IPR2015-01571
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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: IPR2015-01571
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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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`TABLE OF CONTENTS
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`TABLE OF CONTENTS
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`IPR2015-01571
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`IPR2015-01571
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`PAGE
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`PAGE
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`I. 
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`INTRODUCTION .......................................................................................... . . 1
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`State of the Art Prior to the Invention ........................................................... ..2
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`INTRODUCTION ............................................................................................ 1 
`A.  State of the Art Prior to the Invention ............................................................. 2 
`B.  Description of the Invention ............................................................................ 4 
`Description of the Invention .......................................................................... ..4
`II.  DEFINITION OF ONE OF ORDINARY SKILL IN THE ART ..................... 6 
`III. 
`INTERPRETATION OF PRODUCT-BY-PROCESS CLAIMS ..................... 6 
`IV.  THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
`NOT ARGUE MOTIVATION TO COMBINE THE REFERENCES ............ 8 
`V.  GROUND 1 IS LIMITED TO THE SPECIFIC REFERENCES
`IDENTIFIED .................................................................................................... 9 
`VI.  CONCLUSION ............................................................................................... 10 
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`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.
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`THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
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`NOT ARGUE MOTIVATION TO COMBINE THE REFERENCES .......... ..8
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`GROUND 1 IS LIMITED TO THE SPECIFIC REFERENCES
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`IDENTIFIED .................................................................................................. ..9
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`VI.
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`CONCLUSION ............................................................................................. ..1O
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`TABLE OF AUTHORITIES
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`IPR2015-01571
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`Page(s)
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`Cases
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`Amgen Inc. v. F. Hoffman-La Roche Ltd,
`580 F.3d 1340 (Fed. Cir. 2009)..............................................................................................6, 7
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`Biodelivery Scis. Int’l, Inc. v. Monosol RX, LLC,
`IPR2015-00168, Paper 6 ............................................................................................................7
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`Corning Inc. v. DSM IP Assets B.V.,
`IPR2013-00052, Paper 16 ..........................................................................................................7
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`Greenliant Sys., Inc. v. Xicor LLC,
`692 F.3d 1261 (Fed. Cir. 2012)..................................................................................................6
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`TRW Automotive US LLC v. Magna Electronics Inc.,
`IPR2014-00259, Paper 19 (June 26, 2014) ................................................................................8
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`TRW Automotive US LLC v. Magna Electronics Inc.,
`IPR2014-00293 and -294 ...........................................................................................................8
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`Statutes
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`35 U.S.C. § 314 ................................................................................................................................1
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`Other Authorities
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`37 C.F.R. §42.107 ..........................................................................................................................13
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`37 C.F.R. § 42.108 ...........................................................................................................................1
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`53 Fed. Reg. 5,044 (Feb. 19, 1988) ...............................................................................................12
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`53 Fed. Reg. 5,044, 5,045 (Feb. 19, 1988) (Ex. 2003) ....................................................................3
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`U.S. Patent No. 4,874,843........................................................................................................3, 8, 9
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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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`I.
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`INTRODUCTION
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`IPR2015-01571
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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 obvious. Subsequently, the Board
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`granted a joint motion to limit the present Petition to claims 98 and 187. See
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`IPR2015-01571, Paper 15 (September 15, 2015). Therefore, the Petition is now
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`narrowed to claims 98 and 187, challenged in Ground 1. The other claims and,
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`consequently, Ground 2, are no longer at issue. Nevertheless, Fresenius’s Petition,
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`even as narrowed, should not be instituted as there is no reasonable likelihood that
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`Petitioner will prevail on at least one claim.
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`Ground 1 fails to address motivation to combine the asserted references.
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`This deficiency defeats Fresenius’s proposed Ground 1, the only ground at issue,
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`such that there is no reasonable likelihood that the Petitioner will prevail on at least
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`one claim, and the Board should not institute review. 35 U.S.C. § 314; 37 C.F.R.
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`1
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`§ 42.108. Patent Owner also disagrees with the Petition on the merits, but will not
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`IPR2015-01571
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`address the substance of Petitioner’s arguments in this paper.
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`A.
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`State of the Art Prior to the Invention
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`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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`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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`IPR2015-01571
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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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`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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`IPR2015-01571
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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
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`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 endotoxin 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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`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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`IPR2015-01571
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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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`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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`IPR2015-01571
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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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`Claims 98 and 187 are product-by-process claims. Process limitations in
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`product-by-process claims must be considered in evaluating patentability when the
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`claimed process imparts structural and functional differences in the resultant
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`product. Amgen Inc. v. F. Hoffman-La Roche Ltd, 580 F.3d 1340, 1370 (Fed. Cir.
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`2009); see also, Greenliant Sys., Inc. v. Xicor LLC, 692 F.3d 1261, 1268 (Fed. Cir.
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`2012) (“[T]here is an exception to this general rule that the process by which the
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`product is made is irrelevant. As we recognized in Amgen, if the process by which
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`a product is made imparts ‘structural and functional differences’ distinguishing the
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`IPR2015-01571
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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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`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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`IPR2015-01571
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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 ARGUE MOTIVATION TO COMBINE THE REFERENCES
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`The Petition should be denied because Ground 1, the only ground at issue,
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`fails to assert a reason or motivation to combine the specific asserted references.
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`The Board has denied inter partes review in cases where the Petitioner failed to
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`articulate sufficient reasoning to combine the asserted references. See, e.g., TRW
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`Automotive US LLC v. Magna Electronics Inc., IPR2014-00259, Paper 19 (June
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`26, 2014)(denying institution because the Petitioner “fail[ed] to explain sufficiently
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`why one of ordinary skill in the art would have been prompted to combine [the
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`asserted art]”); TRW Automotive US LLC v. Magna Electronics Inc., IPR2014-
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`00293 and -294, Paper 19 (July 1, 2014).
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`Ground 1 alleges that claims 98 and 187 are obvious in view of the
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`Lilly ’843 patent, Mulligan, Lin II, and Lakey, but it does not state that a person of
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`ordinary skill in the art would have been motivated or would have had a reason to
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`combine these specific references. While the Petition makes general assertions,
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`such as that a person of skill in the art would have sought to obtain daptomycin
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`compositions of high purity, it fails to explain with particularity why a person of
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`ordinary skill in the art would have selected, combined, and modified the specific
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`group of asserted references or the specific purification techniques disclosed in the
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`asserted references to obtain the claimed invention. Thus, the Petition should be
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`IPR2015-01571
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`denied because Ground 1, the only ground at issue, fails to allege sufficient
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`motivation or reason to combine the particular group of asserted references.1
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`V. GROUND 1 IS LIMITED TO THE SPECIFIC REFERENCES
`IDENTIFIED
`Several references that are not included in Ground 1 (e.g., the ’226 patent,
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`the ’594 patent, and Lin I) are referenced throughout the Petition and Dr.
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`Tarantino’s Declaration. See, e.g., Corr. Pet. at 15-17; Tarantino Dec. at ¶¶ 142,
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`145 (Ex. 1005). Ground 1 asserts that claims 98 and 187 are obvious in view of
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`the prior art “such as” the Lilly ’843 patent in view of Mulligan, Lin II, and Lakey.
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`See Corr. Pet. at 14. It is unclear what Petitioner means by the use of “such as.”
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`Therefore, Ground 1 must be understood as only including those references that are
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`clearly identified as part of the ground, i.e., the ’843 patent, Mulligan, Lin II, and
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`Lakey. Petitioner should not be allowed to rely on the vague use of “such as” to
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`expand the Ground. Thus, Ground 1 should not include any additional references,
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`including but not limited to the ’594 patent , the ’226 patent, or Lin I.
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`1 Patent Owner reserves the right to argue lack of motivation to combine on the
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`merits should a trial be instituted.
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`VI. CONCLUSION
`The Petition should be denied because there is no reasonable likelihood that
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`IPR2015-01571
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`Petitioner will prevail on at least one claim. Ground 1 fails to address motivation
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`to combine the asserted references. 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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`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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`10
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`Date: October 29, 2015
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`IPR2015-01571
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`PATENT OWNER’S LIST OF EXHIBITS
`IPR2015-01571
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`Description
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`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)
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`Exhibit
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`2001
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`2002
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`2003
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`11
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`IPR2015-01571
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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:
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` 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:
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`Elizabeth J. Holland, Esq.
`eholland@goodwinprocter.com
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`Robert V. Cerwinski, Esq.
`rcerwinski@goodwinprocter.com
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`Cynthia L. Hardman, Esq.
`chardman@goodwinprocter.com
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`
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`/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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`12