaining steps of collecting, tabulating, and reporting the data
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`were “routine practice.” EX1041, 127:18-25, 132:3-134:18, 277:3-14. Moreover, it
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`was known that he and Sanofi were betting on success. Id., 275:5-276:12, 277:3-
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`14; EX1022, 163. Aventis cites no publication expressing contemporaneous
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`skepticism regarding the TROPIC Study.
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`Aventis contends that studies like that described in Pivot “generate false
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`hope, and should not be used if the dose is not certain.” POR, 31-32 (citing
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`EX1029, 277-78). As explained by Dr. Seth, however, Ratain indicates that
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`objective response data was appropriate to demonstrate anti-cancer therapeutic
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`activity of cabazitaxel. EX1043, ¶¶28-30. In short, Aventis assumes without
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`explanation that Ratain’s guidelines prove that Pivot was deficient, as opposed to
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`the more natural conclusion that FDA approved the Pivot trial because it was
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`appropriately designed. EX1043, ¶29; EX1029, 277; EX1041, 127:3-6.
`VI. 20 MG/M2 DOSE WAS OBVIOUS
`Relying on “the risk of Grade 3-4 neutropenia,” Aventis incorrectly contends
`that neither the 20 or 25 mg/m2 dose of cabazitaxel would be obvious to the POSA.
`POR, 44. As Dr. Seth explained, however, Mita and Pivot reported side effect rates
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`(including neutropenia) for cabazitaxel at both doses that were favorable when
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`compared to both docetaxel and mitoxantrone. EX1043, ¶26-27; EX1012, 723;
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`EX1010, 1550-51. Moreover, objective responses were observed in prostate cancer
`at a cabazitaxel dose as low as 15 mg/m2. EX1043, ¶30; EX1012, 727.
`Aventis asserts that Dr. Seth “admitted” that a POSA would not consider
`giving the 20 mg/m2 dose. POR, 44. However, Dr. Seth merely stated that Example
`1 of the ’592 patent does not prove a survival benefit with the 20 mg/m2 dose.
`EX2177, 72:17-73:23. DeBono similarly concluded that the ’592 patent lacks such
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`proof. See EX2055, 1153.
`VII. GROUND 2
`Aventis incorrectly contends that a POSA would ignore Didier’s teaching of
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`an acetone solvate of cabazitaxel and its preparation from an aqueous/acetone
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`solution (Pet., 8-9, 38-40) because Liu also teaches other means of improving
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`solubility. POR, 47-49. These alternatives do not amount to a teaching away.
`VIII. GROUNDS 3-6
`Aventis’s arguments regarding Grounds 3-6 fail for the same reasons
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`discussed for Ground 1. POR, 21.
`IX. SECONDARY CONSIDERATIONS
`A. Lack of Nexus
`Aventis bears the burden of producing objective indicia of nonobviousness.
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`Prometheus Labs., Inc. v. Roxane Labs., Inc., 805 F.3d 1092, 1101-02 (Fed. Cir.
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`2015). Objective indicia require “a nexus to establish that the evidence relied upon
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`traces its basis to a novel element in the claim and not to something in the prior
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`art.” Biomarin, IPR2013-00537, Paper 79, 22; see also Ormco Corp. v. Align
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`Technology, Inc., 463 F.3d 1299, 1311-12, n.14 (Fed. Cir. 2006). Each of
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`Aventis’s objective indicia arguments fail for lack of nexus.
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`For example, Mr. Tate failed to provide any opinion establishing a nexus
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`between alleged commercial success and the claims of the ’592 patent. EX2149,
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`¶25 n.49; EX1042, 64:19-65:20, 78:14-18. He said he relied on Dr. Sartor.
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`EX1042, 65:21-66:8. But Dr. Sartor testified that he understood the invention of
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`the ’592 patent to be cabazitaxel. EX1041, 142:14-144:5, 211:9-14, 150:25-152:6.
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`Aventis’s experts thus erroneously assume that any objec