IPR2015-01570
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`FRESENIUS KABI USA LLC
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`Petitioner,
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`v.
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`CUBIST PHARMACEUTICALS LLC
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`Patent Owner.
`____________________________________________
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`Case: IPR2015-01570
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`Patent No. 8,058,238
`____________________________________________
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`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FRESENIUS KABI USA LLC
`
`Petitioner,
`
`
`
`v.
`
`
`
`CUBIST PHARMACEUTICALS LLC
`
`Patent Owner.
`____________________________________________
`
`Case: IPR2015-01570
`
`Patent No. 8,058,238
`____________________________________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
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`
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`
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`TABLE OF CONTENTS
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`IPR2015-01570
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`PAGE
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`I.
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`INTRODUCTION ........................................................................................... 1
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`A.
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`State of the Art Prior to the Invention ................................................... 2
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`B. Description of the Invention .................................................................. 4
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`II. DEFINITION OF ONE OF ORDINARY SKILL IN THE ART ................... 6
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`III.
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`INTERPRETATION OF PRODUCT-BY-PROCESS CLAIMS ................... 6
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`IV. THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
`NOT ADDRESS EVERY LIMITATION OF CLAIM 98 .............................. 8
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`A.
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`B.
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`C.
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`The Process Limitations of Claim 98 Impart Structural and
`Functional Differences to the Claimed Product .................................... 8
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`The Petition Fails to Establish a Lack of Structural and
`Functional Differences ........................................................................ 11
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`The Petition Improperly Ignores the Process Limitations of Claim
`98 ......................................................................................................... 12
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`V.
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`CONCLUSION .............................................................................................. 14
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`IPR2015-01570
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`TABLE OF AUTHORITIES
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`FEDERAL CASES
`Amgen Inc. v. F. Hoffman-La Roche Ltd,
`580 F.3d 1340 (Fed. Cir. 2009) ...................................................................... 7, 11
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`Page(s)
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`Biodelivery Scis. Int’l, Inc. v. Monosol RX, LLC, IPR2015-00168 ..................... 7, 11
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`Corning Inc. v. DSM IP Assets B.V., IPR2013-00052 ......................................... 7, 10
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`Greenliant Sys., Inc. v. Xicor LLC,
`692 F.3d 1261 (Fed. Cir. 2012) ............................................................................ 7
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`FEDERAL STATUTES
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`35 U.S.C. § 314 .......................................................................................................... 2
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`REGULATIONS
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`37 C.F.R. § 42.104 (b)(4) ......................................................................................... 14
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`37 C.F.R. § 42.107 ................................................................................................... 16
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`37 C.F.R. § 42.108 ..................................................................................................... 2
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`53 Fed. Reg. 5,044 (Feb. 19, 1988) ......................................................................... 15
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`53 Fed. Reg. 5,044, 5,045 (Feb. 19, 1988) (Ex. 2003) .............................................. 3
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`OTHER AUTHORITIES
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`U.S. Patent No. 4,874,843 .................................................................................passim
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`U.S. Patent No. 8,058,238 .................................................................................passim
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`U.S. Patent No. RE39,071 ......................................................................................... 3
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`ii
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`I.
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`INTRODUCTION
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`IPR2015-01570
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`Patent Owner Cubist Pharmaceuticals LLC’s (“Cubist”) 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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`Fresenius Kabi USA LLC (“Fresenius”) filed the present Petition to
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`invalidate certain claims of the ’238 patent as anticipated. Subsequently, the Board
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`granted a joint motion to limit the present Petition to claim 98. See IPR2015-
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`01570, Paper 12 (September 15, 2015). Therefore, the Petition is now narrowed to
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`claim 98, challenged in Ground 1. The other claims and, consequently, Ground 2
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`are no longer at issue. Nevertheless, Fresenius’s Petition, even as narrowed,
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`should not be instituted as there is no reasonable likelihood that Petitioner will
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`prevail on at least one claim.
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`Ground 1 ignores the process limitations of the challenged product-by-
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`process claim, without sufficiently establishing that these limitations do not impart
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`structural and functional differences to the claimed product. Ground 1 thus
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`improperly fails to address each limitation of the challenged claim. This
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`1
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`IPR2015-01570
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`deficiency defeats Fresenius’s proposed ground, such that there is no reasonable
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`likelihood that the Petitioner will prevail on at least one claim, and the Board
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`should not institute review. 35 U.S.C. § 314; 37 C.F.R. § 42.108. Patent Owner
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`also disagrees with Petitioner on the merits, but will not otherwise address the
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`substance of Petitioner’s arguments in this paper.
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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. 2001).
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`Daptomycin is obtained by fermenting the soil microorganism Streptomyces
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`roseosporus (S. roseosporus). ’238 patent at 1:60-63 (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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`IPR2015-01570
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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. 2002). As a result,
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`endotoxin levels are strictly limited in commercial pharmaceutical compositions.
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`Id.; see also Human, Biological, and Animal Drugs and Medical Devices;
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`Availability of Guideline for Use of the Limulus Amebocyte Lysate (LAL) Test,
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`53 Fed. Reg. 5,044, 5,045 (Feb. 19, 1988) (Ex. 2003). Saponins are believed to be
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`biologically active in humans and can interfere with the operation of certain
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`purification processes. See U.S. Patent No. 4,874,843 (the “’843 patent”) at 2:11-
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`16 (Ex. 1007). Thus, saponins also need to be removed from daptomycin
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`compositions intended for pharmaceutical use. In addition, at least two
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`daptomycin-related impurities are known to have biological activity, making them
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`undesirable in pharmaceutical compositions of daptomycin. See U.S. Patent No.
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`RE39,071 (the “RE’071 patent”) at 7:61-8:2 (Ex. 1034).
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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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`IPR2015-01570
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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 molecules are generally larger
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`than daptomycin molecules, the inventors initially tried using ultrafiltration with a
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`filter sized such that it should have retained endotoxins, while allowing
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`daptomycin to pass through. However, unexpectedly, daptomycin did not pass
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`through the ultrafilter. The inventors studied why, eventually determining that the
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`daptomycin molecules had aggregated to form micelles, which were too large to
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`IPR2015-01570
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`pass through the ultrafilter. The inventors also discovered that daptomycin formed
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`micelles at acidic pH, but, unexpectedly, these micelles broke apart into individual
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`daptomycin molecules at neutral pH. The inventors thus discovered that
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`daptomycin’s ability to form 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. Prior to the invention,
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`it was believed that there was an upper limit to the level of purity that could be
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`achieved with respect to daptomycin-related substances, because it was thought
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`that as daptomycin-related substances were removed from the composition,
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`IPR2015-01570
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`daptomycin would naturally break down to form more daptomycin-related
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`substances. However, the inventors devised a method using anion exchange
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`chromatography that could consistently produce daptomycin compositions of
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`greater than 93% purity, and in some cases up to 99% purity, under specific
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`conditions. ’238 patent at 4:4-6, 5:37-45, 12:54-65, 14:8-20, 31:60-32:14 (Ex.
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`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
`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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`III.
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`INTERPRETATION OF PRODUCT-BY-PROCESS CLAIMS
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`Claim 98 is a product-by-process claim. Process limitations in product-by-
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`process claims must be considered in evaluating patentability when the claimed
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`process imparts structural and functional differences in the resultant product.
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`IPR2015-01570
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`Amgen Inc. v. F. Hoffman-La Roche Ltd, 580 F.3d 1340, 1370 (Fed. Cir. 2009); see
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`also, Greenliant Sys., Inc. v. Xicor LLC, 692 F.3d 1261, 1268 (Fed. Cir. 2012)
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`(“[T]here is an exception to this general rule that the process by which the product
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`is made is irrelevant. As we recognized in Amgen, if the process by which a
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`product is made imparts ‘structural and functional differences’ distinguishing the
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`claimed product from the prior art, then those differences ‘are relevant as evidence
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`of no anticipation.’” (quoting Amgen, 580 F.3d at 1370)). Furthermore, structural
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`and functional differences are relevant even when they are not explicitly recited in
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`a product-by-process claim. Amgen, 580 F.3d at 1370 .
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`The Board may not disregard process limitations in challenged product-by-
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`process claims in evaluating patentability when the Petitioner has not sufficiently
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`established that these limitations do not “impart distinctive structural
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`characteristics to the final product.” See Corning Inc. v. DSM IP Assets B.V.,
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`IPR2013-00052, Paper 16 at 2-3 (P.T.A.B.). In Corning, the Board denied a
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`ground challenging a product-by-process claim where the Petition “did not support
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`[its] assertion [that the process limitation is entitled to no patentable weight] with
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`adequate explanation or credible evidence.” Id. The Board rejected the
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`Petitioner’s argument that the burden to demonstrate structural and functional
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`differences is on the Patent Owner. Id. Similarly, in Biodelivery Scis. Int’l, Inc. v.
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`Monosol RX, LLC, IPR2015-00168, Paper 6 at 15 (P.T.A.B.), the Board denied a
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`IPR2015-01570
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`ground challenging a product-by-process claim where a prior art reference’s
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`disclosure of a drying process did not disclose that it resulted in “a film [with] the
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`active so distributed that substantially equal sized individual unit doses do not vary
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`by more than 10% of the amount of the active” – a structural characteristic
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`imparted to the final product by the claimed process limitation.
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`IV. THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
`NOT ADDRESS EVERY LIMITATION OF CLAIM 98
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`Ground 1, the only ground at issue, is based on alleged anticipation of claim
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`98 by Lilly’s ’843 patent. However, the Petition does not argue that each and
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`every limitation of claim 98 is expressly or inherently disclosed by the ’843 patent.
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`In particular, the Ground ignores the process limitations, without first establishing
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`that they do not impart structural and functional differences.
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`A. The Process Limitations of Claim 98 Impart Structural and
`Functional Differences to the Claimed Product
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`Claim 98 requires detailed process limitations including the following:
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`“a) subjecting a daptomycin solution to conditions forming
`a daptomycin aggregate;
`b) separating the daptomycin aggregate from low molecular
`weight contaminants; and
`c) subjecting the daptomycin aggregate to conditions in
`which the daptomycin aggregate dissociates into daptomycin
`monomers” (see ‘238 patent, claim 93);
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`IPR2015-01570
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`“the daptomycin aggregate of step b) is separated from the low molecular
`weight contaminants by a size selection technique” (see ‘238 patent, claim
`94);
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`“the size selection technique is ultrafiltration or size exclusion
`chromatography” (see ‘238 patent, claim 95);
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`“further comprising separating the daptomycin monomers obtained from
`step c) from high molecular weight contaminants” (see ‘238 patent, claim
`96);
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`“the daptomycin monomers are separated from the high molecular weight
`contaminants by a size selection technique” (see ‘238 patent, claim 97);
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`“the size selection technique is ultrafiltration or size exclusion
`chromatography” (see ‘238 patent, claim 98).
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`The process limitations recited in claim 98 impart distinctive structural and
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`functional characteristics to the claimed composition. For example, as the ’238
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`patent itself demonstrates, daptomycin compositions created using the inventive
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`methods as claimed contain lower levels of endotoxins than daptomycin
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`compositions prepared using prior art methods. See ’238 patent, e.g., at 36:40-56
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`(Ex. 1001). Example 15 of the ’238 patent describes as a starting material a
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`daptomycin composition prepared according to Eli Lilly’s prior art ’843 patent,
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`which had “measurable pyrogen” (another term for endotoxins). Id. at 36:42-47.
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`As explained in the ’238 patent, this starting material is then further purified by
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`IPR2015-01570
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`ultrafiltration under conditions in which daptomycin is in monomer form. ’238
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`patent at 36:47-52. This size selection technique separates daptomycin from high
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`molecular weight contaminants, which include pyrogens (endotoxins). See id. at
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`claims 96-98; see also 20:58-66 (discussing purification away from “high
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`molecular weight contaminants, including pyrogens”). Accordingly, in the
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`resulting daptomycin composition purified according to the ’238 patent’s methods,
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`“pyrogen content is reduced to undetectable levels.” Id. at 36:52-56. Example 15
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`refers to additional changes in the impurity profile, namely, that “several impurities
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`that had been present at 0.1-0.2% are removed by the ultrafiltration membrane.”
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`Id. at 36:53-55.
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`Thus, even assuming that the ’843 patent provided 93% pure daptomycin
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`with respect to impurities 1-14, the ’238 specification explicitly demonstrates that
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`performing the process steps of claim 98 structurally and functionally changes the
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`composition by removing pyrogens and additional impurities. The Petition appears
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`to incorrectly assume that all daptomycin compositions that are 93% pure with
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`respect to impurities 1-14 are identical, without considering the remainder of the
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`composition and whether, for example, it contains toxic impurities such as
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`pyrogens. See Pet. at 16-17.
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`Accordingly, the process limitations of claim 98, which result in important
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`differences in the final daptomycin composition, cannot be disregarded. Corning
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`10
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`IPR2015-01570
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`Inc. v. DSM IP Assets B.V., IPR2013-00052, Paper 16 at 2-3 (P.T.A.B.); see also
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`Biodelivery Scis. Int’l, Inc. v. Monosol RX, LLC, IPR2015-00168, Paper 6 at 15
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`(P.T.A.B.); Amgen, 580 F.3d at 1370. The discussion of Example 15 above is
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`included by way of example, and Patent Owner reserves the right to further
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`establish functional and structural differences imparted by the claimed process
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`limitations.
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`B.
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`The Petition Fails to Establish a Lack of Structural and
`Functional Differences
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`The Petition appears to acknowledge that process limitations must be
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`considered in evaluating anticipation where they impart structural and functional
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`differences to the claimed product. See Pet. at 14-15. Moreover, Petitioner
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`concedes that “[s]tructural and functional differences are relevant to the
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`anticipation analysis even where they are not claimed.” Id. at 15. Petitioner also
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`acknowledges that Example 15 of the ’238 patent demonstrates the removal of
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`pyrogens by ultrafiltration as claimed. Id. at 16. However, the Petition incorrectly
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`asserts that “none of [the challenged claims] specify an ultrafiltration membrane of
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`suitable size to ensure removal of pyrogens, which was apparently responsible for
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`removing the additional impurities in Example 15.” Id. at 17. This assertion is
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`belied by the plain language of claim 98, which (through its dependency on claim
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`97) explicitly requires that “daptomycin monomers are separated from the high
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`molecular weight contaminants by a size selection technique” that is
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`IPR2015-01570
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`“ultrafiltration or size exclusion chromatography.” ’238 patent, claims 97-98
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`(emphasis added). The ’238 patent also explicitly refers to pyrogens as among the
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`high molecular weight impurities that are removed by ultrafiltration. Id. at 20:58-
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`66. Petitioner’s suggestion that removal of toxic impurities does not result in
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`functional differences, Pet. at 17, is similarly incorrect: removing pyrogens can
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`make the difference between a pharmaceutically acceptable composition and one
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`that is unacceptably toxic and cannot be administered to patients.1 Indeed, as noted
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`above, this was Cubist’s own experience with its initial clinical batches having
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`endotoxin levels that made them unusable in clinical trials.
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`C. The Petition Improperly Ignores the Process Limitations of Claim
`98
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`Despite failing to establish a lack of structural and functional differences, the
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`Petition completely ignores the process limitations in asserting anticipation of
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`claim 98 by the ’843 patent. For Ground 1 to properly demonstrate anticipation, it
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`1 Petitioner’s assertion that the ’226 patent (which is not part of Ground 1)
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`contemplates the pharmaceutical use of daptomycin compositions, Pet. at 17 n.1, is
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`similarly unavailing. This general reference to pharmaceutical utility does not
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`remedy the Petition’s failure to identify any purity data contradicting the Examples
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`of the ’238 patent demonstrating structural and functional differences.
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`IPR2015-01570
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`must establish that the ’843 patent disclosed each and every limitation in claim 98,
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`including the process limitations.
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`However, the argument for Ground 1 does not address any of the process
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`limitations. For example, the Ground 1 claim chart for claim 98 contains no
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`citations to the’843 patent, or anything else except reference back to an earlier
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`claim. Pet. at 24. The same is true for the Ground 1 claim charts for claims 97, 96,
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`95, 94, and 93, from which claim 98 depends, and all of which set out process
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`limitations for obtaining the claimed daptomycin composition. Id. at 23-24. The
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`claim charts for all of these claims ultimately refer back to claim 49, which does
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`not recite any of the process limitations of claim 98 that expressly require
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`separation of daptomycin from both low and high molecular weight impurities
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`using aggregate formation and disassociation, along with size exclusion techniques
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`including ultrafiltration. Indeed, the Ground 1 claim chart for claim 49 simply
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`asserts that the ’843 patent discloses 93% pure daptomycin with respect to
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`impurities 1-14. Id. at 23.
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`The Petition thus completely fails to assert that the ’843 patent discloses the
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`process steps of claim 98—the same steps that explicitly require separation of
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`daptomycin from low molecular weight and high molecular weight contaminants,
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`and thus result in a structurally and functionally different composition. Because
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`the Petition fails to identify where each and every limitation of the challenged
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`IPR2015-01570
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`claim can be located in the asserted prior art, Ground 1 must be denied. 37 C.F.R.
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`§ 42.104 (b)(4).
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`V. CONCLUSION
`The Petition should be denied because there is no reasonable likelihood that
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`Petitioner will prevail on at least one claim. Ground 1, the only ground at issue,
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`ignores the process limitations of the challenged product-by-process claim, without
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`establishing that these limitations do not impart structural and functional
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`differences in the claimed product. Ground 1 thus improperly fails to address each
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`limitation of the challenged claim. In view of this fundamental deficiency, there is
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`no reasonable likelihood that the Petitioner will prevail on at least one claim, and
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`the Board should deny the Petition.
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`Date: October 29, 2015
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`Respectfully submitted,
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`By: /Emily R. Whelan/
`Emily R. Whelan
`Reg. No. 50,391
`Wilmer Cutler Pickering Hale and Dorr LLP
`60 State Street
`Boston, MA 02109
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`14
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`IPR2015-01570
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`PATENT OWNER’S LIST OF EXHIBITS
`IPR2015-01570
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`Description
`
`CUBICIN® (daptomycin for injection) label approved
`November 26, 2014
`U.S. Pharmacopeial Convention, The United States
`Pharmacopeia (36th prtg. 2012)
`Human, Biological, and Animal Drugs and Medical
`Devices; Availability of Guideline for Use of the Limulus
`Amebocyte Lysate (LAL) Test, 53 Fed. Reg. 5,044 (Feb. 19,
`1988)
`
`Exhibit
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`2001
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`2002
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`2003
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`15
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`IPR2015-01570
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`CERTIFICATE OF SERVICE
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`I hereby certify that, on October 29, 2015, I caused a true and correct copy
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`of the foregoing materials:
`
` Patent Owner’s Preliminary Response Under 37 C.F.R. §42.107
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` Patent Owner’s List of Exhibits
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` Exhibits 2001-2003
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`to be served via electronic mail on the following attorneys of record:
`
`Elizabeth J. Holland, Esq.
`eholland@goodwinprocter.com
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`Robert V. Cerwinski, Esq.
`rcerwinski@goodwinprocter.com
`
`Cynthia L. Hardman, Esq.
`chardman@goodwinprocter.com
`
`
`
`/Emily R. Whelan/
`Emily R. Whelan
`Reg. No. 50,391
`Wilmer Cutler Pickering Hale and Dorr LLP
`60 State Street
`Boston, MA 02109
`
`
`16
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