`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`
`
`AGILA SPECIALTIES INC. AND
`MYLAN PHARMACEUTICALS INC.,
`Petitioners,
`
`v.
`
`CUBIST PHARMACEUTICALS, INC.,
`Patent Owner
`
`Patent No. 8,058,238
`
`________________________
`
`Case IPR2015-00141
`________________________
`
`[CORRECTED] PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,058,238
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`TABLE OF CONTENTS
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`I.
`
`INTRODUCTION .......................................................................................... 1
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`A. Overview of the ‘238 Patent ................................................................. 1
`
`B.
`
`Brief Overview of the Prosecution History .......................................... 1
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`II.
`
`GROUNDS FOR STANDING - § 42.104(a) ................................................. 3
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 .................................. 3
`
`A.
`
`B.
`
`C.
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`Real Party in Interest ............................................................................ 3
`
`Related Matters ..................................................................................... 4
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`Lead and Backup Counsel and Service Information ............................ 4
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR
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`EACH CLAIM CHALLENGED.................................................................... 5
`
`A.
`
`Identification of the Challenge - § 42.104(b) ....................................... 5
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`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART ............................................ 6
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`VI. CLAIM CONSTRUCTION ........................................................................... 6
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`VII. SCOPE AND CONTENT OF THE PRIOR ART .......................................... 8
`
`A. U.S. Patent No. 4,874,843 (“‘843 Patent”) [Ex. 1007] ........................ 8
`
`B.
`
`C.
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`U.S. Patent No. 4,331,594 (“the ‘594 Patent”) [Ex. 1009] .................. 9
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`U.S. Patent No. 5,912,226 (“the ‘226 Patent”) [Ex. 1010] ................ 10
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`ii
`Baltz, Lipopeptide Antibiotics Produced by Streptomyces
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`D.
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`roseosporus and Streptomyces fradiae, in BIOTECHNOLOGY OF
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`ANTIBIOTICS (W.R. Strohl ed. 1997). (“Baltz”) [Ex. 1008] ............... 11
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`E. Mulligan and Gibbs, Recovery of Biosurfactants by
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`Ultrafiltration, JOURNAL OF CHEMICAL TECHNOLOGY &
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`BIOTECHNOLOGY, 47:23-9 (1990). (“Mulligan”) [Ex. 1013] ........... 12
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`F.
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`Lin and Jiang, Recovery and Purification of the Lipopeptide
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`Biosurfactant Bacillus subtilis by Ultrafiltration,
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`BIOTECHNOLOGY TECHNIQUES, 11:413-16 (1997). (“Lin I”)
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`[Ex. 1014] ........................................................................................... 13
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`G.
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`Lin et al., General Approach for the Development of High-
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`Performance Liquid Chromatography Methods for
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`Biosurfactant Analysis and Purification, JOURNAL OF
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`CHROMATOGRAPHY, 825:145-49 (1998). (“Lin II”) [Ex. 1015] ...... 14
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`H. U.S. Patent No. 5,227,294 (“‘294 Patent”) [Ex. 1016] ...................... 15
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`I.
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`Osman et al., Tuning micelles of a bioactive heptapeptide
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`biosurfactant via extrinsically induced conformational
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`transition of surfactin assembly, J. PEPTIDE SCI., 4:449-58
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`(1998 (“Osman”) [Ex. 1017] .............................................................. 16
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`Tally et al., Daptomycin: A Novel Agent for Gram-positive
`
`J.
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`Infections, EXPERT OPIN. INVEST. DRUGS, 8:1223-38 (1999).
`
`[Ex. 1018] ........................................................................................... 16
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`VIII. EXPLANATION OF GROUNDS FOR UNPATENTABILITY ................ 17
`
`A.
`
`B.
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`Biosurfactant Background .................................................................. 17
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`State of the Art in January 2000 ......................................................... 19
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`IX. EACH GROUND OF UNPATENTABILITY DEMONSTRATES A
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`REASONABLE LIKELIHOOD OF PREVAILING AGAINST THE
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`CHALLENGED CLAIMS OF THE ‘238 PATENT ................................... 21
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`A. Ground 1: Claims 1-7, 49, 52-65, 93, 107-111, 125-138 and
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`147-150 of the ‘238 Patent are Anticipated and Obvious Over
`
`the ‘226 Patent .................................................................................... 22
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`B.
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`Ground 2: Claims 1 and 2 of the ‘238 Patent are Obvious Over
`
`the ‘843 Patent In View Of Mulligan and Lin II ................................ 32
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`C.
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`Ground 3: Claims 1-2 of the ‘238 Patent are Obvious Over the
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`‘594 Patent in View of Mulligan and Lin II ....................................... 37
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`D. Ground 4: Claims 3, 6, and 7 of the ‘238 Patent are Obvious
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`Over the ‘843 Patent In View of Mulligan, Lin II and/or the
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`‘226 Patent .......................................................................................... 39
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`Ground 5: Claims 4, 5, 93 and 125-138 of the ‘238 Patent are
`
`E.
`
`Obvious Over the ‘843 Patent In View of Mulligan, Lin I
`
`and/or Lin II and/or the ‘226 Patent ................................................... 42
`
`(i)
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`Claims 4-5 of the ‘238 Patent are Obvious .............................. 42
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`(ii) Claims 93 and 126-138 are Obvious ........................................ 45
`Ground 6: Claims 108-111 and 147-150 of the ‘238 Patent are
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`F.
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`Obvious Over the ‘843 Patent or the ‘594 in View of Mulligan,
`
`Lin II and/or the ‘226 Patent and Further in View of Osman ............ 50
`
`(i)
`
`Claims 108-111 are Obvious ................................................... 50
`
`(ii) Claims 147-150 are Obvious ................................................... 53
`G. Ground 7: Claims 52-65 of the ‘238 Patent are Obvious Over
`
`the ‘843 Patent In View of Mulligan, Lin II, the ‘226 Patent and
`
`Tally .................................................................................................... 55
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`X.
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`THE OFFICE’S REASONS FOR ALLOWANCE OF THE PATENT
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`WAS INCORRECT AND NOT SUPPORTED BY THE PRIOR
`
`ART’S TEACHINGS ................................................................................... 58
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`A.
`
`B.
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`The ‘226 Patent is Prior Art Under 35 U.S.C. § 102(a) ..................... 59
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`The Office Should Have Brought a Rejection Under 35 U.S.C.
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`§ 103(a) Over the ‘226 Patent ............................................................ 59
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`XI. CONCLUSION ............................................................................................. 60
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`XII. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(a) AND 42.103 .......... 62
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`TABLE OF AUTHORITIES
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`Page(s)
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`CASES
`Abbott Labs v. Sandoz Inc., 566 F.3d 1282 (Fed. Cir. 2009) (en banc) .................. 23
`
`Amgen, Inc. v. Hoffman-La Roche Ltd., 580 F.3d, 1340 (Fed. Cir.
`2009) .......................................................................................................... 7, 23
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`Greenliant Systs., Inc. v. Xicor, LLC, 692 F.3d 1261 (Fed. Cir. 2012) ................... 23
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`In re Thorpe, 777 F.2d 695 (Fed. Cir. 1985) ........................................................... 22
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`KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ............................... 19, 33, 34, 35
`STATUTES
`35 U.S.C. § 102(a) ................................................................................ 10, 16, 58, 59,
` 60
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`35 U.S.C. § 102(b) .................................................................................... 8, 9, 11, 12,
` 13, 14, 15, 16, 60
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`35 U.S.C. § 102(e) ................................................................................... 2, 58, 59, 60
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`35 U.S.C. 102(f) ....................................................................................................... 60
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`35 U.S.C. 102(g) ...................................................................................................... 60
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`35 U.S.C. § 103 ........................................................................................................ 58
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`35 U.S.C. § 103(a) ............................................................................................... 2, 59
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`35 U.S.C. § 103(c)(2) ............................................................................................... 59
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`35 U.S.C. § 103(c)(3) ............................................................................................... 59
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`35 U.S.C § 103(c)(3) .................................................................................................. 3
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`35 U.S.C. § 311 .......................................................................................................... 5
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`35 U.S.C. § 311, § 6 of the Leahy-Smith America Invents Act (AIA) ................. 1, 5
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`pre-AIA 35 U.S.C. 102(a) ........................................................................................ 60
`RULES
`21 C.F.R. §600(3)(r) ................................................................................................ 19
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`37 C.F.R. § 42.8(b)(1) ................................................................................................ 3
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`37 C.F.R. § 42.8(b)(2) ................................................................................................ 4
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`37 C.F.R. § 42.8(b)(4) ................................................................................................ 4
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`37 C.F.R. § 42.100 ..................................................................................................... 7
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`37 C.F.R. § 42.104(a) ................................................................................................. 3
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`37 C.F.R. § Part 42 ..................................................................................................... 1
`MISCELLANEOUS
`MPEP § 706.02(l)(3) ................................................................................................ 60
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`[CORRECTED] PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`I.
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`INTRODUCTION
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`1
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`Pursuant to the provisions of 35 U.S.C. § 311, § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and 37 C.F.R. § Part 42, Agila Specialties Inc. (f/k/a
`
`Strides, Inc.) and Mylan Pharmaceuticals Inc. (collectively, “Petitioners”)
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`respectfully request inter partes review of claims 1-7, 49, 52-65, 93, 108-111, 125-
`
`138 and 147-150 of U.S. Patent No. 8,058,238 (“the ‘238 patent”; Ex. 1001) to
`
`Cubist Pharmaceuticals, Inc. (Cubist). Through
`
`this Petition, Petitioners
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`demonstrate that, by a preponderance of the evidence, there is a reasonable
`
`likelihood that claims 1-7, 49, 52-65, 93, 108-111, 125-138 and 147-150 of the
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`‘238 patent are unpatentable over the prior art. Claims 1-7, 49, 52-65, 93, 108-111,
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`125-138 and 147-150 should be found unpatentable and canceled.
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`A. Overview of the ‘238 Patent
`According to the Abstract, the ‘238 patent is directed to daptomycin
`
`purification and to pharmaceutical compositions comprising daptomycin. ‘238
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`patent [Ex. 1001] at Abstract. The ‘238 patent discloses the use of known
`
`processing steps for purifying cyclic lipopeptides, such as daptomycin, including
`
`the steps of micelle formation and ultrafiltration, anion exchange chromatography,
`
`and hydrophobic interaction chromatography. See id. The ‘238 patent also
`
`discloses fermentation of Streptomyces roseosporus for producing daptomycin. Id.
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`Brief Overview of the Prosecution History
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`B.
`The ‘238 patent, entitled High Purity Lipopeptides, was filed April 24, 2007
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`as Application No. 11/739,180 (“‘180 application”). The ‘238 patent is a
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`continuation of U.S. Patent Application No. 10/747,485, filed December 29, 2003,
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`which is a divisional of U.S. Patent Application No. 09/735,191, filed November
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`28, 2000, now U.S. Patent No. 6,696,412. The ‘238 patent claims priority to U.S.
`
`Provisional Application No. 60/177,190, filed January 20, 2000. The ‘238 patent
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`issued November 15, 2011 with 192 claims, and names Thomas Kelleher, Jan-Ji
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`Lai, Joseph P. DeCourcey, Paul Lynch, Maurizio Zenoni and Auro Tagliani as
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`inventors. The assignee on the face of the ‘238 patent is Cubist Pharmaceuticals,
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`Inc. The ‘238 patent is scheduled to expire on November 28, 2020.
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`The Examiner issued anticipation and obviousness rejections under 35
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`U.S.C. §§ 102(e) and 103(a) in view of U.S. Patent No. 5,912,226 to Baker (the
`
`“‘226 patent”), and focused on the purity levels of the claimed daptomycin
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`composition. The Examiner found certain claims (including all independent
`
`claims) unpatentable over the ‘226 patent’s disclosure of antibacterial and
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`pharmaceutical compositions comprising daptomycin in substantially pure form,
`
`i.e., daptomycin that contains less than 2.5% of a combined total of anhydro-
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`daptomycin and β-isomer daptomycin. Ex. 1003, February 19, 2008 Office Action
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`at 2-3. The Examiner also found that the claims were product-by-process claims
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`stating “the patentability of a product does not depend on its method of
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`production” and, again, focused on the purity levels. See, e.g., id.
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`Applicants amended their claims in response, and argued that the ‘226 patent
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`did not disclose “daptomycin purity relative to daptomycin plus anhydro
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`daptomycin ... plus beta-isomer ... plus 12 other impurities.” Ex. 1003, November
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`13, 2009 RCE at 12. Further, Applicants argued that the ‘226 patent is not eligible
`
`as a prior art reference under 35 U.S.C § 103(c)(3). Id. at 9-10.
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`The Examiner withdrew the obviousness claim rejections based on
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`Applicants’ claim that the alleged invention was made by parties to a joint research
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`agreement (Ex. 1003, March 22, 2010, Office Action, at 2) and allowed the
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`“essentially pure” purity levels claimed over the ‘226 patent. Ex. 1003, September
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`7, 2011 Notice of Allowance. The ‘238 patent issued on November 15, 2011.
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`II. GROUNDS FOR STANDING - § 42.104(a)
`Petitioners certify, pursuant to 37 C.F.R. § 42.104(a), that the patent for
`
`which review is sought is available for inter partes review and that the Petitioners
`
`are not barred or estopped from requesting an inter partes review challenging the
`
`patent claims on the grounds identified in this Petition.
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`A. Real Party in Interest
`In accordance with 37 C.F.R. § 42.8(b)(1), Petitioners identify Agila
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`Specialties Inc. (f/k/a Strides, Inc.) and Mylan Pharmaceuticals Inc. as both
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`Petitioners and Real Parties-in-Interest. Additionally, Agila Specialties Private
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`Limited, Mylan Laboratories Limited, Mylan Institutional Inc., and Mylan Inc. are
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`Real Parties-in-Interest.
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`B. Related Matters
`In accordance with 37 C.F.R. § 42.8(b)(2), Petitioners identify the pending
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`action styled Cubist Pharmaceuticals, Inc. v. Strides, Inc. and Agila Specialties
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`Private Limited, Case No. 13-cv-1679-GMS, filed by Cubist Pharmaceuticals, Inc.
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`on October 9, 2013, D.I. 1, Delaware Complaint, Ex. 1033, served on Strides, Inc.
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`and Agila Specialties Private Limited on October 23, 2013, D.I. 6,Service of
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`Strides, Inc., Ex. 1034, D.I. 7, Service of Agila Specialties Private Limited, Ex.
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`1035, in the United States District for the District of Delaware; and the dismissed
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`action styled Cubist Pharmaceuticals, Inc. v. Strides, Inc. and Agila Specialties
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`Private Limited, Case No. 13-cv-06016-NLH, filed by Cubist Pharmaceuticals,
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`Inc. on October 9, 2013, D.I. 1, New Jersey Complaint, Ex. 1036, in the United
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`States District for the District of New Jersey, and voluntarily dismissed without
`
`prejudice on October 24, 2013, D.I. 8, New Jersey Dismissal, Ex. 1037 .
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`C. Lead and Backup Counsel and Service Information
`The service information requested under 37 C.F.R. § 42.8(b)(4) is identified
`
`below. Petitioners hereby consent to electronic service.
`
`Lead Counsel
`Peter R. Munson, Esq.
`Reg. No. 43,821
`Wilson Sonsini Goodrich & Rosati PC
`12235 El Camino Real, Suite 200
`San Diego, CA 92130-3002
`
`Backup Counsel
`Lorelei Westin, Ph.D., Esq.
`Reg. No. 52, 353
`Wilson Sonsini Goodrich & Rosati PC
`12235 El Camino Real, Suite 200
`San Diego, CA 92130-3002
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`Tel: (858) 350-2312
`Facsimile: (858) 350-2399
`E-mail: pmunson@wsgr.com
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`Tel.: (858) 350-2225
`Facsimile: (858) 350-2399
`E-Mail: lwestin@wsgr.com
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED
`A.
`Petitioner challenges claims 1-7, 49, 52-65, 93, 107-111, 125-138 and 147-
`
`Identification of the Challenge - § 42.104(b)
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`150 of the ‘238 patent, and requests review of those claims under 35 U.S.C. § 311
`
`and AIA § 6. Petitioner’s grounds of challenge are that each claim 1-7, 49, 52-65,
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`93, 107-111, 125-138 and 147-150 should be canceled as being unpatentable as
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`follows:
`
`Ground
`1
`
`2
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`3
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`4
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`5
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`6
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`7
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`Claims
`1-7, 49, 52-65, 93,
`107-111, 125-138
`and 147-150
`1-2
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`1-2
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`3, 6, and 7
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`4, 5, 93 and 125-
`138
`147-150 and 108-
`111
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`52-65
`
`Description
`Anticipated by or Obvious Over the ‘226 Patent.
`
`Obvious Over the ‘843 Patent In View Of
`Mulligan and Lin II
`Obvious Over the ‘594 Patent in View of
`Mulligan and Lin II
`Obvious Over the ‘843 Patent In View of
`Mulligan, Lin II and/or the ‘226 Patent
`Obvious Over the ‘843 Patent In View of
`Mulligan, Lin I and/or Lin II /or the ‘226 Patent
`Obvious Over the ‘843 Patent or the ‘594 in
`View of Mulligan, Lin II, the ‘294 Patent and
`Osman and/or the ‘226 Patent
`Obvious Over the ‘843 Patent In View of
`Mulligan, Lin II and Tally and the ‘226 Patent
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`In support of these grounds of unpatentability, this Petition is accompanied
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`[CORRECTED] PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`by the declaration of Catherine N. Mulligan, Ph.D [Ex. 1005] (Mulligan Dec.).
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`V. LEVEL OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the art related to the ‘238 patent would have
`
`had the necessary skill set for purifying, for example, secondary metabolites from
`
`microbial fermentation, including but not limited to filtration and adsorption
`
`techniques, chemical extractions and analysis, including chromatography, such as
`
`anion exchange chromatography, hydrophobic interaction chromatography, HPLC
`
`and gel filtration analysis. Mulligan Dec. [Ex. 1005] at ¶28. Moreover, a person of
`
`ordinary skill in the art for the ‘238 patent would have had the requisite skill set to
`
`analyze biosurfactant products obtained, including the use of chromatography and
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`mass- or charge-based analytical techniques, such as mass spectrometry and
`
`HPLC. Id.
`
`A person of ordinary skill in the art related to the ‘238 patent typically
`
`would have held a Masters degree or Ph.D in Chemistry, Biochemistry or
`
`Chemical Engineering with experience in microbial fermentation and biochemical
`
`processes, including biosurfactant or lipopeptide product purification, or the
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`equivalent. Id. at ¶28.
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`VI. CLAIM CONSTRUCTION
`The claim terms in the ‘238 patent are presumed to take on their ordinary
`
`and customary meaning based on the “broadest reasonable construction in light of
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`the specification of the patent in which it appears.” 37 C.F.R. § 42.100. Petitioners
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`set forth the construction of the following claim phrases, according to their
`
`broadest reasonable interpretation:
`
`All of the challenged claims are product-by-process claims, and as such, for
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`the purpose of any patentability determination, each claim should be interpreted as
`
`compositions of daptomycin at the claimed purity level. See Amgen, Inc. v.
`
`Hoffman-La Roche Ltd., 580 F.3d, 1340, 1369-70, n.14 (Fed. Cir. 2009).
`
`“Essentially pure” daptomycin means “at least 98%” purity levels, or “at
`
`least 99%” daptomycin purity levels. See ‘238 patent at 7:41-46.
`
`“Essentially free” daptomycin means that the daptomycin purity relative to
`
`another compound “is present in an amount that is no more than 0.5% of the
`
`amount of the daptomycin.” ‘238 patent at 7:52-56
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`“Substantially pure” daptomycin means “at least 95%” purity levels, or “at
`
`least 97%” daptomycin purity levels. ‘238 patent at 7:35-40.
`
`“Substantially free” daptomycin means daptomycin purity relative to another
`
`compound “in in an amount that is no more than 1% of the amount of the
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`daptomycin.” ‘238 patent at 7:47-50.
`
`“Free” daptomycin means daptomycin purity relative to another compound
`
`“in an amount that is no more than 0.1% of the amount of the daptomycin.” ‘238
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`patent at 7:57-60.
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`“Purified” daptomycin means daptomycin that is substantially pure,
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`essentially pure, substantially free, essentially free or free of another compound.
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`‘238 patent at 8:1-7.
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`“Micelles” mean “aggregates of amphipathic molecules.” ‘238 patent at
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`8:20-26. One of ordinary skill in the art would have thus recognized that
`
`“daptomycin micelles” are a subset of “daptomycin aggregates”
`
`Petitioners assert that all other claim limitations should be given their plain
`
`and ordinary meanings.
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART
`A. U.S. Patent No. 4,874,843 (“‘843 Patent”) [Ex. 1007]
`The ‘843 patent, titled “Chromatographic purification process” was filed
`
`December 3, 1987, and issued October 17, 1989, and is prior art under 35 U.S.C. §
`
`102(b). The ‘843 patent was not cited by the Examiner during prosecution, but was
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`disclosed by the Applicant in an IDS. Ex. 1003, August 14, 2007 IDS at 1.
`
`The ‘843 patent disclosed “a new chromatographic process for purifying
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`fermentation products, particularly the antibiotic LY146032, from fermentation
`
`broths.” ‘843 patent at Abstract. LY146032 was the previous code name given by
`
`Eli Lilly Co. for daptomycin. See Baltz [Ex. 1008] at 415. The ‘843 patent
`
`disclosed various chromatographic processes, including the use of hydrophobic
`
`interaction chromatography (Diaion HP-20) to adsorb lipopeptide antibiotics such
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`as daptomycin for purification. ‘843 patent at 1:9-14. Purity levels for daptomycin
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`approaching 93% (80-93% purity) were achieved using these methods. See id. at
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`2:40-44. While an improvement from the low 5% yields previously obtained, the
`
`‘843 patent also disclosed a relatively low overall yield of about 35%. Id. at 2:44-
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`45; see also Mulligan Dec. ¶¶ 62-63.
`
`B. U.S. Patent No. 4,331,594 (“the ‘594 Patent”) [Ex. 1009]
`The ‘594 patent, titled “A-21978 Antibiotics and Process for Their
`
`Production” was filed November 14, 1980, and issued May 25, 1982. The ‘594
`
`patent is prior art under 35 U.S.C. § 102(b). The ‘594 patent was not cited by the
`
`Examiner during prosecution, but was cited by the applicant in an IDS. Ex. 1003,
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`August 14, 2007 IDS at 1.
`
`The ‘594 patent disclosed the identification and purification of cyclic
`
`lipopeptides, including daptomycin, contained with antibiotic A-21978 complexes,
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`produced in aerobic fermentation of S. roseosporus. ‘594 patent at Abstract. The
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`‘594 patent disclosed various chromatographic processes to separate the individual
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`cyclic lipopeptides contained within the antibiotic A-21978 complexes, including
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`anion exchange chromatography (Rohn Haas IRA68 Anion Exchange Resin),
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`HPLC and hydrophobic interaction chromatography (Diaion HP-20 resin; nonionic
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`macroporous copolymer of styrene cross-linked with divinylbenzene). Id. at 22:29-
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`41; 25:24-27; see also Ex. 1005, Mulligan Dec. at ¶¶64-65.
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`C. U.S. Patent No. 5,912,226 (“the ‘226 Patent”) [Ex. 1010]
`The ‘226 patent, titled “Anhydro- and Isomer-A-21798 Cyclic Peptides” was
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`filed on December 6, 1991, and issued on June 15, 1999. The ‘226 patent was
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`published less than one year before the earliest possible priority date of the ‘238
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`patent, and thus is prior art under at least 35 U.S.C. § 102(a). The ‘226 patent was
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`cited by the Examiner during prosecution of the ‘238 patent. Ex. 1003, February
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`19, 2008 Office Action at 2.
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`The ‘226 patent disclosed the identification and isolation of “two new
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`groups of A-21978C cyclic peptides, anhydro- and isomer-A21978C peptide
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`derivatives.”1 ‘226 patent at Abstract. The ‘226 patent also “provides an
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`antibacterial composition containing the new drug substance LY 146032 (i.e.
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`daptomycin) in substantially pure form” and “purified form.” Id. at 12:57-13:11.
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`The ‘226 patent disclosed using various chromatographic processes,
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`including HPLC, to purify daptomycin to levels of greater than 97.5%. ‘226 patent
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`at 13:1-3 (“[T]he substance contains no more than 2.5% by weight of a combined
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`total of anhydro-LY146032 and isomer LY146032.”). The ‘226 patent also
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`separated LY146032 (daptomycin) from anhydro-LY146032 (anhydro-
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`1 “Anhydro-LY146032” is anhydro-daptomycin, and “isomer-A21978C”
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`peptide is isomer-daptomycin as referred to in the ‘238 patent.
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`daptomycin) and isomer-LY146032 (isomer-daptomycin), and provided retention
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`times on an HPLC column for each compound, allowing separation of daptomycin,
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`anhydro-daptomycin and isomer-daptomycin through HPLC analysis:
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`See ‘226 patent at 13:45-52.
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`
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`The
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`‘226 patent also disclosed “pharmaceutical
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`formulations” of
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`pharmaceutically purified daptomycin or pharmaceutically acceptable salts thereof.
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`See, e.g., id. at 9:51-53; see also Mulligan Dec. at ¶¶66-69.
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`D. Baltz, Lipopeptide Antibiotics Produced by Streptomyces
`roseosporus and Streptomyces fradiae, in BIOTECHNOLOGY OF
`ANTIBIOTICS (W.R. Strohl ed. 1997). (“Baltz”) [Ex. 1008]
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`Baltz was published in 1997, and is prior art under 35 U.S.C. § 102(b).
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`Baltz was not cited during prosecution.
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`Baltz disclosed the identification and purification of the A21978C factors, a
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`complex of acidic lipopeptide antibiotics” from Streptomyces roseosporus (“S.
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`roseosporus”), including daptomycin. Baltz [Ex. 1008] at 415 (emphasis added).
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`Baltz discusses, in detail, the biosynthesis of daptomycin by S. roseosporus, where
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`daptomycin is normally produced in trace amounts. See Mulligan Dec. at ¶71.
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`Baltz, however, also disclosed increasing daptomycin yield for purification.
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`See Ex. 1008, Mulligan Dec. at ¶¶70-71. Baltz discussed continuously feeding S.
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`roseosporus cultures with decanoic acid rates that avoid the accumulation of
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`decanoic acid. Baltz [Ex. 1008] at 416. Baltz reports, when “[t]he process was
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`modified for large-scale production,” even higher yields of daptomycin, e.g.,
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`“representing 77% of total A21978C factors,” were obtained. Id. (internal citation
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`omitted). Baltz, thus, disclosed large scale production of isolated and purified
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`daptomycin from a fermentation culture and the desire to increase daptomycin
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`yield. See Ex. 1008, Mulligan Dec. at ¶¶70-71.
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`E. Mulligan and Gibbs, Recovery of Biosurfactants by Ultrafiltration,
`JOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, 47:23-9
`(1990). (“Mulligan”) [Ex. 1013]
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`The Mulligan reference was published in 1990, ten years before the earliest
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`priority date of the ‘238 patent, and is prior art under 35 U.S.C. § 102(b). Mulligan
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`was not cited by the Examiner during prosecution of the ‘238 patent, but was cited
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`by the Applicants in an IDS. Ex. 1003, August 14, 2007 IDS at 5.
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`Mulligan disclosed the incorporation of a micelle formation and
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`ultrafiltration technique as a “one-step method to purify and concentrate
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`biosurfactants – surfactin and rhamnolipids—from culture supernatant fluids.”
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`Mulligan at Abstract; see also Mulligan Dec. at ¶¶72-76. By employing micelle
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`formation and ultrafiltration as a purification step, surfactin yields were increased
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`to over 97-98%, with purity levels of over 96%. See Mulligan at 26, Table 1;
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`Mulligan Dec. at ¶75. Yields for rhamnolipid preparations were similar, with up to
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`92% yields obtained. Mulligan at 28, Table 2. The increased yields enabled
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`purification in commercially-relevant quantities, Mulligan disclosed, and “is not
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`restricted to lipopeptide and rhamnolipid biosurfactants but can also be used for
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`molecules that tend to aggregate above certain conditions.” Id. at 27-28, e.g., other
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`cyclic lipopeptides such as daptomycin; see also Mulligan Dec. at ¶¶72-76.
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`F.
`
`Lin and Jiang, Recovery and Purification of the Lipopeptide
`Biosurfactant Bacillus subtilis by Ultrafiltration, BIOTECHNOLOGY
`TECHNIQUES, 11:413-16 (1997). (“Lin I”) [Ex. 1014]
`
`The Lin I reference was published in June 1997, and is prior art to the ‘238
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`patent under 35 U.S.C. § 102(b). Lin I was not cited by the Examiner, but was
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`disclosed by Applicants in an IDS. Ex. 1003, August 14, 2007 IDS at 5.
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`Lin I disclosed the purification of surfactin, which was incorporated into
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`micelles and recovered from fermentation broth by ultrafiltration, reporting final
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`yields of over 95%. Lin I at Abstract. Lin I also demonstrated, using HPLC to
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`monitor purification, that with high molecular weight cut-off ultrafiltration
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`membranes, surfactin yields approached levels of 98.8%. Id. at 414.
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`Lin I disclosed the propensity of micellar formation by surfactants, stating
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`that “[a]t concentrations above the critical micelle concentration (CMC), surfactant
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`molecules associate to form supramolecular structures, such as micelles. . .” Id. at
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`413. Lin I also combined micelle formation/ultrafiltration with further size
`
`exclusion techniques to remove larger molecular weight impurities. Lin I did this
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`by dissociating surfactin micelles retained in the micellar/ultrafiltration preparation
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`with organic solvents, such as alcohol, acetone and methanol, then employing high
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`molecular weight ultrafiltration membranes to retain extracellular proteins,
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`polysaccharides and other relatively high molecular weight substances, and passed
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`through unassociated surfactin molecules in the permeate. See Lin I at 415; see
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`also Ex. 1005, Mulligan Dec. at ¶¶ 77-81.
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`G. Lin et al., General Approach for the Development of High-
`Performance Liquid Chromatography Methods for Biosurfactant
`Analysis and Purification, JOURNAL OF CHROMATOGRAPHY,
`825:145-49 (1998). (“Lin II”) [Ex. 1015]
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`Lin II was published in November 1998, and is prior art under 35 U.S.C. §
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`102(b). Lin II was not cited by the Examiner, but was disclosed by Applicant in an
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`IDS. Ex. 1003, August 14, 2007 IDS at 5.
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`Lin II disclosed purification of three different surfacants: sodium dodecyl
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`sulfate (SDS), cetyl trimethylammonium bromide (CTAB), and surfactin, using
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`micelle formation and ultrafiltration, combined with HPLC purification and
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`analytical steps “without any prior structural information of the biosurfactants.”
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`Lin II at 151, Abstract. Lin II notes the difficulty of prior techniques in the
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`isolation of sufficient amounts of biosurfactant for use in industry. Lin II at 150.
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`Lin II approaches the issue of developing low-cost and efficient purification
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`by recognizing the universal propensity of biosurfactants to form micelles, stating
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`that the approach “can be applied for the development of an HPLC assay for any
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`biosurfactants as long as the concentration of biosurfactants in the fermentation
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`broth is higher than the critical micelle concentration.” Id. at Abstract (emphasis
`
`added). As in Lin I, Lin II exploited the propensity of biosurfactant molecules to
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`both form micelles and dissociate upon association with an organic solvent. Id. Lin
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`II further noted that, due to ability of HPLC to separate out chemical structures
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`similar to surfactin, HPLC “can be also be adapted for the preparation of
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`homogeneous biosurfactant samples useful for” biop