Filed on behalf of: Aventis Pharma S.A.
`
`By:
`
`Dominick A. Conde
`dconde@fchs.com
`(212) 218-2100
`
`Paper No. 8
`Date Filed: May 24, 2016
`
`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 IPR2016-00627
`U.S. Patent No. 5,847,170
`________________
`
`
`
`PRELIMINARY RESPONSE BY PATENT OWNER PURSUANT TO 37
`C.F.R. § 42.107
`
`
`
`
`
`
`
`

`
`
`
`
`
`I.
`
`II.
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`Case IPR2016-00627
`U.S. Patent No. 5,847,170
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`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND OF THE INVENTION ....................................................... 4
`
`A.
`
`B.
`
`The Development of the ’170 Patent .................................................... 5
`
`The ’170 Prosecution History ............................................................... 6
`
`III. PERSON OF ORDINARY SKILL ............................................................... 12
`
`IV. CLAIM CONSTRUCTION .......................................................................... 13
`
`V.
`
`LEGAL STANDARD ................................................................................... 14
`
`VI. MYLAN’S ARGUMENTS ARE BASED ON IMPROPER
`HINDSIGHT .................................................................................................. 16
`
`VII. MYLAN FAILS TO PROPERLY APPLY LEAD
`COMPOUND ANALYSIS ............................................................................ 18
`
`A. Mylan fails to establish that a POSA would have selected
`taxanes as a reasonable starting point for further
`modification ......................................................................................... 19
`
`B. Mylan fails to establish motivation to modify Kant
`Compound 20 or docetaxel to obtain the specific claimed
`compound ............................................................................................ 20
`
`1. Mylan fails to establish that a POSA would have
`sought to increase lipophilicity of taxanes ................................ 20
`
`2. Mylan fails to establish that a POSA would have
`had a reasonable expectation that cabazitaxel
`would successfully increase cytotoxicity and
`activity against drug resistant cell lines .................................... 26
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`U.S. Patent No. 5,847,170
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`3. Mylan improperly suggests a POSA would make
`changes to substitutions of the Klein compounds
`that were key to those disclosures ............................................. 27
`
`VIII. MYLAN’S ALLEGED INVALIDITY GROUNDS ..................................... 30
`
`A. Ground 1: The Board should not institute review based
`on the alleged obviousness over Kant in view of Klein ...................... 30
`
`1. Mylan fails to show a POSA would have selected
`Kant Compound 20 as a lead compound .................................. 31
`
`2.
`
`There is no basis for Mylan to focus on activity of
`compounds with C-7/C-9 modifications in Klein
`and even if a POSA did, Mylan fails to show why
`one would have used only Klein’s C-7
`modification without also making the C-9
`modification .............................................................................. 34
`
`3. Mylan provides no reason why a POSA would
`eliminate the C-9 hydroxyl of Klein where that
`modification improves solubility .............................................. 36
`
`B. Ground 2: The Board should not institute review based
`on the alleged obviousness over Colin in view of Kant
`and Klein ............................................................................................. 38
`
`1.
`
`2.
`
`Colin does not establish docetaxel as a lead
`compound .................................................................................. 38
`
`Kant and Klein do not motivate C-7 or C-10
`methylation ................................................................................ 40
`
`IX. MYLAN FAILS TO REBUT OBJECTIVE EVIDENCE OF
`NON-OBVOUSNESS ................................................................................... 44
`
`A.
`
`B.
`
`It was unexpected that cabazitaxel would show anti-
`tumor efficacy in cancer resistant cell lines in spite of
`being a P-gp substrate ......................................................................... 44
`
`Cabazitaxel met a long-felt need for anti-cancer agent
`capable of overcoming multidrug resistance....................................... 47
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`Case IPR2016-00627
`U.S. Patent No. 5,847,170
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`
`
`C.
`
`D.
`
`E.
`
`Failure of others ................................................................................... 48
`
`The pharmaceutical industry has praised Jevtana® ............................. 49
`
`At least nine companies have copied Jevtana®, which is
`covered by the ’170 patent .................................................................. 51
`
`F.
`
`Jevtana® is a commercial success ........................................................ 51
`
`X.
`
`TRIAL SHOULD NOT BE INSTITUTED ON REDUNDANT
`GROUNDS .................................................................................................... 53
`
`XI. CONCLUSION .............................................................................................. 54
`
`
`
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`U.S. Patent No. 5,847,170
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`TABLE OF AUTHORITIES
`
`
`
`Cases
`
`Abbott Labs v. Syntron Bioresearch Inc., 334 F.3d 1343 (Fed.
`Cir. 2003) .......................................................................................................30
`
`Apple, Inc. v. ITC, 725 F.3d 1356 (Fed. Cir. 2013) .................................................44
`
`ATD Corp. v. Lydall Inc., 159 F.3d 534 (Fed. Cir. 1998) .......................................36
`
`Cheese Sys., Inc. v. Tetra Park Cheese & Powder Sys., Inc., 725
`F.3d 1341 (Fed. Cir. 2013) ............................................................................36
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346 (Fed.
`Cir. 2010) .................................................................................... 17, 19, 27, 28
`
`In re Cuozzo Speed Tech. LLC, 793 F.3d 1268 (Fed. Cir. 2015) ............................14
`
`In re Cyclobenzaprine Hydrocholoride Extended-Release
`Capsule Patent Litig., 676 F.3d 1063 (Fed. Cir. 2012) .................................44
`
`In re Fine, 837 F.2d 1071 (Fed. Cir. 1988) .............................................................36
`
`In re Soni, 54 F.3d 746 (Fed. Cir. 1996) ..................................................................46
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ......................................... 15, 17
`
`Ortho-McNeil Pharms., Inc. v. Mylan Labs., Inc., 348
`F.Supp.2d 713 (N.D. W. Va. 2004) ...............................................................51
`
`Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280 (Fed.
`Cir. 2012) .......................................................................................... 15, 16, 20
`
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) .........................................14
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d
`989 (Fed. Cir. 2009).......................................................................... 20, 24, 25
`
`Sanofi-Synthelabo v. Apotex, Inc., 550 F.3d 1075(Fed. Cir.
`2008) ..............................................................................................................18
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`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d
`1350 (Fed. Cir. 2007).................................................................. 15, 16, 20, 24
`
`Transocean Offshore Deepwater Drilling Inc. v. Maersk
`Drilling USA, Inc., 699 F.3d 1340 (Fed. Cir. 2012) ......................................44
`
`Yamanouchi Pharma. Co., Ltd. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .....................................................................32
`
`Statutes
`
`35 U.S.C. § 103 ................................................................................................. 30, 38
`
`35 U.S.C. § 103(a) ...................................................................................................14
`
`35 U.S.C. § 312(a)(3) ...............................................................................................53
`
`35 U.S.C. § 314(a) ...............................................................................................2, 14
`
`37 C.F.R. § 42.100(b) ..............................................................................................14
`
`37 C.F.R. § 42.108(c) ...........................................................................................2, 14
`
`P.T.A.B.
`
`Ex Parte Yann Foricher, Appeal No. 2012-004073, 2014 WL
`3421407 (P.T.A.B. July 8, 2014) ...................................................................15
`
`Integrated Global Concepts, Inc. v. Advanced Messaging
`Techs., Inc., IPR No. 2014-01027, Paper 16 (P.T.A.B.
`Dec. 22 2014) .......................................................................................... 12, 47
`
`Liberty Mut. Ins. Co. v. Progressive Cas. Ins. Co., CBM2010-
`00003, Papers 7, 8 at 3 (October 25, 2012) ...................................................53
`
`Merial Ltd. v. Virbac, IPR No. 2014-01279, Paper 13 (P.T.A.B.
`Jan. 25, 2015) .......................................................................................... 12, 46
`
`Neil Ziegman, N.P.Z., Inc. v. Stephens, IPR No. 2015-01860,
`2016 WL 1084154 (P.T.A.B. 2016) ..............................................................30
`
`Oracle Corp. v. Clouding IP, LLC, IPR No. 2013-00088, Paper
`13 (P.T.A.B. June 13, 2013) ................................................................... 12, 53
`
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`U.S. Patent No. 5,847,170
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`Praxair Distr. Inc. v. INO Therapeutics, Inc., IPR Nos. 2015-
`00522, 2015-00524, 2015-00525, 2015-00526, Paper 12
`(P.T.A.B. July 29, 2015) ......................................................................... 11, 46
`
`Torrent Pharms. Ltd. v. Merck Frosst Canada & Co., IPR No.
`2014-00559, Paper 8 (P.T.A.B. Oct. 1, 2014) ...............................................16
`
`
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`U.S. Patent No. 5,847,170
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`
`
`Abbreviation
`
`TABLE OF ABBREVIATIONS
`
`
`Description
`
`’170 patent
`
`U.S. Patent No. 5,847,170 [Exh. 1001]
`
`’526 patent
`
`United States Patent No. 5,229,526 [Exh. 2007]
`
`’112 patent
`
`United States Patent No. 5,319,112 [Exh. 2009]
`
`’588 patent
`
`United States Patent No. 5,005,588 [Exh. 2035]
`
`’806 patent
`
`United States Patent No. 5,352,806 [Exh. 1019]
`
`’011
`
`United States Patent Application No. 08/622,011
`
`application
`
`EP’910
`
`European Patent Application Publication No. 0604910 [Exh.
`
`2003]
`
`EP’577
`
`European Patent Application Publication No. 0639577 [Exh.
`
`2004]
`
`EP’841
`
`European Patent Application Publication No. 0336841 [Exh.
`
`2013]
`
`WO’164
`
`PCT Patent Application Publication No. WO94/18164 [Exh.
`
`1018]
`
`WO’878
`
`PCT Patent Application Publication No. WO94/07878 [Exh.
`
`2012]
`
`- vii -
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`Case IPR2016-00627
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`
`
`Abbreviation
`
`Description
`
`Abrams
`
`Abrams et al., “New chemotherapeutic agents for breast cancer,”
`
`74(3 Suppl):1164-76, Cancer, 1994 [Exh. 1009]
`
`Bissery
`
`Bissery et al., “Experimental Antitumor Activity of Taxotere (RP
`
`56976, NSC 628503), a Taxol Analogue,” 51(18): 4845-52,
`
`Cancer Res., 1991 [Exh. 2031]
`
`Bouchard Tr.
`
`Excerpted transcript of the May 12, 2016 videotaped deposition
`
`of Dr. Hervé Bouchard, at 174:1–181:25 [Exh. 2029]
`
`Burger
`
`Burger, A Guide to the Chemical Basis of Drug Design, John
`
`Wiley & Sons, Inc., pp. 69-87 (1983) [Exh. 1013]
`
`Colin
`
`United States Patent No. 4,814,470 [Exh. 1007]
`
`de Bono
`
`de Bono et al., “Prednisone plus cabazitaxel or mitoxantrone for
`
`metastatic castration-resistant prostate cancer progressing after
`
`docetaxel treatment: a randomised open-label trial,”
`
`376(9747):1147-54, Lancet, 2010 [Exh. 2001]
`
`Commerçon
`
`Commerçon et al., Ch. 17 Practical Semisynthesis and
`
`Antimitotic Activity of Docetaxel and Side-Chain Analogues, in
`
`Taxane Anticancer Agents, ACS Symposium Series Vol. 583,
`
`233-46 (Georg et al., eds., 1994) [Exh. 2019]
`
`- viii -
`
`

`
`
`
`Abbreviation
`
`Description
`
`Gallagher
`
`Gallagher et al., “Phase I Clinical & Pharmacokinetic (PK) Trial
`
`Case IPR2016-00627
`U.S. Patent No. 5,847,170
`
`of the Novel Taxane BMS-184476 Administered as a 1-Hour IV
`
`Infusion in Combination with Cisplatin Every 21 Days,” Proc. of
`
`ASCO, Vol. 20, Abstract 420, 2001 [Exh. 2040]
`
`Guéritte-
`
`Guéritte-Voegelein et al., “Relationships between the Structure
`
`Voegelein
`
`of Taxol Analogues and Their Antimitotic Activity,” 34:992-8, J.
`
`Med. Chem., 1991 [Exh. 2026]
`
`Holmes
`
`Holmes et al., Ch. 3 Current Status of Clinical Trials with
`
`Paclitaxel and Docetaxel,” in Taxane Anticancer Agents, ACS
`
`Symposium Series Vol. 583, 31-57 (Georg et al., eds., 1994)
`
`[Exh. 2024]
`
`Hope
`
`Hope, “Last hope’ drug for prostate cancer patients is axed from
`
`the NHS, in a move doctors call a ‘travesty,’” Daily Mail (Jan. 9,
`
`2015) [Exh. 2043]
`
`Kant
`
`Kant et al., “A Chemoselective Approach to Functionalize the C-
`
`10 Position of 10-Deacetylbaccatin III. Synthesis and Biological
`
`Properties of Novel C-10 Taxol® Analogs,” Tetrahedron Letters,
`
`35(31): 5543-5546 (1994) [Exh. 1005]
`
`- ix -
`
`

`
`
`
`Abbreviation
`
`Description
`
`Kingston 1994 Kingston, Ch. 15 Recent Advances in the Chemistry and
`
`Case IPR2016-00627
`U.S. Patent No. 5,847,170
`
`Structure—Activity Relationships of Paclitaxel, in Taxane
`
`Anticancer Agents, ACS Symposium Series Vol. 583, 203-16
`
`(Georg et al., eds., 1994) [Exh. 2017]
`
`Kingston 2009 Kingston, “Tubulin-Interactive Natural Products as Anticancer
`
`Agents,” 72: 507-15, J. Nat. Prod., 2009 [Exh. 2039]
`
`Klein
`
`Klein et al., Ch. 20 Chemistry and Antitumor Activity of 9(R)-
`
`Dihydrotaxanes in Taxane Cancer Agents, ACS Symposium
`
`Series Vol. 58, 276-87 (Georg et al., eds., 1994) [Exh. 1006]
`
`Malhotra
`
`Malhotra et al., “Cabazitaxel: A Novel Drug for Hormone-
`
`Refractory Prostate Cancer,” 13:1-6, Mini Rev. Med. Chem.,
`
`2013 [Exh. 2042]
`
`Mellado
`
`Mellado et al., “Preparation and biological activity of taxol
`
`acetates,” 124(2):329-36, Biochem. Biophys. Res. Commun.,
`
`1984 [Exh. 1015]
`
`Morrow
`
`Morrow & Cowan, “Antineoplastic Drug Resistance and Breast
`
`Cancer,” 698:289-312, Ann. N.Y. Acad. Sci., 1993 [Exh. 2014]
`
`Ojima I
`
`Ojima et al., “Synthesis and biological activity of 3’-alkyl- and
`
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`
`
`
`Abbreviation
`
`Description
`
`3’-alkenyl-3’-dephenyldocetaxels,” 4(21): 2631-34, Bioorg. &
`
`Medicinal Chem. Lett., 1994 [Exh. 2016]
`
`Ojima II
`
`Ojima et al., Ch. 19 Syntheses and Structure—Activity
`
`Relationships of New Taxoids, in Taxane Anticancer Agents
`
`ACS Symposium Series Vol. 583, 262-75 (Georg et al., eds.,
`
`1994) [Exh. 2018]
`
`Petrylak
`
`Crawford et al., “Treating Patients with Metastatic Castration
`
`Resistant Prostate Cancer: A Comprehensive Review of
`
`Available Therapies,” 194(6):1537-47, J. Urol., 2015 [Exh.
`
`2054]
`
`Pezzuto
`
`Alkan-Onyuksel et al., “A mixed micellar formulation suitable
`
`for the parenteral administration of taxol,” 11(2): 206-12, Phar.
`
`Res., 1994 [Exh. 1020]
`
`Rahman
`
`Rahman et al., “Comparative Pharmacokinetics of Free
`
`Doxorubicin & Doxorubicin Entrapped in Cardiolipin
`
`Liposomes,” 46(5): 2295-9, Cancer Res., 1986 [Exh. 2022]
`
`Ramanathan
`
`Ramanathan et al., “A phase II study of milataxel: a novel taxane
`
`analogue in previously treated patients with advanced colorectal
`
`- xi -
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`U.S. Patent No. 5,847,170
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`
`
`Abbreviation
`
`Description
`
`cancer,” 61: 453-58, Cancer Chemother. Pharmacol., 2008 [Exh.
`
`2038]
`
`Remington’s
`
`Harvy, Ch. 35 Drug Absorption, Action and Disposition in
`
`Remington’s Physical Sciences 697-724 (A. Gennaro et al., eds.,
`
`1990) [Exh. 1012]
`
`Robert
`
`Robert, “Epirubicin: Clinical Pharmacology & Dose-Effect
`
`Relationship,” 45 (Suppl. 2):20-30, Drugs, 1993 [Exh. 2021]
`
`Rowinsky
`
`Rowinsky et al., “Taxol: the First of the Taxanes, an Important
`
`New Class of Antitumor Agents,” 19(6): 646-62, Semin. Oncol.,
`
`1992 [Exh. 2015]
`
`Sanofi Press
`
`Sanofi Press Release, “Jevtana® (cabazitaxel) injection now
`
`Release (7-19-
`
`available in the U.S.,” July 19, 2010 [Exh. 2041]
`
`2010)
`
`Sanofi Press
`
`Sanofi-Aventis Press Release, “Resilient Sales & Business EPS
`
`Release (10-28-
`
`in Q3 2010,” (Oct. 28, 2010) [Exh. 2056]
`
`2010)
`
`Sanofi Press
`
`Sanofi-Aventis Press Release, “JEVTANA® (cabazitaxel) for
`
`Release (1-21-
`
`Prostate Cancer Recommended for Approval in the European
`
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`
`Abbreviation
`
`Description
`
`2011)
`
`Union,” (Jan. 21, 2011) [Exh. 2055]
`
`Sanofi Press
`
`Sanofi Press Release, “New hope in advanced prostate cancer:
`
`Release (10-4-
`
`Alberta, Saskatchewan and Ontario fund coverage for Jevtana
`
`2012)
`
`[Cabazitaxel], Press Release CNW (Oct. 4, 2012) (quoting Bob
`
`Shiell, Executive Director, Prostate Cancer Canada Network
`
`(PCCN) Calgary [Exh. 2044]
`
`Stewart
`
`Stewart, Lung cancer resistance to chemotherapy in Lung
`
`Cancer: Prevention, Management, and Emerging Therapies,
`
`Current Clinical Oncology 331-93(Humana Press, 2010) [Exh.
`
`2027]
`
`Stierle
`
`Stierle et al., Ch. 6 Bioactive Metabolites of the Endophytic
`
`Fungi of Pacific Yew, Taxus brevifolia in Taxane Anticancer
`
`Agents, ACS Symposium Series, Vol. 583, 81-97 (Georg et al.,
`
`eds., 1994) [Exh. 2025]
`
`Thürlimann
`
`Thürlimann et al., “Dexverapamil to overcome epirubicin
`
`resistance in advanced breast cancer,” 121 (Suppl. 3):R3-R6, J.
`
`Cancer Res. Clin. Oncol., 1995 [Exh. 2023]
`
`Verweij
`
`Verweij et al., “Paclitaxel (Taxol) and docetaxel (Taxotere): not
`
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`
`
`Abbreviation
`
`Description
`
`simply two of a kind,” 5(6):495-505, Ann. Oncol., 1994 [Exh.
`
`1011]
`
`Vrignaud 2013 Vrignaud et al., “Preclinical Antitumor Activity of Cabazitaxel, a
`
`Semisynthetic Taxane Active in Taxane-Resistant Tumors,”
`
`19(11):2973-83, Clin. Cancer Res., 2013 [Exh. 2033]
`
`Vrignaud 2014 Vrignaud et al., “Preclinical profile of cabazitaxel,” 8:1851-67,
`
`Drug Des. Devel. Ther., 20144 [Exh. 2010]
`
`Wargin
`
`Wargin & Lucas, “The clinical pharmacokinetics of vinorelbine
`
`(Navelbine),” 21(5 Suppl. 10):21-27, Semin. Oncol., 1994
`
`(“Wargin”) [Exh. 2020]
`
`Wils
`
`Wils et al., “Polarized transport of docetaxel and vinblastine
`
`mediated by P-glycoprotein in human intestinal epithelial cell
`
`monolayers,” 48(7): 1528-30, Biochem. Pharmacol., 1994 [Exh.
`
`2032]
`
`FDA
`
`U.S. Food & Drug Administration
`
`Jevtana®
`
`Cabazitaxel brand name
`
`Kingston
`
`Compound 28 described in the ’112 patent to Kingston (Exh.
`
`Compound 28
`
`2009 at 18:30-62.)
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`
`
`Abbreviation
`
`Label
`
`POSA
`
`RPR
`
`Description
`
`Jevtana® Prescribing Information [Exh. 2058]
`
`Person of ordinary skill in the art
`
`Rhône-Poulenc Rorer
`
`Second
`
`Second Declaration Under 37 C.F.R. § 1.132 of Dr. Alain
`
`Commerçon
`
`Commerçon dated April 23, 1998, submitted during prosecution
`
`Declaration
`
`of the ’170 patent (Exh. 1004 at 553-560.)
`
`Taxol®
`
`Paclitaxel brand name
`
`Taxotere®
`
`Docetaxel brand name
`
`TROC
`
`2,2,2-trichloroethoxycarbonyl group (OCOCH2CCl3)
`
`Aventis
`
`Aventis Pharma S.A., Patent Owner
`
`Mylan
`
`Mylan Laboratories Ltd., Petitioner
`
`Exh. ___
`
`This refers to the indicated exhibit
`
`___:___
`
`This refers to the indicated column or page and lines of the patent
`
`or patent publication
`
`
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`
`
`Aventis Pharma S.A. (“Aventis”) respectfully submits this Preliminary
`
`Response to the Petition of Mylan Laboratories Limited (“Mylan”) seeking inter
`
`partes review (“IPR”) of U.S. Patent No. 5,847,170 (“the ’170 patent”).
`
`I.
`
`INTRODUCTION
`
`The groundbreaking anti-cancer drug cabazitaxel (marketed under the brand
`
`name Jevtana®) is the first chemotherapy agent shown to prolong the lives of
`
`patients with castration resistant metastatic prostate cancer, which has progressed
`
`after treatment with docetaxel. A phase III clinical trial revealed that, compared to
`
`a known commercial chemotherapy agent (mitoxantrone), the treatment with
`
`cabazitaxel provided both a statistically significant increase in overall survival and
`
`better disease response rates in these very sick patients. Exh. 2001 (de Bono) at
`
`1154. This led to the fast-track FDA approval of Jevtana® in 2010 after only
`
`eleven weeks of FDA review. Exh. 2002 (FDA Press Release 6-17-10) at 1.
`
`The ’170 patent discloses and claims the cabazitaxel molecule,
`
`pharmaceutical compositions containing cabazitaxel, and processes to prepare
`
`cabazitaxel. Aventis has asserted the ’170 patent in a pending Hatch-Waxman
`
`action against Mylan. (C.A. No. 15-0290 (MAS)(LHG) (D.N.J.).) On the one-
`
`year statutory deadline and advancing grounds largely duplicative of those already
`
`before the district court and considered during prosecution of the ’170 patent,
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`Mylan filed its petition for IPR against the ’170 patent.
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`Case IPR2016-00627
`U.S. Patent No. 5,847,170
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`Mylan seeks to institute an IPR on the basis of obviousness of Claims 1 and
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`2 of the ’170 patent. Claim 1 covers one taxoid compound, cabazitaxel; Claim 2
`
`covers pharmaceutical compositions of cabazitaxel. To institute an IPR, Mylan
`
`must show a reasonable likelihood of prevailing on invalidity. 35 U.S.C. § 314(a)
`
`(IPR may not be instituted absent “a reasonable likelihood that the petitioner would
`
`prevail”); see also 37 C.F.R. § 42.108(c). Mylan’s petition does not establish even
`
`prima facie obviousness, much less a likelihood of success. For at least the
`
`following reasons, the Board should reject Mylan’s petition.
`
`First, Mylan’s petition is entirely the product of impermissible hindsight.
`
`The taxane prior art contains hundreds of patents and articles disclosing thousands
`
`of taxane compounds, all of which were made with the goal of developing a more
`
`effective anti-cancer agent than what was in the art. Mylan plainly took
`
`cabazitaxel, one of only three commercially marketed taxanes, and found
`
`compounds in that sea of prior art that were chemically similar to it, and then
`
`developed a rationale that would allegedly compel a medicinal chemist to make the
`
`necessary changes to arrive at cabazitaxel. Such hindsight reasoning is
`
`impermissible under well-settled case law, and Mylan’s petition should be rejected
`
`for that reason alone.
`
`Second, Mylan fails to properly apply the lead compound analysis as set
`
`forth by the Federal Circuit. Mylan fails to explain why a person of ordinary skill
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`U.S. Patent No. 5,847,170
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`in the art (“POSA”) would select its two particular “lead” compounds, (1) Kant
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`Compound 20 or (2) docetaxel, both of which were before the Examiner prior to
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`allowance of the ’170 patent. Mylan also fails to explain why a POSA would
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`make the “specific molecular modifications” to its lead compounds to obtain
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`cabazitaxel, even though such changes would lead to a compound that is more
`
`insoluble in water (antithetical to a drug that needs to be given intravenously, like
`
`cabazitaxel). And, Mylan fails to show that a POSA would have had a reasonable
`
`expectation that the claimed compound would have the properties that it does, in
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`particular, activity against docetaxel resistant tumors. Nothing in the prior art
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`relied on by Mylan suggested any compound that could overcome docetaxel
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`resistance.
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`Third, Mylan fails to address the inventor’s declarations submitted during
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`prosecution except with a single sentence in its entire petition. In those
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`declarations, Applicants, at the Examiner’s insistence, tested cabazitaxel against
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`(1) docetaxel (one of Mylan’s lead compounds), and (2) compounds that were
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`synthesized based upon the art cited by the Examiner, compounds which were
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`closer to cabazitaxel than any compound actually disclosed in the art, including
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`both lead compounds cited by Mylan. Exh. 1004 (File History) at 554-560, ¶¶ 3-4.
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`Those test results showed that: (1) cabazitaxel is unexpectedly superior to
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`docetaxel and, in fact, is active in cancer cell lines where docetaxel is not, and (2)
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`simultaneously modifying the C-7 and C-10 positions, which is what Mylan says
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`would have been obvious, led to compounds with worse cytotoxicity than
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`docetaxel. Mylan’s failure to address that evidence is fatal to its petition.
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`Fourth, Mylan fails to cite any prior art, or combinations thereof, suggesting
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`that a methyl substitution at the C-7 and/or C-10 positions leads to improved
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`cytotoxicity, or any other desirable property such as overcoming docetaxel drug
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`resistance.
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`Fifth, contrary to Mylan’s assertions, objective indicia support non-
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`obviousness of the invention as claimed in Claims 1 and 2 of the ’170 patent.
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`For at least these reasons, Mylan’s petition should be denied. Even if the
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`Board institutes trial, however, Mylan has not shown why the Board should
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`proceed on both vertically redundant grounds recited in its petition.
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`II. BACKGROUND OF THE INVENTION
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`U.S. Patent No. 5,847,170, entitled “Taxoids, Their Preparation And
`
`Pharmaceutical Compositions Containing Them” claims the cabazitaxel molecule,
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`pharmaceutical compositions containing cabazitaxel, and processes to prepare
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`cabazitaxel. Cabazitaxel also has “activity against tumours which are resistant to
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`Taxol® or to Taxotere®.”1 Exh. 1001 (’170 patent) at 11:59-61. During
`
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`1 Taxol’s® generic name is paclitaxel. Taxotere’s® generic name is docetaxel.
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`prosecution, Applicants demonstrated that cabazitaxel shows improved
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`cytotoxicity in drug resistant cell lines when both compared to docetaxel (one of
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`Mylan’s two lead compounds) and compounds synthesized based on the prior art
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`relied upon by the Examiner, which were closer to cabazitaxel than any compound
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`actually disclosed in the art, including Kant Compound 20 (Mylan’s other
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`proposed lead compound), which was also before the Examiner.
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`Taxol®, Taxotere®, and cabazitaxel are today the only three FDA-approved
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`taxane molecules. At the time of the invention, there were numerous publications
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`disclosing thousands of compounds that had been investigated by research groups
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`at Rhône-Poulenc Rorer (a predecessor company to Aventis, “RPR”) (as explained
`
`in Section II.A), Bristol-Myers Squibb (see, e.g., Exh. 1005 (Kant); Exh. 2003 (EP
`
`’910); Exh. 2004 (EP ’577)); Florida State University (see, e.g., Exh. 2007 (’526
`
`patent); Virginia Tech University (see, e.g., Exh. 2009 (’112 patent)) and SUNY
`
`Stony Brook (see, e.g., Exh. 1018 (WO ’164 application); Exh. 2016 (Ojima I);
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`Exh. 2018 (Ojima II)). None of those researchers came up with cabazitaxel before
`
`the inventors of the ’170 patent, belying Mylan’s hindsight-inspired assertions of
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`obviousness in its petition.
`
`A. The Development of the ’170 Patent
`
`Beginning in 1987 and following the discovery of docetaxel, RPR began a
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`medicinal chemistry program to search for additional taxane analogs to treat
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`cancers. Cabazitaxel was synthesized in November 1994 as part of a ten-year
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`program where 450 taxane analogs were synthesized and tested. See, e.g., Exh.
`
`2010 (Vrignaud 2014). After discovering cabazitaxel, RPR’s scientists continued
`
`to make and test other taxane analogs, but were not able to find a single compound
`
`as promising as cabazitaxel.
`
`B.
`
`The ’170 Prosecution History
`
`The ’170 patent issued on December 8, 1998 from U.S. Pat. Appl. No.
`
`08/622,011 (“the ’011 application”) filed on March 26, 1996. The ’011 application
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`claims priority to U.S. Provisional Appl. No. 60/010,144 filed on January 17, 1996,
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`which in turn claims priority to French Pat. Appl. Nos.: 95-03545 filed March 27,
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`1995 and 95-015381 filed December 22, 1995. Exh. 1001; see also Petition at 2.
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`The claims of the ’170 patent were extensively reviewed. The Examiner
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`considered multiple pieces of prior art including the Kant reference relied upon by
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`Mylan. See Exh. 1004 at 271-76, 702; Exh. 2011. The Examiner also considered
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`multiple references describing docetaxel. See, e.g., Exh. 1001 (References Cited
`
`Section listing Exh. 2007, Exh. 2009, Exh. 2013 (EP ’841), Exh. 2003, Exh. 2012
`
`(WO’878) and, Exh. 1018 all describing docetaxel and docetaxel synthesis).
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`During prosecution, the Examiner made the unusual request that Applicants
`
`provide comparative data of the claimed compound with compounds that were not
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`in the prior art, but were closer to cabazitaxel than what was known in the art.2 In
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`particular, RPR provided in vitro data comparing the antitumor activity of
`
`cabazitaxel, with docetaxel and two compounds that did not exist in the prior art:
`
`(1) docetaxel protected with 2,2,2-trichloroethoxycarbonyl (“TROC”) at the C-7
`
`and C-10 positions (“Comparative A”) and (2) docetaxel acetylated at the C-7 and
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`C-10 positions (“Comparative B”) in resistant and non-resistant carcinoma cell
`
`lines. Exh. 1004 at 553-58, ¶¶ 3-4.
`
`O
`
`O
`
`NH
`
`O
`
`O
`
`OH
`
`H3CO
`
`O
`
`OCH3
`
`7
`H
`
`O
`OCOCH3
`
`O
`
`10
`
`OH
`
`O
`
`O
`
`O
`
`NH
`
`O
`
`HO
`
`O
`
`OH
`
`10
`
`7
`H
`
`O
`
`OH
`
`O
`OCOCH3
`
`OH
`
`O
`
`O
`
`Cabazitaxel
`
`
`
`Docetaxel
`
`
`
`
`2 Notably, at this time, the Examiner had had Kant before him for over two years
`
`but still focused on other compounds as closer prior art. See Exh. 1001, Exh. 1004
`
`at 271-6, 702; Exh. 2011.
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`Cl3CH2COCO
`
`O
`
`OCOCH2CCl3
`
`H3COCO
`
`O
`
`OCOCH3
`
`
`
`O
`
`O
`
`NH
`
`O
`
`O
`
`OH
`
`7
`H
`
`O
`OCOCH3
`
`O
`
`10
`
`OH
`
`O
`
`O
`
`O
`
`NH
`
`O
`
`O
`
`OH
`
`7
`H
`
`O
`OCOCH3
`
`O
`
`10
`
`OH
`
`O
`
`Comparative A
`
`
`
`Comparative B
`
`
`
`
`As replicated in Table 1 below, this testing demonstrated that cabazitaxel
`
`“possesses superior in vitro and in vivo anti-tumor activity compared to the
`
`comparative compounds A and B.” Exh. 1004 at 555.
`
`Table 1: In Vivo and In Vitro Anti-Tumor Activity of Cabazitaxel and
`Comparatives A and B Presented to the Examiner During Prosecution
`
`In vivo
`In vitro
`Cellular
`10-position T/C% Cell
`IC50
`Line
`µg/ml
`
`
`
`7-position
`
`Cell
`Line
`
`-OCH3
`-
`OCOCH2CCl3
`-OCOCH3
`
`-OCH3
`-
`OCOCH2CCl3
`-OCOCH3
`
`Claimed
`Compound
`Comparative
`A
`Comparative
`B
`
`As also seen in Table 1, cabazitaxel was “very active in vivo against B16
`
`0
`
`B16
`
`0.029
`
`KB
`
`54 B16
`
`≥10
`
`P388
`
`177 B16
`
`4.5
`
`KB
`
`melanoma giving a full inhibition of tumor growth (T/C% = 0) and [was] cytotoxic
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`in vitro against KB cells at a concentration of 0.029 µg/ml.”3 Id. As explained in
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`Case IPR2016-00627
`U.S. Patent No. 5,847,170
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`the declaration submitted during prosecution:
`
`[t]he T/C value in percent is an indication of antitumor effectiveness:
`
`T/C (%) = 100 x median tumor weight of the treated groups
`
`
`
`median tumor weight of the control groups.
`
`According to NCI (National Cancer Institute) standards, a T/C < 42%
`is the minimal level to declare activity. A T/C < 10% is considered to
`indicate high anti-tumor activity and is the level used by NCI to
`justify further development. Id.
`
`Likewise, the IC50 value reflects the drug concentration required to inhibit
`
`cell proliferation to 50% versus untreated cells. Exh. 1005 at 5545.
`
`Applicants also tested in vitro activity in resistant cell lines. Exh. 1004 at
`
`556-58. This testing demonstrated that cabazitaxel was 12-fold more active than
`
`docetaxel, and that Comparatives A and B showed no activity against the resistant
`
`cell line. Id. (replicated in Table 2 below). Thus, those results show that the
`
`simultaneous modification at C-7 and C-10 positions with lipophilic groups such as
`
`TROC and acetyl significantly decreased, if not eliminated, activity as compared to
`
`docetaxel.
`
`
`3 In this test, Applicants did not compare the anti-tumor activity of docetaxel.
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`Table 2: In Vitro Anti-Tumor Activit