UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD

Transcription

1 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

2 i TABLE OF CONTENTS I. INTRODUCTION... vi A. Overview of the 238 Patent... 1 B. Brief Overview of the Prosecution History... 1 II. GROUNDS FOR STANDING (a)... 3 III. MANDATORY NOTICES UNDER 37 C.F.R A. Real Party in Interest... 3 B. Related Matters... 4 C. 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 (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. U.S. Patent No. 4,874,843 ( 843 Patent ) [Ex. 1007]... 8 B. U.S. Patent No. 4,331,594 ( the 594 Patent ) [Ex. 1009]... 8 C. U.S. Patent No. 5,912,226 ( the 226 Patent ) [Ex. 1010]... 9

3 ii D. Baltz, Lipopeptide Antibiotics Produced by Streptomyces roseosporus and Streptomyces fradiae, in BIOTECHNOLOGY OF ANTIBIOTICS (W.R. Strohl ed. 1997). ( Baltz ) [Ex. 1008] E. Mulligan and Gibbs, Recovery of Biosurfactants by Ultrafiltration, JOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, 47:23-9 (1990). ( Mulligan ) [Ex. 1013] F. Lin and Jiang, Recovery and Purification of the Lipopeptide Biosurfactant Bacillus subtilis by Ultrafiltration, BIOTECHNOLOGY TECHNIQUES, 11: (1997). ( Lin I ) [Ex. 1014] G. Lin et al., General Approach for the Development of High- Performance Liquid Chromatography Methods for Biosurfactant Analysis and Purification, JOURNAL OF CHROMATOGRAPHY, 825: (1998). ( Lin II ) [Ex. 1015] H. U.S. Patent No. 5,227,294 ( 294 Patent ) [Ex. 1016] I. Osman et al., Tuning micelles of a bioactive heptapeptide biosurfactant via extrinsically induced conformational transition of surfactin assembly, J. PEPTIDE SCI., 4: (1998). ( Osman ) [Ex. 1017]... 15

4 iii J. Tally et al., Daptomycin: A Novel Agent for Gram-positive Infections, EXPERT OPIN. INVEST. DRUGS, 8: (1999). [Ex. 1018] VIII. BACKGROUND FOR UNPATENTABILITY A. Biosurfactant Background B. State of the Art in January IX. EACH GROUND OF UNPATENTABILITY DEMONSTRATES A REASONABLE LIKELIHOOD OF PREVAILING AGAINST THE CHALLENGED CLAIMS OF THE 238 PATENT A. Ground 1: Claims 10-48, and of the 238 Patent are Anticipated and Obvious Over the 226 Patent B. Ground 2: Claims 21-36, 176, 183, and 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 (i) Claims (ii) Claim 176 is Obvious Over the 843 Patent or the 594 Patent in View of Mulligan, Lin II, the 226 Patent and the (iii) Claims 183 and are Obvious C. Ground 3: Claims 10-19, 177 and 179 of the 238 Patent are Obvious Over the 843 Patent or the 594 In View of Mulligan, Lin I and/or Lin II and the 226 Patent... 39

5 (i) iv Claims are Obvious Over the 843 Patent or the 594 In View of Mulligan, Lin I and/or Lin II and the 226 Patent (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 D. Ground 4: Claims 20, 43-47, 178, 180, and of 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 (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 (ii) Claims of the 238 Patent are Obvious (iii) Claim 178 of the 238 Patent is Obvious (iv) Claims 180 and are Obvious E. Ground 5: Claim of the 238 Patent is Obvious Over the 843 Patent In View of Mulligan, Lin II, the 226 Patent and the 594 Patent X. THE OFFICE S REASONS FOR ALLOWANCE OF THE PATENT WAS INCORRECT AND NOT SUPPORTED BY THE PRIOR ART S TEACHINGS A. The 226 Patent is Prior Art Under 35 U.S.C. 102(a)... 59

6 v B. The Office Should Have Brought a Rejection Under 35 U.S.C. 103(a) Over the 226 Patent XI. CONCLUSION XII. PAYMENT OF FEES UNDER 37 C.F.R (a) AND

7 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, U.S.C. 102(b)...8, 9, 11, 12, 13, 14, U.S.C. 102(e)...2, 58, 59, U.S.C. 102(f) U.S.C. 102(g) U.S.C U.S.C. 103(a)...2, U.S.C. 103(c)(2)-(3)...59, U.S.C 103(c)(3) U.S.C U.S.C. 311, 6 of the Leahy-Smith America Invents Act (AIA)...1, 5

8 vii (b)...5 RULES 21 C.F.R. 600(3)(r) C.F.R. Part C.F.R C.F.R. 42.8(b)(1) C.F.R. 42.8(b)(2) C.F.R. 42.8(b)(4) C.F.R C.F.R (a)...3 MISCELLANEOUS MPEP (l)(3)...60

9 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, and 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, and of the 238 patent are unpatentable over the prior art. Claims 10-36, and 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 is a

10 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, 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, 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 anhydrodaptomycin 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

11 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 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, II. GROUNDS FOR STANDING (a) Petitioners certify, pursuant to 37 C.F.R (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 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.

12 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 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 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 El Camino Real, Suite 200 San Diego, CA Tel: (858) Facsimile: (858) pmunson@wsgr.com Backup Counsel Lorelei Westin, Ph.D., Esq. Reg. No. 52, 353 Wilson Sonsini Goodrich & Rosati PC El Camino Real, Suite 200 San Diego, CA Tel.: (858) Facsimile: (858) lwestin@wsgr.com

13 IV. 5 STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH CLAIM CHALLENGED A. Identification of the Challenge (b) Petitioner challenges claims 10-36; 43-47; and 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 should be canceled as unpatentable as follows: Ground Claims Description , 43-47, and Anticipated by and Obvious over the 226 Patent , 176, 183, and Obvious Over the 843 Patent or the 594 Patent In View of Mulligan, Lin II, and the 294 Patent and/or the 226 Patent , 177 and 179 Over the 843 Patent or the 594 In View of 4 20, 43-47, 178, 180, and 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 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

14 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 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, , n.14 (Fed. Cir. 2009).

15 7 Essentially pure daptomycin means at least 98% purity levels, or at least 99% daptomycin purity levels. See 238 patent at 7: 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: Substantially pure daptomycin means at least 95% purity levels, or at least 97% daptomycin purity levels. 238 patent at 7: 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: 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: 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: 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

16 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. LY 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: 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 B. U.S. Patent No. 4,331,594 ( the 594 Patent ) [Ex. 1009] The 594 patent, titled A Antibiotics and Process for Their Production was filed November 14, 1980, and issued May 25, The 594

17 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 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 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 C. U.S. Patent No. 5,912,226 ( the 226 Patent ) [Ex. 1010] The 226 patent, titled Anhydro- and Isomer-A Cyclic Peptides was filed on December 6, 1991, and issued on June 15, 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.

18 10 The 226 patent disclosed the identification and isolation of two new groups of A-21978C cyclic peptides, anhydro- and isomer-a21978c peptide derivatives patent at Abstract. The 226 patent also provides an antibacterial composition containing the new drug substance LY (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-ly and isomer LY ). The 226 patent also separated LY (daptomycin) from anhydro-ly (anhydrodaptomycin) and isomer-ly (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: The 226 patent also disclosed pharmaceutical formulations of 1 Anhydro-LY is anhydro-daptomycin, and isomer-a21978c peptide is isomer-daptomycin as referred to in the 238 patent.

19 11 pharmaceutically purified daptomycin or pharmaceutically acceptable salts thereof. See, e.g., id. at 9: See also Mulligan Dec. at D. Baltz, Lipopeptide Antibiotics Produced by Streptomyces 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 Baltz discussed continuously feeding S. roseosporus cultures with decanoic acid rates that avoid the accumulation of decanoic acid. Ex 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

20 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 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 F. Lin and Jiang, Recovery and Purification of the Lipopeptide Biosurfactant Bacillus subtilis by Ultrafiltration, BIOTECHNOLOGY TECHNIQUES, 11: (1997). ( Lin I ) [Ex. 1014]

21 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 G. Lin et al., General Approach for the Development of High- Performance Liquid Chromatography Methods for Biosurfactant Analysis and

22 Purification, JOURNAL OF CHROMATOGRAPHY, 825: (1998). ( Lin II ) [Ex. 1015] 14 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.

23 Id. at Abstract (emphasis added); see also Ex. 1005, Mulligan Dec. at H. U.S. Patent No. 5,227,294 ( 294 Patent ) [Ex. 1016] 15 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 patent disclosed the purification of surfactin from fermentation cultures of a stable Bacillus subtilis mutant, such that the surfactin was of high purity (99% purity levels) and produced relatively large quantities of surfactin. 294 patent at 5:44-45 ( The method of the present invention produces quantities of from 1.2 to 2.0 g/litre of purified surfactin. ). Surfactin preparation included acidic precipitation of the collected foam supernatant, ultrafiltration followed by organic solvent extraction. Id. at 5: The purified (99% purity levels) surfactin was analyzed by a variety of techniques, including HPLC. Id. at 5:51-54; FIG. 15. See also Mulligan Dec. at I. Osman et al., Tuning micelles of a bioactive heptapeptide biosurfactant via extrinsically induced conformational transition of surfactin assembly, J. PEPTIDE SCI., 4: (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 Ca 2+ ions.

24 16 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 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 bioactive conformation [of surfactin micelles] by manipulating ph, temperature [or] Ca concentrations in surfactin solutions. Id. at abstract. See also Ex. 1005, Mulligan Dec. at J. Tally et al., Daptomycin: A Novel Agent for Gram-positive Infections, EXPERT OPIN. INVEST. DRUGS, 8: (1999). [Ex. 1018] Tally was published in August 1999, within a year before the earliest priority date of the 238 patent, and is prior art under 35 U.S.C. 102(a). Tally was not cited by the Examiner during prosecution of the 238 patent, but was disclosed by applicant in an IDS. Ex. 1003, August 14, 2007 IDS at 6. Tally disclosed daptomycin as a lipopeptide antibiotic with proven bactericidal activity in vitro against all clinically relevant Gram-positive bacteria. See Tally at Abstract. Tally disclosed the use of daptomycin as an antibiotic in skin and soft tissue infections, as well as in the treatment of bacteremia and endocarditis. See id. at Abstract, Tables 1-3; see also Ex. 1005, Mulligan Dec VIII. EXPLANATION OF GROUNDS FOR UNPATENTABILITY A. Biosurfactant Background

25 17 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 Mulligan Dec. at 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: DAPTOMYCIN SURFACTIN Mulligan Dec. at Surfactin has been valued as a bioremediation agent in, e.g., oil or toxic spills and other environmental disasters. Id. at 49. Cyclic lipopeptides, such as daptomycin and surfactin also have in common the longrecognized ability to disrupt cell membranes, making them potent antimicrobials.

26 Id. 18 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 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: Obtaining sufficiently pure biosurfactant preparations was also a goal in the 1980s. Mulligan Dec. at Homogeneous preparations were a necessity for laboratories that specialized in high resolution microscopy in order to determine compound function and mechanism of action, such as through scanning electron microscopy (SEM) and nuclear magnetic resonance (NMR) spectroscopy. Id. at 52. Moreover, therapeutic uses for the biologically produced biosurfactants also required high purity standards. Id. at 59; 21 C.F.R. 600(3)(r) (defining purity for biologically sourced products as relative freedom from extraneous matter in the finished product... includ[ing] but [] not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances. Id. at 60. Accordingly, one of ordinary skill in the art producing a biosurfactant, such

27 19 as surfactin and daptomycin, would have been motivated to seek out and employ processing methods to: 1) increase yield; and 2) attain highly purified preparations, in order to obtain commercially significant quantities for industrial and/or pharmaceutical applications. See, e.g., KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007) ( finite number of identified, predictable solutions obviates claim). B. State of the Art in January 2000 Because of the necessity for high yields and high purity, researchers had worked for many years prior to the 238 patent to develop process steps aimed at increasing purity and yield of biosurfactant compositions, including daptomycin and surfactin, from fermentation cultures. See Mulligan Dec. at For example, daptomycin from S. roseosporus fermentation broth was purified to levels of greater than 97.5% daptomycin relative to the impurities anhydrodaptomycin and β-isomer daptomycin. See, e.g., 226 Patent at 13:1-3. In fact, well before the filing of the 238 patent, biosurfactant preparations, including cyclic lipopeptide preparations, were routinely purified to greater than 99%, and at levels approaching homogeneity (i.e., single-peak) with HPLC. See id. at 57. Additionally, prior to January 2000, skilled artisans had available a robust and extensive tool-box to draw from for purifying cyclic lipopeptide biosurfactants in general, and daptomycin in particular. See Mulligan Dec. at In particular, the propensity for biosurfactants to form micelles, and subsequent

28 20 retention of biosurfactant micelles using ultrafiltration cells, was known and exploited by many researchers to purify biosurfactant preparations, such as surfactin to purity levels above 96%. See Mulligan Dec. at 54. Importantly, the incorporation of a micelle formation and ultrafiltration step enabled a significant increase in product yields (e.g., above 90%), allowing large amounts of biosurfactant to be recovered during purification, an important advance in the production of commercially significant quantities of biosurfactants. Id. Other standard biochemical purification processes, such as anion-exchange chromatography, hydrophobic interaction chromatography, HPLC, and other massand charge-based purification techniques, were also well known (and used) to achieve high purity levels and to remove impurities for biosurfactants, such as surfactin and daptomycin, and these techniques were considered routine and standard to biochemists and chemists in the of biosurfactant field. See id. at 28. Furthermore, it was known (and would have been routine) to repeat and/or combine purification steps and techniques to progressively increase purity levels of a compound. See, e.g., id. at 15, 102. For example, it was known that a micelle formation and ultrafiltration step could be followed by a micelle disruption and ultrafiltration step to further purify biosurfactants. See Lin I [Ex. 1014] and Lin II [Ex. 1015]. It was also known that daptomycin could be purified by first using anionic exchange and hydrophobic interaction chromatography and then using

29 21 HPLC for further purification. 226 patent at 13:8-11. Finally, it was known that a micelle formation and ultrafiltration technique could be combined with HPLC columns to obtain homogenous biosurfactant preparations, i.e., preparations approaching at least 99% purity. See Mulligan Dec. 116 (citing Lin II at 159). Combinations or alternative orders of these various processing steps would have also been routine to one of ordinary skill in the art. Id. Accordingly, biosurfactant preparations approaching homogeneity would have been routinely obtained prior to January IX. EACH GROUND OF UNPATENTABILITY DEMONSTRATES A REASONABLE LIKELIHOOD OF PREVAILING AGAINST THE CHALLENGED CLAIMS OF THE 238 PATENT Each of the challenged claims of the 238 patent are product by process claims. As such, and as recognized by the Office during prosecution of the 238 patent, this means that a patent claim is analyzed through its composition only, and not through the methods that are recited in the claims. See In re Thorpe, 777 F.2d 695, 698 (Fed. Cir. 1985). As shown below, prior art references (alone or in combination) disclose the daptomycin composition required by the challenged claims, and thus, anticipate and/or render obvious these claims. Furthermore, as explained by Dr. Mulligan, daptomycin is only one of many known cyclic lipopeptides with antibiotic activity, of which surfactin is the best characterized and most well-known due to its versatility as a biosurfactant. See

30 22 Mulligan Dec. at 48. It is not surprising, therefore, that all of the processing techniques and analytical tools disclosed in the 238 patent were well-known and utilized by January Accordingly, all of the challenged claims are also obvious in view of prior art references even if the recited process steps are taken into account. A. Ground 1: Claims 10-48, and of the 238 Patent are Anticipated and Obvious Over the 226 Patent At the outset, and as recognized by the Office during prosecution, all claims of the 238 patent are product-by-process claims, i.e., the claimed product is defined by the process recited. As explained by Dr. Mulligan, the expected effect when performing the known process steps of the 238 patent would be a certain purity level as a direct result of the process step performed. Mulligan Dec. at 97. Thus, the only apparent effect of the recited process steps of the 238 patent would be the claimed purity levels, which is already reflected in the claims. See id.; see also Greenliant Systs., Inc. v. Xicor, LLC, 692 F.3d 1261, 1268 (Fed. Cir. 2012). Because the claims are product-by-process claims, the patent claim is analyzed through its composition only, and not through the methods that are recited in the claims. See Amgen, Inc. v. Hoffman-La Roche Ltd., 580 F.3d 1340, , n.14 (Fed. Cir. 2009); see also Abbott Labs v. Sandoz Inc., 566 F.3d 1282, 1292 (Fed. Cir. 2009) (en banc); see also Amgen, 580 F.3d at , n.14. Thus, daptomycin compositions (independent of the process steps used) which

31 23 teach, disclose, or otherwise suggest the claimed purity levels (either expressly or inherently), would anticipate or render obvious the claimed compositions. See Amgen, 580 F.3d at , n.14. As seen in the claim chart below, each of the challenged claims of the 238 patent claim specific purity levels, from 93% purity levels relative to recited impurities (e.g., claim 21) to 99 % purity (e.g., claim 12). In some instances, the claims recite to daptomycin pharmaceutical formulations (e.g., claim 18). The 226 patent disclosed the purification of daptomycin, and identification of anhydro daptomycin and β-isomer daptomycin. See Mulligan Dec. at 99. The 226 patent disclosed standard column chromatography and adsorption/filtration techniques to purify daptomycin so that the substance contains no more than 2.5% by weight of a combined total of anhydro-(daptomycin) and (β-)isomer- (daptomycin). See id. The 226 patent also disclosed the preparation of purified daptomycin using HPLC columns. See Mulligan Dec. at 100; 226 patent at Example 5, 13:5-52. In Example 5 of the 226 patent, the inventors stated that high performance liquid chromatography (HPLC) system is useful for following the processes of Examples 1-3 and for preparing new drug substance LY in substantially purified form. (Emphasis added). As stated by Dr. Mulligan, this would have meant to one of ordinary skill in the art that HPLC could be used to monitor

32 24 components as they appeared during purification as exemplified in Examples 1-3, and also for preparing daptomycin in a purified form. Mulligan Dec. at 100. The 226 patent exemplifies this same procedure, first applying the crude preparation through various chromatography media, assayed by analytical HPLC, after which fractions containing daptomycin are combined and lyophilized. 226 patent at Examples 2-4, 11:39-13:3 ( New drug substance [daptomycin] in pure form is prepared by purifying LY using procedures like those in Examples ) (emphasis added). Dr. Mulligan explained that because the 226 patent disclosed the separation of daptomycin from anhydro-daptomycin and β-isomer daptomycin impurities, one of ordinary skill in the art would recognize that fractions containing daptomycin would be expected to be free of the anhydrodaptomycin and β-isomer daptomycin impurities. Mulligan Dec. at 100. As further explained by Dr. Mulligan, HPLC was already in use by skilled artisans to purify other biosurfactants, such as the cyclic lipopeptide surfactin, to homogeneity. See Mulligan Dec. at 100, citing to Lin [Ex. 1031] at 32. Thus, as stated by Dr. Mulligan one of ordinary skill in the art would have recognized that a purification protocol that uses HPLC chromatography and demonstrates sufficient separation of impurities in the preparation, would have resulted... in daptomycin purity levels approaching or exceeding 99%, i.e., approaching homogeneity, relative to impurities present in the composition. Id. at 100. Thus,

33 25 as opined by Dr. Mulligan, the 226 patent, which disclosed highly purified daptomycin compositions exceeding 99% or approaching homogeneity relative to impurities present would have anticipated claims 10-48, , and At the very least, the 226 patent renders obvious claims 10-48, , and This is because, as Dr. Mulligan explains that, given the need for a high purity level, one of ordinary skill in the art would have simply repeated or combined different purification steps in order to attain that target purity level. This was seen, as Dr. Mulligan explains, when biosurfactant preparations were used for biochemical or biophysical analyses, such as scanning electron microscropy or nuclear magnetic resonance, as well as when pharmaceutically relevant purity levels were needed. See Mulligan Dec. at 101. Accordingly, it would have been obvious given the already highly purified daptomycin preparations in the 226 patent, to obtain the purity levels recited in the 238 claims. Lyophilization as claimed, e.g., in claim 18, was also well-known in January See Mulligan Dec. at 100 (citing 226 patent at Examples 2-4, 11:39-13:3). The claim chart below details the 226 patent disclosure anticipating, or rendering obvious claims 10-48, and US 8,058,238 Challenged Claims 10. A pharmaceutical composition comprising essentially pure daptomycin purified by a process comprising the steps of: (a) forming micelles comprising daptomycin; (b) 226 Patent Disclosure Purified daptomycin approaching homogeneity using

34 26 US 8,058,238 Challenged Claims converting the micelles to a non-micellar daptomycin composition comprising daptomycin in a non-micellar state; and (c) obtaining the purified daptomycin from the micelles, the non-micellar daptomycin composition, or a combination thereof. 11. The pharmaceutical composition of claim 10 comprising daptomycin of at least 98% purity measured relative to daptomycin impurities 1-14 defined by peaks 1-14 shown in FIG The pharmaceutical composition of claim 10 wherein the daptomycin is at least 99% pure. 226 Patent Disclosure column chromatography and HPLC. 12:57-61; 13:8-11. See claim 10. See claim These claims describe only non-limiting process steps See claim The composition of claim 17, wherein the purified See claim 10. daptomycin is obtained by a process further comprising the step of lyophilizing the purified daptomycin. 19. The composition of claim 18, wherein the purified daptomycin is substantially free of each of impurities 1 to 14 defined by peaks 1-14 shown in FIG. 12. Lyophilization of daptomycin. 11: See claim This claim describe only non-limiting process steps See claim A composition comprising daptomycin of greater than or about 93% purity relative to daptomycin impurities that arise in fermentation or purification of daptomycin, and wherein the daptomycin impurities comprise impurities 1-14 defined by peaks 1-14 shown in FIG. 12, and the daptomycin is obtained by a process comprising the step of forming a micelle comprising daptomycin. 13:8-11. Purified daptomycin approaching homogeneity using column chromatography and HPLC. 12:57-61; 22. The composition of claim 21, wherein the daptomycin See claim 21. impurities arise in fermentation. 23. The composition of claim 21, wherein the purity of See claim 21. daptomycin is at least 93%. 24. The composition of claim 23, wherein the daptomycin See claim 21. impurities arise in fermentation. 25. The composition of claim 21 wherein impurity 1 is See claim 21. present in an amount no more than 1%. 26. The composition of claim 25 wherein impurity 8 is See claim 21.

35 27 US 8,058,238 Challenged Claims present in an amount no more than 1%. 27. The composition of claim 21 wherein impurity 2 is present in an amount no more than 0.5%. 28. The composition of claim 21 wherein impurity 3 is present in an amount no more than 1%. 29. The composition of claim 21 wherein impurity 4 is present in an amount no more than 0.5%. 30. The composition of claim 21 wherein impurity 5 is present in an amount no more than 0.5%. 31. The composition of claim 21 wherein impurity 6 is present in an amount no more than 1%. 32. The composition of claim 21 wherein impurity 7 is present in an amount no more than 1%. 33. The composition of claim 21 wherein impurity 8 is present in an amount no more than 4%. 34. The composition of claim 33 wherein impurity 8 is present in an amount no more than 1%. 35. The composition of claim 21 wherein impurity 12 is present in an amount no more than 0.5%. 36. The composition of claim 21 wherein impurity 14 is present in an amount no more than 0.1% and These claims describe only non-limiting process steps A purified daptomycin composition of greater than or 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in FIG. 12, the purified daptomycin composition obtained by a process comprising the steps of: (a) subjecting daptomycin to conditions forming daptomycin micelles and (b) obtaining the purified daptomycin from the daptomycin micelles These claims describe only non-limiting process steps A purified daptomycin composition of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in FIG. 12, the purified daptomycin composition obtained by a process comprising the steps of: (a) subjecting 226 Patent Disclosure See claim 21. See claim 21. See claim 21. See claim 21. See claim 21. See claim 21. See claim 21. See claim 21. See claim 21. See claim 21. See claim 21. Purified daptomycin approaching homogeneity using column chromatography and HPLC. 12:57-61; 13:8-11. See claim 176. Purified daptomycin approaching homogeneity using column

36 28 US 8,058,238 Challenged Claims an aqueous solution comprising daptomycin at or above the critical daptomycin micelle concentration to a ph of 3.0 to 4.8 at a temperature of about 2-15 o C to form a daptomycin preparation; and (b) obtaining the purified daptomycin from the daptomycin preparation obtained in step (a). 226 Patent Disclosure chromatography and HPLC. 12:57-61; 13: These claims recite only non-limiting process steps. See claim A purified daptomycin composition of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in FIG. 12, wherein the percent purity is measured by HPLC analysis, and the purified daptomycin composition is obtained from a lipopeptide aggregate comprising daptomycin These claims describe only non-limiting process steps The composition of claim 183, wherein the daptomycin composition is at least or about 95% pure The composition of claim 183, wherein the daptomycin composition is at least or about 97% pure The composition of claim 183, wherein the daptomycin composition is at least or about 98% pure The composition of claim 183, wherein the daptomycin composition is at least 93% pure The composition of claim 183, wherein the daptomycin composition is essentially free of anhydro daptomycin A purified daptomycin composition of greater than or about 93% purity relative to impurities 1-14 defined by peaks 1-14 shown in FIG. 12, wherein the percent purity is measured by HPLC analysis, and the purified daptomycin composition is obtained by a process comprising the steps of: (a) fermenting a culture of Streptomyces roseosporus to produce daptomycin; (b) contacting the daptomycin from step (a) with an anion exchange resin; (c) eluting the daptomycin from the anion exchange resin in step (b) with a solvent having a ph of about to obtain a daptomycin solution; (d) adjusting the ph of the daptomycin solution from step (c) to about 3.0 to 4.8 and a temperature to about 2-15 o C to Purified daptomycin approaching homogeneity using column chromatography and HPLC. 12:57-61; 13:8-11. See claim 183. See claim 183. See claim 183. See claim 183. See claim 183. See claim 183. Purified daptomycin approaching homogeneity using column chromatography and HPLC. 12:57-61; 13:8-11.

37 29 US 8,058,238 Challenged Claims obtain a daptomycin aggregate solution comprising daptomycin aggregates; and (e) filtering the daptomycin aggregate solution to separate daptomycin aggregates from the daptomycin aggregate solution; and (f) obtaining the purified daptomycin from the daptomycin aggregates The composition of claim 191, wherein the daptomycin aggregates comprise daptomycin micelles. 226 Patent Disclosure See claim 191. B. Ground 2: Claims 21-36, 176, 183, and 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 The challenged claims are also obvious even if the recited process steps are taken into account. As explained by Dr. Mulligan, daptomycin is only one of many known biosurfactants with antibiotic activity. See Mulligan Dec. at 50. Antimicrobial cyclic lipopeptides, such as surfactin, have been exploited since the 1970s. It is not surprising, therefore, that the process techniques and analytical tools disclosed in the 238 patent were known and used in the biosurfactant art well prior to January Id. at 18, 57, 106, 158, 164, 180, 183, 211. The work of Dr. Mulligan and others in the field to significantly increase yield and purity levels would have thus motivated one of ordinary skill in the art to employ these steps in order to attain the product purity levels necessary for pharmaceutical use of purified daptomycin. Id. at (i) Claims Claim 21 of the 238 patent recites: