IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FRESENIUS KABI USA LLC
`
`Petitioner,
`
`
`
`v.
`
`
`
`CUBIST PHARMACEUTICALS, INC.
`
`Patent Owner.
`
`
`
`Case: IPR2015-01572
`Patent No. 8,058,238
`
`
`Corrected Petition for Inter Partes Review of U.S. Patent No. 8,058,238
`
`
`
`
`
`
`
`
`
`
`
`

`
`
`
`EXHIBIT LIST
`
`Reference
`
`Exhibit
`No.
`
`1001 High Purity Lipopeptides, U.S. Patent No. 8,058,238 (filed Apr. 24,
`2007) (issued Nov. 15, 2011).
`
`1002 High Purity Lipopeptides, U.S. Patent No. 8,129,342 (filed Sept. 22,
`2010) (issued Mar. 6, 2012).
`
`1003
`
`1004
`
`1005
`
`1006
`
`File History U.S. Patent No. 8,058,238
`
`File History U.S. Patent No. 8,129,342
`
`Expert Declaration of Ralph Tarantino, Ph.D. Relating to U.S. Patent
`No. 8,052,238
`
`Expert Declaration of Ralph Tarantino, Ph.D. Relating to U.S. Patent
`No. 8,129,342
`
`1007 Chromatographic Purification Process, U.S. Patent No. 4,874,843 (filed
`Dec. 3, 1987) (issued Oct. 17, 1989).
`
`1008 Richard H. Baltz, Lipopeptide Antibiotics Produced by Streptomyces
`roseosporus and Streptomyces fradiae, in BIOTECHNOLOGY OF
`ANTIBIOTICS (W.R. Strohl ed., 1997). (“Baltz”)
`
`1009
`
`Peptide Antibiotics, U.S. Patent No. 4,331,594 (filed Nov. 14, 1980)
`(issued May 25, 1982).
`
`1010 Anhydro- and Isomer-A-21978C Cyclic Peptides, U.S. Patent No.
`5,912,226 (filed Dec. 16, 1991) (issued Jun. 15, 1999).
`
`1011
`
`1012
`
`F.M. Huber et al., The formation of daptomycin by supplying decanoic
`acid to Streptomyces roseosporus cultures producing the antibiotic
`complex A21978C, J. BIOTECHNOL. 7:283-92 (1988).
`
`F.M. Huber et al., Dispersal of insoluble fatty acid precursors in stirred
`reactors as a mechanism to control antibiotic factor distribution, in
`BIOTECHNOLOGY PROCESSES (Ho and Oldshue eds., 1987).
`
`
`
`
`
`

`
`Exhibit
`No.
`
`
`
`Reference
`
`1013 Catherine N. Mulligan & Bernard F. Gibbs, Recovery of Biosurfactants
`by Ultrafiltration, J. CHEM. TECHNOL. BIOTECHNOL. 47:23-9
`(1990).
`
`1014
`
`1015
`
`Sung-Chyr Lin and Horng-Jyh Jiang, Recovery and Purification of the
`Lipopeptide Biosurfactant Bacillus subtilis by Ultrafiltration,
`BIOTECHNOLOGY TECHNIQUES, 11:413-16 (1997). (“Lin I”)
`
`Sung-Chyr 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”)
`
`1016 Method of Producing Surfactin with the Use of Mutant of Bacillus
`Subtilis, U.S. Patent No. 5,227,294 (filed June 20, 1991) (issued Jul. 13,
`1993).
`
`1017 Mohamad 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”)
`
`1018
`
`F.P. Tally et al., Daptomycin: A Novel Agent for Gram-positive
`Infections, EXPERT OPIN. INVEST. DRUGS 8:1223-38 (1999).
`
`1019 BIOSURFACTANTS: RESEARCH TRENDS & APPLICATIONS
`(Catherine N. Mulligan ed., 2014).
`
`1020
`
`Sung-Chyr Lin, Biosurfactant: Recent Advances, J. CHEM. TECH.
`BIOTECHNOL. 66:109-20 (1996).
`
`1021 Kei Arima et al., Surfactin, a crystalline peptide lipid surfactant
`produced by Bacillus subtilis: Isolation, characterization and its
`inhibition of fibrin clot formation, BIOCHEM. BIOPHYS. RES.
`COMM. 31:488-94 (1968).
`
`1022 Atsushi Kakinuma et al., Confirmation of the structure of surfactin by
`mass spectrometry, AG. BIOL. CHEM. 33:1669-72 (1969).
`
`
`
`
`
`

`
`Exhibit
`No.
`
`
`
`Reference
`
`1023 A.W. Bernheimer et al., Nature and properties of a cytolytic agent
`produced by Bacillus subtilis, J. GEN. MICROBIOL. 61:361-69 (1970).
`
`1024 David G. Cooper, Biosurfactants, MICROBIOL. SCI. 3:145-47 (1986).
`
`1025 Dirk Vollenbroich et al., Antimycoplasmaproperties and application on
`cell surface of surfactin, a lipopeptide antibiotic from Bacillus subtilis,
`APPL. ENVIRON. MICROBIOL. 63:44-69 (1997).
`
`1026 Catherine N. Mulligan et al., Selection of microbes producing
`biosurfactants in media without hydrocarbons, J. FERMENT.
`TECHNOL. 62:311-14 (1984).
`
`1027 Catherine N. Mulligan & Bernard F. Gibbs, Correlation of nitrogen
`metabolism with biosurfactant production, APPL. ENVIRON.
`MICROBIOL. 55:3016-69 (1989).
`
`1028 Catherine N. Mulligan et al., Enhanced biosurfactant production by a
`mutant Bacillus subtilis strain, APPL. MlCROBlOL.31:486-69(1989).
`
`1029
`
`Enhanced Production of Biosurfactant Through the Use of a Mutated B
`Subtilis Strain, U.S. Patent No. 5,037,758 (filed Jan. 1989) (issued Aug.
`6, 1991).
`
`1030 H.E. Reiling et al., Pilot plant production of rhamnolipid biosurfactant
`by Pseudomonas aeruoginosa, APPL. ENVIRON. MICROBIOL.,
`51:985-89 (1986).
`
`1031
`
`1032
`
`Sung-Chyr Lin et al., Structural and immunological characterization of
`a biosurfactant produced by Bacillus licheniformis JF-2, APPL. ENV.
`MICROBIOL. 60:31-8 (1994).
`
`Jitendra D. Desai and Ibrahim M. Banat, Microbial production of
`surfactants and their commercial potential, MOL. BIOL. REV.
`61:47¬64, 57 (1997).
`
`1033
`
`Lakey and Ptak, Fluorescence Indicates a Calcium-Dependent
`Interaction Between the Lipopeptide Antibiotic LY146032 and
`
`
`
`
`
`

`
`Exhibit
`No.
`
`
`
`Reference
`
`Phospholipid Membranes, BIOCHEM. 27:4639-4645 (1988).
`
`1034 Anhydro-And Isomer-A-21978C Cyclic Peptides, U.S. Reissued Patent
`No. 39, 071 (filed Apr. 11, 2000) (reissued Apr. 18, 2006).
`
`1035
`
`1036
`
`1037
`
`21 C.F.R. §600(3)(r) (1998)
`
`21 C.F.R. § 610.13 (1998).
`
`Sweadner, K. et al., Filtration Removal of Endotoxin (Pyrogens) in
`Solution in Different States of Aggregation, APPLIED AND
`ENVIRONMENTAL MICROBIOLOGY, 34:382-385 (1997)
`(“Sweadner”)
`
`1038 Kunz, C. et al., Human-milk proteins: analysis of casein and casein
`subunits by anion-exchange chromatography, gel electrophoresis, and
`specific staining methods, AM. J. CLIN. NUTR. 1990; 51:37-46 (1990).
`
`
`
`
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`A. Overview of the ’238 patent .................................................................. 1
`B.
`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.
`D.
`
`REAL PARTY IN INTEREST (37 C.F.R. § 42.8(b)(1)) ..................... 3
`Related Proceedings (37 C.F.R. § 42.8(b)(2)) ...................................... 3
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) ............................. 4
`SERVICE INFORMATION (37 C.F.R. § 42.8(b)(4)) ....................... 4
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`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 ........................................... 7
`
`A. U.S. Patent No. 4,874,843 (“Lilly ’843 Patent”) (Ex. 1007) ................ 7
`B.
`U.S. Patent No. 4,331,594 (“’594 Patent”) (Ex. 1009) ......................... 8
`C. U.S. Patent No. 5,912,226 (“Lilly ’226 Patent”) (Ex. 1010) ................ 8
`D. Mulligan and Gibbs, Recovery of Biosurfactants by Ultrafiltration,
`JOURNAL OF CHEMICAL TECHNOLOGY &
`BIOTECHNOLOGY, 47:23-9 (1990) (“Mulligan”) (Ex. 1013) .......... 9
`Lin and Jiang, Recovery and Purification of the Lipopeptide
`Biosurfactant Bacillus subtilis by Ultrafiltration, BIOTECHNOLOGY
`TECHNIQUES, 11:413-16 (1997) (“Lin I”) (Ex. 1014) .................... 10
`Lin et al., General Approach for the Development of High-
`Performance Liquid Chromatography Methods for Biosurfactant
`Analysis and Purification, JOURNAL OF CHROMATOGRAPHY,
`825:145-59 (1998) (“Lin II”) (Ex. 1015) ............................................ 11
`Tally et al., Daptomycin: A Novel Agent for Gram-positive
`Infections, EXPERT OPIN. INVEST. DRUGS 8:1223-38 (1999)
`(“Tally”) (Ex. 1018) ............................................................................ 12
`
`E.
`
`F.
`
`G.
`
`
`
`i
`
`

`
`
`
`H.
`
`I.
`
`J.
`
`K.
`
`Lakey and M. Ptak, “Fluorescence Indicates a Calcium-Dependent
`Interaction Between the Lipopeptide Antibiotic LY146032 and
`Phospholipid Membranes,” BIOCHEM. 27:4639-4645 (1988)
`(“Lakey”) [Ex. 1033] ........................................................................... 12
`Baltz, Lipopeptide Antibiotics Produced by Streptomyces roseosporus
`and Streptomyces fradiae, in Biotechnology of Antibiotics (W.R.
`Strohl ed. 1997). (“Baltz”) (Ex. 1008) .............................................. 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 (1998). (“Osman”)
`(Ex. 1017) ............................................................................................ 13
`Sweadner, K. et al., “Filtration Removal of Endotoxin (Pyrogens) in
`Solution in Different States of Aggregation , APPLIED AND
`ENVIRONMENTAL MICROBIOLOGY,” 34:382-385 (1977)
`(“Sweadner”) (Ex. 1037) ..................................................................... 14
`
`VIII. Ground 1: Obviousness of Claims 49-52, 54-65, 85-91, 175, 183, and 190 in
`View of the Prior Art, Such as the Lilly ’843 Patent and Lilly ’226 Patent in
`View of Mulligan, Lin II, and Lakey............................................................. 14
`
`A.
`B.
`C.
`
`D.
`E.
`
`Surfactant Background ........................................................................ 14
`State of the Art in January 2000 .......................................................... 16
`Increasing the Purity of Prior Art Daptomycin Compositions,
`Including by Micelle Filtration, Would Have Been Obvious ............. 18
`Secondary Considerations Do Not Support Non-Obviousness .......... 21
`Analysis of Claims .............................................................................. 22
`
`IX. Ground 2: Obviousness of Claims 20, 45-47, 108-111, 147-150, 168-174,
`178, 180, 181 in View of the Prior Art, Such as the Lilly ’843 Patent in View
`of Mulligan, Lin I, Lin II, Lakey, Sweadner, and Osman ............................. 33
`
`X. Ground 3: Obviousness of Claims 66-84, 182, and 191-192 in View of the
`Prior Art, Such as the Lilly ’843 Patent in View of the ’594 Patent,
`Mulligan, Lin I, Lin II, Lakey, Baltz, and Sweadner .................................... 48
`
`
`
`
`
`ii
`
`

`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Labs v. Sandoz Inc.,
`566 F.3d 1282 (Fed. Cir. 2009) (en banc) .......................................................... 18
`
`Amgen, Inc. v. Hoffman-La Roche Ltd.,
`580 F.3d (Fed. Cir. 2009) ......................................................................... 6, 18, 19
`
`Cubist Pharms., Inc. v. Fresenius Kabi USA, LLC,
`13-cv-00914 (D. Del) ............................................................................................ 3
`
`Cubist Pharms. Inc. v. Hospira Inc.,
`12-cv-00367 (D. Del.) ....................................................................................... 3, 4
`
`Cubist Pharms. Inc. v. Hospira Inc.,
`15-1259 (C.A.F.C.). U.S. Patent Application 14/475,319 .................................... 4
`
`Cubist Pharms. Inc. v. Strides Inc. et. al.,
`13-cv-01679 (D. Del) ............................................................................................ 3
`
`Muniauction, Inc. v. Thomson Corp.,
`532 F.3d 1318 (Fed. Cir. 2008) .......................................................................... 21
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 21
`
`Statutes
`
`35 U.S.C. § 102(a) ................................................................................................... 12
`
`35 U.S.C. §§ 102(a) and 102(e) ................................................................................. 8
`
`35 U.S.C. § 102(b) ............................................................................................passim
`
`35 U.S.C. §§ 102(e) and 103(a) ................................................................................. 2
`
`35 U.S.C. § 103(c)(3) ................................................................................................. 3
`
`35 U.S.C. § 311 .......................................................................................................... 5
`
`
`
`iii
`
`

`
`
`
`35 U.S.C. § 311, § 6 of the Leahy-Smith America Invents Act ................................ 1
`
`AIA § 6 ....................................................................................................................... 5
`
`Other Authorities
`
`21 C.F.R. §600(3)(r) (1998) ..................................................................................... 50
`
`21 C.F.R. § 610.13 (1998) ....................................................................................... 50
`
`37 C.F.R. Part 42 ........................................................................................................ 1
`
`37 C.F.R. §§ 42.6(e) and 42.105, I ............................................................................ 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)) ............................................................................................. 3
`
`(37 C.F.R. § 42.8(b)(3)) ............................................................................................. 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
`
`The New York Times ................................................................................................. 1
`
`PETITION FOR INTER PARTES .............................................................................. 1
`
`S. roseosporus. Ex. 1009 ............................................................................................ 8
`
`Tarantino Dec. ¶¶137-149, 172-173. The ’843 ........................................................ 55
`
`Tarantino Dec. ¶158-159. The ’226 ................................................................... 24, 25
`
`U.S. Patent 5,912,226 .......................................................................................passim
`
`U.S. Patent 8,058,238 .......................................................................................passim
`
`U.S. Patent No. 4,331,594 .................................................................................passim
`
`U.S. Patent No. 4,874,843 .................................................................................passim
`
`
`
`iv
`
`

`
`
`
`U.S. Patent No. 5,912,226 .......................................................................................... 8
`U.S. Patent No. 5,912,226 ........................................................................................ ..8
`
`U.S. Patent No. 6,696,412 .......................................................................................... 2
`U.S. Patent No. 6,696,412 ........................................................................................ ..2
`
`U.S. PATENT NO. 8,058,238 ................................................................................... 1
`U.S. PATENT NO. 8,058,238 ................................................................................. ..1
`
`
`
`
`
`v
`
`

`
`I.
`
`INTRODUCTION
`
`
`
`Pursuant to 35 U.S.C. § 311, § 6 of the Leahy-Smith America Invents Act
`
`(AIA), and 37 C.F.R. Part 42, Fresenius Kabi USA LLC (“Fresenius” or
`
`“Petitioner”) respectfully requests inter partes review of claims 20, 45-47, 49-52,
`
`54-91, 108-111, 147-150, 168-175, 178, 180-83, and 190-92 of U.S. Patent
`
`8,058,238 (“’238 patent”; Ex. 1001) to Cubist Pharms. Inc. (“Patent Owner” or
`
`“PO”). As will be shown by a preponderance of the evidence, there is a reasonable
`
`likelihood that claims 20, 45-47, 49-52, 54-91, 108-111, 147-150, 168-175, 178,
`
`180-83, and 190-92 are unpatentable and should be canceled.
`
`The required fees are submitted herewith. If any additional fees are due at
`
`any time, the office is authorized to charge Deposit Account No. 06-0923.
`
`A. Overview of the ’238 patent
`The ’238 patent is directed to daptomycin purification and to pharmaceutical
`
`compositions comprising daptomycin. ’238 patent (Ex. 1001) at Abstract. It
`
`discloses the application of well-known purification methods to purify daptomycin,
`
`including micelle formation and ultrafiltration, anion exchange chromatography,
`
`and hydrophobic interaction chromatography. Id.
`
`Brief Overview of the Prosecution History
`
`B.
`The ’238 patent was filed April 24, 2007 as Application No. 11/739,180
`
`(“180 application”). The ’180 application is a continuation of U.S. Patent
`
`
`
`1
`
`

`
`
`
`Application 10/747,485, filed December 29, 2003, which is a divisional of U.S.
`
`Patent Application 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
`
`60/177,190, filed January 20, 2000.
`
`During prosecution, the Examiner issued rejections under 35 U.S.C. §§
`
`102(e) and 103(a) in view of RE39,071 (a reissue of U.S. Patent 5,912,226 (the
`
`“Lilly ’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 that “the patentability of a product does not depend on its method of
`
`production.” See, e.g., id.
`
`In response, Applicants amended their claims, and argued that the Lilly ’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
`
`
`
`2
`
`

`
`
`
`as a prior art reference under 35 U.S.C. § 103(c)(3) because the alleged invention
`
`was made by parties to a joint research agreement. Id. at 9-10.
`
`The Examiner withdrew the rejections (Ex. 1003, March 22, 2010, Office
`
`Action, at 2) and allowed the claims. Ex. 1003, September 7, 2011 Notice of
`
`Allowance.
`
`II. GROUNDS FOR STANDING (§ 42.104(a))
`
`Petitioner certifies pursuant to 37 C.F.R. § 42.104(a) that the ’238 patent 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. Petitioner was served with a complaint asserting
`
`the ’238 patent no earlier than July 11, 2014, and this petition is being filed on July
`
`10, 2015.
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`A. REAL PARTY IN INTEREST (37 C.F.R. § 42.8(b)(1))
`The real party-in-interest is Fresenius-Kabi USA LLC (“Fresenius” or
`
`“Petitioner”).
`
`B. Related Proceedings (37 C.F.R. § 42.8(b)(2))
`The following proceedings may affect or be affected by a decision in this
`
`proceeding: Cubist Pharms., Inc. v. Fresenius Kabi USA, LLC, 13-cv-00914 (D.
`
`Del); Cubist Pharms. Inc. v. Strides Inc. et. al., 13-cv-01679 (D. Del); Cubist
`
`Pharms. Inc. v. Hospira Inc., 12-cv-00367 (D. Del.). In 12-cv-00367, on Dec. 8,
`3
`
`
`
`

`
`
`
`2014, Judge Sleet held the claims of the ’342 patent that were asserted in the
`
`Hospira action, claims 23 and 53, invalid as obvious. The case is currently pending
`
`appeal, Cubist Pharms. Inc. v. Hospira Inc., 15-1259 (C.A.F.C.). U.S. Patent
`
`Application 14/475,319 (USPTO) is related to the ’342 patent. Note that IPR2015-
`
`00141, -142, -143, and -144, all now settled, involved the ’238 patent. Several
`
`additional district court cases on this patent have settled. Concurrently herewith,
`
`Petitioner is filing two additional petitions for IPR on the ’238 patent, as well as a
`
`petition on a related patent, U.S. 8,129,342.
`
`C. Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3))
`Lead counsel is Elizabeth J. Holland, Reg. No. 47,657. Back up counsel are
`
`Robert V. Cerwinski and Cynthia Lambert Hardman, Reg. No. 53,179. All counsel
`
`are with Goodwin Procter LLP, 620 Eighth Avenue, New York, NY, 10018, tel.
`
`212-813-8800,
`
`fax
`
`212-355-3333. Email
`
`contact
`
`for
`
`counsel
`
`is
`
`eholland@goodwinprocter.com,
`
`rcerwinski@goodwinprocter.com,
`
`and
`
`chardman@goodwinprocter.com.
`
`SERVICE INFORMATION (37 C.F.R. § 42.8(b)(4))
`
`D.
`Please direct all correspondence to counsel at the contact information above.
`
`Petitioner consents to service by electronic mail at eholland@goodwinprocter.com,
`
`rcerwinski@goodwinprocter.com, and chardman@goodwinprocter.com.
`
`
`
`4
`
`

`
`
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`IDENTIFICATION OF THE CHALLENGE (§ 42.104(b))
`
`Petitioner challenges claims 20, 45-47, 49-52, 54-91, 108-111, 147-150,
`
`168-175, 178, 180-83, and 190-92 of the ’238 patent, and requests review of these
`
`claims under 35 U.S.C. § 311 and AIA § 6. Petitioner’s grounds of challenge are
`
`that each of these claims is unpatentable as follows:
`
`Ground Claims
`1
`49-52, 54-65, 85-91,
`175, 183, and 190
`
`2
`
`3
`
`20, 45-47, 108-111,
`147-150, 168-174, 178,
`and 180, 181
`66-84, 182, and 191-
`192
`
`Description
`Obviousness under § 103 Over the Lilly ’843
`Patent and Lilly ’226 Patent in View of
`Mulligan, Lin II, and Lakey
`Obviousness under § 103 Over the Lilly ’843
`Patent in View of Mulligan, Lin I, Lin II,
`Lakey, Sweadner, and Osman
`Obviousness under § 103 Over the Lilly ’843
`Patent in View of Mulligan, Lin I, Lin II,
`Lakey, Baltz, and Sweadner
`
`
`In support of these grounds of unpatentability, this Petition is accompanied by the
`
`declaration of Ralph Tarantino, Ph.D. (“Tarantino Dec.”).
`
`V. LEVEL OF ORDINARY SKILL IN THE ART
`
`A person of ordinary skill in the art (“POSA”) related to the ’238 patent
`
`typically would have held a Master’s degree or Ph.D. in chemistry, biochemistry,
`
`chemical engineering, or a related field, and several years of experience in
`
`manufacturing, analyzing, characterizing, and/or purifying proteins, peptides, or
`
`lipopeptides for medicinal use. See Tarantino Dec. at ¶38.
`
`
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`5
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`

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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
`
`the specification of the patent in which it appears.” 37 C.F.R. § 42.100. All of the
`
`challenged claims are product-by-process claims, and as such, are analyzed
`
`through the composition only, and not through the claimed process steps. See
`
`Amgen, Inc. v. Hoffman-La Roche Ltd., 580 F.3d, 1340, 1369-70, n.14 (Fed. Cir.
`
`2009). Petitioner sets forth the construction of the following claim phrases in the
`
`’238 claims, according to their broadest reasonable interpretation:
`
`Daptomycin is “essentially pure” when at least 98% of a sample is
`
`daptomycin. ’238 patent (Ex. 1001) at 7:41-46. Daptomycin is “essentially free”
`
`of another compound when the other compound is present in an amount that is no
`
`more than 0.5% of the amount of the daptomycin preparation. Id. at 7:52-56.
`
`Daptomycin is “substantially pure” when at least 95% of a sample is daptomycin.
`
`Id. at 7:35-40. Daptomycin is “substantially free” of another compound when the
`
`other compound is present in an amount that is no more than 1% of the amount of
`
`the daptomycin preparation. Id. at 7:46-51. Daptomycin is “free” of another
`
`compound when the other compound is present in an amount that is no more than
`
`0.1% of the amount of the daptomycin, or when the compound cannot be detected
`
`by HPLC under conditions of maximum sensitivity in which a limit of detection is
`
`
`
`6
`
`

`
`
`
`approximately 0.05% or less of the amount of the daptomycin preparation. Id. at
`
`7:57-67. “Purified” daptomycin means daptomycin that is substantially pure,
`
`essentially pure, substantially free, essentially free, or free of another compound.
`
`Id. at 8:1-7. “Micelles” mean “aggregates of amphipathic molecules.” Id. at 8:20-
`
`26. 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 (“Lilly ’843 Patent”) (Ex. 1007)
`The Lilly ’843 patent, titled “Chromatographic purification process,” issued
`
`October 17, 1989, and is prior art under 35 U.S.C. § 102(b). The Lilly ’843 patent
`
`disclosed “a new chromatographic process for purifying fermentation products,
`
`particularly the antibiotic LY146032, from fermentation broths.” Ex. 1007 at
`
`Abstract. LY146032 was the code name given by Eli Lilly Co. for daptomycin. See
`
`Baltz (Ex. 1008) at 415. The Lilly ’843 patent disclosed various chromatographic
`
`processes, including hydrophobic interaction chromatography (Diaion HP-20) to
`
`adsorb lipopeptide antibiotics such as daptomycin for purification. Ex. 1007 at
`
`3:21-32. Purity levels for daptomycin up to 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 disclosed a low overall yield of about
`
`35%. Id. at 2:44-45; see also Tarantino Dec. ¶¶79-80.
`
`
`
`7
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`

`
`
`
`B. U.S. Patent No. 4,331,594 (“’594 Patent”) (Ex. 1009)
`The ’594 patent, titled “A-21978 Antibiotics and Process for Their
`
`Production,” issued May 25, 1982. The ’594 patent is prior art under 35 U.S.C. §
`
`102(b). The ’594 patent disclosed the identification and purification of cyclic
`
`lipopeptides, including daptomycin, contained within the antibiotic A-21978
`
`complexes, produced in aerobic fermentation of S. roseosporus. Ex. 1009 at
`
`Abstract. The ’594 patent disclosed various chromatographic processes to separate
`
`the individual cyclic lipopeptides contained within the antibiotic A-21978
`
`complexes, including the use of anion exchange chromatography (Rohm & 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 Tarantino
`
`Dec. ¶¶81-82.
`
`C. U.S. Patent No. 5,912,226 (“Lilly ’226 Patent”) (Ex. 1010)
`The Lilly ’226 patent, titled “Anhydro- and Isomer-A-21798 Cyclic
`
`Peptides,” issued June 15, 1999. The Lilly ’226 patent is prior art at least under 35
`
`U.S.C. §§ 102(a) and 102(e). The ’226 patent is one of several daptomycin patents
`
`obtained by Eli Lilly and Company, the original developers of daptomycin. The
`
`Lilly ’226 patent was cited by the Examiner during prosecution. Ex. 1004, Dec. 30,
`
`2011 Notice of Allowance at 3.
`
`
`
`8
`
`

`
`
`
`The Lilly ’226 patent disclosed “two new groups of A-21978C cyclic
`
`peptides, anhydro- and isomer-A21978C peptide derivatives.” Ex. 1010 at
`
`Abstract. The Lilly ’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 Abstract; 12:57-61; 13:8-11. “Anhydro-
`
`LY146032” is anhydro-daptomycin, and “isomer-A21978C” peptide is β-isomer-
`
`daptomycin as referred to in the ’342 patent. Tarantino Dec. ¶¶84-85.
`
`The Lilly ’226 patent disclosed various chromatographic processes for
`
`purifying daptomycin. Ex. 1010 at 12:62-13:3 (“[T]he substance contains no more
`
`than 2.5% by weight of a combined total of anhydro-LY146032 and isomer
`
`LY146032.”). The Lilly
`
`’226 patent also
`
`further separated LY146032
`
`(daptomycin) from anhydro-LY146032 and isomer-LY146032 using HPLC. See
`
`Ex. 1010 at 13:5-52; see also Tarantino Dec. ¶¶85-86.
`
`D. Mulligan and Gibbs, Recovery of Biosurfactants by
`Ultrafiltration, JOURNAL OF CHEMICAL TECHNOLOGY
`& BIOTECHNOLOGY, 47:23-9 (1990) (“Mulligan”) (Ex.
`1013)
`
`Mulligan published in 1990, and is prior art under 35 U.S.C. § 102(b).
`
`Mulligan disclosed the incorporation of ultrafiltration as a “one-step method to
`
`purify and concentrate biosurfactants—surfactin and rhamnolipids—from culture
`
`supernatant fluids.” Id. at Abstract; see also Tarantino Dec. at ¶¶88-91. Surfactin
`
`yields increased to over 97-98% with 10,000 mw, 30,000 mw and 50,000 mw cut-
`
`
`
`9
`
`

`
`
`
`off ultrafiltration membranes, with purity levels of over 96%. See Mulligan at 26,
`
`Table 1; Tarantino Dec. at ¶¶88-91. The increased yields obtained after
`
`fermentation and cell removal, which enabled purification in commercially-
`
`relevant quantities, “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., such as daptomycin. See also Tarantino Dec. at ¶¶66-68.
`
`E.
`
`Lin and Jiang, Recovery and Purification of the Lipopeptide
`Biosurfactant
`Bacillus
`subtilis
`by
`Ultrafiltration,
`BIOTECHNOLOGY TECHNIQUES, 11:413-16 (1997) (“Lin
`I”) (Ex. 1014)
`
`Lin I published in June 1997, and is prior art under 35 U.S.C. § 102(b). Lin I
`
`disclosed the purification of the cyclic lipopeptide biosurfactant surfactin, which
`
`was incorporated into micelles and recovered from fermentation broth by
`
`ultrafiltration with a 30,000 mw cut-off ultrafiltration membranes, reporting final
`
`yields of over 95%. Ex. 1014 at Abstract. Lin I 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 also combined micelle/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, then employing high molecular weight ultrafiltration
`
`membranes that retained extracellular proteins, polysaccharides, and other
`
`
`
`10
`
`

`
`
`
`relatively high molecular weight substances, but passed through unassociated
`
`surfactin molecules. See Ex. 1014 at 415. See also Tarantino Dec. ¶¶93-96.
`
`F.
`
`Lin et al., General Approach for the Development of High-
`Performance Liquid Chromatography Methods
`for
`Biosurfactant Analysis and Purification, JOURNAL OF
`CHROMATOGRAPHY, 825:145-59 (1998) (“Lin II”) (Ex.
`1015)
`
`Lin II in published November 1998, and is 35 U.S.C. § 102(b) prior art. Lin
`
`II disclosed the purification of surfactants including surfactin, using ultrafiltration
`
`and micelle formation, as well as HPLC purification and other analytical
`
`techniques. Ex. 1015 at Abstract. Lin II exploited the propensity of biosurfactant
`
`molecules to aggregate into micelles in aqueous solution, and to de-aggregate upon
`
`exposure to an organic solvent. Id. at 150-51. Lin II recognized the universal
`
`propensity of biosurfactants to form micelles, stating that the approach “can be
`
`applied for the development of an HPLC assay for any biosurfactant as long as the
`
`concentration of biosurfactants in the fermentation broth is higher than the critical
`
`micelle concentration.” Id. Lin II further noted that due to the ability of HPLC to
`
`separate out similar chemical structures to surfactin, HPLC “can be also be adapted
`
`for the preparation of homogeneous biosurfactant samples useful for” biophysical
`
`and chemical analysis. Id. at Abstract; Tarantino Dec. ¶¶98-100.
`
`
`
`11
`
`

`
`
`
`G. Tally et al., Daptomycin: A Novel Agent for Gram-positive
`Infections, EXPERT OPIN. INVEST. DRUGS 8:1223-38
`(1999) (“Tally”) (Ex. 1018)
`
`Tally published in August 1999, and is prior art under 35 U.S.C. § 102(a).
`
`Tally, a review article, disclosed daptomycin as a “lipopeptide antibiotic with
`
`proven bactericidal activity in vitro against all clinically relevant Gram-positive
`
`bacteria.” See Ex. 1018 at Abstract. Tally included a list of gram-positive bacteria
`
`susceptible to daptomycin. See i