Paper No. ____
`Filed: Feburary 17, 2016
`
`Filed on behalf of: Mylan Laboratories Limited
`By: Steven W. Parmelee
`
`Michael T. Rosato
`
`Jad A. Mills
`WILSON SONSINI GOODRICH & ROSATI
`701 Fifth Avenue
`Suite 5100
`Seattle, WA 98104-7036
`Tel.: 206-883-2542
`Fax: 206-883-2699
`Email: sparmelee@wsgr.com
`Email: mrosato@wsgr.com
`Email: jmills@wsgr.com
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MYLAN LABORATORIES LIMITED,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA S.A.,
`Patent Owner.
`_____________________________
`
`Patent No. 5,847,170
`IPR2016-00627
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 5,847,170
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`Introduction .................................................................................................. 1
`
`A.
`
`Brief Overview of the ’170 Patent....................................................... 2
`
`B.
`
`C.
`
`Brief Overview of the Prosecution History ......................................... 3
`
`Brief Overview of the Scope and Content of the Prior Art .................. 5
`
`D.
`
`Brief Overview of Level of Skill in the Art ......................................... 9
`
`II.
`
`Grounds for Standing .................................................................................. 11
`
`III. Mandatory Notices under 37 C.F.R. § 42.8 ................................................. 11
`
`IV. Statement of the Precise Relief Requested for Each Claim Challenged ....... 13
`
`V.
`
`Statement of Non-Redundancy ................................................................... 14
`
`VI. Claim Construction ..................................................................................... 15
`
`VII. Background Knowledge in the Art Prior to March 27, 1995 ....................... 16
`
`VIII. Overview of Differences Between the Asserted Prior Art and the
`Claims......................................................................................................... 27
`
`IX. Detailed Explanation of Grounds For Unpatentability................................. 29
`
`A.
`
`B.
`
`[Ground 1] Claims 1 and 2 are Obvious Under 35 U.S.C. § 103
`Over Kant in View of Klein .............................................................. 29
`
`[Ground 2] Claims 1 and 2 are Obvious Under 35 U.S.C. § 103
`Over Colin in View of Klein and Kant .............................................. 38
`
`C.
`
`No Secondary Considerations of Non-Obviousness .......................... 49
`
`X.
`
`Conclusion .................................................................................................. 50
`
`XI. Payment of Fees under 37 C.F.R. §§ 42.15(a) and 42.103........................... 51
`
`XII. Appendix – List of Exhibits ........................................................................ 52
`
`-i-
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`

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`
`I.
`
`INTRODUCTION
`
`Pursuant to the provisions of 35 U.S.C. § 311 and § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and to 37 C.F.R. Part 42, Mylan Laboratories
`
`Limited, (“Petitioner”) requests review of United States Patent No. 5,847,170 to
`
`Bouchard et al. ( “the ’170 patent,” Ex. 1001) that issued on December 8, 1998,
`
`and is currently assigned to Aventis Pharma S.A. (“Patent Owner”). This Petition
`
`demonstrates, by a preponderance of the evidence, that there is a reasonable
`
`likelihood that claims 1 and 2 of the ’170 patent are unpatentable for failing to
`
`distinguish over prior art.
`
`The claimed anti-cancer compound, 4α-acetoxy-2α-benzoyloxy-5β,20-
`
`epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-
`
`butoxycarbonylamino-2-hydroxy-3-phenylpropionate, referred to herein as 7,10-
`
`dimethoxy docetaxel, which subsequently became known as “cabazitaxel,” differs
`
`from the well-known prior art anti-cancer drug docetaxel (Taxotere®) only by
`
`methylation at the C-7 and C-10 hydroxyls. At the time of the earliest claimed
`
`priority date, however, substitution (including simultaneous substitution) of
`
`docetaxel at each of these positions was known. In fact, methylation at each of the
`
`C-10 and C-7 hydroxyls was known in the art to increase the potency of docetaxel
`
`analogues. An exemplary prior art compound is shown below adjacent to the
`
`claimed compound. As shown in bold, the only difference between the two is the
`
`methyl group on the C-7 hydroxyl.
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`-1-
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`

`

`
`
`The prior art provides an analogue of docetaxel methylated at position C-10
`
`
`
`
`
`having potent activity against cancer cells. The prior art also teaches the C-7
`
`hydroxyl is available for substitution, and that a methoxy group at C-7 yields a
`
`compound with potent activity against cancer cells. The evidence and detailed
`
`explanation provided in this Petition establish that one of ordinary skill in the art
`
`would have had good reason to combine these teachings and produce an improved
`
`docetaxel analogue as recited in claims 1 and 2, i.e., 7,10-dimethoxy docetaxel,
`
`and would have done so with a reasonable expectation of success in synthesizing
`
`thereby a compound with improved potency, a simpler synthetic pathway, and
`
`improved lipophilicity.
`
`A. Brief Overview of the ’170 Patent
`
`The ’170 patent is entitled “Taxoids, Their Preparation And Pharmaceutical
`
`Compositions Containing Them.” In a general sense, the ’170 patent is directed to
`
`the compound 7,10-dimethoxy docetaxel and its pharmaceutical compositions and
`
`methods of making it. The compound is said to find use in the inhibition of
`
`abnormal cell proliferation. Ex. 1001, col. 26, ll. 32-36. Independent claim 1
`
`recites a single compound as follows:
`
`-2-
`
`

`

`
`
`1. 4α-Acetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,10β-
`
`dimethoxy-9-oxo-11-taxen-13α-yl(2R,3S)-3-tert-
`
`butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
`
`The structure of 7,10-dimethoxy docetaxel is shown below:
`
`
`
`Dependent claim 2 recites a pharmaceutical composition as follows:
`
`2. A pharmaceutical composition comprising at least the product
`
`according to claim 1 in combination with one or more
`
`pharmaceutically acceptable diluents or adjuvants and optionally one
`
`or more compatible and pharmacologically active compounds.
`
`B.
`
`Brief Overview of the Prosecution History
`
`U.S. Patent Application 622,011 was filed on March 26, 1996, and issued on
`
`December 8, 1998, as U.S. Patent No. 5,847,170. Its earliest claimed priority date,
`
`to French Patent Application No. 95 03545, is March 27, 1995.
`
`Prosecution focused on whether or not the methyl groups added to the C-7
`
`and C-10 hydroxyls on the claimed 7,10-dimethoxy docetaxel constituted
`
`protecting groups. Finding that they were, the examiner rejected the claims, citing
`
`a patent to Holton et al. (US Patent No. 5,229,526) under 35 U.S.C. § 102(b). Ex.
`
`1004 at 00697-00701. The examiner relied on Holton for teaching
`
`functionalization of the C-7 and C-10 positions of analogous taxanes with
`
`-3-
`
`

`

`
`
`protecting groups, in view of Greene et al. (“Protective Groups in Organic
`
`Synthesis,” 2nd ed., 1991), which taught methyl groups as conventional hydroxyl
`
`protecting groups. Ex. 1004 at 00699-00700.
`
`Applicants responded with a § 1.132 Declaration from one of the co-
`
`inventors (Ex. 1004 at 00653), and provided experimental data that suggested the
`
`methyl groups could not be removed from the C-7 and C-10 hydroxyls under three
`
`deprotection conditions set forth in Holton, and therefore were not protecting
`
`groups. Id. at 00653. In a second Office action, the examiner concluded: “It would
`
`have been prima facie obvious to replace the disclosed hydroxy protecting group of
`
`Holton with the hydroxy protecting groups as taught by Greene et al and Holton et
`
`al to form the claimed compounds without the loss of the same utility.” Id. at
`
`00592. Commenting on the Rule 132 Declaration, the examiner stated, “the
`
`hydroxy protecting technique is well known and conventional to any one of
`
`ordinary [skill] in the art and it is not a break[-]through to show that a certain
`
`hydroxy protecting group can be or can not be deprotected by various reagents
`
`and/or condition.” Id.at 00593.
`
`A second § 1.132 Declaration was submitted by the same co-inventor, and
`
`compared the activity of the claimed 7,10-dimethoxy docetaxel against other
`
`“comparative structures.” Ex. 1004 at 00553. The first comparative structure was a
`
`docetaxel analogue functionalized at the C-7 and C-10 hydroxyls with TROC
`
`(2,2,2-trichloroethoxycarbonyl) groups, and the second was a docetaxel analogue
`
`acetylated at the same position. Id. at 00554. The applicant did not compare the
`
`activity of the claimed 7,10-dimethoxy docetaxel with other known compounds
`
`-4-
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`

`

`
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`that were methylated at the C-7 or C-10 hydroxyl positions. In a supplemental
`
`response, the applicant did identify prior art references in which the C-7 or C-10
`
`hydroxyl was methylated, in support of its argument that methyl groups “are not
`
`hydroxy protecting groups.” Ex. 1004 at 00273 (citing, inter alia, J. Kant, 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 LETT. 5543 (1994) (“Kant,” Ex. 1005)). The
`
`applicant characterized these references in part in a footnote, saying: “[T]here is no
`
`suggestion in these [publications] that the substituents at the 7- and 10-positions
`
`can be the same, let alone that they can both be methoxy.” Id. at 00273 (emphasis
`
`in original). The examiner, however, did not comment further on these references.
`
`A Notice of Allowability followed shortly thereafter without explanation. Ex. 1004
`
`at 00264-00265.
`
`C. Brief Overview of the Scope and Content of the Prior Art
`
`J. Kant, 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 LETT. 5543 (1994) (“Kant,” Ex. 1005) qualifies as
`
`prior art under 35 U.S.C. § 102(b). Kant discloses analogues of docetaxel and
`
`paclitaxel with a range of substitutions at the C-10 hydroxyl. Kant teaches
`
`“replacing the C-10 . . . moiety with other functionalities . . . [w]ith the aim of
`
`obtaining drugs having more desirable properties” than paclitaxel. See Ex. 1005 at
`
`Abstract; Ex. 1002, ¶ 60. Following the synthesis of these C-10 analogues, Kant
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`-5-
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`

`

`
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`teaches their relative anti-tumor activities. Kant discloses 10-methoxy docetaxel
`
`(compound 20), which contains the same methoxy group at the C-10 position as
`
`7,10-dimethoxy docetaxel. Ex. 1005 at 5545, Table II. Kant reports that compound
`
`20 displays the best tubulin binding properties of all of the analogues studied and
`
`the most efficacy against cancer cell line HCT 116 of any of the docetaxel
`
`analogues studied. Ex. 1005 at 5545, Table II; Ex. 1002, ¶¶ 62-63. Kant teaches
`
`the greater potency of docetaxel analogues with a C-10 methoxy group as opposed
`
`to a C-10 acetyl group, or to an unfunctionalized, free hydroxyl group. Ex. 1005 at
`
`5545; Ex. 1002, ¶¶ 61-63. Kant states that:
`
`Analogues with C-10 methyl ether ([compound] 20) or methyl
`carbonate ([compound] 22) with [the] TaxotereTM side chain (i.e., 3’-
`
`NHBOC) were found to be more cytotoxic than paclitaxel
`
`([compound] 1) or 10-acetyl taxotere ([compound] 15).
`
`Ex. 1005 at 5546, Table II. Thus, Kant teaches that “the functional group present
`
`at the C-10 position does modulate antitumor activity” (Ex. 1005 at 5546), and that
`
`the presence of a methoxy group at the C-10 position of docetaxel results in greater
`
`potency than that exhibited by paclitaxel or C-10 acetylated docetaxel. Compound
`
`20, which is methylated at the C-10 hydroxyl is shown below on the left, adjacent
`
`to 7,10-dimethoxy docetaxel for comparison:
`
`-6-
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`

`

`
`
`Klein et al., Chapter 20: Chemistry and Antitumor Activity of 9(R)-
`
`
`
`
`
`Dihydrotaxanes, TAXANE ANTICANCER AGENTS (1994) (“Klein,” Ex. 1006)
`
`qualifies as prior art under 35 U.S.C. § 102(b). Klein discloses 9-dihydrotaxane
`
`analogues. Ex. 1006 at 280-81. Klein compares the activity of docetaxel
`
`(Taxotere®) with its C-9 hydroxyl analogue (“9-dihydrotaxotere,” also referred to
`
`as compound 13) and reported diminished tumor cell cytotoxicity upon reduction
`
`of the carbonyl at the C-9 position. Ex. 1006 at 280, Table I; Ex. 1002, ¶¶ 65-66.
`
`Klein reports that the C-9 substitution “allows for access to novel chemistry and
`
`ring systems from this taxane template.” Ex. 1006 at Abstract.
`
`Klein discloses entry 10 of Table III, a docetaxel analogue with the same
`
`methoxy substituent at the C-7 carbon as 7,10-dimethoxy docetaxel and the same
`
`acetyl substituent at the C-10 carbon as paclitaxel. Ex. 1006 at 281; see also, Ex.
`
`1002, ¶ 67. Klein further teaches increased antitumor activity of compounds with a
`
`C-7 methoxy group versus those with a hydroxyl group at the C-7 position. Klein
`
`states, “masking of the C-7/9 hydroxyls leads to analogs of greater potency.” Ex.
`
`1006 at 282. Entry 10, the analogue of docetaxel with a methoxy group at C-7,
`
`was the most potent compound evaluated in Table III, as well as the most potent
`
`-7-
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`

`

`
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`compound disclosed in the entire publication. Id.; Ex. 1002, ¶ 78. Klein states that
`
`“(entry 10) exhibits potent tubulin assembly activity” and “extremely potent
`
`cytotoxicity.” Ex. 1006 at 282. Entry 10, which is methylated at the C-7 hydroxyl,
`
`is shown below adjacent compound 20 of Kant and 7,10-dimethoxy docetaxel for
`
`comparison:
`
`
`
`U.S. Patent No. 4,814,470 to Colin et al. (filed July 14, 1987) (“Colin,” Ex.
`
`1007) issued on March 21, 1989, qualifies as prior art under 35 U.S.C. §§ 102(b),
`
`(e). Colin describes four taxane analogues, which are “useful anti-tumor agents”
`
`with efficacies greater than paclitaxel. Ex. 1007, col. 3, ll. 19-37; id. at abstract; see
`
`also, Ex. 1002, ¶¶ 69-71. Colin specifically describes a compound which is known
`
`as docetaxel (Taxotere®) as having “valuable biological activities” and being
`
`“approximately twice as active as taxol.” Ex. 1007, col. 3, ll. 19-23, 29-30; Ex.
`
`-8-
`
`

`

`1002, ¶ 70. The structure of docetaxel is shown below, adjacent to paclitaxel.
`
`
`
`
`
`In addition to describing the synthesis of docetaxel in Example 1, Colin
`
`describes formulating docetaxel for intravenous administration. Ex. 1007, col. 6, l.
`
`46 - col. 7, l. 16; Ex. 1002, ¶ 72. This formulation involves the use of ethanol,
`
`which is a pharmaceutically acceptable diluent, as well as Emulphor EL 620, a
`
`pharmaceutically acceptable vehicle. Ex. 1007, col. 10, ll. 5-9; Ex. 1002, ¶ 72.
`
`Colin states that “the parenteral route, and especially the intravenous route, is the
`
`preferential route for administration.” Ex. 1007, col. 9, ll. 23-26.
`
`D. Brief Overview of Level of Skill in the Art
`
`At the time of the invention, a person having ordinary skill in the art would
`
`have some combination of the following skills and experience: (i) experience with
`
`synthesis of organic compounds; (ii) experience designing antitumor drugs; (iii)
`
`understanding of general principles of drug design and delivery; and (iv) the ability
`
`to understand work presented or published by others in the field, including the
`
`publications discussed by Dr. Jacobsen in his declaration, Ex. 1002, at, e.g., ¶¶ 31-
`
`56, representing the state of the art, and including the references asserted in
`
`-9-
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`

`

`
`
`Grounds 1-2 in this petition. Ex. 1002, ¶¶ 25-28.
`
`Typically, a person of ordinary skill in the relevant field as of the earliest
`
`alleged priority date, i.e., March 27, 1995, would have an advanced degree (e.g., a
`
`Ph.D.) in organic chemistry, medicinal chemistry, or a related field. Alternatively,
`
`a person of ordinary skill in the relevant field might have less education but
`
`considerable professional experience in one or more of these fields. Ex. 1003, ¶¶
`
`25-28.
`
`Petitioner’s expert, Dr. Eric Jacobsen, is currently a Professor in the
`
`Department of Chemistry and Chemical Biology at Harvard University. Ex. 1002,
`
`¶ 1. Dr. Jacobsen has been a member of the faculty and Full Professor at Harvard
`
`since 1993, and served as Department Chair from 2010 to 2015. Ex. 1002, ¶¶1-2.
`
`Dr. Jacobsen received a B.S. in Chemistry from New York University in 1982 and
`
`a Ph.D. in Chemistry from the University of California, Berkeley in 1986. Ex.
`
`1002, ¶¶ 1-2. He conducted research at the Massachusetts Institute of Technology
`
`as an NIH Postdoctoral Fellow from 1986 to 1988, and was on the faculty at the
`
`University of Illinois at Urbana-Champaign prior to joining Harvard. Id.
`
`Dr. Jacobsen has authored or co-authored more than 190 scientific
`
`publications, the vast majority of which are peer-reviewed journal articles. Id. at ¶
`
`5. He has authored 20 book chapters, given numerous invited lectures at scientific
`
`meetings, educational institutions, and pharmaceutical companies, including over
`
`70 named and plenary lectures. A summary of his education, experience, awards
`
`and honors, patents, publications, and presentations is provided in his CV,
`
`submitted as Ex. 1003. See also, Ex. 1002, ¶¶ 1-6.
`
`-10-
`13-
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`

`

`
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`Dr. Jacobsen’s research uses knowledge and tools from inorganic chemistry,
`
`biochemistry, spectroscopy, and organic chemistry to engineer molecules having
`
`specific desirable chemical and/or biological properties. Ex. 1002, ¶ 4.
`
`Additionally, his research involves the development of new chemical
`
`methodologies for use in organic synthesis, and in the early 1990’s he developed a
`
`new reaction technique, now called Jacobsen Epoxidation, for making epoxide ring
`
`structures in organic molecules in a stereoselective manner. Id. Dr. Jacobsen is a
`
`well-qualified expert in the field of organic synthesis and related fields. Ex. 1003;
`
`see also, Ex. 1002, ¶¶ 1-6.
`
`Dr. Jacobsen is well qualified as an expert, possessing the necessary
`
`scientific, technical, and other specialized knowledge to assist in an understanding
`
`of the evidence presented herein, as well as possessing the expertise necessary to
`
`determine and explain the level of ordinary skill in the art during the relevant time
`
`frame.
`
`II. GROUNDS FOR STANDING
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’170 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’170 patent on the grounds identified.
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)): The following real parties-
`
`in-interest are identified: Mylan Laboratories Limited, which is the Petitioner in
`
`this matter and which is a wholly owned subsidiary of Mylan Inc.; Mylan
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`-11-
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`
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`Pharmaceuticals Inc., which is a wholly owned subsidiary of Mylan Inc; Mylan
`
`Inc., which is an indirectly wholly owned subsidiary of Mylan N.V.; and Mylan
`
`N.V.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)):
`
`The ʼ170 patent issued from US Patent Application No. 08/622,011, which
`
`claims priority to U.S. Provisional Patent Application No. 60/010,144, filed
`
`January 17, 1996, and to French Patent Applications 95/03545 filed March 27,
`
`1995 and 95/15381, filed December 22, 1995. Other patents of which Petitioner is
`
`aware that claim priority to US Patent Application No. 08/622,011 include US
`
`Patent No. 6,331,635; US Patent No. 6,372,780, and US Patent No. 6,387,946.
`
`Petitioner and other entities have been involved in litigation over the ’170
`
`patent and other patents, including the 7,241,907 patent, titled “Acetone Solvate of
`
`Dimethoxy Docetaxel And Its Process of Preparation”) in the action styled Sanofi-
`
`Aventis U.S. LLC, Aventis Pharma S.A. and Sanofi v. Mylan Laboratories Ltd.
`
`Civil Action No. 3:15-cv-00290 (MAS)(LHG) (previously captioned Sanofi-
`
`Aventis U.S. LLC et al. v. Onco Therapies Limited, C. A. No. 3:15-00290
`
`(MAS/LHG), filed in the District of New Jersey. A complaint asserting the ’170
`
`patent against Petitioner was served by waiver of service no earlier than February
`
`17, 2015. To Petitioner’s knowledge, the ’170 patent is also at issue in Sanofi-
`
`Aventis U.S. LLC et al. v. Fresenius Kabi USA, LLC, C. A. No. 14-07869
`
`(MAS)(LHG); Sanofi-Aventis U.S. LLC et al. v. Accord Healthcare, Inc., C. A. No.
`
`14-08079 (MAS)(LHG); Sanofi-Aventis U.S. LLC et al. v. BPI Labs, LLC et al., C.
`
`A. No. 14-08081 (MAS)(LHG); Sanofi-Aventis U.S. LLC et al. v. Fresenius Kabi
`
`-12-
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`
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`USA, LLC, C. A. No. 14-08082 (MAS)(LHG); Sanofi-Aventis U.S. LLC et al. v.
`
`Apotex Corp. et al., C. A. No. 15-0287 (MAS)(LHG); Sanofi-Aventis U.S. LLC et
`
`al. v. Breckenridge Pharmaceutical, Inc., C. A. No. 15-0289 (MAS)(LHG);
`
`Sanofi-Aventis U.S. LLC et al. v. Mylan Laboratories Limited, C. A. No. 15-0290
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`(MAS)(LHG); and Sanofi-Aventis U.S. LLC et al. v. Actavis LLC et al., C. A. No.
`
`15-0776 (MAS)(LHG).
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3))
`
`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
`
`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
`
`Back-Up Counsel: Jad A. Mills (Reg. No. 63,344)
`
`Service Information – 37 C.F.R. § 42.8(b)(4). Petitioner hereby consents to
`
`electronic service.
`
`Email: sparmelee@wsgr.com; mrosato@wsgr.com; jmills@wsgr.com
`
`Post: WILSON SONSINI GOODRICH & ROSATI, 701 Fifth Avenue, Suite 5100,
`
`
`
`Seattle, WA 98104-7036
`
`Fax: 206-883-2699
`
`Tel.: 206-883-2542
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM
`CHALLENGED
`
`Petitioner requests review of claims 1 and 2 of the ’170 patent under 35
`
`U.S.C. § 311 and AIA § 6. Petitioner challenges claims 1 and 2 of the ʼ170 patent
`
`on the grounds that each of the claims should be canceled as unpatentable as
`
`follows:
`
`
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`-13-
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`
`
`Ground
`
`Claims
`
`Description
`
`1
`
`2
`V.
`
`1, 2
`
`1, 2
`
`§ 103 Obvious over Kant in view of Klein
`
`§ 103 Obvious over Colin in view of Klein and Kant
`
`STATEMENT OF NON-REDUNDANCY
`
`Each of the two Grounds raised in this Petition is meaningfully distinct:
`
`1. Ground 1 presents obviousness of claims 1 and 2 based on a combination
`
`of Kant and Klein, which differs from the remaining asserted ground. Kant
`
`describes C-10 methoxy docetaxel, compound 20, which displays the best tubulin
`
`binding properties of all analogues studied by Kant, the highest efficacy of the
`
`studied analogues having a docetaxel side chain, and higher efficacy than
`
`paclitaxel. Klein teaches methylation at the C-7 hydroxyl position of docetaxel
`
`analogues, as in entry 10, which is the most potent compound described by Klein.
`
`Thus, Klein provides motivation to methylate the C-7 hydroxyl group of Kant’s
`
`compound 20. The resulting compound is identical to 7,10-dimethoxy docetaxel.
`
`
`
`2. Ground 2 is materially different from Ground 1 in proving the
`
`obviousness of claims 1 and 2 based on a combination of Colin, Klein, and Kant.
`
`Colin describes docetaxel as a potent anticancer compound formulated for
`
`pharmaceutical administration. As discussed above, Klein teaches methylation at
`
`the C-7 hydroxyl leads to potent docetaxel analogues. Klein further teaches
`
`-14-
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`

`

`
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`acetylization at the C-10 position. Thus, Klein teaches a docetaxel analogue which
`
`is functionalized at both C-10 and C-7. Kant teaches that C-10 methylated
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`analogues of docetaxel are more potent than C-10 acylated analogues. Thus Kant
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`provides motivation for replacing the C-10 acyl group, as taught in Klein, with a
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`C-10 methoxy group. The resulting compound is identical to 7,10-dimethoxy
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`docetaxel.
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`
`VI. CLAIM CONSTRUCTION
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`A claim subject to inter partes review receives the broadest reasonable
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`construction or interpretation in light of the specification of the patent in which it
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`appears because, among other reasons, the patent owner has an opportunity to
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`amend the claims. 37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793
`
`F.3d 1268, 1275-1280 (Fed. Cir. 2015), cert. granted, Cuozzo Speed Techs., LLC v.
`
`Lee, 2016 U.S. LEXIS 632 (U.S. Jan. 15, 2016) (No. 15-446).
`
`A phrase that warrants discussion is set forth below.
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` “pharmaceutically acceptable adjuvants”
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`Claim 2 recites “pharmaceutically acceptable . . . adjuvants” that are
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`components of a pharmaceutical composition. The ’170 patent specification does
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`not define the term “pharmaceutically acceptable . . . adjuvants.” As such, for
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`prior art purposes, the term “pharmaceutically acceptable . . . adjuvants” can
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`reasonably be understood to include “a substance added to a drug product
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`formulation which affects the action of the active ingredient in a predictable way.”
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`Stedman’s Medical Dictionary, 25th Ed., 1990, at 28 (Ex. 1022); Ex. 1002, ¶ 30.
`VII. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO MARCH 27, 1995
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`The following background publications are discussed in the context of the
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`knowledge and perspective of one of ordinary skill in the relevant art. This
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`provides a factual basis for the discussion about what one of ordinary skill in the
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`relevant art would have known at the time of the invention, assumed for the
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`purposes of this Petition to be the earliest alleged foreign priority date, i.e., March
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`27, 1995, and documents the knowledge that skilled artisans would bring to bear in
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`reading the prior art. Ariosa Diagnostics v. Verinata Health, Inc., 805 F.3d 1359
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`(Fed. Cir. 2015). This knowledge assists in understanding why one of ordinary
`
`skill would have been motivated to combine or modify the references asserted in
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`the grounds of this petition to arrive at the claimed invention. As KSR established,
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`the knowledge of such an artisan is part of the store of public knowledge that must
`
`be consulted when considering whether a claimed invention would have been
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`obvious. Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir. 2013).
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`The state of the art as of March 27, 1995: (i) provided the basis for one of
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`ordinary skill in the art to select a taxane-based compound for the treatment of
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`cancer, (ii) identified the relationship between structure and activity for the various
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`taxoid functional groups, and (iii) identified numerous factors motivating those of
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`ordinary skill in the art to modify the taxoid core to produce more efficient
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`chemotherapeutic candidates. Ex. 1002, ¶ 31.
`
`Taxanes are a class of diterpenoids produced by plants of the genus Taxus,
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`which have a long and significant history in treating cancer. P. Potier et al.,
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`Chemical Studies of 10-Deacetyl Baccatin III: Hemisynthesis of Taxol Derivatives
`
`42 TETRAHEDRON 4451 (1986) (“Potier,” Ex. 1008). Paclitaxel, known by the
`
`trade name Taxol®, was the first formally isolated taxane, and was extracted from
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`the stem bark of the very slow-growing yew tree at a low yield. See id. at 4451;
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`Ex. 1011 at 1; Ex. 1002, ¶¶ 32-34. The structure of paclitaxel is shown below:
`
`
`
`In the decades following its isolation, paclitaxel was shown to have efficacy
`
`both in vitro and in vivo against a range of cancers in mice. See L. Kelland et al.,
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`Comparative In Vitro Cytotoxicity of Taxol and Taxotere against Cisplatin-
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`Sensitive and –Resistant Human Ovarian Carcinoma Cell Lines 30 CANCER
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`CHEMOTHER. PHARMACOL. 444 (1992) (“Kelland,” Ex. 1010) at 445. Paclitaxel
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`was subsequently approved by the Food and Drug Administration (FDA) for the
`
`treatment of cancer and is known to exhibit impressive biological activities against
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`a range of human cancers. See id.at 445; Ex. 1002, ¶¶ 34-35. Paclitaxel’s high
`
`activity has been attributed, in part, to its ability to promote tubulin polymerization
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`and stabilization of microtubules, thereby leading to cell death. See Ex. 1010 at
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`445; Ex. 1002, ¶ 34.
`
`Despite paclitaxel’s promising biological profile, its development as a
`
`therapeutic agent was hindered by its scarcity. Paclitaxel is produced in very low
`
`concentration by yew trees, and its isolation required destruction of the plant.
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`Furthermore, paclitaxel possesses an intricate chemical structure, making its
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`complete synthesis from commercially available precursors impractical. See Ex.
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`1010 at 445; Ex. 1002, ¶ 35.
`
`The 1981 discovery of 10-deacetyl baccatin III, structure shown below, was
`
`a critical development in the advancement of taxoid anti-cancer agents:
`
`
`
`
`
`Ex. 1010 at 445; Ex. 1002, ¶ 36. 10-Deacetyl baccatin III could be isolated from a
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`renewable source, the needles of the English yew, Taxus baccata, without harming
`
`the plant itself. See Ex. 1010 at 445. In addition, the English yew has a growth rate
`
`far faster than the Pacific yew, making 10-deacetyl baccatin III a more accessible
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`starting compound for the development of future drug candidates. See Ex. 1010;
`
`Ex. 1002, ¶ 36. 10-Deacetyl baccatin III possesses the identical polycyclic, taxoid
`
`core structure of paclitaxel, differing only at two positions: the C-10 and C-13
`
`positions of paclitaxel bear specific acyl groups, whereas those of 10-deacetyl
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`baccatin III are hydroxyl groups. Ex. 1002, ¶ 37. A synthetic route from 10-
`
`deacetyl baccatin III to paclitaxel was later identified in 1981, thereby significantly
`
`increasing access to paclitaxel. Ex. 1018 at 1008; Ex. 1002, ¶ 38. Identifying 10-
`
`deacetyl baccatin III proved to be important in the advancement of taxane therapy
`
`because it (i) allowed for more efficient bulk production of paclitaxel and (ii)
`
`served as an advanced precursor from which related taxoids could be synthesized.
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`Ex. 1002, ¶ 38. Esterification of 10-deacetyl baccatin III with a synthetic side
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`chain resulted in the compound now known as docetaxel (Taxotere®), shown
`
`below:
`
`Ex. 1002, ¶ 38, citing Kelland, Ex. 1010.
`
`By March 1995, it was understood in the art that taxanes, as a group, possess
`
`a common biological mechanism. Ex. 1002, ¶ 39. As described by Verweij,
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`docetaxel and paclitaxel were shown to have the same mode of action resulting in
`
`
`
`cell death:
`
`Taxanes bind preferentially and reversibly to the β-subunit of tubulin
`
`in the microtubules . . . enhanc[ing] polymerization of the tubulin into
`
`stable microtubules . . . This disruption of the normal equilibrium
`
`ultimately leads to cell death.
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`
`J. Verweij et al., Paclitaxel (Taxol) and Docetaxel (Taxotere): Not Simply Two of a
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`Kind, 5 ANN. ONCOL. 495 (1994) (“Verweij,” Ex. 1011) at 496.
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`Docetaxel was shown to have greater activity than paclitaxel against a
`
`variety of cancer cell lines. Ex. 1002, ¶ 40, citing Ex. 1010 at 444. Docetaxel had
`
`greater efficacy than paclitaxel in in vivo cancer models using the L1210 and P388
`
`cancer cell lines. Id. Verweij (Ex. 1011) also describes variations in activity
`
`between docetaxel and paclitaxel, and highlights the greater potency of docetaxel
`
`in terms of its depolymerization inhibition and activity against various cancer cell
`
`lines:
`
`Paclitaxel and docetaxel . . . share major parts of their structures and
`
`mechanisms of action, but differ in several other aspects. For instance,
`
`there is a difference in their tubulin polymer generation, and
`
`docetaxel appears twice as active in depolymerization inhibition. In
`
`vitro docetaxel also tends to be more potent in different cell lines
`
`and investigational models.
`
`Ex. 1011 at 495. (emphasis added).
`
`
`
`In addition to greater potency against certain cancers, docetaxel also
`
`demonstrates a longer half-life relative to paclitaxel. Ex. 1002, ¶¶ 40-41, 99, citing
`
`Verweij, Ex. 1011, at 496. Further, Verweij teaches that a higher percentage of
`
`cancer cell lines respond more strongly to docetaxel:
`
`[I]n a head to head comparison, 29 specimens were found to be more
`
`sensitive to docetaxel, while only 13 were more sensitive to paclitaxel.
`
`Thus these data suggested . . . a higher potency of docetaxel in the
`
`majority of specimens.
`
`Ex. 1002, ¶ 41, quoting from Ex. 1011 at 496 (emphasis added).
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`
`
`Following the identification of docetaxel as a potent drug candidate, Verweij
`
`describes the importance of the taxane compounds and notes that practitioners
`
`would be pursuing the development of further analogues, stating:
`
`It is clear that the taxane drugs will be a major addition to the
`
`presently available classes of drugs . . . As the mechanism of action of
`
`these drugs is new, analogue development will undoubtedly be one of
`
`the main topics in the next few years.
`
`Ex. 1011 at 503; see also, Ex. 1002, ¶ 42.
`
`Similarly, in a 1994 discus