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 ......................................................................................... vi
`
`A.
`
`B.
`
`Overview of the ‘238 Patent................................................................. 1
`
`Brief Overview of the Prosecution History.......................................... 1
`
`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............................................ 5
`
`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. 4,331,594 (“the ‘594 Patent”) [Ex. 1009].................. 8
`
`U.S. Patent No. 5,912,226 (“the ‘226 Patent”) [Ex. 1010].................. 9
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`ii
`Baltz, Lipopeptide Antibiotics Produced by Streptomyces
`
`D.
`
`roseosporus and Streptomyces fradiae, in BIOTECHNOLOGY OF
`
`ANTIBIOTICS (W.R. Strohl ed. 1997). (“Baltz”) [Ex. 1008]............... 11
`
`E. Mulligan and Gibbs, Recovery of Biosurfactants by
`
`Ultrafiltration, JOURNAL OF CHEMICAL TECHNOLOGY &
`
`BIOTECHNOLOGY, 47:23-9 (1990). (“Mulligan”) [Ex. 1013] ........... 12
`
`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]........................................................................................... 12
`
`G.
`
`Lin et al., General Approach for the Development of High-
`
`H.
`
`I.
`
`Performance Liquid Chromatography Methods for
`
`Biosurfactant Analysis and Purification, JOURNAL OF
`
`CHROMATOGRAPHY, 825:145-49 (1998). (“Lin II”) [Ex. 1015] ...... 13
`
`U.S. Patent No. 5,227,294 (“‘294 Patent”) [Ex. 1016]...................... 15
`
`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]............................................................ 15
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`iii
`Tally et al., Daptomycin: A Novel Agent for Gram-positive
`
`J.
`
`Infections, EXPERT OPIN. INVEST. DRUGS, 8:1223-38 (1999).
`
`[Ex. 1018]........................................................................................... 16
`
`VIII. BACKGROUND FOR UNPATENTABILITY........................................... 16
`
`A.
`
`B.
`
`Biosurfactant Background.................................................................. 16
`
`State of the Art in January 2000......................................................... 19
`
`IX.
`
`EACH GROUND OF UNPATENTABILITY DEMONSTRATES A
`
`REASONABLE LIKELIHOOD OF PREVAILING AGAINST THE
`
`CHALLENGED CLAIMS OF THE ‘238 PATENT ................................... 21
`
`A.
`
`Ground 1: Claims 10-48, 139-143 and 176-192 of the ‘238
`
`Patent are Anticipated and Obvious Over the ‘226 Patent................. 22
`
`B.
`
`Ground 2: Claims 21-36, 176, 183, and 186-190 of the ‘238
`
`Patent are Obvious Over the ‘843 Patent or the ‘594 Patent In
`
`View of Mulligan, Lin II, the ‘226 Patent, and the ‘294 Patent ........ 29
`
`(i)
`
`(ii)
`
`Claims 21-36............................................................................ 29
`
`Claim 176 is Obvious Over the ‘843 Patent or the ‘594
`Patent in View of Mulligan, Lin II, the ‘226 Patent and
`the ‘294 .................................................................................... 35
`
`(iii) Claims 183 and 186-190 are Obvious...................................... 36
`Ground 3: Claims 10-19, 177 and 179 of the ‘238 Patent are
`
`C.
`
`Obvious Over the ‘843 Patent or the ‘594 In View of Mulligan,
`
`Lin I and/or Lin II and the ‘226 Patent .............................................. 39
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`(i)
`
`iv
`Claims 10-19 are Obvious Over the ‘843 Patent or the
`‘594 In View of Mulligan, Lin I and/or Lin II and the
`‘226 Patent ............................................................................... 39
`
`(ii)
`
`Claims 177 and 179 are Obvious Over the ‘843 Patent or
`the ‘594 In View of Mulligan, Lin I and/or Lin II and the
`‘226 Patent ............................................................................... 44
`Ground 4: Claims 20, 43-47, 178, 180, 184-185 and 191-192 of
`
`D.
`
`the ‘238 Patent are Obvious Over the ‘843 Patent or the ‘594 in
`
`View of Mulligan, Lin II, the ‘226 Patent and the ‘294 Patent
`
`and Further in View of Osman........................................................... 46
`
`(i)
`
`Claim 20 of the ‘238 Patent is Obvious Over the ‘843
`Patent or the ‘594 in View of Mulligan, Lin II, the ‘226
`Patent and the ‘294 Patent and Further in View of Osman ..... 47
`
`(ii)
`
`Claims 43-47 of the ‘238 Patent are Obvious.......................... 49
`
`(iii) Claim 178 of the ‘238 Patent is Obvious................................. 51
`
`(iv) Claims 180 and 184-185 are Obvious...................................... 53
`Ground 5: Claim 181-182 of the ‘238 Patent is Obvious Over
`
`E.
`
`the ‘843 Patent In View of Mulligan, Lin II, the ‘226 Patent and
`
`the ‘594 Patent.................................................................................... 56
`
`X.
`
`THE OFFICE’S REASONS FOR ALLOWANCE OF THE PATENT
`
`WAS INCORRECT AND NOT SUPPORTED BY THE PRIOR
`
`ART’S TEACHINGS................................................................................... 58
`
`A.
`
`The ‘226 Patent is Prior Art Under 35 U.S.C. § 102(a)..................... 59
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`v
`The Office Should Have Brought a Rejection Under 35 U.S.C.
`
`B.
`
`§ 103(a) Over the ‘226 Patent ............................................................ 59
`
`XI. CONCLUSION............................................................................................. 60
`
`XII. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(a) AND 42.103.......... 62
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`vi
`TABLE OF AUTHORITIES
`
`Page
`
`CASES
`Amgen, Inc. v. Hoffman-La Roche Ltd., 566 F.3d 1282 (Fed. Cir.
`2009) ..............................................................................................................22
`
`Amgen, Inc. v. Hoffman-La Roche Ltd., 580 F.3d, 1340 (Fed. Cir.
`2009) ....................................................................................................7, 22, 23
`
`Greenliant Systs., Inc. v. Xicor, LLC, 692 F.3d 1261 (Fed. Cir. 2012)...................22
`
`In re Thorpe, 777 F.2d 695 (Fed. Cir. 1985) ...........................................................21
`
`KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007)....................................19, 31, 32,
`33
`
`STATUTES
`
`35 U.S.C. § 102(a) ........................................................................................9, 16, 58,
`59, 60
`
`35 U.S.C. § 102(b) ..........................................................................................8, 9, 11,
`12, 13, 14,
`15
`
`35 U.S.C. § 102(e) ...................................................................................2, 58, 59, 60
`
`35 U.S.C. § 102(f)....................................................................................................60
`
`35 U.S.C. § 102(g) ...................................................................................................60
`
`35 U.S.C. § 103........................................................................................................58
`
`35 U.S.C. § 103(a) ...............................................................................................2, 59
`
`35 U.S.C. § 103(c)(2)-(3)...................................................................................59, 60
`
`35 U.S.C § 103(c)(3)..................................................................................................3
`
`35 U.S.C. § 311..........................................................................................................5
`
`35 U.S.C. § 311, § 6 of the Leahy-Smith America Invents Act (AIA) .................1, 5
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`vii
`§ 42.104(b).................................................................................................................5
`
`RULES
`
`21 C.F.R. §600(3)(r) ................................................................................................18
`
`37 C.F.R. Part 42........................................................................................................1
`
`37 C.F.R. § 42.8 .........................................................................................................3
`
`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 .....................................................................................................6
`
`37 C.F.R. § 42.104(a).................................................................................................3
`
`MPEP § 706.02(l)(3)................................................................................................60
`
`MISCELLANEOUS
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`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. Part 42, Agila Specialties Inc. (f/k/a
`
`Strides,
`
`Inc.) and Mylan Pharmaceuticals
`
`Inc.
`
`(collectively, “Petitioners”)
`
`respectfully request inter partes review of claims 10-36, 43-47 and 176-192 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 10-36,
`
`43-47 and 176-192 of the ‘238 patent are unpatentable over the prior art. Claims
`
`10-36, 43-47 and 176-192 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.
`
`B.
`
`Brief Overview of the Prosecution History
`
`The ‘238 patent, entitled High Purity Lipopeptides, was filed April 24, 2007
`
`as Application No. 11/739,180 (“‘180 application”). The ‘238 patent
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`is a
`
`

`

`2
`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
`
`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
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`3
`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 Petitioners
`
`are 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
`
`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.
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`B.
`
`Related Matters
`
`4
`
`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, N.J. 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, N.J. 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
`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
`
`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
`Tel.: (858) 350-2225
`Facsimile: (858) 350-2399
`E-Mail: lwestin@wsgr.com
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`IV.
`
`5
`STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED
`
`A.
`
`Identification of the Challenge - § 42.104(b)
`
`Petitioner challenges claims 10-36; 43-47; and 176-192 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 10-36, 43-47; and 176-192
`
`should be canceled as unpatentable as follows:
`
`Ground
`1
`
`2
`
`3
`
`4
`
`5
`
`Description
`Anticipated by and Obvious over the ‘226 Patent
`
`Claims
`10-36, 43-47, and
`176-192
`21-36, 176, 183,
`and 186-190
`
`Obvious Over the ‘843 Patent or the ‘594 Patent In
`View of Mulligan, Lin II, and the ‘294 Patent
`and/or the ‘226 Patent
`10-20, 177 and 179 Over the ‘843 Patent or the ‘594 In View of
`Mulligan, Lin I and/or Lin II and/or the ‘226 Patent
`Obvious Over the ‘843 Patent or the ‘594 in View
`of Mulligan, Lin II, and the ‘294 Patent and/or the
`‘226 Patent and Further in View of Osman
`Obvious Over the ‘843 Patent In View of Mulligan,
`Lin II, and the ‘594 Patent and/or the ‘226 Patent
`
`20, 43-47, 178, 180,
`184-185 and 191-
`192
`181-182
`
`In support of these grounds of unpatentability, this Petition is accompanied
`
`by the declaration of Catherine N. Mulligan, Ph.D. [Ex. 1005] (Mulligan Dec.).
`
`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
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`6
`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 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
`
`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).
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`7
`“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
`
`“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
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`and ordinary meanings.
`
`8
`
`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
`
`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. ¶¶ 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
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`9
`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. 1005, Mulligan Dec. ¶¶ 64-65.
`
`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
`
`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.
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`10
`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
`
`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 separation 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
`
`1 “Anhydro-LY146032” is anhydro-daptomycin, and “isomer-A21978C”
`peptide is isomer-daptomycin as referred to in the ‘238 patent.
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`11
`pharmaceutically purified daptomycin or pharmaceutically acceptable salts thereof.
`
`See, e.g., id. at 9:51-53. See also Mulligan Dec. at ¶¶66-69.
`
`Baltz, Lipopeptide Antibiotics Produced by Streptomyces
`D.
`roseosporus and Streptomyces fradiae, in BIOTECHNOLOGY OF ANTIBIOTICS
`(W.R. Strohl ed. 1997). (“Baltz”) [Ex. 1008]
`
`Baltz was published in 1997, and is prior art under 35 U.S.C. § 102(b).
`
`Baltz was not cited during prosecution.
`
`Baltz disclosed the identification and purification of the A21978C factors, a
`
`complex of acidic lipopeptide antibiotics” from Streptomyces roseosporus (“S.
`
`roseosporus”), including daptomycin. Baltz [Ex. 1008] at 415 (emphasis added).
`
`Baltz discusses, in detail, the biosynthesis of daptomycin by S. roseosporus, where
`
`daptomycin is normally produced in trace amounts. See Mulligan Dec. at ¶ 71.
`
`Baltz, however, also disclosed increasing daptomycin yield for purification.
`
`See Ex. 1008, Mulligan Dec. ¶¶70-71. Baltz discussed continuously feeding S.
`
`roseosporus cultures with decanoic acid rates that avoid the accumulation of
`
`decanoic acid. Ex. 1008 Baltz at 416. Baltz reports, when “[t]he process was
`
`modified for large-scale production,” even higher yields of daptomycin, e.g.,
`
`“representing 77% of total A21978C factors,” were obtained. Id. (internal citation
`
`omitted). Baltz, thus, disclosed large scale production of isolated and purified
`
`daptomycin from a fermentation culture and the desire to increase daptomycin
`
`yield. See Ex. 1005, Mulligan Dec. ¶¶ 70-71.
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`12
`E. 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
`
`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. [Ex. 1005] 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. Mulligan 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, other cyclic lipopeptides such as daptomycin; Mulligan Dec. at ¶¶72-76.
`
`Lin and Jiang, Recovery and Purification of the Lipopeptide
`F.
`Biosurfactant Bacillus subtilis by Ultrafiltration, BIOTECHNOLOGY TECHNIQUES,
`11:413-16 (1997). (“Lin I”) [Ex. 1014]
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`13
`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
`
`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 [Ex. 1014] at
`
`415, Mulligan Dec. [Ex. 1005] at ¶¶ 77-81.
`
`Lin et al., General Approach for the Development of High-
`G.
`Performance Liquid Chromatography Methods for Biosurfactant Analysis and
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`14
`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.
`
`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 Abstract (emphasis
`
`added). As in Lin I, Lin II exploited the propensity of biosurfactant molecules to
`
`both form micelles 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.
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,058,238
`
`

`

`15
`Id. at Abstract (emphasis added); see also Ex. 1005, Mulligan Dec. at ¶¶82-85.
`
`H.
`
`U.S. Patent No. 5,227,294 (“‘294 Patent”) [Ex. 1016]
`
`The ‘294 patent, titled “Method of producing surfactin with the use of
`
`mutant of Bacillus subtilis” issued July 13, 1993 and is prior art under 35 U.S.C. §
`
`102(b). The ‘294 patent was not cited during prosecution of the ‘238 patent.
`
`The ‘294 pa