` Paper No. 1
`Filed: October 31, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`NEPTUNE GENERICS, LLC
`
`PETITIONER
`
`V.
`
`AVENTIS PHARMA S.A.
`
`PATENT OWNER
`
`___________________
`
`CASE NO.: IPR2019-00136
`PATENT NO. 5,847,170
`FILED: MARCH 26, 1996
`ISSUED: DECEMBER 8, 1998
`INVENTORS: HERVÉ BOUCHARD,
`JEAN-DOMINIQUE BOURZAT, ALAIN COMMERÇON
`
`
`TITLE: TAXOIDS, THEIR PREPARATION, AND PHARMACEUTICAL
`COMPOSITIONS CONTAINING THEM
`___________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 5,847,170
`
`
`
`
`
`
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`
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`

`

`TABLE OF CONTENTS
`
`
`I.
`Introduction ........................................................................................................ 1
`II. Grounds for Standing (37 C.F.R. § 42.104(a)) .................................................. 7
`III. Mandatory Notices (37 C.F.R. § 42.8) .......................................................... 7
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) ........................................... 7
`B. Related Judicial and Administrative Matters (37 C.F.R. § 42.8(b)(2)) ......... 8
`C. Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4)) ..................................................................... 9
`IV.
`Payment of Fees (37 C.F.R. § 42.15(a) and 37 C.F.R. § 42.103)................ 10
`V.
`Identification of Challenge .............................................................................. 10
`A. Overview of U.S. Patent No. 5,847,170 ...................................................... 10
`1. The Challenged Claims ............................................................................ 11
`2. The Prosecution History .......................................................................... 12
`B. Claim Construction ...................................................................................... 15
`C. Statement of Relief ...................................................................................... 15
`1. Claims for Which Review is Requested .................................................. 15
`2. Statutory Grounds of Challenge .............................................................. 16
`Overview of the State of the Art as of March 27, 1995 ............................... 16
`VI.
`A. Paclitaxel Was An Approved Cancer Therapeutic and 10-DAB-III Was A
`Well-Accepted Starting Material Used to Synthesize Paclitaxel and its
`Analogs. ............................................................................................................... 17
`B. Worldwide Paclitaxel Analog Research Was Well Underway, Utilizing
`Best Laboratory Practices .................................................................................... 20
`C. A POSA Would Have Known that a BOC Group at C-3’ on Paclitaxel’s
`Side-chain Enhanced Therapeutic Activity, and C-7 and C-10 Were Receptive to
`Modification ......................................................................................................... 24
`D. Summary of Prior Art References ............................................................... 26
`
`
`
`i
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`

`1. Commerçon (Ex.1009) ............................................................................. 26
`2. Kant (Ex.1010) ......................................................................................... 29
`3. Wong (Ex.1011) ....................................................................................... 31
`4. Bouchard (Ex.1014) ................................................................................. 32
`E. Ordinary Skill in the Art .............................................................................. 33
`VII. The District Court’s Validity Findings are not Pertinent to the Grounds
`Herein ............................................................................................................. 34
`VIII. Detailed Explanation of the Challenge ........................................................ 36
`A. Ground 1: Claim 1 is obvious in view of Commerçon, Kant, Wong, and a
`POSA’s knowledge. ............................................................................................. 36
`1. A POSA Would Have Chosen Paclitaxel as a Lead Compound. ............ 37
`2. Commerçon, Kant, Wong and a POSA’s Knowledge Motivated
`Modifying Paclitaxel to Obtain Cabazitaxel. ................................................... 38
`3. A POSA Would Have Reasonably Expected to Successfully Synthesize
`Cabazitaxel in view of Commerçon, Kant, and Wong. .................................... 51
`B. Claim 2 is Obvious In View of the Above Prior Art and a POSA’s
`Knowledge. .......................................................................................................... 57
`C. Ground 2: Claim 2 is Obvious in View of Bouchard. ................................. 59
`IX.
`Alleged Unexpected results are Insufficient to Overcome the Obviousness
`of the Challenged Claims. .................................................................................... 61
`A. The Commerçon Declaration Failed to Show Unexpectedly Superior
`Activity Over Prior Art Taxanes. ......................................................................... 62
`1. Prior Art SAR Studies at C-7 and C-10 Disclosed Superiority of
`Cabazitaxel Over Comparatives A and B Was Expected. ............................... 63
`2. Comparatives A and B Were Not the Closest Prior Art; Proper
`Comparisons Show Cabazitaxel is Not Superior. ............................................ 66
`3. Cabazitaxel’s Activity Would Need to be Vastly Superior to be
`Unexpected. ...................................................................................................... 68
`B. Cabazitaxel’s Alleged Superior Activity Against Resistant Cell Strains Was
`Not Unexpected. ................................................................................................... 71
`
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`ii
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`X. Other Secondary Considerations Do Not Overcome the Prima Facie Case of
`Obviousness ............................................................................................................. 74
`1. Commercial Success ................................................................................ 75
`2. Long Felt Need/Failure of Others ............................................................ 76
`3. Copying .................................................................................................... 76
`This Petition Presents New Art and Arguments to the Board ..................... 77
`XI.
`XII. Conclusion ................................................................................................... 79
`
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`
`iii
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`

`Cases
`
`TABLE OF AUTHORITIES
`
`Acorda Therapeutics, Inc. v. Roxane Laboratories Inc.,
` No. 2017-2078, 2017-2134, 2018 U.S. App. LEXIS 25536
` (Fed. Cir. Sep. 10, 2018) ....................................................................................... 76
`Anacor Pharms., Inc. v. Iancu,
` 2018 U.S. App. LEXIS 12499 (Fed. Cir. May 14, 2018) .................................... 57
`Bayer Healthcare Pharm. v. Watson Pharm.,
` 713 F.3d 1369 (Fed. Cir. 2013)............................................................................ 76
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
` 923 F. Supp. 2d 602 (D. Del. 2013) .................................................................... 21
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
` 923 F. Supp.2d 602 (D. Del. 2013) ...................................................................... 46
`Daiichi Sankyo Co. v. Matrix Labs, Ltd.,
` 619 F.3d 1346 (Fed. Cir. 2010)............................................................................ 62
`Daiichi Sankyo Co. v. Mylan Pharm. Inc.,
` 670 F. Supp. 2d 359 (D.N.J. 2009) ...................................................................... 62
`Dystar Textilfarben GmbH v. C.H. Patrick Co.,
` 464 F.3d 1356 (Fed. Cir. 2006)............................................................................ 45
`Ethicon, Inc. v. Quigg,
` 849 F.2d 1422 (Fed. Cir. 1988)............................................................................ 34
`Galderma Labs., L.P. v. Tolmar, Inc.,
` 737 F.3d 731 (Fed. Cir. 2013).............................................................................. 75
`In re Baxter Travenol Labs,
` 952 F.2d 388 (Fed. Cir. 1991).............................................................................. 66
`In re Mayne,
` 104 F.3d 1339 (Fed. Cir. 1997)............................................................................ 39
`In re Merck & Co.,
` 800 F.2d 1091, 1096 (Fed. Cir. 1986) ................................................................. 36
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988).............................................................................. 51
`In re Swanson,
` 540 F.3d 1368 (Fed. Cir. 2008)............................................................................ 34
`
`
`
`
`iv
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`

`

`Intelligent Bio-Systems, Inc. v. Illumina Cambridge, Ltd.,
` 821 F.3d 1359 (Fed. Cir. 2016)............................................................................ 51
`Kao Corp. v. Unilever U.S., Inc.,
` 441 F.3d 963 (Fed. Cir. 2006).............................................................................. 66
`Merck & Co. v. Biocraft Laboratories, Inc.,
`874 F.2d 804 (1989) ............................................................................................. 51
`Otsuka Pharm. Co. v. Sandoz, Inc.,
` 678 F.3d 1280 (Fed. Cir. 2012)..................................................................... 36, 51
`Purdue Pharma Prods. L.P. v. Par Pharm.,
` 377 F. App’x 978 (Fed. Cir. 2010) ...................................................................... 76
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
` 492 F.3d 1350 (Fed. Cir. 2007)............................................................................ 37
`Therasense, Inc. v. Becton, Dickinson & Co.,
` 593 F.3d 1289, 1299 (Fed. Cir. 2010) ................................................................ 75
`Statutes
`
`35 U.S.C. § 102 ........................................................................................................ 15
`35 U.S.C. § 102(e) ...................................................................................... 16, 31, 32
`35 U.S.C. § 103 ........................................................................................................ 16
`35 U.S.C. § 311 ........................................................................................................ 15
`35 U.S.C. § 325(d) ............................................................................................ 77, 78
`35 U.S.C. §§ 311–19 .................................................................................................. 1
`37 C.F.R. § 42.100 ..................................................................................................... 1
`37 C.F.R. § 42.103 ................................................................................................... 10
`37 C.F.R. § 42.103(a) ............................................................................................... 10
`37 C.F.R. § 42.104(a) ................................................................................................. 7
`37 C.F.R. § 42.15(A)................................................................................................ 10
`37 C.F.R. § 42.8 ......................................................................................................... 7
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 7
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 8
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 9
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 9
`
`
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`v
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`

`

`Other Authorities
`
`Cisco Systems, Inc. v. Crossroads Systems, Inc.,
`Case IPR2014-01544 (PTAB Apr. 3, 2015) ........................................................ 77
`Microsoft Corp. v. Parallel Networks Licensing, LLC,
`Case IPR2015-00486 (PTAB July 15, 2015)....................................................... 77
`Mylan Labs. Limited v. Aventis Pharma S.A.,
`IPR2016-00712 (PTAB Sept. 21, 2017) ...................................................... 75, 76
`Mylan Pharms., Inc., v. Allergan, Inc.,
`IPR2016-01129 (PTAB Dec. 8, 2016) ................................................................ 74
`
`
`
`
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`
`vi
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`

`TABLE OF EXHIBITS
`
`
`Description
`Exhibit No.
`Exhibit 1001 U.S. Patent No. 5,847,170 to Hervé Bouchard, Jean-Dominique
`Bourzat, and Alain Commerçon (“’170 patent”)
`Exhibit 1002 Expert Declaration of Dr. John L. Wood, Ph.D.
`Exhibit 1003 C.V. of Dr. John L. Wood
`Exhibit 1004 Prosecution file history to U.S. Patent No. 5,847,170 (“FH”)
`Exhibit 1005 P. Potier et al., Chemical Studies of 10-Deacetyl Baccatin III:
`Hemisynthesis of Taxol Derivatives 42 TETRAHEDRON 4451-
`4460 (1986)
`Exhibit 1006 L. Kelland et al., Comparative In Vitro Cytotoxicity of Taxol and
`Taxotere against Cisplatin- Sensitive and Resistant Human
`Ovarian Carcinoma Cell Lines, 30 CANCER CHEMOTHER.
`PHARMACOL. 444 (1992)
`Exhibit 1007 J. Verweij et al., Paclitaxel (Taxol) and Docetaxel (Taxotere): Not
`Simply Two of a Kind, 5 ANN. ONCOL. 495 (1994)
`Exhibit 1008 J. S. Abrams et al., New Chemotherapeutic Agents for Breast
`Cancer, 74 CANCER SUPP. 1164 (1994)
`Exhibit 1009 Commerçon et al., Practical Semisynthesis and Antimitotic Activity
`of Docetaxel and Side-Chain Analogues, in TAXANE ANTICANCER
`AGENTS (Chapter 17), pp. 233-246 (Georg, G. et al. ed., American
`Chemical Society Symposium Series, 1994) (“Commerçon”)
`Exhibit 1010 J. 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 Analogues, 35 TETRAHEDRON
`LETTERS No. 31, pp. 5543-5546 (1994) (“Kant”)
`Exhibit 1011 U.S. Patent No. 6,201,140 to Henry Wong and Mark. D. Wittman
`(“Wong”)
`Exhibit 1012 Y. Ueda et al., Synthesis and Antitumor Evaluation of 2’-
`Oxycarbonylpaclitaxels (Paclitaxel-2’-Carbonates), 4
`BIOORGANIC & MEDICINAL CHEMISTRY LETTERS No. 15, pp. 1861-
`1864 (1994)
`
`
`
`vii
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`

`

`Description
`Exhibit No.
`Exhibit 1013 Y. Ueda et al., Novel Water Soluble Phosphate Prodrugs of
`Taxol® Possessing In Vivo Antitumor Activity, 3 BIOORGANIC &
`MEDICINAL CHEMISTRY LETTERS No. 8, pp. 1761-1766 (1993)
`Exhibit 1014 U.S. Patent No. 5,587,493 to Hervé Bouchard, Jean-Dominique
`Bourzat, and Alain Commerçon (“Bouchard”)
`Exhibit 1015 Volume 7, September 28, 2017 Trial Testimony from Sanofi-
`Aventis U.S. LLC v. Fresenius Kabi USA, LLC, Civil Action
`Number 3:14-cv-07869-MAS-LHG (D.N.J.).
`Exhibit 1016 Klein et al., Chemistry and Antitumor Activity on 9(R)-
`Dihydrotaxanes, in TAXANE ANTICANCER AGENTS (Chapter 20),
`pp. 276-287 (Georg, G. et al. ed., American Chemical Society
`Symposium Series, 1994) (“Klein”)
`Exhibit 1017 M. Inaba et al., Evaluation of Antitumor Activity in a Human
`Breast Tumor/Nude Mouse Model with a Special Emphasis on
`Treatment Dose, 64 Cancer pp. 1577-1582 (1989)
`Exhibit 1018 Margraff, Bézard, Bourzat, and Commerçon, Synthesis of 19-
`Hydroxy Docetaxel from a Novel Baccatin, 4 BIOORGANIC &
`MEDICINAL CHEMISTRY LETTERS, No. 2, pp. 233-236 (1994)
`Exhibit 1019 Untch et al, Comparison of paclitaxel and docetaxel (Taxotere) in
`gynecologic and breast cancer cell lines with the ATP-cell viability
`assay, 5 ANTI-CANCER DRUGS, pp. 24-30 (1994)
`Exhibit 1020 A. Joshi et al., Results of a phase II randomized controlled clinical
`trial comparing efficacy of Cabazitaxel versus Docetaxel as
`second line or above therapy in recurrent head and neck cancer,
`75 ORAL ONCOLOGY pp. 54-60 (2017)
`Exhibit 1021 P. Vrignaud et al, Preclinical Antitumor Activity of Cabazitaxel, a
`Semisynthetic Taxane Active in Taxane-Resistant Tumors, 19 Clin
`Cancer Res No. 11 pp. 2973-2983 (2013)
`Exhibit 1022 U.S. Patent No. 5,489,601 to Robert Holton and Kasthuri Rengan
`Exhibit 1023 Publication information regarding Kant, Ex.1010.
`Exhibit 1024 National Cancer Institute Division of Cancer Treatment and
`Diagnosis, Developmental Therapeutics Program (DTP) website
`and timeline entitled: “Success Story Taxol® (NSC 125973)” at
`https://dtp.cancer.gov/timeline/flash/success_stories/s2_taxol.htm
`
`
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`Exhibit 1026
`
`Description
`Exhibit No.
`Exhibit 1025 U.S. Food & Drug Administration website printout New Drug
`Application 020262 (Taxol) with Original Approval and
`Supplements shown, from:
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=
`overview.process&ApplNo=020262
`I. Ojima et al, Structure-Activity Relationships of New Taxoids
`Derived from 14β-Hydroxy-10-Deacetylbaccatin III, 37 J. MED.
`CHEM. No. 10 pp. 1408-1410 (1994)
`Exhibit 1027 Abstract to E.K. Rowinsky et al., Clinical toxicities encountered
`with paclitaxel (Taxol), SEMIN. ONCOLO. 20 (4 Suppl. 3), pp. 1-15
`(Aug. 1993)
`Exhibit 1028 E.A. Eisenhauer et al., European-Canadian Randomized Trial of
`Paclitaxel in Relapsed Ovarian Cancer: High-Dose Versus Low-
`Dose and Long Versus Short Infusion, 12 J. CLINICAL ONCOLOGY,
`PP. 2654-2666 (Aug. 1993)
`Exhibit 1029 K. Diergarten et al., Taxol: A New Antineoplastic Agent, 16
`ONKOLOGIE, pp. 329-337 (1993)
`Exhibit 1030 J. D. Hainsworth et al., Paclitaxel Administered by 1-Hour
`Infusion—Preliminary Results of a Phase I/II Trial Comparing
`Two Schedules, 74 CANCER No. 4, pp. 1377-1382 (Aug. 15, 1994)
`Exhibit 1031 R.S. Finley et al., Patient Care Issues: The Management of
`Paclitaxel-Related Toxicities, 28 THE ANNALS OF
`PHARMACOTHERAPY, pp. S27-S30 (May 1994)
`Exhibit 1032 “Taxol Approved for Breast Cancer,” THEPHARMALETTER—UP TO
`DATE NEWS FOR THE PHARMACEUTICAL AND BIOTECHNOLOGY
`INDUSTRIES-- https://www.thepharmaletter.com/article/taxol-
`approved-for-breast-cancer (April 25, 1994) (visited July 2, 2018)
`Exhibit 1033 L. Webster et al., Measurement of Cremophor EL Following
`Taxol: Plasma Levels Sufficient to Reverse Drug Exclusion
`Mediated by the Multidrug Resistant Phenotype, 85 J. NATL.
`CANCER INST., No. 20 pp. 1685-1690 (October 20, 1993)
`Exhibit 1034 F. Gueritte-Voegelein, P. Potier et al., Relationships between the
`Structure of Taxol Analogues and Their Antimitotic Activity, 34 J.
`MED. CHEM., No. 3 pp. 992-998 (1991)
`
`
`
`ix
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`

`Exhibit No.
`Exhibit 1035
`
`Description
`I. Ojima et al., Syntheses and Structure-Activity Relationships of
`New Taxoids, in TAXANE ANTICANCER AGENTS (Chapter 19), pp.
`262-275 (Georg, G. et al. ed., American Chemical Society
`Symposium Series, 1994)
`Exhibit 1036 Golick J. et al., Phosphonooxymethyl ethers of taxane derivatives,
`European Patent Application Publication No. 0 604 910 A1,
`Application No. 93120801.1, filed December 23, 1993, published
`July 6, 1994.
`Exhibit 1037 H. Lataste, V. Senilh, M. Wright, D. Guenard, and P. Potier,
`Relationships between the structures of taxol and baccatine III
`derivatives and their in vitro action on the disassembly of
`mammalian brain and Physarum amoebal microtubules, in 81
`PROC. NATL. ACAD. SCI USA, pp. 4090-4094 (July 1984)
`Exhibit 1038 A. Greene, Pierre Potier et al., A Highly Efficient, Practical
`Approach to Natural Taxol, in 110 J. AM. CHEM. SOC. No. 17, pp.
`5917-5919 (1988) (“Potier 1988”)
`Exhibit 1039 Excerpt [Chapter 2] from R. SILVERMAN, THE ORGANIC
`CHEMISTRY OF DRUG DESIGN AND DRUG ACTION, pp. 4-51 (1992)
`Exhibit 1040 D. Guenard, F. Gueritte-Voegelein, and P. Potier, Taxol and
`Taxotere: Discovery, Chemistry, and Structure-Activity
`Relationships, 26 ACC. CHEM. RES. No. 4, pp. 160-167 (1993)
`(“Potier 1993”)
`Exhibit 1041 J. Pezzuto et al., A Mixed Micellar Formulation Suitable for the
`Parenteral Administration of Taxol, in 11 PHARMACEUTICAL
`RESEARCH No. 2, pp. 206-212 (1994)
`Exhibit 1042 Second Declaration of Alain Commerçon, dated April 23, 1998,
`excerpted from prosecution history (Ex.1004) of the U.S. Patent
`No. 5,847,170 (Ex.1001) (“Commerçon Declaration” or
`“Declaration”).
`Exhibit 1043 Bissery, M.C. et al., Experimental Antitumor Activity of Taxotere
`(RP 56976, NSC 628503), a Taxol Analogue, in 51 CANCER
`RESEARCH, pp. 4845-4852 (Sept. 15, 1991)
`Exhibit 1044 Riou, J.F. et al., Effects of Taxotere on Murine and Human Tumor
`Cell Lines, in 187 BIOCHEMICAL AND BIOPHYSICAL RESEARCH
`COMMUNICATIONS, No. 1, pp. 164-170 (Aug. 31, 1992)
`
`
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`

`Description
`Exhibit No.
`Exhibit 1045 U.S. Food & Drug Administration website printout for New Drug
`Application 020449 (Taxotere/Docetaxel) with Original Approval
`and Supplements shown, from:
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=
`overview.process&ApplNo=020449
`Exhibit 1046 Georg, G., et al, Preface to TAXANE ANTICANCER AGENTS (Georg,
`G. et al. ed., American Chemical Society Symposium Series, 1994)
`Exhibit 1047 Abstract of Oudard, S. et al, Cabazitaxel versus Docetaxel as First-
`Line Therapy for Patients with Metastatic Castration-Resistant
`Prostate Cancer: A Randomized Phase III Trial—FIRSTANA, 35
`J. Clinical Oncology No. 28 pp. 3189-3197 (Oct. 1, 2017)
`Exhibit 1048 U.S. Patent No. 8,927,592 to Sunil Gupta
`Exhibit 1049 Redacted Opinion, Document No. 328, from Case No. 14-7869,
`Sanofi-Aventis U.S. LLC v. Fresenius Kabi USA, LLC, (D. NJ
`December 19, 2017) (“Opinion”)
`Exhibit 1050 Nicolaou, K.C. et al., Total synthesis of taxol, in 367 NATURE pp.
`630-634 (Feb. 17, 1994)
`Exhibit 1051 Holton, R.A. et al, First Total Synthesis of Taxol. 1.
`Functionalization of the B Ring, and 2. Completion of the C and D
`Rings, in 367 J. AM. CHEM. SOC., No. 4, pp. 1597-1600 (1994)
`Exhibit 1052 Ojima, I., et al, New and Efficient Approaches to the Semisynthesis
`of Taxol and its C-13 Side Chain Analogs by Means of β-Lactam
`Synthon Method, in 48 TETRAHEDRON, No. 34, pp. 6985-7012
`(1992)
`Exhibit 1053 Suffness, Matthew, Chapter 1 Overview of Paclitaxel Research –
`Progress on Many Fronts, in TAXANE ANTICANCER AGENTS
`(Chapter 1), pp. 1-17, (Georg, G. et al. ed., American Chemical
`Society Symposium Series, 1994)
`Exhibit 1054 Excerpts from MEDICINAL CHEMISTRY: PRINCIPLES AND PRACTICE
`(King, Frank. ed., Royal Society of Chemistry, 1994)
`Exhibit 1055 Excerpts from Larock, Richard, COMPREHENSIVE ORGANIC
`TRANSFORMATIONS, VCH Publishers (1989)
`
`
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`

`I.
`
`INTRODUCTION
`
`Neptune Generics, LLC (“Neptune”), requests an Inter Partes Review
`
`(“IPR”) of Claims 1 and 2 (collectively, the “Challenged Claims”) of U.S. Patent
`
`No. 5,847,170 (the “’170 patent”) pursuant to 35 U.S.C. §§ 311–19 and 37 C.F.R.
`
`§§ 42.100 et seq.
`
`Challenged claim 1 is directed to cabazitaxel, a taxane compound
`
`represented by the molecular structure below:
`
`
`The only distinguishing features of the cabazitaxel compound from prior art
`
`paclitaxel are the BOC (tert-butyloxycarbonyl) group at C-3’ and the methoxy
`
`groups at C-7 and C-10. But attaching the BOC group at C-3’ was well-known in
`
`the art to increase biological activity of taxane analogs and methylating C-7 and C-
`
`10 (both positions known to be flexible) would have been obvious to a person of
`
`ordinary skill in the art (“POSA”) based on both prior art, as well as best
`
`laboratory practices in analog research. Thus claim 1 of the ’170 patent is obvious.
`
`
`
`1
`
`

`

`Long before March 27, 1995 (the earliest priority date of the ’170 patent),
`
`taxanes were well-known anticancer agents, acting to bind microtubules and
`
`preventing the division of cancer cells, thus promoting cell death. Paclitaxel (the
`
`first known taxane) had been identified more than twenty years earlier, its
`
`molecular structure had been isolated and its biological activity was well-known in
`
`the art.
`
`Paclitaxel’s structure includes a core carbon skeleton with various functional
`
`groups, including an acetate group at C-10 and a hydroxyl group at C-7 as well as a
`
`side-chain comprising a phenylisoserine portion and a benzoyl group portion.
`
`Although paclitaxel was initially available only in small amounts from its
`
`natural tree source, by the 1980s a strategy for synthesizing paclitaxel had been
`
`developed using the relatively abundant and readily available natural product 10-
`
`
`
`
`
`2
`
`

`

`DAB-III as a starting material. 10-DAB III (pictured below) contains the entire
`
`core carbon skeleton present in paclitaxel and all of the core skeleton’s functional
`
`groups, but for a hydroxyl rather than acetate group at C-10.
`
`
`
`The ability to readily access paclitaxel semi-synthetically from 10-DAB-III
`
`propelled advances in taxane research. By 1994 the FDA had approved Bristol-
`
`Myers Squibb’s Taxol® (paclitaxel) for both ovarian and breast cancer treatments,
`
`and structure activity relationship (SAR) studies of paclitaxel analogs were well
`
`underway in the hopes of discovering the next taxane chemotherapeutic. Thus, by
`
`1994 published SAR studies identified key components of the paclitaxel molecule,
`
`including the “crucial” portions of the molecule (necessary to biological activity)
`
`and the “flexible” portions (able to tolerate substitutions without significantly
`
`decreasing biological activity). Prior art Commerçon (Ex.1009) summarized the
`
`
`
`3
`
`

`

`status of SAR research as of December 1994, publishing the results in Figure 2
`
`below:
`
`
`Commerçon plainly identified the lower portion of the molecule and the
`
`phenylisoserine side-chain as crucial to biological activity. Although the benzoyl
`
`group (PhCO) attached to the nitrogen atom at C-3’ of the side-chain was
`
`identified as “flexible,” the Commerçon reference confirmed that a BOC group at
`
`this position was known to increase activity. The art reported that the biological
`
`activity or pharmacophore of paclitaxel was centered on the lower portion of the
`
`molecule in conjunction with the phenylisoserine side-chain and further confirmed
`
`that replacing the benzoyl with a BOC group on the side-chain would present
`
`highly desirable increases in activity. Additionally, a POSA would have
`
`understood from Commerçon that the top part of the molecule, particularly C-7
`
`
`
`4
`
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`

`through C-10 was “flexible” and thus a primary location for modification. The
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`disclosures and motivations of Commerçon are reflected below:
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`
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`Thus, as of December 1994, a POSA would have: (1) been motivated to
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`focus on the C-7 through C-10 locations of paclitaxel in developing additional
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`active analogs and furthering taxane research and (2) would have undoubtedly
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`consulted references concerning SAR studies at the C-7 through C-10 location.
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`Accordingly, prior art Kant (Ex.1010) already demonstrated that when a
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`BOC group replaced the benzoyl group in the side-chain, substituting the acetate
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`group at C-10 with a methoxy group further increased the analog’s biological
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`activity and improved its activity relative to known paclitaxel. (Ex.1010, Kant
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`5545). Similarly, other SAR studies demonstrated that a paclitaxel analog with a
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`methoxy group at the C-7 location showed improved biological activity over
`
`paclitaxel. (Ex.1011, Wong 9:15-27, 22:46-23:30; Ex.1013, Ueda 1765). Thus,
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`5
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`prior art references disclosed that methoxy groups at the C-7 and C-10 locations
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`demonstrated increased activity over paclitaxel.
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`Best laboratory practices in analog generation would have further motivated
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`a POSA to specifically focus on and methylate C-7 and C-10 because the 10-DAB
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`III starting material contains hydroxyl groups (well-known candidates for
`
`replacement and change) at the readily accessible C-7 and C-10 locations.
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`Additionally, homologation—a well-known laboratory technique to generate
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`analogs by adding one or more carbon units in a functional group—would have
`
`motivated a POSA to substitute methoxy groups at the two locations with expected
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`results.
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`Accordingly, a POSA would have been motivated to combine the prior art
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`references of Commerçon (Ex.1009), Kant (Ex.1010), and Wong (Ex.1011), along
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`with the knowledge of ordinary skill in the art, including best laboratory practices,
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`thus rendering claim 1 obvious.
`
`Claim 2 is uninspired and likewise invalid. Claim 2 is directed to the
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`pharmaceutical composition containing the cabazitaxel compound of claim 1,
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`together with a pharmaceutically acceptable diluent or adjuvant. No specific
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`diluents or adjuvants are claimed and a POSA would have been well-versed in
`
`utilizing diluents or adjuvants to facilitate drug delivery—indeed, diluents and
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`adjuvants were already being used with prior art paclitaxel. Furthermore, the
`
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`6
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`language used in claim 2 appears to be directly lifted from prior art Bouchard
`
`(Ex.1014) which also lists the same three co-inventors on its face.
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`II. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ’170 patent is
`
`available for IPR and that Petitioner is not barred or estopped from requesting IPR
`
`on the Challenged Claims of the ’170 patent on the grounds identified in this
`
`Petition.
`
`III. MANDATORY NOTICES (37 C.F.R. § 42.8)
`A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Neptune
`
`Generics, LLC, Niagara FundingCo, LLC, GKC Partners II, LP, GKC General
`
`Partner II, LP, Burford Capital Ireland DAC, GKC PII Holdings, LLC, Burford
`
`Capital Investment Management LLC, Burford Capital Holdings (UK) Limited,
`
`and Burford Capital Limited are the real parties in interest (collectively, “RPI”).
`
`Neptune Generics, LLC, a New York limited liability company, is 100% owned by
`
`Niagara FundingCo, LLC, a New York limited liability company, which itself is
`
`100% owned by GKC Partners II, LP, a Delaware limited partnership. GKC
`
`General Partner II, LLC, a Delaware limited liability company, is the general
`
`partner of GKC Partners II, LP, and Burford Capital Investment Management LLC
`
`is the investment manager to GKC Partners II, LP. No other person has authority
`
`
`
`7
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`to direct or control (i) the timing of, filing of, content of, or any decisions or other
`
`activities relating to this Petition or (ii) any timing, future filings, content of, or any
`
`decisions or other activities relating to the future proceedings related to this
`
`Petition. All of the costs associated with this Petition are expected to be borne by
`
`Neptune Generics, LLC, Niagara FundingCo, LLC, GKC Partners II, LP, GKC
`
`General Partner II, LP, Burford Capital Investment Management LLC and Burford
`
`Capital Holdings (UK) Limited.
`
`B. Related Judicial and Administrative Matters (37 C.F.R. § 42.8(b)(2))
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner states that the ’170 patent has
`
`been the subject of the following proceedings, none of which involved Petitioner as
`
`a party:
`
`Sanofi-Aventis US LLC et al v. Fresenius Kabi USA, LLC, DED 1-14-cv-
`
`01496 (filed Dec. 18, 2014); Sanofi-Aventis US LLC et al. v. Fresenius Kabi USA,
`
`LLC, DED 1-14-cv-01533 (filed Dec. 30, 2014); Sanofi-Aventis US LLC et al. v.
`
`Apotex Corp. et al, DED 1-15-cv-00044 (filed Jan. 15, 2015); Sanofi-Aventis US
`
`LLC et al v. BPI Labs, LLC et al, FLMD 8-14-cv-03233 (filed Dec. 30, 2014);
`
`Sanofi-Aventis US LLC et al v. Breckenridge Pharmaceutical, Inc., FLSD 9-15-cv-
`
`80056 (filed Jan. 15, 2015); Sanofi-Aventis US LLC et al v. Accord Healthcare,
`
`Inc. NCMD 1-15-cv-00018 (filed Jan. 07, 2015); Sanofi-Aventis US LLC et al v.
`
`Fresenius Kabi USA, LLC, NJD 3-14-cv-07869 (filed Dec. 17, 2014); Sanofi-
`
`
`
`8
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`

`

`Aventis US LLC et al v. Accord Healthcare, Inc., NJD 3-14-cv-08079 (filed Dec.
`
`29, 2014); Sanofi-Aventis US LLC et al v. BPI Labs, LLC et al, NJD 3-14-cv-
`
`08081 (filed Dec. 29, 2014); Sanofi-Aventis US LLC et al v. Fresenius Kabi USA,
`
`LLC, NJD 3-14-cv-08082 (filed Dec. 29, 2014); Sanofi-Aventis US LLC et al v.
`
`Apotex Corp. et al, NJD 3-15-cv-00287 (filed Jan. 14, 2015); Sanofi-Aventis US
`
`LLC et al v. Breckenridge Pharmaceutical, Inc., NJD 3-15-cv-00289 (filed Jan. 14,
`
`2015); Sanofi-Aventis US LLC et al v. Onco Therapies Limited, NJD 3-15-cv-
`
`00290 (filed Jan. 14, 2015); Sanofi-Aventis US LLC et al v. Actavis LLC et al, NJD
`
`3-15-cv-00776 (filed Feb. 02, 2015); Sanofi-Aventis US LLC et al v. Dr. Reddy’s
`
`Laboratories, Inc. et al, NJD