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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________________________________________
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`AGILA SPECIALTIES INC.
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`AND MYLAN PHARMACEUTICALS INC.,
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`Petitioners,
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`v.
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`CUBIST PHARMACEUTICALS, INC.,
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`Patent Owner.
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`____________________________________________
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`Case IPR2015-00144
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`Patent No. 8,058,238
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`____________________________________________
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`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
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`TABLE OF CONTENTS
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`Page
`Introduction ...................................................................................................... 1
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`I.
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`A.
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`B.
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`State of the Art Prior to the Invention ................................................... 2
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`Description of the Invention .................................................................. 4
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`II.
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`Definition of One of Ordinary Skill in the Art ................................................ 6
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`III. Claim Construction .......................................................................................... 8
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`A.
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`B.
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`The Process Limitations Cannot Be Disregarded ................................. 8
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`Proposed Terms for Construction ....................................................... 11
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`1.
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`The claim term “essentially pure” daptomycin should be
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`construed to mean “at least 98% of a sample is
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`daptomycin.” ............................................................................. 12
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`2.
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`The claim term “substantially pure” daptomycin should be
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`construed to mean “at least 95% of a sample is
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`daptomycin.” ............................................................................. 13
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`3.
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`Claim terms regarding daptomycin “substantially free,”
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`“essentially free,” or “free of” another compound. .................. 13
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`IV. Ground 1 should be denied because it fails to address each limitation of
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`the challenged claims ..................................................................................... 15
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`V.
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`The Petition should be denied because the asserted grounds are
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`duplicative, redundant, and unclear ............................................................... 18
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`A.
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`The Petition Alleges No Fewer than 27 Grounds of Invalidity,
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`None of Which Are Identified with Particularity. ............................... 18
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`1.
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`2.
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`3.
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`4.
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`5.
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`Ground 1 includes two separate grounds. ................................. 22
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`Ground 2 includes at least two separate grounds. ..................... 23
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`Ground 3 includes at least 14 separate grounds. ....................... 26
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`Ground 4 includes at least six separate grounds. ...................... 30
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`Ground 5 includes at least three separate grounds. ................... 37
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`B.
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`The Petition Provides No Meaningful Distinction Among the
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`Horizontally and Vertically Redundant Grounds. ............................... 39
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`VI. Ground 1 should be denied under 35 U.S.C. § 325(d) because it presents
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`grounds previously considered by the Office ................................................ 41
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`VII. Conclusion ..................................................................................................... 46
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`TABLE OF AUTHORITIES
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`FEDERAL CASES
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`PAGE(S)
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`Amgen Inc. v. F. Hoffman-La Roche Ltd,
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`580 F.3d 1340 (Fed. Cir. 2009) ...................................................................... 8, 11
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`Cubist Pharms., Inc. v. Hospira, Inc.,
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`C.A. No. 12-376 (GMS), slip op. (D. Del. May 20, 2013) ................................. 11
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`Cubist Pharms., Inc. v. Hospira, Inc.,
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`Claim Construction Chart (D. Del. Feb. 1, 2013) ......................................... 11, 12
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`Cubist Pharms., Inc. v. Hospira, Inc.,
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`Memorandum Opinion, dated December 8, 2014 .............................................. 11
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`Greenliant Sys., Inc. v. Xicor LLC,
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`692 F.3d 1261 (Fed. Cir. 2012) ............................................................................ 8
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`In re Robertson,
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`169 F.3d 743 (Fed. Cir. 1999) ............................................................................ 17
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`Schumer v. Lab. Computer Sys., Inc.,
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`308 F.3d 1304 (Fed. Cir. 2002) .......................................................................... 21
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`BOARD DECISIONS
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`CallCopy, Inc. v. Verint Americas, Inc.,
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`IPR2013-00492, Paper 14 (P.T.A.B.) ................................................................. 21
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`Corning Inc. v. DSM IP Assets B.V.,
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`IPR2013-00052, Paper 16 (P.T.A.B.) ............................................................. 8, 11
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`Edmund Optics, Inc. v. Semrock, Inc.,
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`IPR2014-00583, Paper 9 (P.T.A.B.) ................................................................... 20
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`Excelsior Med. Corp. v. Lake and Tennant,
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`IPR2013-00494, Paper 10 (P.T.A.B.) ................................................................. 41
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`Illumina, Inc. v. Trs. of Columbia Univ.,
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`IPR2012-00006, Paper 43 (P.T.A.B.) ................................................................. 40
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`JST Performance, Inc. d/b/a Rigid Industries v. Koninklijke Philips N.V.,
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`IPR2014-00874, Paper 11 (P.T.A.B.) ................................................................. 17
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`Liberty Mut. Ins. Co. v. Progressive Cas. Ins. Co.,
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`CBM2012-00003, Paper 7 (P.T.A.B.) ................................................................ 39
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`Mitsubishi Plastics, Inc. v. Celgard, LLC,
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`IPR2014-00524, Paper 27 (P.T.A.B.) ................................................................. 15
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`Prism Pharma Co. LTD v. Choongwae Pharma Corp.,
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`IPR2014-00315, Paper 14 (P.T.A.B.) ................................................................. 41
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`Zetec, Inc. v. Westinghouse Elec. Co., LLC,
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`IPR2014-00384, Paper 10 (P.T.A.B.) ........................................................... 21, 40
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`STATUTES
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`35 U.S.C. § 312(a)(3) ............................................................................................... 18
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`35 U.S.C. § 314 .......................................................................................................... 2
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`35 U.S.C. § 316(b) ....................................................................................... 18, 21, 39
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`35 U.S.C. § 325(d) ............................................................................................. 41, 46
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`FEDERAL REGULATIONS
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`37 C.F.R. § 42.1(b) ................................................................................ 18, 21, 39, 40
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`37 C.F.R. § 42.8(b) .................................................................................................. 11
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`37 C.F.R. § 42.22(a)(2) ............................................................................................ 18
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`37 C.F.R. § 42.100(b) .............................................................................................. 11
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`37 C.F.R. § 42.104(b) ............................................................................ 15, 18, 20, 22
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`37 C.F.R. § 42.108 ............................................................................................... 2, 19
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`I.
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`INTRODUCTION
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`Patent Owner Cubist Pharmaceuticals, Inc.’s (“Cubist’s”) U.S. Patent No.
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`8,058,238 (the “’238 patent”) claims highly purified daptomycin compositions and
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`pharmaceutical compositions thereof. The ’238 patent discloses techniques that
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`allow for the production of highly purified daptomycin compositions on a
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`commercial scale. Previous purification techniques for daptomycin did not
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`effectively remove these harmful impurities and resulted in extremely low yields,
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`which made commercial-scale production of daptomycin infeasible.
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`Agila Specialties Inc. and Mylan Pharmaceuticals Inc. (“Agila”) filed the
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`present Petition to invalidate certain claims of the ’238 patent as anticipated or
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`obvious. However, Agila’s Petition suffers from at least three key deficiencies,
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`such that there is no reasonable likelihood that the Petitioners will prevail on at
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`least one claim.
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`First, the Petition requests that the Board ignore the process limitations of
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`the challenged product-by-process claims, without even attempting to establish that
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`these limitations do not impart structural or functional differences to the claimed
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`product. Ground 1 thus improperly fails to address each limitation of the
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`challenged claims. Second, the Petition asserts a multitude of grounds that are
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`duplicative, redundant, and unclear. The Board should decline the undue burden of
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`attempting to parse this complex web of arguments. Third, Ground 1 rests on the
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`same prior art reference and substantially the same arguments previously raised by
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`the Patent Office and overcome during prosecution.
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`These deficiencies defeat all of Agila’s proposed grounds, such that there is
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`no reasonable likelihood that the Petitioners will prevail on at least one claim, and
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`the Board should not institute review. 35 U.S.C. § 314; 37 C.F.R. § 42.108.
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`State of the Art Prior to the Invention
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`A.
`Daptomycin is a potent antibiotic effective for treating serious infections
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`caused by certain Gram-positive bacteria including Staphylococcus aureus and
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`methicillin-resistant Staphylococcus aureus (“MRSA”). See CUBICIN®
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`(daptomycin for injection) label approved November 26, 2014, at 2 (Ex. 2014).
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`Daptomycin is obtained by fermenting the soil microorganism Streptomyces
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`roseosporus (S. roseosporus). ’238 patent at 1:58-63 (Ex. 1001). Fermenting S.
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`roseosporus produces a complex mixture containing many undesirable compounds.
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`Separating daptomycin from these compounds is difficult, particularly while
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`obtaining quantities on a commercial scale.
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`The mixture resulting from fermentation of S. roseosporus may contain,
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`among other things, endotoxins, saponins, and a group of daptomycin-related
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`impurities identified in Table 3 of the ’238 patent. Id. at 33:63-34:19. Each of
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`these substances is undesirable in a pharmaceutical daptomycin composition. Even
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`very small amounts of endotoxins (also referred to as pyrogens) can cause fever
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`and other symptoms in humans. See U.S. Pharmacopeial Convention, The United
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`States Pharmacopeia 90-91 & n.2 (36th prtg. 2012) (Ex. 2015). As a result,
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`endotoxin levels are strictly limited in pharmaceutical compositions. Id.; see also
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`Human, Biological, and Animal Drugs and Medical Devices; Availability of
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`Guideline for Use of the Limulus Amebocyte Lysate (LAL) Test, 53 Fed. Reg.
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`5,044, 5,045 (Feb. 19, 1988) (Ex. 2013). Saponins are believed to be biologically
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`active in humans and can interfere with the operation of certain purification
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`processes. See U.S. Patent No. 4,874,843 (the “’843 patent”) at 2:11-16 (Ex. 1007).
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`Thus, saponins also need to be removed from daptomycin compositions intended
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`for pharmaceutical use. In addition, at least two daptomycin-related impurities are
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`known to have biological activity, making them undesirable in pharmaceutical
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`compositions of daptomycin. See U.S. Patent No. RE39,071 (the “RE’071 patent”)
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`at 7:61-8:2 (Ex. 2005).
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`Eli Lilly began clinical development of daptomycin in the early 1980’s, but
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`could not develop a safe and effective dosing regimen for the drug and eventually
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`abandoned it. Francis P. Tally, et al., Daptomycin: A Novel Agent Gram-positive
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`Infections, Expert Opin. Investig. Drugs 8(8):1224 (1999) (Ex. 1018). Cubist in-
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`licensed daptomycin from Lilly in 1997 and began producing daptomycin for use
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`in clinical trials. Id.
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`Cubist initially began purifying daptomycin using multiple rounds of
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`hydrophobic interaction chromatography in attempt to separate daptomycin from
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`the other compounds in the mixture resulting from the fermentation of S.
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`roseosporus. However, Cubist soon determined that this technique did not
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`adequately remove endotoxins, saponins, or daptomycin-related substances. In
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`particular, Cubist’s initial batches had endotoxin levels that made them unusable in
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`clinical trials. In addition to failing to remove harmful impurities, the hydrophobic
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`interaction chromatography process resulted in recovery of daptomycin that was
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`far too low for commercial production.
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`B. Description of the Invention
`The inventors thus set out to develop a new purification process that would
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`enable the production of daptomycin compositions containing acceptable levels of
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`impurities and also provide a commercially viable yield. ’238 patent, e.g., at 3:36-
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`66 (Ex. 1001). The inventors first set out to remove endotoxins, so that the drug
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`could be used in clinical trials. Because endotoxins are generally larger than
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`daptomycin, the inventors initially tried using ultrafiltration with a filter sized such
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`that it should have retained endotoxins, while allowing daptomycin to pass through.
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`However, unexpectedly, daptomycin did not pass through the ultrafilter. The
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`inventors studied why, eventually determining that the daptomycin molecules had
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`aggregated to form micelles, which were too large to pass through the ultrafilter.
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`The inventors also discovered that daptomycin formed micelles at acidic pH, but,
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`unexpectedly, these micelles broke apart into individual daptomycin molecules at
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`neutral pH. The inventors thus discovered that daptomycin’s ability to form
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`micelles is reversible.
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`This surprising discovery – that daptomycin formed reversible micelles
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`under conditions compatible with purification – enabled the inventors to develop
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`their novel purification technique. First, the daptomycin fermentation mixture
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`could be ultrafiltered at acidic pH. Small impurities, like saponins, would pass
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`through the ultrafilter and be removed, while daptomycin micelles would be
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`retained on the ultrafilter, along with larger impurities like endotoxins. Then, the
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`pH could be raised to neutral to break up the micelles. The individual daptomycin
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`molecules would then pass through the ultrafilter, while the larger impurities, such
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`as endotoxins, would be retained on it. Using both steps, large and small
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`impurities could be separated from daptomycin. ’238 patent, e.g., at 20:42-66;
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`18:23-39 (Ex. 1001).
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`The inventors also developed a method to further separate daptomycin from
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`daptomycin-related substances in the fermentation mixture. At the time, it was
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`believed that there was an upper limit to the level of purity that could be achieved
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`with respect to daptomycin-related substances, because it was thought that as
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`daptomycin-related substances were removed from the composition, daptomycin
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`would naturally break down to form more daptomycin-related substances.
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`However, the inventors devised a method using anion exchange chromatography
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`that could consistently produce daptomycin compositions of greater than 93%
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`purity, and in some cases up to 99% purity, under specific conditions. ’238 patent
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`at 4:4-6, 5:37-45, 12:54-65, 14:8-20, 31:60-32:14 (Ex. 1001).
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`The combined processes discovered by the inventors consistently produce
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`daptomycin compositions with undetectable levels of endotoxins, almost no
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`saponins, and low levels of daptomycin related substances. Id. at, e.g., 31:8-14;
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`35:6-12; 36:52-56. Moreover, the processes provide high enough recovery to
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`enable commercial production of daptomycin. Id. at, e.g., 3:54-66.
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`II. DEFINITION OF ONE OF ORDINARY SKILL IN THE ART
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`A person of ordinary skill in the art at the time of the invention would hold a
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`degree in chemistry, biochemistry, chemical engineering, or complementary
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`discipline and have laboratory experience in the manufacturing, purification,
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`analysis, and/or characterization of pharmaceutical products for medicinal use.
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`According to Agila’s definition:
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`A person of ordinary skill in the art related to the ’238 patent would
`have had the necessary skill set for purifying, for example, secondary
`metabolites from microbial fermentation, including but not limited to
`filtration and adsorption techniques, chemical extractions and analysis,
`including chromatography, such as anion exchange chromatography,
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`hydrophobic interaction chromatography, HPLC and gel filtration
`analysis. Mulligan Dec. [Ex. 1005] at ¶28. Moreover, a person of
`ordinary skill in the art for the ’238 patent would have had the
`requisite skill set to analyze biosurfactant products obtained, including
`the use of chromatography and mass- or charge-based analytical
`techniques, such as mass spectrometry and HPLC. Id. A person of
`ordinary skill in the art related to the ’238 patent typically would have
`held a Masters degree or Ph.D in Chemistry, Biochemistry, or
`Chemical Engineering with experience in microbial fermentation and
`biochemical processes, including biosurfactant or lipopeptide product
`purification, or the equivalent. Id. at ¶28.
`Corr. Pet. at 5-6.
`The Board should reject Agila’s definition of one of ordinary skill in the art
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`because it improperly confers a heightened level of skill and specialized skill set
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`focused in hindsight on the claimed invention, by requiring expertise with certain
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`claimed process steps as part of the definition of ordinary skill, as well as assuming
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`specific experience with fermentation processes, obtaining and analyzing
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`biosurfactant products, and purifying biosurfactants or lipopeptides. One of
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`ordinary skill in the art would be unlikely to possess such specialized expertise
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`specifically targeted at the claimed process steps.
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`III. CLAIM CONSTRUCTION
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`A. The Process Limitations Cannot Be Disregarded
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`Agila asserts that for purposes of evaluating patentability the challenged
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`product-by-process claims should be interpreted as simply directed to compositions
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`of daptomycin with the claimed purity level, without regard to the process
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`limitations. Corr. Pet. at 6. However, process limitations in product-by-process
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`claims must be considered in evaluating patentability when the claimed process
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`imparts structural and functional differences in the resultant product. Amgen Inc. v.
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`F. Hoffman-La Roche Ltd, 580 F.3d 1340, 1370 (Fed. Cir. 2009).
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`Agila asks the Board to disregard the process limitations in each of the
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`challenged claims without establishing that these limitations do not “impart
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`distinctive structural characteristics to the final product.” Corning Inc. v. DSM IP
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`Assets B.V., IPR2013-00052, Paper 16 at 2-3 (P.T.A.B.); see also Greenliant Sys.,
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`Inc. v. Xicor LLC, 692 F.3d 1261, 1268 (Fed. Cir. 2012) (“[T]here is an exception
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`to this general rule that the process by which the product is made is irrelevant. As
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`we recognized in Amgen, if the process by which a product is made imparts
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`‘structural and functional differences’ distinguishing the claimed product from the
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`prior art, then those differences ‘are relevant as evidence of no anticipation.’”
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`(quoting Amgen, 580 F.3d at 1370)).
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`In fact, the process limitations recited in the challenged claims do impart
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`distinctive structural and functional characteristics. For example, as the ’238
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`patent itself demonstrates, daptomycin compositions created using the inventive
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`methods disclosed and claimed in the ’238 patent contain lower levels of
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`endotoxins than daptomycin compositions prepared using prior art methods.
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`See ’238 patent, e.g., at 36:40-56 (Ex. 1001). Example 15 of the ’238 patent
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`describes as a starting material a daptomycin composition prepared according to
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`Eli Lilly’s prior art ’843 patent, which had “measurable pyrogen” (another term for
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`endotoxins). Id. at 36:42-47. As explained in the patent, this starting material is
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`then further purified by ultrafiltration under conditions in which daptomycin is in
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`monomer form. Id. at 36:47-52. In the resulting daptomycin composition,
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`“pyrogen content is reduced to undetectable levels.” Id. at 36:52-56.
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`Daptomycin compositions prepared using the processes of the ’238 patent
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`also contain lower levels of various daptomycin-related impurities than
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`daptomycin compositions prepared using prior art methods. Id. at 21:59-22:8.
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`Example 10 of the ’238 patent recreates the material produced by Eli Lilly’s ’843
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`patent process and reports its impurity profile, concluding that the product of
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`the ’843 patent process has fourteen daptomycin-related impurities at particular
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`levels, ranging in some instances as high as between 1.0% and 4.0%. See ’238
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`patent at 33:58-35:3 (Ex. 1001); see also id. at 30:61-64 (stating that the bulk
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`preparation, which was categorized in Example 10, was the product of the ’843
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`patent process).
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`Example 10 describes that further purification of the daptomycin
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`composition using the methods of the ’238 patent results in daptomycin purity
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`greater than 99.0% with two particular daptomycin-related impurities of interest
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`below the level of detection. ’238 patent at 35:4-13 (Ex. 1001). Example 15 of
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`the ’238 patent further demonstrates that the process steps of the ’238 patent
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`remove several of the daptomycin-related impurities from the claimed daptomycin
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`compositions, and reduce the levels of other impurities compared to the prior art
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`composition. Id. at 36:52-56 (noting that “several impurities that had been present
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`at 0.1-0.2% are removed”).
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`The Petition refers to Dr. Mulligan’s declaration in asserting that “the only
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`apparent effect of the recited process steps of the ’238 patent would be the claimed
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`purity levels, which is already reflected in the claims.” Corr. Pet. at 22. However,
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`this unsupported assertion cannot be credited, given the failure to provide any
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`actual comparison demonstrating a lack of structural and functional differences,
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`particularly when the specification of the ’238 patent itself demonstrates such
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`differences, as noted above. As one example, many of the claimed purity
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`limitations are stated with respect to particular impurities (such as impurities 1-14
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`defined by peaks 1-14 shown in FIG. 12), and thus do not address other impurities
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`(such as endotoxins) that are nevertheless removed by the claimed processes,
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`creating differences in the claimed compositions.
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`Accordingly, the process limitations in the asserted claims, which do impart
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`structural differences in the final daptomycin composition, cannot be disregarded.
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`Corning Inc. v. DSM IP Assets B.V., IPR2013-00052, Paper 16 at 2-3 (P.T.A.B.);
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`see also Amgen, 580 F.3d at 1370.
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`B.
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`Proposed Terms for Construction
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`A claim subject to inter partes review is given its “broadest reasonable
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`construction in light of the specification of the patent in which it appears.” 37
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`C.F.R. § 42.100(b). Solely for purposes of this proceeding, the following
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`discussion proposes Cubist’s construction for two terms and identifies support for
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`the construction. Any claim terms not included in the following discussion are to
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`be given their broadest reasonable interpretation in light of the specification as
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`commonly understood by those of ordinary skill in the art.1
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`1 Other terms have been construed in district court litigation. See, e.g., Cubist
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`Pharms., Inc. v. Hospira, Inc., C.A. No. 12-376 (GMS), slip op. (D. Del. May 20,
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`2013) (Ex. 2006); id., Claim Construction Chart (D. Del. Feb. 1, 2013) (Ex. 2007).
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`Agila failed to comply with 37 C.F.R. § 42.8(b) because it never identified the
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`Cubist v. Hospira case as a related matter in its mandatory notices, despite
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`To the extent not addressed below, Cubist agrees that the terms Agila has
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`proposed for construction should be construed as Agila proposes, which is
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`consistent with the ’238 patent specification.
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`1.
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`The claim term “essentially pure” daptomycin should be
`construed to mean “at least 98% of a sample is daptomycin.”
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`Agila proposes that the term “essentially pure” daptomycin be construed to
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`mean “at least 98%” purity levels, or “at least 99%” daptomycin purity levels.
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`Corr. Pet. at 7. Cubist disagrees, because the “or at least 99%” language is
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`superfluous. The specification states that “[d]aptomycin or daptomycin-related
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`lipopeptide is ‘essentially pure’ when at least 98% of a sample is daptomycin or
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`daptomycin-related lipopeptide.” ’238 patent at 7:41-43 (Ex. 1001). During the
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`Hospira litigation, the parties agreed that “essentially pure daptomycin” means “at
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`least 98% of a sample is daptomycin,” reflecting the precise wording of the
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`specification. See Claim Construction Chart at Exhibit A (D. Del. Feb. 1, 2013)
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`(Ex. 2007). The Board should adopt this same construction.
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`submitting the Court’s opinion (Ex. 1045) in a paper titled Notice of Decision in
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`Related Judicial Matter.
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`2.
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`The claim term “substantially pure” daptomycin should be
`construed to mean “at least 95% of a sample is daptomycin.”
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`Agila proposes that the term should be construed to mean “at least 95%”
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`purity levels, or “at least 97%” daptomycin purity levels. Corr. Pet. at 7. Cubist
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`disagrees, because the “at least 97%” language is superfluous. The specification
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`states that daptomycin is “substantially pure” when “at least 95% of a sample is
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`daptomycin.” ’238 patent at 7:35-37 (Ex. 1001). The Board should adopt this
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`construction to precisely reflect the language of the specification.
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`3.
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`Claim terms regarding daptomycin “substantially free,”
`“essentially free,” or “free of” another compound.
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`Cubist proposes that the claim term “daptomycin that is substantially free of
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`[another compound]” be construed to mean that “the other compound is present in
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`an amount that is no more than 1% of the amount of the daptomycin preparation.”
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`This construction is consistent with the specification of the ’238 patent, which
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`states, “[d]aptomycin or daptomycin-related lipopeptide is ‘substantially free’ of
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`another compound when the other compound is present in an amount that is no
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`more than 1% of the amount of the daptomycin or daptomycin-related lipopeptide
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`preparation.” ’238 patent at 7:47-51 (Ex. 1001).
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`Cubist proposes that the claim term “daptomycin that is essentially free of
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`[another compound]” be construed to mean that “the other compound is present in
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`an amount that is no more than 0.5% of the amount of the daptomycin preparation.”
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`This construction is consistent with the specification of the ’238 patent, which
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`states, “[d]aptomycin or daptomycin-related lipopeptide is ‘essentially free’ of
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`another compound when the other compound is present in an amount that is no
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`more than 0.5% of the amount of the daptomycin or daptomycin-related
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`lipopeptide preparation.” ’238 patent at 7:52-56 (Ex. 1001).
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`Cubist proposes that the claim term “daptomycin that is free of [another
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`compound]” be construed to mean that “the other compound is present in an
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`amount that is no more than 0.1% of the amount of the daptomycin preparation.”
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`This construction is consistent with the specification of the ’238 patent, which
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`states, “[d]aptomycin or daptomycin-related lipopeptide is ‘free’ of another
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`compound when the other compound is present in an amount that is no more than
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`0.1% of the amount of the daptomycin or daptomycin-related lipopeptide
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`preparation.” Id. at 7:57-60.
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`Agila’s proposed constructions for these terms are similar, but do not reflect
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`the language of the specification as precisely, for example, failing to reference the
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`daptomycin “preparation.” Corr. Pet. at 7. Therefore, the Board should adopt
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`Cubist’s proposed constructions to precisely reflect the language of the
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`specification.
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`IV. GROUND 1 SHOULD BE DENIED BECAUSE IT FAILS TO
`ADDRESS EACH LIMITATION OF THE CHALLENGED CLAIMS
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`As an initial matter, the Board’s decision on whether to institute inter partes
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`review must be based on the record of this proceeding. See Mitsubishi Plastics, Inc.
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`v. Celgard, LLC, IPR2014-00524, Paper 27 at 8 (P.T.A.B.) (“The question before
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`the Board is whether Petitioner has shown that the record in this proceeding
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`establishes a reasonable likelihood that claims are unpatentable. . . . Petitioners
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`have the responsibility to present, through argument and evidence, a reasonable
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`likelihood of unpatentability of the challenged claims.”) (emphasis omitted).
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`Pursuant to 37 C.F.R. § 42.104(b)(4), the petition “must specify where each
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`element of the claim is found in the prior art patents or printed publications relied
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`upon.” (emphasis added). Agila’s Ground 1 completely fails to identify where at
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`least one element of each of the challenged claims is found in the prior art relied on,
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`and therefore should be denied.
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`Ground 1 asserts that all challenged claims, i.e., claims 10-48, and 176-1922
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`are anticipated by and obvious over U.S. Patent No. 5,912,226 (“the ’226 patent”)
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`(Ex. 1010). Corr. Pet. at 22. Each of the challenged claims includes at least one
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`2 As discussed below, the statement of the precise relief requested for each claim
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`challenged required by 37 C.F.R. § 42.104(b) states that only claims “10-36, 43-47,
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`and 176-192” are challenged under Ground 1. Corr. Pet. at 5.
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`purification step requiring the use of daptomycin micelles or aggregates. See ’238
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`patent independent claim 10 (“(a) forming micelles comprising daptomycin; (b)
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`converting the micelles to a non-micellar daptomycin composition comprising
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`daptomycin in a non-micellar state; and (c) obtaining the purified daptomycin from
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`the micelles, the non-micellar daptomycin composition, or a combination thereof”),
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`independent claim 21 (“the daptomycin is obtained by a process comprising the
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`step of forming a micelle comprising daptomycin”), independent claim 176 (“(a)
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`subjecting daptomycin to conditions forming daptomycin micelles and (b)
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`obtaining the purified daptomycin from the daptomycin micelles”), independent
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`claim 180 (“(a) subjecting an aqueous solution comprising daptomycin at or above
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`the critical daptomycin micelle concentration to a pH of 3.0 to 4.8 at a temperature
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`of about 2-15 ºC to form a daptomycin preparation; and (b) obtaining the purified
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`daptomycin from the daptomycin preparation obtained in step (a)”), independent
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`claim 183 (“the purified daptomycin composition is obtained from a lipopeptide
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`aggregate comprising daptomycin”), and independent claim 191 (“(d) adjusting the
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`pH … to obtain a daptomycin aggregate solution comprising daptomycin
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`aggregates; and (e) filtering the daptomycin aggregate solution to separate
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`daptomycin aggregates from the daptomycin aggregate solution; and (f) obtaining
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`the purified daptomycin from the daptomycin aggregates”) (Ex. 1001). The
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`remaining challenged claims depend directly or indirectly from one of these claims
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`and, therefore, incorporate all of their limitations. See ’238 patent at 38:21-50:16
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`(Ex. 1001).
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`Agila has not identified any teaching in the ’226 patent that expressly or
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`inherently provides these process steps, because there is none. The ’226 patent
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`does not teach or suggest purification of daptomycin using micelles or aggregates,
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`as required by all of the challenged claims.
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`The Petition states that “daptomycin compositions (independent of the
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`process steps used) which teach, disclose, or otherwise suggest the claimed purity
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`levels (either expressly or inhere
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