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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`_____________________________
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`IN THE UNITED STATES PATENT TRIAL AND APPEAL BOARD
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`_____________________________
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`AMNEAL PHARMACEUTICALS LLC
`Petitioner
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`v.
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`CUBIST PHARMACEUTICALS LLC
`Patent Owner
`
`
`_____________________________
`
`CASE IPR2020-00193
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`U.S. PATENT NO. 9,138,456 B2
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`____________________________
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`PETITION FOR INTER PARTES REVIEW
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`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`I.
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`Table of Contents
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`INTRODUCTION………………………………………………………….1
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`II. MANDATORY NOTICES (37 C.F.R. § 42.8)…………………….............1
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`A. Real Parties-In-Interest (37 C.F.R. § 42.8(b)(1))…………...............1
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`B. Related Matters (37 C.F.R. § 42.8(b)(2))…………………….……...1
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`C. Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3))………….…….2
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`D.
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`Service Information (37 C.F.R. § 42.8(b)(4))………………....…….2
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`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))………….…...…..3
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`IV.
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`V.
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`IDENTIFICATION OF CHALLENGES…………………….……...........3
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`BACKGROUND….………………………….…………………………..…4
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`A.
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`Technology….………………………….…………………………….4
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`B.
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`The ‘456 Patent……….….………………………….……………….7
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`VI. PERSON OF ORDINARY SKILL IN THE ART……………………….10
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`VII. CLAIM CONSTRUCTION...….…………………………………………11
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`A. Challenge #1: Claims 1, 2, and 7-11 are obvious under
`pre-AIA 35 U.S.C. § 103(a) over the Cubicin® label in
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`view of Neururkar, Mittal, or Sawai…….……..….………………..12
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`VIII. IDENTIFICATION OF HOW EACH CHALLENGED
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`CLAIM OF THE ’456 PATENT IS UNPATENTABLE……...………..12
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`1.
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`Claim 1……………………………………………….……....12
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`2.
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`Claim 2……………………………………………….……....27
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`3.
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`Claim 7..……………………………………………….……..32
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`4.
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`Claim 8…..…………………………………………….……..37
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`5.
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`Claim 9..……………………………………………….……..39
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`6.
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`Claim 10……………………………………………….……..42
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`7.
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`Claim 11……………………………………………….……..44
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`IX. PETITION SHOULD NOT BE DENIED……..………………………...60
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`B. Challenge #3: Claims 1, 2, and 7-11 are obvious under
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`pre-AIA 35 U.S.C. § 103(a) over Inman in view of
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`Neururkar, Sawai, or Mittal…………………………….…..……...45
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`1.
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`Claim 1……………………………………………….……....45
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`2.
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`Claim 2……………………………………………….……....49
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`3.
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`Claim 7……………………………………………….……....51
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`4.
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`Claim 8……………………………………………….……....54
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`5.
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`Claim 9……………………………………………….……....55
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`6.
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`Claim 10……………………………………………….……..57
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`7.
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`Claim 11……………………………………………….……..59
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`X. CONCLUSION………………………………………..…………………..61
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`List of Exhibits
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`Ex. 1001 United States Patent No. 9,138,456 B2
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`Ex. 1002
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`Prosecution history of United States Patent No. 9,138,456 B2
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`Ex. 1003 Declaration of Dr. Raj Suryanarayanan
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`European Patent Application Publication No. EP 0 386 951 A2
`(“Inman”)
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`Ex. 1004 Cubicin® label (downloaded on December 7, 2018 from
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`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-
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`572_Cubicin_Prntlbl.pdf)
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`Ex. 1005 United States Patent No. 6,136,783 (“Neururkar”)
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`Ex. 1006 United States Patent No. 7,112,565 B2 (“Sawai”)
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`Ex. 1007 United States Patent Application Publication No. 2010/0137197 A1
`(“Mittal”)
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`Ex. 1008
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`Ex. 1009 United States Patent No. 8,835,382 B2
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`Ex. 1010 Caspofungin® label (downloaded on December 12, 2018 from
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`https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/21227s01
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`5lbl.pdf)
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`Ex. 1011 Carpenter, J.F., et al., “Rational Design of Stable Lyophilized Protein
`Formulations: Some Practical Advice,” Pharmaceutical Research,
`
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`vol. 14, no. 8, pp. 969-976 (1997).
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`Ex. 1012 Diven, D.G., et al., “Extending Shelf Like Just Makes Sense,” Mayo
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`Clin. Proc., vol. 90, no. 11, pp. 1471-1474 (2015).
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`Ex. 1013
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`European Patent Application Publication No. EP 2 918 324 A1.
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`Physicians’ Desk Reference, 60th ed., pp. 1038-1042 (2006).
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`Ex. 1014
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`Ex. 1015 European Medicines Agency, Caspofungin Accord: European Public
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`Assessment Report (2015) (downloaded on July 25, 2019 from
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`https://www.ema.europa.eu/en/documents/assessment-
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`report/caspofungin-accord-epar-public-assessment-report_en.pdf)
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`Ex. 1016
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`European Medicines Agency, Cubicin: European Public Assessment
`Report – Scientific Discussion (2006) (downloaded on July 25, 2019
`from https://www.ema.europa.eu/en/documents/scientific-
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`discussion/cubicin-epar-scientific-discussion_en.pdf).
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`v
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`I.
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`INTRODUCTION
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`Amneal Pharmaceuticals LLC (“Petitioner”) hereby petitions for Inter
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`Partes Review of claims 1, 2, and 7-11 (the “challenged claims”) of U.S. Patent
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`No. 9,138,456 B2 (“the ‘456 Patent”) (Ex. 1001) under 35 U.S.C. §§ 311–319 and
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`37 C.F.R. § 42. According to the records of the United States Patent & Trademark
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`Office (the “USPTO”), the ‘456 Patent is assigned to Cubist Pharmaceuticals LLC
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`(the “Patent Owner”). For the reasons provided in detail below, the challenged
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`claims should be found unpatentable and canceled.
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`II. MANDATORY NOTICES (37 C.F.R. § 42.8)
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`A. Real Parties-In-Interest (37 C.F.R. § 42.8(b)(1))
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`The real parties-in-interest in this matter are Amneal Pharmaceuticals LLC,
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`Amneal Pharmaceuticals Company GmbH, Amneal Pharmaceuticals of NY LLC,
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`and Amneal Pharmaceuticals Company (India) Private Limited.
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`B. Related Matters (37 C.F.R. § 42.8(b)(2))
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`As of the filing date of this Petition, Petitioner is aware of the following
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`matters involving the ‘456 Patent pending now or in the past in any United States
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`court or administrative agency:
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`
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`(1) Cubist Pharmaceuticals LLC v. Amneal Pharmaceuticals, LLC and
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`Amneal Pharmaceuticals of New York LLC, Civil Action No. 3:19-cv-15439, filed
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`July 16, 2019 in the United States District Court for the District of New Jersey; and
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`
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`(2) Cubist Pharmaceuticals LLC v. Cipla USA, Inc. and Cipla Limited,
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`Civil Action No. 3:19-cv-12920-BRM, filed May 25, 2019 in the United States
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`District Court for the District of New Jersey.
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`
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`C. Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3))
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`Lead Counsel:
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`Donald R. McPhail (USPTO Reg. No. 35,811)
`DICKINSON WRIGHT PLLC
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`1825 Eye Street, NW, Suite 900
`Washington, DC 20006
`Tel: (202) 659-6928
`Fax: (844) 670-6009
`Email: dmcphail@dickinson-wright.com
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`Backup Counsel:
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`Jacqueline Lu (USPTO Reg. No. 68,342)
`DICKINSON WRIGHT PLLC
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`607 W. 3rd Street, Suite 2500
`Austin, TX 78701-4713
`Tel: (737) 484-5535
`Fax: (844) 670-6009
`Email: jlu@dickinson-wright.com
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`D.
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`Service Information (37 C.F.R. § 42.8(b)(4))
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`Please address all correspondence to L ead Counsel at the mailing address
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`shown above. Petitioner also consents to electronic service by email.
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`U.S. Patent No. 9,138,456 B2
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`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
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`
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`Petitioner hereby certifies that: (1) the ‘456 'Patent issued on September 22,
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`2015 and so is eligible for Inter Partes Review; (2) Petitioner was served with a
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`complaint alleging infringement of claims 1, 2 and 7-11 of the ‘456 patent on July
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`16, 2019, and so is therefore not barred or estopped from requesting Inter Partes
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`Review of the ‘456 Patent on the grounds identified herein; and (3) Petitioner has
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`not filed a complaint challenging the validity of the ‘456 Patent. This Petition is
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`being filed in accordance with 37 C.F.R. § 42.106(a).
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`IV.
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`IDENTIFICATION OF CHALLENGES
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`Petitioner asks that the Board review the accompanying prior art and
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`analysis thereof, and the supporting evidence, institute a trial for Inter Partes
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`Review of claims 1, 2 and 7-11 of the ‘456 Patent, and cancel those claims as
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`invalid under 35 U.S.C. § 103 on the following grounds:
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`
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`Challenge #1: Claims 1, 2, and 7-11 are obvious under pre-AIA 35 U.S.C.
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`103(a) over the original label for Cubicin® (Ex. 1004) in view of any one of U.S.
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`Patent No. 6,136,783 (Ex. 1005; “Neururkar”), U.S. Patent No. 7,112,565 (Ex.
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`1006; “Sawai”) or U.S. Patent Application Publication No. 2010/0137197 (Ex.
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`1007; “Mittal”). Cubicin® was approved for sale by the U.S. Food & Drug
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`Administration in 2003, following which the package labeling was published in the
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`U.S. Patent No. 9,138,456 B2
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`Physician’s Desk Reference (Ex. 1014 is from the 60th edition, published in 2006),
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`and so is prior art under pre-AIA 35 U.S.C. § 102(b). Neururkar was issued
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`October 24, 2000 and Sawai was issued on September 26, 2006; both are therefore
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`prior art under pre-AIA 35 U.S.C. § 102(b). Mittal was published on June 3, 2010,
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`but claims benefit of the filing date of U.S. Provisional Patent Application No.
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`60/937,360, which was filed on June 26, 2007, and so is prior art under pre-AIA 35
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`U.S.C. § 102(e).
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`
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`Challenge #2: Claims 1, 2, and 7-11 are obvious under pre-AIA 35 U.S.C.
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`103(a) over Inman (Ex. 1008) in view of any one of Neururkar (Ex. 1005), Sawai
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`(Ex. 1006), or Mittal (Ex. 1007). Inman was published on September 9, 1990, and
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`so is prior art to the ‘456 Patent under pre-AIA 5 U.S.C. § 102(b).
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`
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`V.
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`BACKGROUND
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`A. Technology
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`The ‘456 Patent is directed to formulations of daptomycin, a cyclic
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`lipopeptide having the following structure:
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`It is and was known by those skilled in the art that pharmaceuticals,
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`particularly those containing cyclic lipopeptide active agents, can be lyophilized
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`prior to storage in order to increase the shelf life of the active agent. Ex. 1003 at ¶
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`32. Caspofungin, for example, an FDA-approved cyclic lipopeptide
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`pharmaceutical composition, is supplied commercially as a lyophilized powder that
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`is reconstituted with water (or other aqueous-based solvent) prior to administration
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`to a patient. Id.
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`Moreover, it is and was also known by those skilled in the art that cyclic
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`lipopeptides could be combined with a sugar prior to lyophilization in order to
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`improve the stability of the resulting lyophilized cake. Ex. 1005 at 3:20-26, Ex.
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`1006 at 15:54-65, Ex. 1007 at ¶ 4, Ex. 1013 at 9:23-24.
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`
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`Among potential stabilizers, disaccharides have proven to be most effective
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`in stabilizing peptide products during lyophilization. Ex. 1003 at ¶ 39. Sucrose
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`5
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`and trehalose are both inert and known to be useful for stabilizing peptide
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`formulations. Id. When choosing between these two disaccharides for practical
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`application, however, a person of ordinary skill in the relevant art (a “POSA”)
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`would have been aware that there are no approved parenteral formulations
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`containing trehalose. Ex. 1011 at 973.
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`Daptomycin was first approved for human use by the U.S. Food & Drug
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`Administration in 2003. Much like many other approved cyclic lipopeptide
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`pharmaceuticals, the approved daptomycin product (Cubicin®) consists of a
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`lyophilized cake. Ex. 1004 at ll. 14-18. When used, this cake is first reconstituted
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`with sterile water and then administered to a patient intravenously. Id.
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`The Cubicin® cake, however, must be stored at reduced temperature (2°C -
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`8°C) to prevent degradation of the active ingredient. Ex.1004 at ll. 514-515. The
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`Cubicin® label also notes the need to avoid exposing the cake to excessive heat, i.e.
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`temperatures above 40°C. Id.
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`It is, and was at the relevant time, known to a POSA that storing and
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`shipping lyophilized materials at room temperature is easier and cheaper than
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`storing and shipping the same materials at low temperature. See, e.g., Ex. 1007 at
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`¶ 4; Ex. 1011 at 969; Ex. 1003 at ¶ 47. For example, when a product can be stored
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`and shipped at room temperature, there is no longer a need for expensive cooling
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`equipment and no requirements for special handling. Ex. 1003 at ¶ 47. There was,
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`6
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`therefore, a need in the art to improve the stability of lyophilized daptomycin
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`compositions at non-refrigerated temperatures.
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`B. The ‘456 Patent
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`1.
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`The Claimed Invention
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`The ‘456 Patent claims pharmaceutical compositions containing the cyclic
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`lipopeptide daptomycin. More specifically, independent claims 1 and 15 recite a
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`solid pharmaceutical daptomycin composition prepared by lyophilizing an aqueous
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`solution of daptomycin and sucrose. Claims 2-9 depend from claim 1, with claim
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`2 limiting the molar ratio of daptomycin to sucrose, claims 3-6 requiring the
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`present of a buffer in the aqueous solution, and claims 7-9 limiting the pH of the
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`aqueous solution. Claims 10 and 11 claim a pharmaceutical product containing the
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`solid pharmaceutical daptomycin composition of claim 1 plus a pharmaceutically
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`acceptable diluent, such as sterile water for injection. Claims 12-14 claim a solid
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`pharmaceutical daptomycin composition prepared by lyophilizing an aqueous
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`solution of daptomycin, sucrose, and a buffering agent.
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`2.
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`The Specification
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`The ‘346 Application, from which the ‘456 Patent issued, was filed after the
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`Cubicin® product was first approved for commercial sale by the FDA.
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`Accordingly, in describing the BACKGROUND of the invention, the specification
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`of the ‘456 Patent notes that Cubicin® “is supplied as a lyophilized powder that is
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`U.S. Patent No. 9,138,456 B2
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`reconstituted and compounded as a pharmaceutical composition for parenteral
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`administration.” Ex. 1001 at 1:33-37. The specification further notes that the
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`reconstituted formulation can be prepared from the lyophilized cake by
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`“combination with a medically appropriate amount of pharmaceutical diluent (e.g.,
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`0.9% aqueous sodium chloride).” Id. at 1:37-41.
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`Although not expressly stating that there are problems and/or limitations
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`associated with Cubicin®, the specification nevertheless states that “[t] here is a need
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`for solid lipopeptide compositions that rapidly reconstitute (e.g., in less than about 5
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`minutes) . . ..” Ex. 1001 at 2:39-43. The specification further states that “[t]here is
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`also a need for solid daptomycin compositions with improved chemical stability . . .
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`(i.e., higher total percent daptomycin purity over time), providing advantages of
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`longer shelf life, increased tolerance for more varied storage conditions (e.g., higher
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`temperature or humidity) . . ..” Id. at 2:51-58.
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`3.
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`The Prosecution History
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`As originally filed, the broadest claim of the ‘346 Application was directed
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`to solid pharmaceutical daptomycin compositions having certain dissolution
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`characteristics, but was not limited to any particular process of preparation. Nor
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`did the claimed composition contain any sucrose.
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`While the ‘346 Application was pending, however, this claim was rejected
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`by the examiner at the PTO on various grounds. Among those grounds, the
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`examiner rejected certain claims as being identically disclosed by Inman (Ex.
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`1008).
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`In response to the rejection over Inman, the applicant amended the claim to
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`require that the solid pharmaceutical daptomycin solution be prepared by
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`lyophilizing an aqueous solution of daptomycin and sucrose. In the REMARKS
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`that accompanied that amendment, applicant’s representative argued that this
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`distinguished the claims from Inman because “Inman fails to disclose solid
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`pharmaceutical formulations, the subject-matter of Applicants’ claims. In addition,
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`Inman discloses buffered solutions of dextrose, not sucrose, as required by the
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`instant claims.” Ex. 1002 at 61 (emphasis in original).
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`In addition, in response to the examiner’s rejection for obviousness,
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`applicant’s representative argued that the cited prior art
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`does not teach the surprising stabilizing effect of sucrose on solid
`daptomycin as discovered by the instant inventors, as shown in Table
`4 . . . and in Table 9 (Figure 8) of the application as filed. For
`example, as shown in Table 4, combining 15-20% sucrose with
`daptomycin in a lyophilized composition increases daptomycin
`stability by about 78-96% . . .. In addition, Table 9 (Figure 8) shows
`that sucrose increases the chemical stability of solid daptomycin
`compositions over time at elevated temperature.
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`Ex. 1002 at 63. Applicant’s representative also contended that the prior art did not
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`“teach or suggest the surprising rapid reconstitution of solid daptomycin
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`compositions containing sucrose.” Id. at 64.
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`Following applicant’s amendment, the examiner allowed the claims of the
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`‘346 Application on the grounds that “[a] solid pharmaceutical daptomycin
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`composition comprising daptomycin and sucrose recited in [the] instant claims . . .
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`is free of prior art.” Ex. 1002 at 34. The examiner further stated that “Applicant
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`has presented unexpected results of surprising rapid reconstitution of solid
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`daptomycin compositions comprising sucrose and increased chemical stability of
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`such composition [sic] . . ..” Id. The ‘346 Application subsequently issued as the
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`‘456 Patent. Id. at 1.
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`VI. PERSON OF ORDINARY SKILL IN THE ART
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`
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`A United States patent is read and understood from the perspective of a
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`POSA at the time the invention was made. Here, the relevant date is November
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`23, 2009, i.e. when the inventors named on the ‘456 Patent filed the provisional
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`patent application to which they claimed benefit.
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`A POSA is a hypothetical person presumed to know the relevant prior art. A
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`POSA is of ordinary creativity, not merely an automaton, and is capable of
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`combining the teachings of the prior art. Factors that may be used to determine the
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`level of skill of a POSA may include the education level of those working in the
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`field, the sophistication of the technology, the types of problems encountered in the
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`10
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`art, prior art solutions to those problems and the speed at which innovations in the
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`art are made and implemented.
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`
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`In this case, the ‘456 Patent is directed to a particular lyophilized
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`formulation of daptomycin and processes of making the same. Accordingly, a
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`POSA in the relevant field at that time would have had at least a bachelor of
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`science degree in one of the pharmaceutical sciences, including pharmaceutical
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`chemistry and/or pharmaceutics, or a related technical field, and either an advanced
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`degree (such as a masters or doctorate) or an equivalent amount of work
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`experience, i.e. 3-5 years, in an area relating to lyophilized pharmaceutical
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`formulations. Ex. 1003 at ¶ 57.
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`
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`VII. CLAIM CONSTRUCTION
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`
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`The following construction is proposed using the “plain and ordinary
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`meaning” standard. See 37 C.F.R. § 42.100(b).
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`A.
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`“about” (challenged claims 2, 7-9)
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`This term appears in challenged claims 2 and 7-9. See, e.g., Ex. 1001 at
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`27:6-8, 25-33; 28:7-8, 14, 34. It is not, however, defined in the specification, nor
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`was this term defined, implicitly or explicitly, during prosecution of either the ‘456
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`Patent or its parent, U.S. Patent No. 8,835,382 (Ex. 1010).
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`11
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`Petitioner submits that this term should therefore be construed according to
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`its plain and ordinary meaning as understood by a POSA, which is generally
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`accepted to be “approximately.” Ex. 1003 at ¶¶ 60-61. See also, e.g., Merck &
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`Co., Inc. v. Teva Pharmaceuticals USA, Inc., 395 F.3d 1364, 1369 (Fed. Cir.
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`2005)(“We reverse the district court's construction of ‘about’ and hold that such
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`term should be given its ordinary meaning of ‘approximately.’”); Ferring B.V. v.
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`Watson Laboratories, Inc., 764 F3d 1382, 1389 (Fed Cir. 2014)(“We affirm the
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`district court's construction of ‘about’ to mean ‘approximately,’ as well as its
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`refusal to construe ‘about’ to represent a particular numerical error rate.”).
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`
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`VIII. IDENTIFICATION OF HOW EACH CHALLENGED CLAIM OF
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`THE ‘456 PATENT IS UNPATENTABLE
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`
`
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`The challenged claims are unpatentable over the prior art for at least the
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`following reasons.
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`
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`A. Challenge #1: Claims 1, 2, and 7-11 are obvious under
`pre-AIA 35 U.S.C. 103(a) over the Cubicin® label in view
`
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`of any one of Neururkar, Sawai, or Mittal
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`
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`1.
`
`Claim 1
`
`Claim 1 of the ‘456 Patent is directed to “[a] solid pharmaceutical
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`daptomycin composition” prepared by a specified process. Ex. 1001 at 27:2-5.
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`This same process, however, and the resulting composition are disclosed by the
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`
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`12
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`
`
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`combination of the original label for Cubicin® (Ex. 1004) and any one of
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`Neururkar (Ex. 1005), Sawai (Ex. 1006), or Mittal (Ex. 1007). Ex. 1003 at ¶ 63.
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
`
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`
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`a.
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`The Scope and Content of the Prior Art
`
`
`
`i.
`
`The Cubicin® label
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`The Cubicin® label discloses that “Cubicin is supplied as a sterile,
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`preservative-free, pale yellow to light brown, lyophilized cake containing
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`approximately 900 mg/g of Daptomycin . . ..” Ex. 1004 at ll. 14-16. The Cubicin®
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`label also discloses that the lyophilized daptomycin cake must be stored at
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`refrigerated temperature, avoiding excess heat. Id. at ll. 515-516. The Cubicin®
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`label does not, however, disclose that the cake is prepared by lyophilizing an
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`aqueous solution of daptomycin and sucrose. Ex. 1003 at ¶ 64. Nor does the
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`Cubicin label disclose that the lyophilized daptomycin cake contains any sucrose.
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`Id.
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`
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`ii.
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`Neururkar
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`Neururkar (Ex. 1005) issued as a United States Letters Patent on October
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`24, 2000 and therefore qualifies as prior art against the ‘456 Patent under pre-AIA
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`35 U.S.C. § 102(b).
`
`
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`Neururkar teaches that stability and shelf-life are important factors in
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`determining whether a lyophilized pharmaceutical product will be “attractive as a
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`13
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`
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`commercial product.” Ex. 1005 at 2:66-3:2. To satisfy the need for increased
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`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`stability and extended shelf-life, Neururkar further teaches that
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`The formulations of th[is] invention provide enhanced chemical
`stability to the pharmaceutical compositions. One advantage of such
`stability is extended pharmaceutical product shelf life. . . . Extended
`pharmaceutical shelf life offers significant economic advantages.
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`Ex. 1005 at 2:20-28.
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`
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`Regarding the specifics of the inventive formulation, Neururkar discloses
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`that
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`The invention relates to a pharmaceutical composition comprising:
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`a) a pharmaceutically effective amount of [a cyclic
`lipopeptide] and the pharmaceutically acceptable salts thereof;
`
`b) a pharmaceutically acceptable amount of an acetate buffer
`effective to provide a pH of between about 4 and 7; and
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`c) a pharmaceutically acceptable amount of an excipient
`such as a sucrose/mannitol mixture to form a lyophilized cake.
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`Ex. 1005 at 1:36-2:3 (emphasis added).1
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`
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`To explain the selection of the particular excipient employed, Neururkar
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`discloses that
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`Excipients such as bulking agents, i.e., excipient sugars, are used to
`provide an aesthetically suitable lyophilized cake, solid dilution of the
`active ingredient, and sorption of available moisture. Sugars useful
`in the invention include sucrose, lactose, mannitol or combinations
`thereof. It has been found that sucrose and mannitol provide a
`
`
`1 Although Neururkar discloses the use of a mixture of sucrose and mannitol in the
`solution to be lyophilized, the claims of the ‘456 Patent do not preclude the
`presence of other excipients in the solution in addition to sucrose. See, e.g., Ex.
`1001 at 27:2-5 (“solution comprising daptomycin and sucrose.” (emphasis added)).
`
`
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`14
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
`
`
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`more stable formulation and form a pharmaceutically elegant
`cake for the composition.
`
`Ex. 1005 at 3:20-26.
`
`
`
`Neururkar discloses that the inventive pharmaceutical composition, having
`
`enhanced stability and increased shelf-life, can be prepared by lyophilizing an
`
`aqueous solution of the active cyclic lipopeptide and sucrose. Ex. 1003 at ¶ 70.
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`More specifically, Neururkar discloses that
`
`The compositions of the invention are generally prepared as
`
`follows:
`
`1) a bulking agent [e.g. sucrose] or combination of agents is
`dissolved in water;
`
`2) acetic acid is added and the pH is adjusted to about 3.7, if
`required;
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`3) [the cyclic lipopeptide] is added and dissolved with the pH
`subsequently adjusted to about 5 to about 6 with base;
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`4) the solution is filtered and filled into a lyophilization vial and
`frozen at -50 ºC;
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`5) the frozen formulation is freeze dried at -20 ºC, with a
`secondary drying at 15ºC (the complete cycle takes over two days);
`and
`
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`6) lyophilized vials are stoppered and stored at about 5ºC.
`
`
`Ex. 1005 at 3:36-50.
`
`
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`Neururkar therefore teaches preparing a lyophilized pharmaceutical
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`composition exhibiting enhanced stability and prolonged shelf life by lyophilizing
`
`an aqueous solution containing a cyclic lipopeptide and sucrose. Ex. 1003 at ¶ 71.
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`Neururkar does not, however, disclose daptomycin as the cyclic lipopeptide in the
`
`inventive pharmaceutical composition. Id.
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`
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`15
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
`
`
`
`
`
`
`
`
`
`
`
`
`iii. Mittal
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`Mittal (Ex. 1007) was published on June 3, 2010, but claims benefit of the
`
`filing date of U.S. Provisional Patent Application No. 60/937,360, which was filed
`
`on June 26, 2007, and so is prior art under pre-AIA 35 U.S.C. § 102(e).
`
`
`
`Mittal also teaches that stability and shelf-life are important features in a
`
`lyophilized cyclic lipopeptide pharmaceutical product. Ex. 1003 at ¶ 72. More
`
`specifically, Mittal teaches that
`
`Lyophilized, acetate-buffered, caspofungin products such as
`CANCIDAS are characterized by good storage stability at low
`temperature (e.g., 2ºC to 8 ºC) under ambient storage conditions.
`More particularly, the compositions can be stored at low temperature
`(e.g., 5ºC) for many months with minimal formation of degradates.
`Nonetheless, lyophilized caspofungin-containing products with
`improved storage stability at low temperatures and/or satisfactory
`storage stability at higher temperatures is desirable. Improved
`storage stability at about 5 ºC would provide for a longer shelf life
`thereby reducing the potential for product loss. Satisfactory
`storage stability at room temperature would eliminate the need
`for refrigeration and the special handling and extra costs
`associated therewith.
`
`Ex. 1007 at ¶ 4 (emphasis added). Mittal discloses that “[t]he lyophilized anti-
`
`fungal composition of the present invention has good chemical and storage
`
`stability at and below room temperature (i.e., at or below about 30ºC).” Ex. 1007
`
`at ¶ 13.
`
`Mittal discloses that
`
`
`
`
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`16
`
`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
`
`
`
`A first embodiment of the present invention (alternatively referred to
`herein as "Embodiment E1") is a lyophilized composition as originally
`described (i.e., as described in the Summary of the Invention) wherein
`the one or more non-reducing sugars is selected from the group
`consisting of trehalose, sucrose, raffinose, sorbitol and combinations
`thereof.
`
`Ex. 1007 at ¶ 15 (emphasis added).
`
`
`
`Mittal further discloses that this lyophilized composition can be
`
`prepared by the following process:
`
`(A) preparing an aqueous solution with a pH in a range of
`from about 5 to about 7 and comprising an effective amount of
`caspofungin or a pharmaceutically acceptable salt thereof,
`[and] one or more non-reducing sugars having a glass
`transition temperature Tg(s) of at least about 90ºC, and an
`acetate buffer, wherein the concentration ratio, on a weight per
`unit volume basis, of the one or more non-reducing sugars to
`caspofungin is in a range of from about 1.1:1 to about 10:1; and
`(B) freeze-drying the aqueous solution to provide the
`lyophilized anti-fungal composition.
`
`
`Ex. 1007 at ¶¶ 68-69 (emphasis added).
`
`
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`Mittal therefore teaches preparing a lyophilized pharmaceutical composition
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`exhibiting enhanced stability, including stability at higher temperatures, and longer
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`shelf life by lyophilizing an aqueous solution containing a cyclic lipopeptide and
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`sucrose. Ex. 1003 at ¶ 75. Mittal does not, however, disclose daptomycin as the
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`cyclic lipopeptide in the inventive pharmaceutical composition. Id.
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`
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`17
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
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`
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`iv.
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`Sawai
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`Sawai (Ex. 1006) issued as a United State Letters Patent on September 26,
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`2006 and therefore qualifies as prior art against the ‘456 Patent under pre-AIA 35
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`U.S.C. § 102(b).
`
`
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`Although not expressly stating the benefits thereof like Neururkar and
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`Mittal, Sawai teaches that
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`The present invention relates to a stabilized pharmaceutical
`composition in lyophilized form containing a cyclic polypeptide
`compound. More particularly, the present invention relates to a
`stabilized pharmaceutical composition in lyophilized form containing
`a cyclic polypeptide compound or its pharmaceutically acceptable salt
`and a stabilizer.
`
`Ex. 1006 at 1:11-17. Sawai further teaches that
`
`According to the present invention, provided is a composition in
`lyophilized form in which the cyclic polypeptide compound (I) or
`its pharmaceutically acceptable salt are stabilized by a stabilizer
`such as polysaccharide, disaccharide and sodium chloride. The
`mechanism of the stabilization of the cyclic polypeptide compound (I)
`or its pharmaceutically acceptable salt by the stabilizer such as
`polysaccharide, disaccharide and sodium chloride is still to be
`unknown, but it may be that the stabilizer adsorbs water in lyophilized
`cakes and that the stabilizer serves to disperse the compound or its
`pharmaceutically acceptable salt uniformly in the composition.
`
`Ex. 1006 at 15:54-65 (emphasis added).
`
`
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`To prepare this inventive stabilized pharmaceutical compositions, Sawai
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`discloses that
`
`
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`18
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`
`
`Petition for Inter Partes Review
`U.S. Patent No. 9,138,456 B2
`
`
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`The lyophilized composition may be obtained by preparing an
`aqueous solution of the cyclic polypeptide compound (I) or its
`pharmaceutically acceptable salt and the stabilizer, optionally adding
`a pH adjustor (citric acid anhydrous, sodium hydroxide, etc.) as
`required to attain pH 4.0 7.5, preferably pH 4.5 7.0, and then
`lyophilizing the resulting solution in vial according to a
`conventional method. Thus, the stabilized pharmaceutical composition
`in lyophilized form, when dissolved in purified water, preferably
`gives a solution of pH 4.0 to 7.5, more preferably pH 4.5 to 7.0.
`
`Ex. 1006 at 10:34-43 (emphasis added).
`
`
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`Finally, with respect to the particular stabilizer to employ in the lyophilized
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`composition, Sawai teaches that
`
`As the stabilizer, may be mentioned polysaccharides, disaccharides,
`sodium chloride and a combination thereof. Examples of the
`polysaccharide are dextran, starch, cellulose and hyaluronic acid; and
`examples of the disaccharide are lactose, maltose and sucrose. The
`polysaccharide or disaccharide contained in the pharmaceutical
`composition of the present invention may be -monohydrate, -
`anhydride, -anhydride or a combination thereof.
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`Ex. 1006 at 9:34-41 (emphasis added).
`
`
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`Sawai therefore teaches preparing a stabilized lyophilized pharmaceutical
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`composition by lyophilizing an aqueous solution containing a cyclic lipopeptide
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`and sucrose. Ex. 1003 at ¶ 79. Sawai does not, however, disclose daptomycin as
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`the cyclic lipopeptide in the inventive pharmaceutical composition. Id.
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`
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`19
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`
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`Petition for Inter Partes Review
`U.S. P
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