UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
`
`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 UNASSIGNED
`________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,058,238
`
`

`

`i
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION .......................................................................................... 1
`
`A.
`
`B.
`
`Overview of the ‘238 Patent................................................................. 1
`
`Brief Overview of the Prosecution History.......................................... 2
`
`II.
`
`GROUNDS FOR STANDING - § 42.104(a)................................................. 3
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8.................................. 3
`
`A.
`
`B.
`
`C.
`
`Real Party in Interest ............................................................................ 3
`
`Related Matters..................................................................................... 4
`
`Lead and Backup Counsel and Service Information............................ 4
`
`IV.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED FOR
`
`EACH CLAIM CHALLENGED.................................................................... 5
`
`A.
`
`Identification of the Challenge - § 42.104(b)....................................... 5
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART............................................ 6
`
`VI. CLAIM CONSTRUCTION ........................................................................... 6
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART.......................................... 8
`
`A.
`
`B.
`
`C.
`
`U.S. Patent No. 4,874,843 (“‘843 Patent”) [Ex. 1007]........................ 8
`
`U.S. Patent No. 5,912,226 (“the ‘226 Patent”) [Ex. 1010].................. 9
`
`Mulligan and Gibbs, Recovery of Biosurfactants by
`
`Ultrafiltration, JOURNAL OF CHEMICAL TECHNOLOGY &
`
`BIOTECHNOLOGY, 47:23-9 (1990). (“Mulligan”) [Ex. 1013] ........... 10
`
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`

`

`ii
`Lin and Jiang, Recovery and Purification of the Lipopeptide
`
`D.
`
`Biosurfactant Bacillus subtilis by Ultrafiltration,
`
`BIOTECHNOLOGY TECHNIQUES, 11:413-16 (1997). (“Lin I”)
`
`[Ex. 1014]........................................................................................... 11
`
`E.
`
`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] ...... 12
`
`U.S. Patent No. 4,331,594 (“the ‘594 Patent”) [Ex. 1009]................ 13
`
`Osman et al., Tuning micelles of a bioactive heptapeptide
`
`biosurfactant via extrinsically induced conformational
`
`transition of surfactin assembly, J. PEPTIDE SCI., 4:449-58
`
`F.
`
`G.
`
`(1998). (“Osman”) [Ex. 1017]............................................................ 14
`
`VIII. EXPLANATION OF GROUNDS FOR UNPATENTABILITY ................ 15
`
`A.
`
`B.
`
`Biosurfactant Background.................................................................. 15
`
`State of the Art in January 2000......................................................... 17
`
`IX.
`
`EACH GROUND OF UNPATENTABILITY DEMONSTRATES A
`
`REASONABLE LIKELIHOOD OF PREVAILING AGAINST THE
`
`CHALLENGED CLAIMS OF THE ‘238 PATENT ................................... 19
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`iii
`Ground 1: Claims 8-9, 49-51, 85-92, 105-107, 113-124, 144-
`
`A.
`
`146, 151-162, 164, 165-175 of the ‘238 Patent are Anticipated
`
`and/or Obvious Over the ‘226 Patent................................................. 20
`
`B.
`
`Ground 2: Claims 8-9 of the ‘238 Patent are Invalid as Obvious
`
`Over the ‘843 Patent in View of Mulligan, Lin I, Lin II and/or
`
`the ‘226 Patent.................................................................................... 31
`
`C.
`
`Ground 3: Claims 49 and 50 and Dependent Claims 51, 85-92,
`
`105-107, 113-124, 144-146, 151-162, 164, 165, and 175 of the
`
`‘238 Patent Are Invalid as Obvious Over the ‘843 Patent in
`
`View of Mulligan, Lin II and/or the ‘226 Patent ............................... 38
`
`D.
`
`Ground 4: Claims 166-167, 171, 173-174 are Invalid as
`
`Obvious over the ‘843 Patent or ‘594 patent in view of
`
`Mulligan, Lin I, Lin II and/or the ‘226 patent.................................... 47
`
`E.
`
`Ground 5: Claims 168-170, and 172 of the ‘238 Patent are
`
`Obvious Over the ‘843 Patent or ‘594 Patent In View of
`
`Mulligan, Lin II and/or the ‘226 Patent and Further In View of
`
`Osman................................................................................................. 50
`
`X.
`
`THE OFFICE’S REASONS FOR ALLOWANCE OF THE PATENT
`
`WAS INCORRECT AND NOT SUPPORTED BY THE PRIOR
`
`ART’S TEACHINGS................................................................................... 53
`
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`iv
`The ‘226 Patent is Prior Art Under 35 U.S.C. § 102(a)..................... 53
`
`The Office Should Have Brought a Rejection Under 35 U.S.C.
`
`A.
`
`B.
`
`§ 103(a) Over the ‘226 Patent ............................................................ 54
`
`XI. CONCLUSION............................................................................................. 56
`
`XII. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(a) AND 42.103.......... 57
`
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`v
`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Abbott Labs v. Sandoz Inc., 566 F.3d 1282 (Fed. Cir. 2009) (en banc) ..................21
`
`Amgen, Inc. v. Hoffman-La Roche Ltd., 580 F.3d, 1340 (Fed. Cir.
`2009) ..........................................................................................................7, 21
`
`Amgen, Inc. v. Hoffman-La Roche Ltd., 580 F.3d, 1340 (Fed. Cir.
`2009) ..............................................................................................................21
`
`Aventis Pharms., Inc. v. Amino Chems. Ltd., 715 F.3d 1363 (Fed. Cir.
`2013) ..............................................................................................................35
`
`Greenliant Systs., Inc. v. Xicor, LLC, 692 F.3d 1261 (Fed. Cir. 2012)...................21
`
`In re Thorpe, 777 F.2d 695 (Fed. Cir. 1985) ...........................................................20
`
`KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007).........................17, 33, 35, 40, 48
`STATUTES
`35 U.S.C. § 102(a) ...................................................................................9, 53, 54, 55
`
`35 U.S.C. § 102(b) .......................................................................8, 10, 11, 12, 14, 55
`
`35 U.S.C. § 102(e) ...................................................................................2, 53, 54, 55
`
`35 U.S.C. § 102(f)....................................................................................................55
`
`35 U.S.C. § 102(g) ...................................................................................................55
`
`35 U.S.C. § 103........................................................................................................53
`
`35 U.S.C. § 103(a) ...............................................................................................2, 54
`
`35 U.S.C. § 103(c)(2)...............................................................................................54
`
`35 U.S.C § 103(c)(3)............................................................................................3, 54
`
`35 U.S.C. § 311..........................................................................................................5
`
`35 U.S.C. § 311, § 6 of the Leahy-Smith America Invents Act AIA §6...............1, 5
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`vi
`RULES
`21 C.F.R. §600(3)(r) ................................................................................................17
`
`37 C.F.R. § 42.8(b)(1)................................................................................................3
`
`37 C.F.R. § 42.8(b)(2)................................................................................................4
`
`37 C.F.R. § 42.8(b)(4)................................................................................................4
`
`37 C.F.R. § 42.100 .....................................................................................................7
`
`37 C.F.R. § 42.100 et seq...........................................................................................1
`
`37 C.F.R. § 42.104(a).................................................................................................3
`MISCELLANEOUS
`MPEP § 706.02(l)(3)................................................................................................55
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`

`

`I.
`
`INTRODUCTION
`
`1
`
`Pursuant to the provisions of 35 U.S.C. § 311, § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and 37 C.F.R. § 42.100 et seq., Agila Specialties
`
`Inc.
`
`(f/k/a Strides,
`
`Inc.)
`
`and Mylan Pharmaceuticals
`
`Inc.
`
`(collectively,
`
`“Petitioners”) respectfully request inter partes review of claims 8-9, 49-51, 85-92,
`
`105-107, 113-124, 144-146, 151-162 and 164-175 of U.S. Patent No. 8,058,238
`
`(“the ‘238 patent”; Ex. 1001) to Cubist Pharmaceuticals, Inc. (Cubist). Through
`
`this Petition, Petitioners demonstrate that, by a preponderance of the evidence,
`
`there is a reasonable likelihood that claims 8-9, 49-51, 85-92, 105-107, 113-124,
`
`144-146, 151-162 and 164-175 of the ‘238 patent are unpatentable over the prior
`
`art. Claims 8-9, 49-51, 85-92, 105-107, 113-124, 144-146, 151-162 and 164-175
`
`should be found unpatentable and canceled.
`
`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
`
`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.
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`

`

`2
`Brief Overview of the Prosecution History
`
`B.
`
`The ‘238 patent, entitled High Purity Lipopeptides, was filed April 24, 2007
`
`as Application No. 11/739180 (“‘180 application”). The ‘238 patent
`
`is a
`
`continuation of U.S. Patent Application No. 10/747,485, filed December 29, 2003,
`
`which is a divisional of U.S. Patent Application No. 09/735,191, filed November
`
`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
`
`issued November 15, 2011 with 192 claims, and names Thomas Kelleher, Jan-Ji
`
`Lai, Joseph P. DeCourcey, Paul Lynch, Maurizio Zenoni and Auro Tagliani as
`
`inventors. The assignee on the face of the ‘238 patent is Cubist Pharmaceuticals,
`
`Inc. The ‘238 patent is scheduled to expire on November 28, 2020.
`
`The Examiner issued anticipation and obviousness rejections under 35
`
`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
`
`composition. The Examiner found certain claims (including all
`
`independent
`
`claims) unpatentable over
`
`the ‘226 patent’s disclosure of antibacterial and
`
`pharmaceutical compositions comprising daptomycin in substantially pure form,
`
`i.e., daptomycin that contains less than 2.5% of a combined total of anhydro-
`
`daptomycin and β-isomer daptomycin. Ex. 1003, February 19, 2008 Office Action
`
`at 2-3. The Examiner also found that the claims were product-by-process claims
`
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`3
`stating “the patentability of a product does not depend on its method of
`
`production” and, again, focused on the purity levels. See, e.g., id.
`
`Applicants amended their claims in response, and argued that the ‘226 patent
`
`did not disclose “daptomycin purity relative to daptomycin plus anhydro
`
`daptomycin ... plus beta-isomer ... plus 12 other impurities.” Ex. 1003, November
`
`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.
`
`The Examiner withdrew the obviousness claim rejections based on
`
`Applicants’ claim that the alleged invention was made by parties to a joint research
`
`agreement (Ex. 1003, March 22, 2010, Office Action, at 2) and allowed the
`
`“essentially pure” purity levels claimed over the ‘226 patent. (Ex. 1003, September
`
`7, 2011 Notice of Allowance._ The ‘238 patent issued on November 15, 2011.
`
`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 Petitioner is
`
`not barred or estopped from requesting an inter partes review challenging the
`
`patent claims on the grounds identified in this Petition.
`
`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
`
`Specialties Inc. (f/k/a Strides, Inc.) and Mylan Pharmaceuticals Inc. as both
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`4
`Petitioners and Real Parties-in-Interest. Additionally, Agila Specialties Private
`
`Limited, Mylan Laboratories Limited, Mylan Institutional Inc. and Mylan Inc. are
`
`Real Parties-in-Interest.
`
`B.
`
`Related Matters
`
`In accordance with 37 C.F.R. § 42.8(b)(2), Petitioners identify the pending
`
`action styled Cubist Pharmaceuticals, Inc. v. Strides, Inc. and Agila Specialties
`
`Private Ltd., Case No. 13-cv-1679-GMS, filed by Cubist on October 9, 2013, D.I.
`
`1, Delaware Complaint, Ex. 1033, served on Strides, Inc. and Agila Specialties
`
`Private Limited on October 23, 2013, D.I. 6,Service of Strides, Inc., Ex. 1034, D.I.
`
`7, Service of Agila Specialties Private Limited, Ex. 1035, in the United States
`
`District Court, District of Delaware; and the dismissed action styled Cubist
`
`Pharmaceuticals, Inc. v. Strides, Inc. and Agila Specialties Private Ltd., Case No.
`
`13-cv-06016-NLH, filed by Cubist on October 9, 2013, D.I. 1, New Jersey
`
`Complaint, Ex. 1036, in the United States District Court, District of New Jersey,
`
`and voluntarily dismissed without prejudice on October 24, 2013, D.I. 8, New
`
`Jersey Dismissal, Ex.1037.
`
`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
`
`Backup Counsel
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`

`

`5
`
`Peter R. Munson, Esq.
`Reg. No. 43,821
`Wilson Sonsini Goodrich & Rosati PC
`12235 El Camino Real, Suite 200
`San Diego, CA 92130-3002
`Tel: (858) 350-2312
`Facsimile: (858) 350-2399
`E-mail : pmunson@wsgr.com
`
`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
`Tel.: (858) 350-2225
`Facsimile: (858) 350-2399
`E-Mail: lwestin@wsgr.com
`
`IV.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED
`
`A.
`
`Identification of the Challenge - § 42.104(b)
`
`Petitioner challenges claims 8-9, 49-51, 85-92, 105-107, 113-124, 144-146,
`
`151-162, 164-175 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 of the
`
`claims 8-9, 49-51, 85-92, 105-107, 113-124, 144-146, 151-162 and 164-175 should
`
`be canceled as unpatentable as follows:
`
`Ground
`1
`
`2
`
`3
`
`4
`
`5
`
`Claims
`8-9, 49-51, 85-92, 105-
`107, 113-124, 144-146,
`151-162, 164, 165-175
`8-9
`
`49-51, 85-92, 105-107,
`113-124, 144-146, 151-
`162, 164, 165, 175
`166-167, 171, 173-174
`
`168-170, and 172
`
`Description
`Anticipated and Obvious over the ‘226
`Patent
`
`Obvious Over the ‘843 Patent in View of
`Mulligan, Lin I, Lin II and/or the ‘226
`Patent
`Obvious over the ‘843 Patent in View of
`Mulligan, Lin II and/or the ‘226 Patent
`
`Obvious over the ‘843 Patent or ‘594 patent
`in view of Mulligan, Lin I, Lin II and/or the
`‘226 patent.
`Obvious Over the ‘843 Patent or ‘594 Patent
`In View of Mulligan, Lin II and/or the ‘226
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`6
`Patent and Further In View of Osman
`
`In support of these grounds of unpatentability, this Petition is accompanied by the
`
`declaration of Catherine N. Mulligan, Ph.D. [Ex. 1005].
`
`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
`
`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
`
`equivalent. Id.at ¶ 28.
`
`VI. CLAIM CONSTRUCTION
`
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`7
`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
`
`the specification of the patent in which it appears.” 37 C.F.R. § 42.100. Petitioners
`
`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
`
`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
`
`“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
`
`daptomycin.” ‘238 patent at 7:47-50.
`
`“Free” daptomycin means daptomycin purity relative to another compound
`
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`8
`“in an amount that is no more than 0.1% of the amount of the daptomycin.” ‘238
`
`patent at 7:57-60.
`
`“Purified” daptomycin means daptomycin that
`
`is
`
`substantially pure,
`
`essentially pure, substantially free, essentially free or free of another compound.
`
`‘238 patent at 8:1-7.
`
`“Micelles” mean “aggregates of amphipathic molecules.” ‘238 patent at
`
`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
`
`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
`
`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
`
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`9
`disclosed various chromatographic processes, including the use of hydrophobic
`
`interaction chromatography (Diaion HP-20) to adsorb lipopeptide antibiotics such
`
`as daptomycin for purification. ‘843 patent at 1:9-14. Purity levels for daptomycin
`
`approaching 93% (80-93% purity) were achieved using these methods. See id. at
`
`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-
`
`45; see also Mulligan Dec. ¶¶ 64-65.
`
`B.
`
`U.S. Patent No. 5,912,226 (“the ‘226 Patent”) [Ex. 1010]
`
`The ‘226 patent, titled “Anhydro- and Isomer-A-21798 Cyclic Peptides” was
`
`filed on December 6, 1991, and issued on June 15, 1999. The ‘226 patent was
`
`published less than one year before the earliest possible priority date of the ‘238
`
`patent, and thus is prior art under at least 35 U.S.C. § 102(a). The ‘226 patent was
`
`cited by the Examiner during prosecution of the ‘238 patent. Ex. 1003, February
`
`19, 2008 Office Action at 2.
`
`The ‘226 patent disclosed the identification and isolation of “two new
`
`groups of A-21978C cyclic peptides, anhydro- and isomer-A21978C peptide
`
`derivatives.”1 ‘226 patent at Abstract. The ‘226 patent also “provides an
`
`1 “Anhydro-LY146032” is anhydro-daptomycin, and “isomer-A21978C”
`peptide is isomer-daptomycin as referred to in the ‘238 patent. See Mulligan Dec.
`¶¶ 66-69.
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
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`

`

`10
`antibacterial composition containing the new drug substance LY 146032 (i.e.
`
`daptomycin) in substantially pure form” and “purified form.” Id. at 12:57-13:11.
`
`The ‘226 patent disclosed using various chromatographic processes,
`
`including HPLC, to purify daptomycin to levels of greater than 97.5%. ‘226 patent
`
`at 13:1-3 (“[T]he substance contains no more than 2.5% by weight of a combined
`
`total of anhydro-LY146032 and isomer LY146032.”). The ‘226 patent also
`
`separated LY146032 (daptomycin) from anhydro-LY146032 (anhydro-
`
`daptomycin) and isomer-LY146032 (isomer-daptomycin), and provided retention
`
`times on an HPLC column for each compound, allowing distinct identification of
`
`daptomycin, anhydro-daptomycin and isomer-daptomycin through HPLC analysis:
`
`See ‘226 patent at 13:45-52.
`
`The
`
`‘226 patent
`
`also disclosed “pharmaceutical
`
`formulations” of
`
`pharmaceutically purified daptomycin or pharmaceutically acceptable salts thereof.
`
`See, e.g., id. at 9:51-53;see also Mulligan Dec. ¶¶ 66-69.
`
`C.
`
`Mulligan and Gibbs, Recovery of Biosurfactants by Ultrafiltration,
`JOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, 47:23-9
`(1990). (“Mulligan”) [Ex. 1013]
`
`The Mulligan reference was published in 1990, ten years before the earliest
`
`priority date of the ‘238 patent, and is prior art under 35 U.S.C. § 102(b). Mulligan
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`11
`was not cited by the Examiner during prosecution of the ‘238 patent, but was cited
`
`by the Applicants in an IDS. Ex. 1003, August 14, 2007 IDS at 5.
`
`Mulligan disclosed the
`
`incorporation of
`
`a micelle
`
`formation and
`
`ultrafiltration technique as a “one-step method to purify and concentrate
`
`biosurfactants – surfactin and rhamnolipids—from culture supernatant fluids.”
`
`Mulligan at Abstract; see also Mulligan Dec. at ¶¶ 72-76 . By employing micelle
`
`formation and ultrafiltration as a purification step, surfactin yields were increased
`
`to over 97-98%, with purity levels of over 96%. See Mulligan at 26, Table 1;
`
`Mulligan Dec. at ¶ 75. Yields for rhamnolipid preparations were similar, with up to
`
`92% yields obtained. Id. at 28, Table 2. The increased yields enabled purification
`
`in commercially-relevant quantities, Mulligan disclosed, and “is not restricted to
`
`lipopeptide and rhamnolipid biosurfactants but can also be used for molecules that
`
`tend to aggregate above certain conditions.” Id. at 27-28, e.g., other cyclic
`
`lipopeptides such as daptomycin; see also Mulligan Dec. at ¶¶ 72-76 .
`
`D.
`
`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
`
`patent under 35 U.S.C. § 102(b). Lin I was not cited by the Examiner, but was
`
`disclosed by Applicants in an IDS. Ex. 1003, August 14, 2007 IDS at 5.
`
`Lin I disclosed the purification of surfactin, which was incorporated into
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`12
`micelles and recovered from fermentation broth by ultrafiltration, reporting final
`
`yields of over 95%. Lin I at Abstract. Lin I also demonstrated, using HPLC to
`
`monitor purification,
`
`that with high molecular weight cut-off ultrafiltration
`
`membranes, surfactin yields approached levels of 98.8%. Id. at 414.
`
`Lin I disclosed the propensity of micellar formation by surfactants, stating
`
`that “[a]t concentrations above the critical micelle concentration (CMC), surfactant
`
`molecules associate to form supramolecular structures, such as micelles. . .” Id. at
`
`413. Lin I also combined micelle formation/ultrafiltration with further size
`
`exclusion techniques to remove larger molecular weight impurities. Lin I did this
`
`by dissociating surfactin micelles retained in the micellar/ultrafiltration preparation
`
`with organic solvents, such as alcohol, acetone and methanol, then employing high
`
`molecular weight ultrafiltration membranes to retain extracellular proteins,
`
`polysaccharides and other relatively high molecular weight substances, and passed
`
`through unassociated surfactin molecules in the permeate. See Lin I at 415; see
`
`also Ex. 1014, Mulligan Dec. at ¶¶ 77-81.
`
`E.
`
`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]
`
`Lin II was published in November 1998, and is prior art under 35 U.S.C. §
`
`102(b). Lin II was not cited by the Examiner, but was disclosed by Applicant in an
`
`IDS. Ex. 1003, August 14, 2007 IDS at 5.
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`Lin II disclosed purification of three different surfacants: sodium dodecyl
`
`sulfate (SDS), cetyl trimethylammonium bromide (CTAB), and surfactin, using
`
`micelle formation and ultrafiltration, combined with HPLC purification and
`
`analytical steps “without any prior structural information of the biosurfactants.”
`
`Lin II at 151, Abstract. Lin II notes the difficulty of prior techniques in the
`
`isolation of sufficient amounts of biosurfactant for use in industry. Lin II at 150.
`
`Lin II approaches the issue of developing low-cost and efficient purification
`
`by recognizing the universal propensity of biosurfactants to form micelles, stating
`
`that the approach “can be applied for the development of an HPLC assay for any
`
`biosurfactants as long as the concentration of biosurfactants in the fermentation
`
`broth is higher than the critical micelle concentration.” Id. at 150-151 (emphasis
`
`added). As in Lin I, Lin II exploited the propensity of biosurfactant molecules to
`
`both form and dissociate upon association with an organic solvent. Id. Lin II
`
`further noted that, due to ability of HPLC to separate out chemical structures
`
`similar to surfactin, HPLC “can be also be adapted for the preparation of
`
`homogeneous biosurfactant samples useful for” biophysical and chemical analysis.
`
`Id. at Abstract (emphasis added); see also Ex. 1015, Mulligan Dec. at ¶¶ 82-85 .
`
`F.
`
`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
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`14
`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,
`
`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,
`
`produced in aerobic fermentation of S. roseosporus. ‘594 patent at Abstract. The
`
`‘594 patent disclosed various chromatographic processes to separate the individual
`
`cyclic lipopeptides contained within the antibiotic A-21978 complexes, including
`
`anion exchange chromatography (Rohn Haas IRA68 Anion Exchange Resin),
`
`HPLC and hydrophobic interaction chromatography (Diaion HP-20 resin; nonionic
`
`macroporous copolymer of styrene cross-linked with divinylbenzene). Id. at 22:29-
`
`41; 25:24-27; see also Ex. 1009, Mulligan Dec. at ¶¶ 64-65..
`
`G. Osman et al., Tuning micelles of a bioactive heptapeptide
`biosurfactant via extrinsically induced conformational transition of
`surfactin assembly, J. PEPTIDE SCI., 4:449-58 (1998). (“Osman”)
`[Ex. 1017]
`
`Osman was published in November 1998, and is prior art under 35 U.S.C. §
`
`102(b). Osman was not cited during prosecution of the ‘238 patent.
`
`Osman disclosed the effect of extrinsic environmental conditions on the
`
`conformation behavior of surfactin, including pH, temperature and Ca2+ ions.
`
`Osman particularly looked at the ability of these extrinsic environmental factors to
`
`affect the propensity for micellar aggregation, as well as stability of the micelles
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`15
`formed, and found that temperature, pH and calcium ion concentration affects
`
`micellar aggregation and stability. Osman found that external environmental
`
`factors could “tune[] in the bioacive conformation [of surfactin micelles] by
`
`manipulating pH, temperature [or] Ca2+ ... concentrations in surfactin solutions.”
`
`Id. at abstract. See also Ex 1005, Mulligan Dec. at ¶¶ 88-92..
`
`VIII. EXPLANATION OF GROUNDS FOR UNPATENTABILITY
`
`A.
`
`Biosurfactant Background
`
`There is no question that biosurfactants, or secondary metabolites of
`
`microbial cultures, have a large industrial and pharmaceutical commercial
`
`potential, which was recognized prior to January 2000. Mulligan Dec. at ¶¶51-57.
`
`All biosurfactants are amphiphiles, which means that they can reduce the free
`
`energy of a system by replacing bulk molecules of higher energy at an interface
`
`and enhance solubility.
`
`Id. at ¶ 45. This translates into the reduction of
`
`interfacial/surface tension at liquid-liquid and liquid-gas interfaces, making these
`
`compounds invaluable as solubility enhancers and surface tension reducers. Id.
`
`Biosurfactants, including the cyclic lipopeptides daptomycin and surfactin
`
`(the most studied biosurfactant known), are biologically produced surfactants from
`
`the fermentation of microbial organisms, such as fungi, yeast or bacteria:
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`
`DAPTOMYCIN
`
`SURFACTIN
`
`Mulligan Dec. at ¶¶46. Surfactin has been valued as a bioremediation agent in, e.g.,
`
`oil or toxic spills or other environmental disasters. Id. at ¶49. Cyclic lipopeptides,
`
`such as daptomycin and surfactin also have in common the long-recognized ability
`
`to disrupt cell membranes, making them potent antimicrobials. Id.
`
`One of the obstacles in the 1980s to the development of surfactin and other
`
`biosurfactants for commercial and industrial applications, however, was the
`
`difficulty in isolating and purifying large quantities of the biosurfactant compound.
`
`See Mulligan Dec. at ¶¶51-57. For example, surfactin from fermentation was
`
`recovered at yields of less than 60%, resulting in a loss of nearly half of the
`
`product produced in fermentation. See Mulligan Dec. at ¶55. Similarly,
`
`daptomycin also had low overall yields, for example, from 5-35%. See id. at ¶ 63,
`
`citing to ‘843 patent [Ex. 1007] at 2:44-45.
`
`Obtaining sufficiently pure biosurfactant preparations was also a goal in the
`
`1980s. Mulligan Dec. at ¶51. Homogeneou