IPR2015-01572
`
`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: IPR2015-01572
`
`Patent No. 8,058,238
`____________________________________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`

`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS
`
`IPR2015-01572
`
`IPR2015-01572
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`PAGE
`
`PAGE
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`INTRODUCTION ......................................................................................... .. 1
`
`A.
`
`A.
`
`State of the Art Prior to the Invention ................................................... 2
`
`State of the Art Prior to the Invention ................................................. ..2
`
`B. Description of the Invention .................................................................. 4
`B.
`Description of the Invention ................................................................ ..4
`
`II. DEFINITION OF ONE OF ORDINARY SKILL IN THE ART ................... 6
`
`DEFINITION OF ONE OF ORDINARY SKILL IN THE ART ................. ..6
`
`III.
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`III.
`
`INTERPRETATION OF PRODUCT-BY-PROCESS CLAIMS ................... 6
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`INTERPRETATION OF PRODUCT-BY-PROCESS CLAIMS ................. ..6
`
`IV.
`
`THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
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`IV. THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
`NOT ADDRESS EVERY LIMITATION OF CLAIM 91 .............................. 8
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`NOT ADDRESS EVERY LIMITATION OF CLAIM 91 ............................ ..8
`
`V.
`
`THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
`
`THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
`NOT ARGUE MOTIVATION TO COMBINE THE REFERENCES ........... 9
`
`NOT ARGUE MOTIVATION TO COMBINE THE REFERENCES ......... ..9
`
`VI.
`
`GROUND 1 IS LIMITED TO THE SPECIFIC REFERENCES
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`VI. GROUND 1 IS LIMITED TO THE SPECIFIC REFERENCES
`IDENTIFIED ................................................................................................. 10
`
`IDENTIFIED ............................................................................................... . . 1 0
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`VII. CONCLUSION .............................................................................................. 11
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`CONCLUSION ............................................................................................ ..1 1
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`VII.
`
`i
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`

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`
`
`TABLE OF AUTHORITIES
`
`IPR2015-01572
`
` Page(s)
`
`Cases
`Amgen Inc. v. F. Hoffman-La Roche Ltd,
`580 F.3d 1340 (Fed. Cir. 2009) ........................................................................ 6, 7
`
`Biodelivery Scis. Int’l, Inc. v. Monosol RX, LLC,
`IPR2015-00168, Paper 6 ....................................................................................... 7
`
`Corning Inc. v. DSM IP Assets B.V.,
`IPR2013-00052, Paper 16 ..................................................................................... 7
`
`Greenliant Sys., Inc. v. Xicor LLC,
`692 F.3d 1261 (Fed. Cir. 2012) ............................................................................ 6
`
`TRW Automotive US LLC v. Magna Electronics Inc.,
`IPR2014-00259, Paper 19 (June 26, 2014) ........................................................... 9
`
`TRW Automotive US LLC v. Magna Electronics Inc.,
`IPR2014-00293 and -294 ...................................................................................... 9
`
`Statutes
`
`35 U.S.C. § 314 .......................................................................................................... 2
`
`Other Authorities
`
`37 C.F.R. § 42.107 ................................................................................................... 13
`
`37 C.F.R. § 42.108 ..................................................................................................... 2
`
`53 Fed. Reg. 5,044 (Feb. 19, 1988) ......................................................................... 12
`
`U.S. Patent No. 4,874,843 .......................................................................... 3, 9, 10, 11
`
`U.S. Patent No. 8,058,238 .................................................................................passim
`
`U.S. Patent No. RE39,071 ......................................................................................... 3
`
`
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`IPR2015-01572
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`I.
`
`INTRODUCTION
`
`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 claim 91. See IPR2015-
`
`01572, Paper 15 (September 15, 2015). Therefore, the Petition is now narrowed to
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`claim 91, challenged in Ground 1. The other claims and, consequently, Grounds 2
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`and 3, 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 fails to address each limitation of challenged claim 91.
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`Furthermore, Ground 1 fails to address motivation to combine the asserted
`
`references. These deficiencies defeat Fresenius’s proposed ground, such that there
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`is no reasonable likelihood that the Petitioner will prevail on at least one claim, and
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`IPR2015-01572
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`the Board should not institute review. 35 U.S.C. § 314; 37 C.F.R. § 42.108. Patent
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`Owner also disagrees with Petitioner on the merits, but will not 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
`
`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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`and other symptoms in humans. See U.S. Pharmacopeial Convention, The United
`
`States Pharmacopeia 90-91 & n.2 (36th prtg. 2012) (Ex. 2002). As a result,
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`IPR2015-01572
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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.
`
`RE39,071 (the “RE’071 patent”) at 7:61-8:2 (Ex. 1034).
`
`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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`Description of the Invention
`
`B.
`The inventors thus set out to develop a new purification process that would
`
`enable the production of daptomycin compositions containing acceptable levels of
`
`impurities and also provide a commercially viable yield. ‘238 patent, e.g., at 3:36-
`
`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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`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).
`
`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.
`
`1001).
`
`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
`
`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
`
`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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`Process limitations in product-by-process claims must be considered in
`
`evaluating patentability when the claimed process imparts structural and functional
`
`differences in the resultant product. Amgen Inc. v. F. Hoffman-La Roche Ltd, 580
`
`F.3d 1340, 1370 (Fed. Cir. 2009); see also, Greenliant Sys., Inc. v. Xicor LLC, 692
`
`F.3d 1261, 1268 (Fed. Cir. 2012) (“[T]here is an exception to this general rule that
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`the process by which the product is made is irrelevant. As we recognized in
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`Amgen, if the process by which a product is made imparts ‘structural and
`
`functional differences’ distinguishing the claimed product from the prior art, then
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`those differences ‘are relevant as evidence of no anticipation.’” (quoting Amgen,
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`580 F.3d at 1370)). Furthermore, structural and functional differences are relevant
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`even when they are not explicitly recited in a product-by-process claim. Amgen,
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`580 F.3d at 1370 .
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`The Board may not disregard process limitations in challenged product-by-
`
`process claims in evaluating patentability when the Petitioner has not sufficiently
`
`established that these limitations do not “impart distinctive structural
`
`characteristics to the final product.” See Corning Inc. v. DSM IP Assets B.V.,
`
`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.
`
`Monosol RX, LLC, IPR2015-00168, Paper 6 at 15 (P.T.A.B.), the Board denied a
`
`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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`IPR2015-01572
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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 91
`
`Claim 91 requires that the claimed daptomycin composition is “essentially
`
`free of each of impurities 1 to 14 defined by peaks 1-14 shown in FIG. 12.” ‘238
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`patent, claim 91. Petitioner acknowledges that, as provided in the specification,
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`“[d]aptomycin is ‘essentially free’ of another compound when the other
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`compound is present in an amount that is no more than 0.5% of the amount of the
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`daptomycin preparation.” Corr. Pet. at 6; ‘238 patent at 7:52-56. However, the
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`Petition fails to address how this limitation is disclosed or rendered obvious by the
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`prior art references asserted in Ground 1.
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`The Petition asserts that daptomycin of 93% purity against impurities 1-14
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`was in the prior art, and makes general assertions regarding known purification
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`techniques and desirability of more highly pure compositions. See Corr. Pet. at 17-
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`18. However, the Petition does not explain specifically how the limitation
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`“essentially free of each of impurities 1 to 14 defined by peaks 1-14 shown in FIG.
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`12” in claim 91 is disclosed or rendered obvious by the prior art references asserted
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`in Ground 1. Indeed, the Ground 1 claim chart for claim 91 includes no citation or
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`support for this limitation other than “see claim 85.” Corr. Pet. at 31. Claim 85
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`IPR2015-01572
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`does not include the limitation requiring daptomycin “essentially free of each of
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`impurities 1 to 14.” Instead, claim 85 adds a limitation relating to a
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`pharmaceutically acceptable carrier, and the claim chart also refers back to claim
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`49. Id. at 30. Claim 49 requires greater than or about 93% purity relative to
`
`impurities 1-14, but does not recite any particular levels of the individual
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`impurities as required by claim 91. Id. at 26-27.
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`Accordingly, Ground 1, the only ground at issue, does not address every
`
`limitation of claim 91, the only claim at issue, and the Petition should be denied.
`
`V. THE PETITION SHOULD BE DENIED BECAUSE GROUND 1 DOES
`NOT ARGUE MOTIVATION TO COMBINE THE REFERENCES
`
`The Petition should be denied because Ground 1, the only ground at issue,
`
`fails to assert a reason or motivation to combine the specific asserted references.
`
`The Board has denied inter partes review in cases where the Petitioner failed to
`
`articulate sufficient reasoning to combine the asserted references. See, e.g., TRW
`
`Automotive US LLC v. Magna Electronics Inc., IPR2014-00259, Paper 19 (June
`
`26, 2014)(denying institution because the Petitioner “fail[ed] to explain sufficiently
`
`why one of ordinary skill in the art would have been prompted to combine [the
`
`asserted art]”); TRW Automotive US LLC v. Magna Electronics Inc., IPR2014-
`
`00293 and -294, Paper 19 (July 1, 2014).
`
`Ground 1 alleges that claim 91 is obvious in view of the Lilly ‘843 patent,
`
`the Lilly ‘226 patent, Mulligan, Lin II, and Lakey, but it does not state that a
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`IPR2015-01572
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`person of ordinary skill in the art would have been motivated or would have had a
`
`reason to combine this particular group of references. While the Petition makes
`
`general assertions, such as that a person of skill in the art would have sought to
`
`obtain daptomycin compositions of high purity, it fails to explain with particularity
`
`why a person of ordinary skill in the art would have selected, combined, and
`
`modified the specific group of asserted references or the specific purification
`
`techniques disclosed in the asserted references to obtain the claimed invention.
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`Thus, the Petition should be denied because Ground 1, the only ground at issue,
`
`fails to allege sufficient motivation or reason to combine the asserted references.1
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`VI. GROUND 1 IS LIMITED TO THE SPECIFIC REFERENCES
`IDENTIFIED
`Several references that are not included in Ground 1 (e.g., the ‘594 patent,
`
`and Lin I) are referenced throughout the Petition and Dr. Tarantino’s Declaration.
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`See, e.g., Corr. Pet. at 16-17; Tarantino Dec. at ¶¶ 142, 145(Ex. 1005). Ground 1
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`asserts that claim 91 is obvious in view of the prior art “such as” the Lilly ‘843
`
`patent and Lilly ‘226 patent in view of Mulligan, Lin II, and Lakey. See Corr. Pet.
`
`at 14. It is unclear what Petitioner means by the use of “such as.” Therefore,
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`Ground 1 must be understood as only including those references that are clearly
`
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`1Patent 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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`IPR2015-01572
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`identified as part of the ground, i.e., the ‘843 patent, the ‘226 patent, Mulligan, Lin
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`II, and Lakey. Petitioner should not be allowed to rely on the vague use of “such
`
`as” to expand the Ground. Thus, Ground 1 should not include any additional
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`references including but not limited to the ‘594 patent or Lin I.
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`VII. CONCLUSION
`The Petition should be denied because there is no reasonable likelihood that
`
`Petitioner will prevail on at least one claim. Ground 1 fails to address each
`
`limitation of challenged claim 91. Furthermore, Ground 1 fails to address
`
`motivation to combine the specific asserted references. In view of these
`
`fundamental deficiencies, there is no reasonable likelihood that the Petitioner will
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`prevail on at least one claim, and the Board should deny the Petition.
`
`Date: October 29, 2015
`
`
`
`
`
`Respectfully submitted,
`
`By: /Emily R. Whelan/
`Emily R. Whelan
`Reg. No. 50,391
`Wilmer Cutler Pickering
`Hale and Dorr LLP
`60 State Street
`Boston, MA 02109
`
`11
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`IPR2015-01572
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`PATENT OWNER’S LIST OF EXHIBITS
`IPR2015-01572
`
`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
`
`2001
`
`2002
`
`2003
`
`
`
`12
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`IPR2015-01572
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`CERTIFICATE OF SERVICE
`
`I hereby certify that, on October 29, 2015, I caused a true and correct copy
`
`of the foregoing materials:
`
` Patent Owner’s Preliminary Response Under 37 C.F.R. §42.107
`
` Patent Owner’s List of Exhibits
`
` Exhibits 2001-2003
`
`to be served via electronic mail on the following attorneys of record:
`
`Elizabeth J. Holland, Esq.
`eholland@goodwinprocter.com
`
`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
`
`13