`Paper No. ______
`Date Filed: May 11, 2017
`
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01479
`
`Patent No. 9,006,224
`
`
`
`
`
`NOVARTIS’S PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`THE POSA ...................................................................................................... 4
`
`III.
`
`STATE OF THE ART ..................................................................................... 7
`
`A. NETs Were Known To Comprise A Heterogeneous
`Group Of Tumors .................................................................................. 7
`
`B.
`
`C.
`
`D.
`
`It Was Known That Advanced PNETs Were Distinct
`From Other Tumors Of The Pancreas ................................................. 11
`
`Advanced PNETs Were Harder To Treat After Failure Of
`Cytotoxic Chemotherapy ..................................................................... 13
`
`The Role Of mTOR Inhibitors In Treating Cancer Was
`Uncertain ............................................................................................. 15
`
`E.
`
`The Etiology Of PNETs Was Poorly Understood .............................. 19
`
`IV. THE ’224 PATENT ....................................................................................... 21
`
`V. GROUND 1: CLAIMS 1–3 ARE NOT OBVIOUS OVER
`ÖBERG 2004, BOULAY 2004, AND O’DONNELL .................................. 23
`
`A. A POSA Would Not Have Been Motivated To Select
`Everolimus Over Other Prior Art Compounds ................................... 23
`
`B.
`
`C.
`
`D.
`
`Öberg 2004 Would Not Have Motivated A POSA To
`Select Everolimus Over Other Prior Art Compounds ......................... 26
`
`Dr. Ratain’s New Öberg 2004 Deposition Argument Is
`Unsupported And Wrong As A Matter Of Law .................................. 29
`
`Boulay 2004 Would Not Have Motivated A POSA To
`Select Everolimus Or Provided A Reasonable
`Expectation Of Success ....................................................................... 30
`
`
`
`i
`
`
`
`
`
`1.
`
`2.
`
`A POSA Would Have Known That CA20948 In
`Boulay 2004 Is A Rat Pancreatic Adenocarcinoma
`Cell Line .................................................................................... 30
`
`A POSA Would Not Have Reasonably Expected A
`Drug Active In Vivo Against CA20948 To Be
`Effective To Treat PNETs ........................................................ 33
`
`E.
`
`O’Donnell Would Not Have Motivated A POSA To
`Select Everolimus Or Provided A Reasonable
`Expectation Of Success ....................................................................... 38
`
`1.
`
`2.
`
`O’Donnell Was Not An Efficacy Study ................................... 38
`
`O’Donnell Did Not Suggest That Everolimus
`Would Be Effective To Treat Advanced PNETs
`After Failure Of Cytotoxic Chemotherapy ............................... 40
`
`F.
`
`Claims 1–3 Are Not Obvious Over The Combination Of
`Öberg 2004, Boulay 2004, And O’Donnell ........................................ 42
`
`VI. GROUND 2: CLAIM 2 IS NOT OBVIOUS OVER ÖBERG
`2004, BOULAY 2004, O’DONNELL, AND TABERNERO....................... 46
`
`VII. GROUND 3: CLAIMS 1–3 ARE NOT OBVIOUS OVER
`BOULAY 2004, O’DONNELL, AND DURAN .......................................... 48
`
`A. Duran Did Not Suggest That Temsirolimus Would Be
`Effective To Treat Advanced PNETs After Failure Of
`Cytotoxic Chemotherapy ..................................................................... 48
`
`B.
`
`C.
`
`D.
`
`Duran Did Not Suggest That Everolimus Would Be
`Effective To Treat Advanced PNETs After Failure Of
`Cytotoxic Chemotherapy ..................................................................... 53
`
`Dr. Ratain’s New Boulay 2004 Deposition Argument Is
`Wrong And Should Be Rejected ......................................................... 55
`
`Claims 1–3 Are Not Obvious Over The Combination Of
`Boulay 2004, O’Donnell, And Duran ................................................. 56
`
`VIII. GROUND 4: CLAIM 2 IS NOT OBVIOUS OVER BOULAY
`2004, O’DONNELL, DURAN, AND TABERNERO .................................. 59
`
`
`
`ii
`
`
`
`
`
`IX. CLAIMS 1–3 ARE NOT OBVIOUS OVER PAR’S
`REMAINING PRIOR ART ........................................................................... 59
`
`X. OBJECTIVE EVIDENCE OF NON-OBVIOUSNESS ................................ 61
`
`A.
`
`Claims 1–3 Demonstrate Unexpected Results .................................... 61
`
`B.
`
`C.
`
`Claims 1–3 Satisfied A Long-Felt Unmet Need That
`Existed In November 2005 .................................................................. 65
`
`The ’224 Patent Inventors Succeeded Where Others
`Failed ................................................................................................... 67
`
`XI. CONCLUSION .............................................................................................. 67
`
`
`
`iii
`
`
`
`
`
`
`
`
`
`Cases
`
`TABLE OF AUTHORITIES
`
`
`Coal. For Affordable Drugs V LLC. v. Biogen Ma Inc.,
`IPR2015-01993, Paper 63 (P.T.A.B. Mar. 21, 2017) ....................................62
`
`Costco Wholesale Corp. v. Robert Bosch LLC,
`IPR2016-00041, Paper 70 (P.T.A.B. April 12, 2017) .................................5, 6
`
`Cumberland Pharms. Inc. v. Mylan Institutional LLC,
`846 F.3d 1213 (Fed. Cir. 2017) .............................................................. 45, 48
`
`Eli Lilly & Co. v. Actavis Elizabeth LLC,
`435 F. App’x 917 (Fed. Cir. 2011) ................................................................43
`
`Eli Lilly & Co. v. Teva Pharms. USA, Inc.,
`619 F.3d 1329 (Fed. Cir. 2010) .....................................................................30
`
`In re Cyclobenzaprine Hydrochloride Extended-Release
`Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. 66, 67
`
`Insite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ................................................................ 23, 25
`
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2015-01633, Paper 10 (P.T.A.B. Jan. 4, 2016) .......................................58
`
`Knoll Pharm. Co. v. Teva Pharms. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) .....................................................................67
`
`L.A. Biomed. Research Inst. v. Eli Lilly & Co.,
`849 F.3d 1049 (Fed. Cir. 2017) ............................................................. passim
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .....................................................................50
`
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ................................................................ 25, 26
`
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
`803 F. Supp. 2d 409 (E.D. Va. 2011) ............................................................26
`
`
`
`iv
`
`
`
`
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ................................................................ 61, 65
`
`Sanofi v. Glenmark Pharms. Inc.,
`204 F. Supp. 3d 665 (D. Del. 2016) ....................................................... 30, 36
`
`Schott Gemtron Corp. v. SSW Holding Co.,
`IPR2013-00358, Paper 106 (P.T.A.B. Aug. 20, 2014),
`aff’d per curiam 612 Fed. Appx. 614 (Fed. Cir. 2015) ................................... 6
`
`Star Scientific, Inc. v. R.J. Reynolds Tobacco Co.,
`655 F.3d 1364 (Fed. Cir. 2011) .....................................................................52
`
`Rules
`
`37 C.F.R. § 42.65 .....................................................................................................58
`
`
`
`v
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Stadler
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`Wang, D-G., et al., “Oncogene
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`2096
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`2097
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`World Health Organization, Chapter 10,
`“Tumours Of The Exocrine Pancreas,”
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`251(Hamilton, S.R. & Aaltonen, L.A.
`eds. 2000)
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`World Health Organization, Chapter 4,
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`And Genetics, Tumours Of Endocrine
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`al., eds. 2004)
`
`“Wyeth Pharmaceuticals Announces
`Termination Of Phase 3 Clinical Program
`With Oral Temsirolimus In Women With
`Metastatic Breast Cancer Ongoing Phase
`3 Studies With I.V. Temsirolimus In
`Renal Cell Carcinoma And Mantle Cell
`Lymphoma Continue,” Wyeth
`Pharmaceuticals (March 16, 2006)
`
`WHO 2000
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`WHO 2004
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`Wyeth Press
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`(streptozocin) (accessed 5/8/2017)
`
`Zanosar®
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`Approval History
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`2099
`
`2100
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`Kulke, M., et al., “Results Of A Phase II
`Study With Sunitinib Malate (SU11248)
`In Patients (pts) With Advanced
`Neuroendocrine Tumours (NETs),” Eur.
`J. Cancer 3(2): 204 (Abs. 718) (abstract
`book) (2005)
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`Srkalovic, G., et al., “Evaluation Of
`Receptors For Somatostatin In Various
`Tumors Using Different Analogs,” J.
`Clin. Endocrinology & Metabolism
`70(3): 661-669 (1990)
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`Kulke 2005
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`Srkalovic
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`xvi
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`
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`2101
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`2102
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`2103
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`2104
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`2105
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`2106
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`Eisen, T., et al., “Sorafenib In Advanced
`Melanoma: A Phase II Randomised
`Discontinuation Trial Analysis,” British
`J. Cancer 95(5): 581-586 (2006)
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`Pacey, S., et al., “Efficacy And Safety Of
`Sorafenib In A Subset Of Patients With
`Advanced Soft Tissue Sarcoma From A
`Phase II Randomized Discontinuation
`Trial,” Invest. New Drugs 29: 481-488
`(2011)
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`Ratain, M.J., et al., “Phase II Placebo-
`Controlled Randomized Discontinuation
`Trial Of Sorafenib In Patients With
`Metastatic Renal Cell Carcinoma,” J.
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`Ratain, M.J., “Phase II Studies Of
`Modern Drugs Directed Against New
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`22(22): 4442-4445 (2004)
`
`Excerpts of Transcript of Deposition of
`M. Ratain, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA)
`(D. Del. Apr. 11, 2016), Pages 1-5, 93-
`95, 198, 349-350
`
`Excerpts of Transcript of Deposition of
`M. Ratain, Novartis v. Par (Inter Partes
`Review No. 2016-00084) (Pat. Tr. App.
`Bd. December 16, 2016), Pages 1-5, 119-
`120, 141
`
`
`
`
`
`
`
`Ratain 2004
`
`Ratain Dep. Tr. I
`
`Ratain Dep. Tr. II
`
`xvii
`
`
`
`
`
`
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`As of November 2005, no mTOR inhibitor was approved to treat cancer.
`
`“There remain[ed] a number of unresolved questions regarding the function and
`
`the mechanism of action of mTOR,” and whether mTOR inhibitors would be
`
`effective to treat any cancer was uncertain. The mTOR inhibitor temsirolimus had
`
`failed to demonstrate efficacy in multiple human cancers in Phase II clinical trials
`
`and the claimed compound everolimus had only completed Phase I clinical trials
`
`not designed to test efficacy as an anticancer agent. Nonetheless, Par relies on
`
`improper hindsight to single out prior art concerning mTOR inhibitors. Par’s
`
`failure to provide credible reasons why a POSA would have been motivated to
`
`select everolimus over other compounds to treat advanced pancreatic
`
`neuroendocrine tumors (“PNETs”1) after failure of cytotoxic chemotherapy, or
`
`would have reasonably expected success with such treatment, is fatal to its
`
`obviousness case.
`
`Par’s cited prior art does not render the invention obvious.
`
`
`
` A Table of Terminology and Definitions of key terms is included in Ex. 2041,
`
` 1
`
`1
`
`Kulke pp.xxxiv-xxxvii.
`
`
`
`
`
`
`
`Öberg 2004 identified the mTOR inhibitor rapamycin as an “experimental”
`
`therapy that could be tested in neuroendocrine tumors (“NETs”), but Par’s reliance
`
`on teaching relating to unspecified NETs is misplaced because NETs were known
`
`to be an unusual “family of distinct or even individual tumors.” Moreover, a
`
`POSA would not have selected rapamycin—the least studied of all the compounds
`
`in Öberg 2004—over the more promising and more extensively studied prior art
`
`compounds, particularly when the art did not suggest that the mTOR pathway was
`
`involved in PNET oncogenesis (i.e., the transformation of normal cells to tumor
`
`cells).
`
`Boulay 2004 does not overcome these shortcomings. It tested everolimus
`
`only in vivo against the CA20948 cell line. CA20948 is not a “pancreatic NET
`
`tumor” cell line but a rat pancreatic adenocarcinoma cell line. A POSA would
`
`have known that pancreatic adenocarcinomas and PNETs are distinct tumors that
`
`differ in multiple respects, including their responses to pharmacotherapies.
`
`The results from the Phase I everolimus clinical trials in non-PNET tumors
`
`in O’Donnell and Tabernero, two non-peer-reviewed abstracts, were preliminary
`
`and inconclusive. A POSA would have known that most oncology drugs failed in
`
`Phase II clinical trials, and would not have reasonably expected everolimus to be
`
`effective to treat advanced PNETs based on isolated instances of stable disease or a
`
`single response in other distinct tumors.
`
`2
`
`
`
`
`
`
`
`Duran does not compel a different conclusion; it is a non-peer-reviewed
`
`abstract containing only interim observations from a single-arm uncontrolled
`
`Phase II clinical trial. Duran did not disclose whether any patients had advanced
`
`PNETs or advanced PNETs after failure of cytotoxic chemotherapy, and it tested
`
`only temsirolimus, a different compound from everolimus. A POSA would have
`
`known that interim observations, like those in Duran, were subject to change in the
`
`final study report. Dr. Ratain’s assertion that Duran demonstrated that
`
`temsirolimus was effective to treat advanced NETs, which include PNETs, reflects
`
`his lack of expertise with these specific tumors. By contrast, Novartis’s expert Dr.
`
`Kulke, an undisputed expert in PNETs, explained that the interim observations in
`
`Duran did not demonstrate efficacy because they were consistent with the ordinary
`
`course of the disease, even in the absence of treatment.
`
`Moreover, in November 2005, a POSA would have known that, after failure
`
`of cytotoxic chemotherapy, advanced PNET patients generally had a more resistant
`
`or aggressive disease, and were more difficult to treat than chemotherapy-naïve
`
`patients (i.e., patients who had not previously been treated with cytotoxic
`
`chemotherapy). And at that time, no pharmacotherapy had proven efficacy in
`
`these tumors. In Grounds 1 and 2, Par does not allege that a POSA would have
`
`reasonably expected everolimus to be effective in these hard-to-treat tumors. That
`
`alone should end the Board’s inquiry for these Grounds. And Par’s claim that a
`
`3
`
`
`
`
`
`
`
`POSA would have had an expectation of success in Grounds 3 and 4 is not
`
`supported by any prior art or Par’s expert.
`
`Finally, there is objective evidence of non-obviousness of the claimed
`
`methods, including an undisputed long-felt unmet need, failure of others to satisfy
`
`that need, as well as unexpected and “unprecedented” efficacy that led to the first
`
`new FDA-approved method of treating advanced PNETs after failure of cytotoxic
`
`chemotherapy in almost thirty years. In contrast to the invention, the final Duran
`
`Phase II clinical trial report concluded that “[t]emsirolimus appear[ed] to have little
`
`activity and [did] not warrant further single-agent evaluation in advanced [NETs],”
`
`including PNETs. Still today, temsirolimus is not FDA-approved to treat advanced
`
`PNETs.
`
`II. THE POSA
`
`The November 21, 2005 priority date is undisputed. Pet. 15. At that time, a
`
`POSA would have had Par’s proposed qualifications. Ex. 1003, Ratain ¶21; Ex.
`
`2041, Kulke ¶21. A POSA also would have had experience conducting preclinical,
`
`clinical, and/or laboratory research relating to NETs, including PNETs. Ex. 2041,
`
`4
`
`
`
`
`
`
`
`Kulke ¶22.2 This is because NETs were an unusual “family of distinct or even
`
`individual tumors,” and rare tumors, like PNETs, “represent[ed] a diagnostic and
`
`therapeutic challenge for non-specialized physicians….” Id. (Ex. 1052,
`
`Wiedenmann pp.94-95); Section III.A. See Costco Wholesale Corp. v. Robert
`
`Bosch LLC, IPR2016-00041, Paper 70 at 10 (P.T.A.B. April 12, 2017) (rejecting
`
`POSA definition that omitted “any actual knowledge or experience in the … field
`
`of endeavor”).
`
`Par’s expert Dr. Ratain does not “have any special expertise in PNET, nor
`
`did [he] in 2005.” Ex. 2040, Ratain Tr. 304:8-9. At deposition, Dr. Ratain could
`
`not identify any journal article he published relating to PNETs and confirmed that,
`
`prior to November 2005, he had not been a principal investigator for any clinical
`
`trial in NET patients.3 Id. 295:13-19. Not surprisingly, Dr. Ratain’s opinions fail
`
`
`
` The claims of the ’224 Patent would not have been obvious even if the Board
`
` 2
`
`finds that a POSA would not have had experience with NETs or PNETs. Ex. 2041,
`
`Kulke ¶23.
`
`3 Although Dr. Ratain claimed to have been involved in one clinical trial involving
`
`NET patients prior to November 2005 (Ex. 2040, Ratain Tr. 295:20-296:11), none
`
`of his related publications mentions NET patients. Exs. 2101-2103.
`
`5
`
`
`
`
`
`
`
`to account for the unique clinical challenges presented by advanced PNETs after
`
`failure of cytotoxic chemotherapy in November 2005. Section III.C. And he
`
`wrongly concluded that temsirolimus effectively treated advanced PNETs based on
`
`the Duran interim observations. Section VII.A.
`
`Accordingly, Dr. Ratain’s opinions should be given little weight. Costco,
`
`IPR2016-00041, Paper 70 at 10 (declining to credit expert witness testimony in
`
`part because his experience did not include the specific technology at issue and
`
`“provide[d] little insight into the knowledge of a [POSA]”); Schott Gemtron Corp.
`
`v. SSW Holding Co., IPR2013-00358, Paper 106 at 17-18 (P.T.A.B. Aug. 20, 2014)
`
`(according expert witness’s testimony less weight where the witness did not
`
`qualify as a POSA either at the time of the invention or the proceeding), aff’d per
`
`curiam 612 Fed. Appx. 614 (Fed. Cir. 2015).
`
` By contrast, it is undisputed that Dr. Kulke is an expert in PNETs. Ex.
`
`2040, Ratain Tr. 15:3-20. In November 2005, Dr. Kulke was an oncologist
`
`specializing in treating NETs, including PNETs. Ex. 2041, Kulke ¶¶2, 24. He
`
`treated 30-40 NET patients per week, about one third of whom had PNETs. Id.
`
`Dr. Kulke also played a leading role in clinical trials of new agents for treating
`
`NETs, including advanced PNETs after failure of cytotoxic chemotherapy. Id.
`
`(Ex. 2042, Kulke 2017 C.V. pp.4-10. 34). And his work was published in peer-
`
`6
`
`
`
`
`
`
`
`reviewed journals, review articles, and book chapters prior to November 2005. Id.
`
`(Ex. 2042, Kulke 2017 C.V. pp.21-32, 34).
`
`Since November 2005, Dr. Kulke has maintained his specialization. He is
`
`now a Professor of Medicine at Harvard Medical School and Director of the Dana-
`
`Farber Cancer Institute/Brigham and Women’s Program in Neuroendocrine and
`
`Carcinoid Tumors. Id. ¶¶1, 3-8. Dr. Kulke has led the clinical development of
`
`novel pharmacotherapies for treating NETs and co-authored the clinical guidelines
`
`used today for treating NETs. Id. ¶24 (Ex. 2042, Kulke 2017 C.V. pp.32-33).
`
`III. STATE OF THE ART
`
`A. NETs Were Known To Comprise
`A Heterogeneous Group Of Tumors
`
`PNETs are a type of NET arising in the pancreas. Ex. 2041, Kulke ¶34.
`
`But not all NETs are PNETs. Id. ¶35 (Ex. 1020, Kaltsas p.458; Ex. 1003, Ratain
`
`¶54). Instead, a POSA in November 2005 would have known that NETs are a
`
`broad class of tumors arising from endocrine cells, which secrete hormones into
`
`the blood, and encompass both PNETs and carcinoid tumors (i.e., tumors arising
`
`from endocrine cells outside of the pancreas). Id. (Ex. 2013, Kulke 2003a p.1133);
`
`Ex. 2040, Ratain Tr. 27:13-19, 53:12-20. NETs may be benign or malignant, i.e.,
`
`capable of spreading to other organs. Ex. 2041, Kulke ¶36. Malignant NETs may
`
`be localized or advanced, meaning they have spread to nearby areas (locally
`
`advanced) or more distant areas (metastatic) and are generally unresectable (i.e.,
`
`7
`
`
`
`
`
`
`
`cannot be cured by surgery). Id. ¶¶37-38 (Ex. 2005, Laughlin Cancer Glossary
`
`p.4; Ex. 1023, Moertel p.520; Ex. 2074, Ramanathan p.1139; Ex. 1003, Ratain
`
`¶59).
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