`
`AO 120 fRev. 08/10)
`
`TO:
`
`Mail Stop 8
`Director of the U.S. Patent and Trademark
`Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`REPORT ON THE
`FILING OR DETERMINATION OF AN
`ACTION REGARDING A PATENT OR
`TRADEMARK
`
`In Compliance with 35 U.S.C. § 290 and/or 15 U.S.C. § 1116 you are hereby advised that a court action has been
`filed in the U.S. District Court for the District of New Jersey on the following:
`__ Trademarks or X Patents. ( __ the patent action involves 35 U.S.C. § 292.)
`
`[dDATE FILED
`DOCKET NO.
`3:14-cv-08079-MAS-LH 12/30/2014
`PLAINTIFF
`SANOFI-AVENTIS U.S. LLC
`
`U.S. DISTRICT COURT
`TRENTON NJ
`DEFENDANT
`ACCORD HEALTHCARE, INC.
`
`DATE OF PATENT
`OR TRADEMARK
`12/8/1998
`
`HOLDER OF PATENT OR TRADEMARK
`
`AVENTIS PHARMA S.A.
`
`PATENTOR
`TRADEMARK NO.
`15,847170
`2
`3
`4
`5
`
`In the above--entitled case the followimr natent( s )/trademark( s) have been included:
`DATE INCLUDED
`INCLUDED BY
`
`-
`
`Amendment
`
`-
`
`Answer
`
`-
`
`Cross Bill
`
`_ Other Pleading
`
`DATE OF PATENT
`OR TRADEMARK
`
`HOLDER OF PATENT OR TRADEMARK
`
`PATENTOR
`TRADEMARK NO.
`1
`2
`3
`4
`5
`
`In the above--entitled case the followin!l decision has been rendered or iud!lement issued:
`DECISION/JUDGEMENT
`
`CLERK
`William T. Walsh
`
`(BY) DEPUTY CLERK
`s/ JAWEIA CAMPBELL
`
`DATE
`12/30/2014
`
`Copy 1--Upon initiation of action, mail this copy to Director Copy 3--Upon termination of action, mail this copy to Director
`Copy 2--Upon filing document adding patent(s), mail this copy to Director Copy 4--Case file copy
`
`NEPTUNE GENERICS EX. 00001
`
`
`
`Case 3:14-cv-08082-~..;iAS-LHG Docurnent 3 Filed 12/29/14 Page 1of1 Page!D: 51
`
`AO 120 fRev. 08/10)
`
`TO:
`
`Mail Stop 8
`Director of the U.S. Patent and Trademark
`Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`REPORT ON THE
`FILING OR DETERMINATION OF AN
`ACTION REGARDING A PATENT OR
`TRADEMARK
`
`In Compliance with 35 U.S.C. § 290 and/or 15 U.S.C. § 1116 you are hereby advised that a court action has been
`filed in the U.S. District Court for the District of New Jersey on the following:
`__ Trademarks or X Patents. ( __ the patent action involves 35 U.S.C. § 292.)
`
`[dDATE FILED
`DOCKET NO.
`3:14-cv-08082-MAS-LH 12/29/2014
`PLAINTIFF
`SANOFI-AVENTIS U.S. LLC
`
`U.S. DISTRICT COURT
`TRENTON. NJ
`DEFENDANT
`FRESENIUS KABI USA, LLC
`
`DATE OF PATENT
`OR TRADEMARK
`12/8/1998
`7/10/2007
`
`HOLDER OF PATENT OR TRADEMARK
`
`Aventis Pharma S.A.
`Aventis Pharma S.A.
`
`PATENTOR
`TRADEMARK NO.
`15,847170
`2 7,241,907
`3
`4
`5
`
`In the above--entitled case the followimr natent( s )/trademark( s) have been included:
`DATE INCLUDED
`INCLUDED BY
`
`-
`
`Amendment
`
`-
`
`Answer
`
`-
`
`Cross Bill
`
`_ Other Pleading
`
`DATE OF PATENT
`OR TRADEMARK
`
`HOLDER OF PATENT OR TRADEMARK
`
`PATENTOR
`TRADEMARK NO.
`1
`2
`3
`4
`5
`
`In the above--entitled case the followin!l decision has been rendered or iud!lement issued:
`DECISION/JUDGEMENT
`
`CLERK
`William T. Walsh
`
`(BY) DEPUTY CLERK
`s/ Melissa M. Haneke
`
`DATE
`12/29/2014
`
`Copy 1--Upon initiation of action, mail this copy to Director Copy 3--Upon termination of action, mail this copy to Director
`Copy 2--Upon filing document adding patent(s), mail this copy to Director Copy 4--Case file copy
`
`NEPTUNE GENERICS EX. 00002
`
`
`
`Case 3:15-cv-00287-~..;iAS-LHG Docurnent 3 Filed 01/15/15 Page 1of1 Page!D: 55
`
`AO 120 fRev. 08/10)
`
`TO:
`
`Mail Stop 8
`Director of the U.S. Patent and Trademark
`Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`REPORT ON THE
`FILING OR DETERMINATION OF AN
`ACTION REGARDING A PATENT OR
`TRADEMARK
`
`In Compliance with 35 U.S.C. § 290 and/or 15 U.S.C. § 1116 you are hereby advised that a court action has been
`filed in the U.S. District Court for the District of New Jersey on the following:
`X Trademarks or __ Patents. ( __ the patent action involves 35 U.S.C. § 292.)
`
`IDATE FILED
`DOCKET NO.
`3:15-cv-00287-MAS-LHG 1/15/2015
`PLAINTIFF
`SANOFI-AVENTIS U.S. LLC
`
`U.S. DISTRICT COURT
`TRENTON NJ
`DEFENDANT
`APOTEX CORP.
`
`DATE OF PATENT
`OR TRADEMARK
`12/8/99
`7/10/2007
`
`HOLDER OF PATENT OR TRADEMARK
`
`Aventis Pharma S.A.
`Aventis Pharma S.A.
`
`PATENTOR
`TRADEMARK NO.
`15847170
`2 7,241,907
`3
`4
`5
`
`In the above--entitled case the followimr natent( s )/trademark( s) have been included:
`DATE INCLUDED
`INCLUDED BY
`
`-
`
`Amendment
`
`-
`
`Answer
`
`-
`
`Cross Bill
`
`_ Other Pleading
`
`DATE OF PATENT
`OR TRADEMARK
`
`HOLDER OF PATENT OR TRADEMARK
`
`PATENTOR
`TRADEMARK NO.
`1
`2
`3
`4
`5
`
`In the above--entitled case the followin!l decision has been rendered or iud!lement issued:
`DECISION/JUDGEMENT
`
`CLERK
`William T. Walsh
`
`(BY) DEPUTY CLERK
`s/ BETH JONIAK
`
`DATE
`1/15/2015
`
`Copy 1--Upon initiation of action, mail this copy to Director Copy 3--Upon termination of action, mail this copy to Director
`Copy 2--Upon filing document adding patent(s), mail this copy to Director Copy 4--Case file copy
`
`NEPTUNE GENERICS EX. 00003
`
`
`
`Case 3:15-cv-00290-~..;iAS-LHG Docurnent 4 Filed 01/15/15 Page 1of1 Page!D: 55
`
`AO 120 fRev. 08/10)
`
`TO:
`
`Mail Stop 8
`Director of the U.S. Patent and Trademark
`Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`REPORT ON THE
`FILING OR DETERMINATION OF AN
`ACTION REGARDING A PATENT OR
`TRADEMARK
`
`In Compliance with 35 U.S.C. § 290 and/or 15 U.S.C. § 1116 you are hereby advised that a court action has been
`filed in the U.S. District Court for the District of New Jersey on the following:
`__ Trademarks or X Patents. ( __ the patent action involves 35 U.S.C. § 292.)
`
`IDATE FILED
`DOCKET NO.
`3:15-cv-00290-PGS-LHG 1/15/2015
`PLAINTIFF
`SANOFI-AVENTIS U.S. LLC
`
`U.S. DISTRICT COURT
`TRENTON NJ
`DEFENDANT
`ONCO THERAPIES LIMITED
`
`DATE OF PATENT
`OR TRADEMARK
`12/8/1998
`7/10/2007
`
`HOLDER OF PATENT OR TRADEMARK
`
`AVENTIS PHARMA S.A.
`AVENTIS PHARMA S.A.
`
`PATENTOR
`TRADEMARK NO.
`15,847170
`2 7,241,907
`3
`4
`5
`
`In the above--entitled case the followimr natent( s )/trademark( s) have been included:
`DATE INCLUDED
`INCLUDED BY
`
`-
`
`Amendment
`
`-
`
`Answer
`
`-
`
`Cross Bill
`
`_ Other Pleading
`
`DATE OF PATENT
`OR TRADEMARK
`
`HOLDER OF PATENT OR TRADEMARK
`
`PATENTOR
`TRADEMARK NO.
`1
`2
`3
`4
`5
`
`In the above--entitled case the followin!l decision has been rendered or iud!lement issued:
`DECISION/JUDGEMENT
`
`CLERK
`William T. Walsh
`
`(BY) DEPUTY CLERK
`s/ JAWEIA CAMPBELL
`
`DATE
`1/15/2015
`
`Copy 1--Upon initiation of action, mail this copy to Director Copy 3--Upon termination of action, mail this copy to Director
`Copy 2--Upon filing document adding patent(s), mail this copy to Director Copy 4--Case file copy
`
`NEPTUNE GENERICS EX. 00004
`
`
`
`Case 3:15-cv-00776-~..;iAS-LHG Docurnent 3 Filed 02/02/15 Page 1of1 Page!D: 56
`
`AO 120 fRev. 08/10)
`
`TO:
`
`Mail Stop 8
`Director of the U.S. Patent and Trademark
`Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`REPORT ON THE
`FILING OR DETERMINATION OF AN
`ACTION REGARDING A PATENT OR
`TRADEMARK
`
`In Compliance with 35 U.S.C. § 290 and/or 15 U.S.C. § 1116 you are hereby advised that a court action has been
`filed in the U.S. District Court for the District of New Jersey on the following:
`__ Trademarks or X Patents. ( __ the patent action involves 35 U.S.C. § 292.)
`
`IDATE FILED
`DOCKET NO.
`3:15-cv-00776-MAS-LHG 2/2/2015
`PLAINTIFF
`SANOFI-AVENTIS U.S. LLC
`
`U.S. DISTRICT COURT
`TRENTON.NJ
`DEFENDANT
`ACTAVISLLC
`
`DATE OF PATENT
`OR TRADEMARK
`12/8/1998
`7/10/2007
`
`HOLDER OF PATENT OR TRADEMARK
`
`AVENTIS PHARMA S.A.
`AVENTIS PHARMA S.A.
`
`PATENTOR
`TRADEMARK NO.
`15,847170
`2 7,241,907
`3
`4
`5
`
`In the above--entitled case the followimr natent( s )/trademark( s) have been included:
`DATE INCLUDED
`INCLUDED BY
`
`PATENTOR
`TRADEMARK NO.
`
`DATE OF PATENT
`OR TRADEMARK
`
`HOLDER OF PATENT OR TRADEMARK
`
`-
`
`Amendment
`
`-
`
`Answer
`
`-
`
`Cross Bill
`
`_ Other Pleading
`
`1
`2
`3
`4
`5
`
`In the above--entitled case the followin!l decision has been rendered or iud!lement issued:
`DECISION/JUDGEMENT
`
`CLERK
`William T. Walsh
`
`(BY) DEPUTY CLERK
`s/ JAWEIACAMPBELL
`
`DATE
`2/2/2015
`
`Copy 1--Upon initiation of action, mail this copy to Director Copy 3--Upon termination of action, mail this copy to Director
`Copy 2--Upon filing document adding patent(s), mail this copy to Director Copy 4--Case file copy
`
`NEPTUNE GENERICS EX. 00005
`
`
`
`Case 3:16~cv-0567fHv1AS-U-IG Document 3 Filed 09/19/16 Page 1of1 PagelD: 68
`
`AO 120 (Rev. 08/10)
`
`TO:
`
`Mail Stop8
`Director of the U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`REPORT ON THE
`FILING OR DETERMINATION OF AN
`ACTION REGARDING A PATENT OR
`TRADEMARK
`
`In Compliance with 35 U.S.C. § 290 and/or 15 U.S.C. § l 116 you are hereby advised that a court action has been
`for the District of New Jersey
`filed in the U.S. D.istrict Court
`on the following
`D Trademarks or
`~Patents. ( D the patent action involves 35 U.S.C. § 292.):
`
`DOCKET NO.
`If;-..$~ 'f ~
`PLAINTIFF
`
`DATE FILED
`9/16/2016
`
`U.S. DISTRICT COURT
`for the District of New Jersev
`DEFENDANT
`
`SANOFI-AVENTIS U.S. LLC, AVENTIS PHARMA S.A.
`and SANOFI
`
`SANDOZ INC.
`
`PATENTOR
`TRADEMARK NO.
`
`DATE OF PATENT
`OR TRADEMARK
`
`HOLDER OF PATENT OR TRADEMARK
`
`1 5,847,170
`
`2 8,927,592
`
`12/8/1998
`
`1/6/2015
`
`Aventis Pharma S.A.
`
`Aventis Pharma S.A.
`
`3
`
`4
`
`5
`
`In the above----entitled c.ase, the following patent(s)/ trademark(s) have been included:
`
`DATE INCLUDED
`
`PATENTOR
`TRADEMARK NO.
`
`INCLUDED BY
`
`D Amendment
`DATE OF PATENT
`OR TRADEMARK
`
`D Answer
`
`D CrossBill
`
`D Other Pleading
`
`HOLDER OF PA TENT OR TRADEMARK
`
`I
`
`2
`
`3
`
`4
`
`5
`
`In the above--entitled case, the following decision has been rendered or judgement issued:
`
`DECISION/JUDGEMENT
`
`CLERK
`
`WILLIA
`
`DATE
`
`Copy 1-Upon initiation of action, mail this copy to Director Copy 3.-Upon termination of action, mail this copy to Director
`Copy 2-Upon filing document adding patent(s), mail this copy to Director Copy 4----Case file copy
`
`NEPTUNE GENERICS EX. 00006
`
`
`
`Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 10
`Entered: August 23, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN LABO RA TORIES LIMITED,
`Petitioner,
`
`v.
`
`AVENTIS PHARMA S.A.,
`Patent Owner.
`
`Case IPR2016-00627
`Patent 5,847,170
`
`Before: BRIAN P. MURPHY, TINA E. HULSE, and CHRISTOPHER M.
`KAISER, Administrative Patent Judges.
`
`MURPHY, Administrative Patent Judge.
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`NEPTUNE GENERICS EX. 00007
`
`
`
`IPR2016-00627
`Patent 5,847,170
`
`I.
`
`INTRODUCTION
`
`Mylan Laboratories Limited ("Petitioner") filed a Petition requesting
`
`an inter partes review of claims 1 and 2 of U.S. Patent No. 5,847,170 (Ex.
`
`1001, "the '170 patent"). Paper 3 ("Pet."). Aventis Pharma S.A. ("Patent
`
`Owner"), filed a Preliminary Response to the Petition. Paper 8 ("Prelim.
`
`Resp."). We have statutory authority under 35 U.S.C. § 314(a), which
`
`provides that an inter partes review may not be instituted "unless ... there is
`
`a reasonable likelihood that the petitioner would prevail with respect to at
`
`least 1 of the claims challenged in the petition."
`
`Petitioner challenges claims 1 and 2 of the '170 patent as unpatentable
`
`under 35 U.S.C. § 103(a). Pet. 13-14. Based on the arguments and
`
`evidence presented in the Petition and Preliminary Response, we are not
`
`persuaded there is a reasonable likelihood Petitioner would prevail with
`
`respect to at least one of the claims challenged in the Petition. Therefore, we
`
`decline to institute inter partes review.
`
`A. Related Proceedings
`
`Petitioner identifies the following as related district court proceedings
`
`in the District of New Jersey regarding the' 170 patent: Sanofi-Aventis US.
`
`LLC, Aventis Pharma SA. and Sanofi v. Mylan Laboratories Ltd., C. A. No.
`
`3: l 5-cv-00290 (MAS)(LHG); Sanofi-Aventis US. LLC et al. v. Fresenius
`
`Kabi USA, LLC, C. A. No. 14-07869 (MAS)(LHG); Sanofi-Aventis US.
`
`LLC et al. v. Accord Healthcare, Inc., C. A. No. 14-08079 (MAS)(LHG);
`
`Sanofi-Aventis US. LLC et al. v. BPI Labs, LLC et al., C. A. No. 14-08081
`
`(MAS)(LHG); Sanofi-Aventis US. LLC et al. v. Fresenius Kabi USA, LLC,
`
`C. A. No. 14-08082 (MAS)(LHG); Sanofi-Aventis US. LLC et al. v. Apotex
`
`Corp. et al., C. A. No. 15-0287 (MAS)(LHG); Sanofi-Aventis US. LLC et
`
`2
`
`NEPTUNE GENERICS EX. 00008
`
`
`
`IPR2016-00627
`Patent 5,847,170
`
`al. v. Breckenridge Pharmaceutical, Inc., C. A. No. 15-0289 (MAS)(LHG);
`
`Sanofi-Aventis US LLC et al. v. Mylan Laboratories Limited, C. A. No. 15-
`
`0290 (MAS)(LHG); and Sanofi-Aventis US. LLC et al. v. Actavis LLC et al.,
`
`C. A. No. 15-0776 (MAS)(LHG). Pet. 12-13.
`
`B. Proposed Grounds of Unpatentability
`
`Petitioner advances two grounds of unpatentability under 35 U.S.C.
`
`§ 103( a) in relation to the challenged claims in the '170 patent:
`
`Reference[s]
`
`Kant (Ex. 1005) 1 in view of Klein (Ex.
`1006)2
`
`Colin (Ex. 1007)3 in view of Klein and
`Kant
`
`Statutory Challenged
`Basis
`Claims
`§ 103
`1 and2
`
`§ 103
`
`1and2
`
`Pet. 13-14. Petitioner supports its challenge with a Declaration by Eric N.
`
`Jacobsen, Ph.D. ("Jacobsen Deel."). Ex. 1002.
`
`C. The '170 Patent
`
`The '170 patent, titled "Taxoids, Their Preparation and
`
`Pharmaceutical Compositions Containing Them," issued December 8, 1998,
`
`1 Kant et al., A Chemoselective Approach to Functionalize the C-10
`Position of 10-Deacetylbaccatin Ill Synthesis and Biological Properties of
`Novel C-10 Taxol®Analogues, Tetrahedron Letters, 35 (31), 5543-46
`(1994) ("Kant"). Ex. 1005.
`2 Klein et al., Ch. 20 Chemistry and Antitumor Activity of 9(R)(cid:173)
`Dihydrotaxanes in Taxane Cancer Agents, ACS Symposium
`Series Vol. 58, 276-287 (Georg et al., eds., 1994). Ex. 1006.
`3 U.S. Patent No. 4,814,470 issued March 21, 1989 to Colin et al. ("Colin").
`Ex. 1007.
`
`3
`
`NEPTUNE GENERICS EX. 00009
`
`
`
`IPR2016-00627
`Patent 5,847,170
`
`from an application filed March 26, 1996. Ex. 1001.4 The '170 patent is
`
`directed to new taxoids of general formula (I):
`
`(C)
`
`Z-0111
`
`0
`
`in which:
`Z represents a hydrogen atom or a radical of general
`formula (II):
`
`(H)
`
`OH
`
`Ex. 1001, 1 :7-28. The '170 patent discloses and claims, in particular, a
`
`compound known as cabazitaxel, pharmaceutical compositions containing
`
`cabazitaxel, and processes to prepare cabazitaxel. Id. at 12:52-13:33. The
`
`compounds of the '170 patent, including cabazitaxel, inhibit abnormal cell
`
`proliferation and have "antitumour properties, and more especially activity
`
`against tumours which are resistant to Taxol® or to Taxotere®."5 Id. at
`
`11:59-61, 26:32-37. Cabazitaxel is indicated for treatment of certain types
`
`of prostate cancer. Ex. 2002.
`
`4 The '170 patent claims priority to a provisional application dated January
`17, 1996 and to French applications 95 03545 and 95 15381, dated March
`27, 1995 and December 22, 1995, respectively. Ex. 1001, [60], [30].
`5 Taxol® is the brand name for paclitaxel. Taxotere® is the brand name for
`docetaxel. We also refer to "Taxol" and "Taxotere" in this Decision.
`4
`
`NEPTUNE GENERICS EX. 00010
`
`
`
`IPR2016-00627
`.Patent 5,847, 170
`
`.
`-
`.
`The chemical name for cabazitaxel is 4a-acetoxy-2a-benzoyloxy-
`
`5P,20-epoxy-lp-hydroxy-7p, 1 op-dimethoxy-9-oxo-11-taxen-13a-yl(2R,3 S)-
`
`.
`
`I
`
`3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpro~ionate. Id. at 13:9-12,
`
`28:57-60. The chemical structure of cabazitaxel is:
`
`I
`
`~ rhCO
`·o~~H O·
`v
`~o"'
`6H
`
`I
`
`\
`Pet. 3. Of particular interest in cabazitaxel are the presence of a methoxy
`
`group ( OCH3) at both the C-7 position (Rs in formula I) and C-10 position
`
`(R4 in formula I), and a carbonyl (C=O) at the C-9 position. Ex. 1001, 2:40-
`
`'
`
`I
`
`•
`
`42, 3:1-3.
`
`The prior art paclitaxel and docetaxel compound structures are.shown
`
`below.
`
`AcO
`
`CJ·
`O:ZH -
`0
`1~~0'"
`V
`6H
`.
`Paclltaxel
`(Taxol®)
`
`·, ~o.
`
`OHo 6Ac 00
`
`~ 0
`
`··. , o
`OANH dio·"
`· (Col~~:~~e 1; . c°)-;Ac
`Taxotere®) u
`
`Pet. 9; Ex. 1002 ~~ 36-38. Paclitaxel and docetaxel are synthesized from a
`
`key "advanced precursor" known as 10-deacetyl baccatin III ("10-DAB").
`5
`
`NEPTUNE GENERICS EX. 00011
`
`
`
`IPR2016-00627
`Patent 5,847,170
`
`Ex. 1002 ifif 37-38. Paclitaxel has a different synthetic side chain (left side
`of molecule) than docetaxel, attached to the C-13 position of the core taxoid
`
`structure, and an acetyl (CH3CO or "Ac") group rather than a hydroxyl (OH}
`
`group at C-10. In contrast to cabazitaxel, neither paclitaxel nor. docetaxel
`
`has a ~ethoxy group at C-7 or C-10, although both have a carbonyl at C-9 .,
`
`Id. Cabazitaxel has a docetaxel side chain (i.e., 3'_-NHBOC or(3-tert(cid:173)
`butoxycaronylamino)). Id. ifif 11, 38.
`D. Challenged Claims
`
`Petitioner challenges claims 1 and 2 of the '170 patent, which are
`
`reproduced below:
`
`.
`1. 4a-acetoxy-2a-benzoyloxy-5~,20-epoxy-l~-hydroxy-7~,1 O~-
`dimethoxy-9-oxo-ll-taxen-13a-yl(2R,3S)-3-tert(cid:173)
`butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
`
`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.
`
`II.
`
`ANALYSIS
`
`A. Claim Cunstruction
`
`We determine that no claim terms require express construction for
`
`purposes of this Decision. See, e.g, Wellman, Inc. v. Eastman Chem. Co.,
`
`642 F.3d 1355, 1361 (Fed. Cir. 2011) ("[C]laim ~erms need only be
`
`construed 'to the extent necessary to·resolve the controversy."') (quotation
`
`omitted).
`
`B. Asserted Obviousness of Claims 1 and 2,over Kant and Klein
`
`Petitioner asserts that the subject matter of claims 1 and 2 of the '170
`
`. patent would have ·been obvious to a person of or~inary skill in th,e art .
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`6
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`NEPTUNE GENERICS EX. 00012
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`Patent 5,847,170
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`("POSA") based on the combined teachings of Kant and Klein. Pet. 29-38.
`
`Patent Owner opposes. Prelim. Resp. 18-38. We address the parties'
`
`arguments below.
`
`1. Kant
`
`Kant discloses a "chemoselective approach to functionalize the C-10
`
`. position of 10-deacetyl baccatin III [ 10-DAB ], a key intermediate for the
`
`semi-synthesis of paclitaxel." Ex. 1005, 5543 (Abstract). Kant selects 10-
`
`DAB as "the ideal starting material" for synthesizing analogues of paclitaxel
`
`with the ''aim of obtaining drugs having more desirable properties." Id.
`
`j
`
`~~ 2-3. Kant's reasoning is that "with the more reactive C-7 hydroxyl
`
`protected, an opportunity was available to selectively deprotonate the C-10
`
`hydroxyl." Id. at 5544. Thus, Kant selectively introduced a variety of
`
`,
`
`substituents at the C-10 position of 10-DAB to synthesize "a variety of C-10
`
`paclitaxel analogues" shown in our annotated Table II, below.
`
`r
`
`·7
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`NEPTUNE GENERICS EX. 00013
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`IPR2016-0062 7
`Patent 5,847,170
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`Pndltnel
`A..a-e
`Taxol•
`lS
`16
`17
`
`18
`19
`20
`21
`22
`23
`24
`
`Ri
`
`Ri
`
`TableD
`9& Yll!ld
`.
`go
`
`Pb
`COMc
`<X>Bu
`
`co<J
`
`CONt'Meh
`Me
`Me
`CO., Mc
`
`~Ml!!.
`OOPh
`COPh
`
`Pb
`OSut
`Pb
`Ph
`
`Pb
`Pb
`OBut
`Pb
`OBut
`Ph
`OBut
`
`l"Ubulln
`Rafloll
`1.0
`0.7
`1.S
`1.1
`
`IC.(ll'M)il
`BCl'l16
`l.O
`2.0
`3.4
`2.3
`
`1.0
`1.0
`0.3
`l.l
`0.8
`19
`2.1
`
`1.1
`12.0
`1.3
`3.0
`1.S
`2.2
`2.0
`
`78
`SS
`
`88
`73
`83
`76
`83
`82
`74
`
`-&ulo of°"""'"" rdlillhc to pocl/Mx.d <ECo.01 @S µ/ttl).
`b•Drug t:OllU111N1111Nt rllqlllrd ro ll!/llbll Ct1U proll/mslliHI ro $Q'K, n. 11/fW-.il ct"6 (iltalbalted ill 17-C /Of' n II).
`
`Id. at 5545. Kant Compound 20 contains a methoxy group at C-10 (R1 is
`
`"Me" (methyl)), a hydroxyl group at C-7, a carbonyl at C-9, and a docetaxel
`
`side chain (R2 is "OBut" (tert-butoxy)). Id. Kant concludes "it is reasonable
`
`to suggest that the functional group present at the C-10 position does
`
`modulate the antitumor activity, which is quite contrary to some of the
`
`earlier predictions." Id. at 5546.
`
`1
`
`2. Klein
`
`Klein discloses 9(R)-dihydrotaxanes, ~new family of compounds
`
`having "increased water solubility and stability as compared to taxol
`
`[paclitaxel] and also exhibit[ing] excellent activity in tumor models." Ex.
`
`1006, 276 (Abstract). Klein highlights several advantages of replacing the
`
`C-9 carbonyl with a hydroxyl in both Taxol (paclitaxel) and Taxotere
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`8
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`( docetaxel): 1) the C-9 hydroxyl "serves as an additional site for
`
`modifications," 2) the C-9 hydroxyl "increase[s] the water solubility of these
`
`analogs," and 3) the absence of a C-9 carbonyl "stabilize[s] the system." Id.
`
`at 277. Klein discloses the synthesis of 9(R)-dihydrotaxol and 9(R)(cid:173)
`
`dihydrotaxotere, which exhibit enhanced stability and aqueous solubility
`
`compared to paclitaxel and docetaxel due to the C-9 hydroxyl replacing the
`
`C-9 carbonyl, while maintaining "good efficacy." Id. at 279-280 (Table I).
`
`Klein also experiments with substituting the C-7 and/or the C-9
`
`hydroxyl groups with various alkylating substituents. Id. at 281. The
`
`experimental compounds include a methoxy group at C-9 (entry 7) or at C-7
`
`(entries 8 and 10, with a hydroxyl at C-9), and all have an acetyl at C-10, as
`
`shown in our annotated Table III, below.
`
`9
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`NEPTUNE GENERICS EX. 00015
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`IPR2016-00627
`Patent 5,847,170
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`C-l<lco C-9
`o
`OR1
`,.,·"'NH o ~R2 c-7
`n.~o-
`....
`HO
`
`HO
`
`I II
`
`lllO """
`
`0
`
`Table Ill. Tumor Cell Cytotoxicity or C-7,9 Analogs
`Tumor cell tines, ICso (ng/mL)
`Compound
`Entry R1 C-9
`R1 C-7
`A549
`Hl·29
`BJ6FlQ
`25
`16-22
`6.4-9.6
`1.
`H
`H
`12
`S>·Dihyd.-otaxol
`2. H
`CH20lCOH)CH:zQH >100
`
`>100
`
`>100
`
`P388
`4§.57
`>100
`
`>100
`
`>100
`
`42
`
`35
`
`7.8
`
`3.9
`
`5.3
`
`0.6
`
`>100
`79
`
`26
`
`11
`
`3.1
`
`1.4
`
`1.2
`
`>100
`
`25
`
`19
`
`4.7
`
`1.2
`
`1
`
`>100
`
`90
`
`34
`
`20
`
`4.8
`
`1.5
`
`2.7
`
`0.2
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`H
`
`OH
`
`*OM
`
`CH3
`
`H
`
`H
`
`CH3
`
`9. H
`
`10.
`
`H
`
`CH2CH--oI2
`
`CH3 (3' -NBoc)
`
`0.21
`
`0.15
`
`Id. at 281. Klein observes that the methylated C-7 analog in entry 10
`
`exhibits "extremely potent cytotoxicity." Id. at 282.
`
`3. Analysis
`
`Petitioner acknowledges that "Kant does not describe the C-7
`
`methoxy substitution needed to form" cabazitaxel. 6 Pet. 28. Petitioner
`
`further acknowledges that "Klein does not disclose the C-10 methoxy
`
`substitution" in cabazitaxel. Id. Petitioner argues, however, that a POSA
`
`would have selected Kant's Compound 20 "for further modification" (a so-
`
`6 Petitioner refers to cabazitaxel as 7, 10-dimethoxy docetaxel. Pet. 28.
`10
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`NEPTUNE GENERICS EX. 00016
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`.
`.
`,
`called "lead compound") because of its superior binding ability and
`
`(
`
`cytotoxicity among the chemical analogues having the docetaxel side chain.
`
`Pet. 31 (citing Ex. 1002 ~~ 79-81). Petitioner reaso~s that a POSA would
`.
`have modified Kant Compound 20 in view of Klein's Table III (compounds
`
`'
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`8 and 10), teaching increased anti-tumor potency by s,t:tbstituting a methoxy
`
`group for a hydroxyl group at C-7, which would have led to the synthesis of
`
`cabazitaxel. Id. at 32-33.
`
`We agree with Patent Owner that Petitioner's evidence is insufficient
`
`to establish a sufficient motivation for a POSA to have selected Kant's
`
`Compound 20 as a lead compound for further modification in view of
`
`Klein's Table III (compounds 8 and 10), to synthesize cabazitaxel with a
`
`reasonable expectation of success. Prelim. Resp. 20-37. For compositions
`
`containing new chemical compounds, there must have been a reason for a
`'
`POSA to: (1) select the prior art "most promising to modify" (referred to as
`
`the "lead compound"), and (2) make all of the necessary modifications to
`
`arrive at tlie claimed invention. Otsuka Pharm. ·co., Ltd. v. Sandoz, Inc.,
`
`678 F.3d 1280, 1291-92 (Fed. 'cir. 2012); see also Daiichi Sankyo Co. v.
`
`Matrix Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010) ("[T]he attribution
`
`of a compound as a lead compound after the fact must avoid hindsight bias;
`
`it must look at the state of the art at the time the invention was made to find
`
`a motivation to select and then modify a lead compound to arrive at the
`.
`claimed invention."). There also must have been a "reasonable expectation"
`""
`both of making the new compound, and of its advantageous properties.
`
`"
`
`Otsuka Pharm., 678 F.3d at 1292 (cit~ng Takeda Chem. Indus., Ltd. v.
`
`Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)).
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`11
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`a. Kant Compound 20 as a lead compound
`
`~
`
`We begin by observing that Kant uses IO-DAB as ''the ideal starting
`.
`material" to synthesize paclitaxel analogues by selective substitution at only
`' the C-10 position. Ex. 1005, 5543 ~ 3. Kant does not teach or suggest
`additional structural modifications to Compound 20 or docetaxel, which cuts
`
`(
`
`against the notion of selecting"K~t Compound 20 as a lead compound for .
`
`further modification of this docetaxel analogue. Kant itself indicates the
`
`authors chose to use 10-DAB as the starting material for making selective C-
`
`10 substitutions in order to synthesize "novel paclitaxel analogues." Id.
`
`We agree with Patent Owner that Petitioner also errs by starting with a
`
`hinqsight-biased structural comparison of docetaxt:l, Kant Compound 20,
`
`and cabazitaxel in side-b~-side fashion .. Prelim. Resp. 31-34 (citing Pet.
`
`31 ). As noted by Patent Owner, without a docetaxel control, Kant does not
`
`provide any information as to whether a particular compound performs
`
`better or worse than docetaxel. Id. at 33. Kant inakes clear that the authors
`
`wer~ synthesizing paclitaxel analogues and using paclitaxel, not docetaxel,
`
`as a control. Ex. 1005, 5545 Table II n.a (ICso cytotoxicity measured as a
`
`"[r]atio of analogue relative to paclitaxel"). In addition to Compound 20,
`
`Kant also identifies Compound 22, which has a methyl carbonate group
`
`rather than a methoxy group at C-10, as more cytotoxic than paclitaxel or C(cid:173)
`
`l 0 acetyl taxotere ( docetaxel). Ex. 1005, 5546. Kant does not otherwise
`
`analyze the significance of the structural differences between Compounds 20
`
`\
`
`and 22 or the other synthesized compouhds, apart from generally
`
`recognizing that the functional group at C-10 modulates antitumor activity.
`
`Id.
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`12
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`Kant also does not teach or suggest the possibility of simultaneous ,
`
`substitution of both the C-7 and C-10 positions, whether to increase potency
`
`and lipophilicity (cell membrane permeability) as argued by Petitioner (Pet.
`
`21-22, 33), or for some other reason. Prelim. Resp. 20-26. Rat~er, Kant
`
`focuses on the possibility of improving anti-tumor cyto~oxicity of paclitaxel
`
`analogues by selective substitution and functionalization of only the C-10
`
`position, a point aptly made in the title, abstract, and text of Kant's article.
`
`Ex. 1005, 5543 ("a chemoselective approach to functionalize the C-10
`
`position of 10-deacetyl baccatin III'.'), 5544 ("with the more reactive C-7
`
`hydroxyl protected, an opportunity was available to selectively deprotonate
`
`the C-10 hydroxyl'~), 5545 ("a variety of C-10 paclitaxel analogues were
`
`synthesized").
`
`Patent Owner persuasively argues that Petitioner does not address
`
`why a POSA would have ~imultaneously moqified the C-7 and C-10
`
`positions in Kant Compound 20 to optimize lipophilicity, thereby
`
`minimizing aqueous solubility, when a POSA would have known docetaxel
`
`and paclitaxel were highly lipophilic and insoluble in water, which made
`
`their commercial formulatioi;i challenging. Prelim. Resp. 21-24 (citing Ex.
`
`1006; Ex. 1011, 495 ("[Paclitaxel] is highly lipophilic and insoluble in
`
`water, but soluble in Cremophor EL, polyethylene glycols 300 and 400,
`
`./
`
`chloroform, acetone, ethanol and methanol. For dinical use paclitaxel is
`
`formulated in 50% Cremophor EL and 50% dehydrated alcohol ....
`
`[Docetaxel] is insoluble in water . . . . The formulation used in the most
`
`recent clinical studies consists of 100% polysorbate 80."); Ex. 1015; Ex.
`
`1019, 1:64-67; Ex. 1020, 206 ("Taxol is a promising antitumor agent with
`
`poor water solubility. Intravenous administration of a current taxol
`
`13
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`formulation in a non-aqueous vehicle containing Cremophor EL may cause
`
`allergic reaction and precipitation upon aqueous dilution. . . . The purpose
`
`of this study was to develop an aqueous based i.v. formulation oftaxol that
`
`did not cause precipitation of the drug upon dilution and did not contain
`
`Cremophor EL."); Ex. 2004, 2:42-44; Ex. 2015, 648 ("Because of its limited
`
`aqueous solubility, it was necessary to formulate taxol in a vehicle
`
`consisting of 50% ethanol and 50% Cremophor EL (polyoxyethlated castor
`
`oil), a vehicle with known toxicity in dogs."); Ex. 2024, 45 ("Docetaxel ...
`
`is practically insoluble in water but freely soluble in alcohol, and is currently
`
`formulated in polysorbate 80"); Ex. 2025, 91 ("[Paclitaxel's] poor water
`
`solubility poses delivery problems that have not been adequately resolved.");
`
`Ex. 2026, 996. Petitioner recognizes that alkylating the C-7 and C-10
`
`functional groups would optimize lipophilicity (Pet. 22) but does not address
`
`the well-known problems with lipophilicity and limited aqueous solubility of
`
`intravenously administered paclitaxel and docetaxel. Therefore, we are not
`
`persuaded by Petitioner's argument that a POSA would have been motivated
`
`to optimize lipophilicity in a paclitaxel or docetaxel analogue via
`
`simultaneous substitution of the C-7 and C-10 positions.
`
`For the reasons given above, there is insufficient evidence for us to
`
`conclude that a POSA would have selected Kant Compound 20 as a lead
`
`compound for further modification of both the C-7 and C-10 positions.
`
`b. Rationale for further modifYing Kant Compound 20 based
`on the teachings of Klein
`We also are not persuaded by Petitioner's rationale and supporting
`
`evidence that a POSA would have modified Kant Compound 20 in view of
`
`Klein to make the required substitutions at C-7 and C-10 to synthesize
`
`14
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`'·
`cabazitaxel. According to Petitioner, after selecting ·Kant Compound 20 for
`
`further modi~cation, a POSA would have needed to make at least three more
`
`significant decisions to achieve the cabazitaxel structure from the teachings
`
`of Klein: 1) S?bstitute Kant Compound 20's protected c.:.7 hydroxyl group
`
`with Klein's methoxy group, 2) retain KantCompound 20's methoxy group
`
`at C-10 inste~d of Klein's C-10 acetyl group, and 3) retain Kant's carbonyl
`
`~t C-9 instead of using Klein's C-9 hydroxyl to improve chemical stability
`
`and aqueous solubility of the compound. Pet. 32-34. Petitioner represents
`•
`
`the proffered structural teachings below.
`
`More potent
`than-OAC
`
`l
`
`//±1
`HaCOL 0 OH
`;{10 '. i'/
`
`10-Methoxy
`Docctaxcl
`(Kant, Compound 20)
`
`,
`
`More potent
`than-OH
`
`~
`fl.Co~~ OCf-la \
`-x10 -1~'/
`
`""r"
`7-Methoxy-9-dihydro-
`10-acetyl Oooctaxcl
`(Klein, Table Ill, Entry 10)
`
`Id. at 32-33. The Petition, however, does not explain persuasively why a
`
`POSA would have disregarded two key teachings of Klein - i) increase
`
`aqueous solubility and chemical stability by reducing the C-9 carbonyl to a
`
`hydroxyl, and ii) maintain the c-·10 acetyl (9-dihydrotaxol) to modulate
`
`activify while retaining go<?d efficacy - in order to synthesize cabazitaxel
`
`from Kant Compc;mnd 20: Prelim. Resp.'27-30, 34-38 (citing Ex. 1006,
`
`276-77);Ex. 1006,279-280.
`
`Klein expressly teaches the reduction of the C-9 carbonyl to a C-9
`
`hydroxyl to increase aqueous solubility and chemical stability of the
`
`compounds, while maintaining "excellent in vivo activity in several solid
`
`15
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`NEPTUNE GENERICS EX. 00021
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`tumor models." Ex. 1006, 276; Prelim. Resp. 28 (citing Ex. 1006, 276-77).
`
`Petitioner argues that Klein teaches a "reduction at C-9 results in reduced
`
`potency" when compared to docetaxel (Pet. 34, 42-43), but the cytotocity
`
`data in Klein Table I shows that 9-Dihydrotaxotere (docetaxel with a C-9
`
`hydroxyl) has comparable activity to docetaxel (Table I) and compound 10
`
`(Table III) in at least 3 out of 4 cell lines. Ex. 1006, 280 (Table I), 281
`
`(Table III). Klein, moreover, clearly teaches that "[t]hese products [i.e.,
`
`those with a C-9 hydroxyl] were shown to have excellent tubulin assembly
`
`activity and similar in vitro activity as compared to taxol and taxotere;
`
`therefore, these preliminary results establish that the C-9 carbonyl is not
`
`required for activity." id. at 279 (emphasis added). Contrary to Petitioner's
`
`argument, Klein teaches that