Paper No. 20
` Entered: January 28, 2016
`
`Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`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 8,058,238 B2
`____________
`
`
`
`Before BRIAN P. MURPHY, JON B. TORNQUIST, and
`TINA E. HULSE, Administrative Patent Judges.
`
`
`TORNQUIST, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
` Entered: January 28, 2016
`
`Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`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 8,058,238 B2
`____________
`
`
`
`Before BRIAN P. MURPHY, JON B. TORNQUIST, and
`TINA E. HULSE, Administrative Patent Judges.
`
`
`TORNQUIST, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`
`I. INTRODUCTION
`
`
`
`Fresenius Kabi USA LLC (“Petitioner”) filed a corrected Petition
`
`(Paper 7, “Pet.”) requesting institution of inter partes review of claims 20,
`
`45–47, 49–52, 54–91, 108–111, 147–150, 168–175, 178, 180–183, and 190–
`
`192 of U.S. Patent No. 8,058,238 B2 (“the ’238 patent”). On September 15,
`
`2015, we granted the parties’ joint motion to limit the Petition to claim 91.
`
`Paper 15, 3. Cubist Pharmaceuticals LLC (f/k/a Cubist Pharmaceuticals,
`
`Inc., “Patent Owner”) timely filed a Preliminary Response (Paper 18,
`
`“Prelim. Resp.”) to the limited Petition.
`
`
`
`We have jurisdiction under 35 U.S.C. § 314(a), which provides that an
`
`inter partes review may not be instituted “unless . . . there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the
`
`claims challenged in the petition.” For the reasons given below, we
`
`determine that Petitioner has not demonstrated a reasonable likelihood of
`
`prevailing with respect to claim 91. Accordingly, we do not institute an
`
`inter partes review.
`
`
`
`
`
`A. Related Proceedings
`
`The parties indicate that the ’238 patent is at issue in: Cubist
`
`Pharms., Inc. v. Hospira, Inc., 1:12-cv-00367-GMS (D. Del.); Cubist
`
`Pharms., Inc. v. Agila Specialties Inc. and Mylan Laboratories Limited,
`
`1:13-cv-01679-GMS (D. Del); Cubist Pharms., Inc. v. Fresenius-Kabi USA
`
`LLC, 1:14-cv-00914-GMS (D. Del.); and Cubist Pharmaceuticals, Inc. v.
`
`Hospira, Inc., 805 F.3d 1112 (Fed. Cir. 2015) (pending request for
`
`rehearing). Pet. 3–4; Paper 5, 2–3; Paper 19, 1. The ’238 patent is also at
`
`issue in inter partes review proceedings: IPR2015-01566, IPR2015-01570,
`
`and IPR2015-01571. Pet. 4; Paper 5, 3.
`
`
`
`2
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`
`
`B. The ’238 Patent
`
`
`
`The ’238 patent, titled “High Purity Lipopeptides,” discloses a highly
`
`purified form of daptomycin (also known as LY146032), “a lipopeptide
`
`antibiotic with potent bactericidal activity against gram-positive bacteria.”
`
`Ex. 1001, 1:21–24, 1:58–61. More particularly, the ’238 patent is directed to
`
`“providing commercially feasible methods to produce high levels of purified
`
`lipopeptides,” such as daptomycin. Id. at 3:50–52.
`
`
`
`The ’238 patent describes several methods of purifying lipopeptides,
`
`and daptomycin in particular, to achieve a highly pure composition. One
`
`method involves a size separation technique, where a lipopeptide is
`
`converted from a monomer to a micelle (aggregate) and back to a monomer
`
`during the purification process, in order to separate the lipopeptide from low
`
`molecular weight and high molecular weight impurities. Id. at 5:56–6:10.
`
`The ’238 patent indicates that ultrafiltration is preferred for purifying
`
`lipopeptides using this size separation technique. Id. at 6:11–13.
`
`
`
`
`
`C. Illustrative Claims
`
`Claim 91 depends from claim 85, which in turn depends from
`
`independent claim 49. Claims 49, 85, and 91 are reproduced below:
`
` 49. A purified daptomycin composition comprising
`daptomycin of greater than or about 93% purity relative to
`impurities 1–14 defined by peaks 1–14 shown in FIG. 12, the
`daptomycin being obtained by a process comprising the step of
`forming an aggregate comprising daptomycin.
`
`Ex. 1001, 40:33–37.
`
`85. A method for preparing a pharmaceutical composition
`comprising combining the composition of claim 49 with a
`pharmaceutically acceptable carrier or excipient.
`
`Id. at 42:54–56.
`
`
`
`3
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`
`91. The method of claim 85 wherein the composition is
`daptomycin that is essentially free of each of impurities 1 to 14
`defined by peaks 1-14 shown in FIG. 12.
`
` Id. at 43:4–6.
`
`
`
`
`
`D. Prior Art Relied Upon
`
`Petitioner relies upon the following prior art references, as well as the
`
`declaration testimony of Dr. Ralph Tarantino (Ex. 1005):
`
`U.S. Patent No. 4,874,843, issued October 17, 1989 (Ex. 1007, “the ’843
`patent”).
`
`U.S. Patent No. 5,912,226, issued June 15, 1999 (Ex. 1010, “the ’226
`patent”).
`
`Catherine N. Mulligan & Bernard F. Gibbs, Recovery of Biosurfactants by
`Ultrafiltration, 47 J. CHEM. TECH. BIOTECHNOLOGY 23–29 (1990) (Ex. 1013,
`“Mulligan”);
`
`Lin et. al., General Approach for the Development of High-performance
`Liquid Chromatography Methods for Biosurfactant Analysis and
`Purification, 825 JOURNAL OF CHROMATOGRAPHY A 149–159 (1998)
`(Exhibit 1015, “Lin II”); and
`
`Jeremy H. Lakey and Marius Ptak, Fluorescence Indicates a Calcium-
`Dependent Interaction Between the Lipopeptide Antibiotic LY146032 and
`Phospholipid Membranes, BIOCHEMISTRY 27, 4639–4645 (1988) (Exhibit
`1033, “Lakey”).
`
`
`
`
`
`E. Asserted Ground of Unpatentability
`
`Petitioner contends that claim 91 would have been obvious under
`
`35 U.S.C. § 103 over ’843 patent, the ’226 patent, Mulligan, Lin II, and
`
`Lakey. Pet. 5; Paper 15, 2.
`
`II. ANALYSIS
`
`A. Claim Construction
`
`In an inter partes review, “[a] claim in an unexpired patent shall be
`
`
`
`
`
`given its broadest reasonable construction in light of the specification of the
`
`patent in which it appears.” 37 C.F.R. § 42.100(b); In re Cuozzo Speed
`
`
`
`4
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`Tech., LLC, 793 F.3d 1268, 1275 (Fed. Cir. 2015). Under this standard, we
`
`may take into account definitions or other explanations provided in the
`
`written description of applicant’s specification. See In re Morris, 127 F.3d
`
`1048, 1054 (Fed. Cir. 1997). Any special definition for a claim term must
`
`be set forth in the specification with reasonable clarity, deliberateness, and
`
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`
`
`Upon review of Petitioner’s and Patent Owner’s arguments, as well as
`
`the recited prior art references, we conclude that no claim terms require
`
`construction for purposes of this Decision. Vivid Techs., Inc. v. Am. Sci. &
`
`Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (noting that only those claim
`
`terms that are in dispute and necessary to resolve the controversy need be
`
`construed).
`
`
`
`
`
`
`B. Obviousness of Claim 91 over the ’843 patent, the ’226 patent,
`Mulligan, Lin II, and Lakey
`
`
`Petitioner asserts that claim 91 would have been obvious over the
`
`’843 patent, the ’226 patent, Mulligan, Lin II, and Lakey. Pet. 14–31. In
`
`support of this argument, Petitioner relies upon the declaration testimony of
`
`Dr. Tarantino. Ex. 1005. Patent Owner opposes. Prelim. Resp. 6–11.
`
`
`
`
`
`1. The ’843 Patent
`
`The ’843 patent issued October 17, 1989, and is prior art under
`
`35 U.S.C. § 102(b). Pet. 7. The ’843 patent is directed to a “new
`
`chromatographic process for purifying fermentation products, particularly
`
`the antibiotic LY146032 [(daptomycin)], from fermentation broths by use of
`
`a non-functional resin in reverse mode.” Ex. 1007, 1:5–8. This “reverse
`
`method” removes impurities from daptomycin and “improves the final purity
`
`
`
`5
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`from about 80% to about 93%” and the overall yield “from about 5% to
`
`about 35%.” Id. at 2:40, 43–45; Ex. 1005 ¶ 79.
`
`
`
`
`
`2. The ’226 Patent
`
`The ’226 patent discloses, inter alia, “an improved antibacterial
`
`composition” of daptomycin that is in “substantially pure form.”1 Ex. 1010,
`
`8:53–55. In Example 5 of the ’226 patent, high performance liquid
`
`chromatography (“HPLC”) is used to identify and purify daptomycin. Id. at
`
`13:5–52. This example discloses HPLC retention times of 847 seconds for
`
`β-isomer daptomycin, 880 seconds for daptomycin, and 1238 seconds for
`
`anyhdro-daptomycin. Id. at 13:45–52.
`
`
`
`The ’226 patent also discloses that the purified daptomycin may be
`
`formulated for therapeutic treatment of bacterial infections: “For example, a
`
`compound of this invention can be admixed with conventional
`
`pharmaceutical carriers and excipients and used in the form of tablets,
`
`capsules, elixirs, suspensions, syrups, wafers and the like.” Id. at 9:51–60.
`
`
`
`
`
`3. Mulligan
`
`Mulligan published in 1990 and is prior art under 35 U.S.C. § 102(b).
`
`Pet. 9. Mulligan discloses the use of ultrafiltration to purify micelle-forming
`
`biosurfactants, such as surfactant. Ex. 1013, Abstract. Mulligan reports that
`
`the “ability of surfactant molecules to form micelles at concentrations above
`
`the critical micelle concentration allows these aggregates to be retained by
`
`
`1 In the ’226 patent, “substantially pure form” refers to daptomycin that
`“contains less than 2.5 percent of a combined total of anhydro-[daptomycin]
`and isomer-[daptomycin].” Ex. 1010, 8:58–60. Anhydro-daptomycin and
`β-daptomycin are the major impurities identified in the ’238 patent as
`impurity numbers 13 and 8, respectively. Ex. 1001, 33:63–34:19, 34:49–52,
`62–65.
`
`
`
`6
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`relatively high molecular weight cut-off membranes.” Id. Mulligan further
`
`reports that the use of certain identified ultrafiltration membranes increased
`
`surfactin yields to over 97% and “dramatically reduced” recovery costs. Id.
`
`at 26, 27 (Table 1); Ex. 1005 ¶ 90. Mulligan also notes that the disclosed
`
`method of purification using ultrafiltration may be used for any “molecules
`
`that tend to aggregate above certain concentrations.” Ex. 1013, 27–28.
`
`
`
`
`
`4. Lin II
`
`Lin II was published in November 1998 and is prior art under
`
`35 U.S.C. § 102(b). Pet. 11. Lin II discloses the use of a combination of
`
`ultrafiltration (size separation) and HPLC to purify biosurfactant molecules
`
`“without any prior structural information of the biosurfactants.” Ex. 1015,
`
`151, Abstract; Ex. 1005 ¶ 100. The Lin II method first separates
`
`biosurfactant micelles from small molecule impurities using ultrafiltration.
`
`Ex. 1015, 151. The biosurfactant micelles are then dissociated through the
`
`addition of alcohol to form monomers that pass through an ultrafiltration
`
`membrane, thereby separating the monomeric biosurfactant molecules from
`
`larger macromolecule impurities. Id. at 153–154, 156.
`
`
`
`Lin II reports that the size-separated biosurfactant molecules may be
`
`further purified using HPLC to form “homogeneous biosurfactant samples
`
`useful for biophysical and chemical analysis.” Pet. 11 (citing Ex. 1005
`
`¶¶ 98–100). Lin II further reports that the disclosed method “can be applied
`
`for the development of an HPLC assay for any biosurfactant as long as the
`
`concentration of biosurfactants in the fermentation broth is higher than the
`
`critical micelle concentration.” Id. (citing Ex. 1015, 150–51).
`
`
`
`7
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`
`
`5. Lakey
`
`
`
`Lakey was published in 1988 and is prior art under 35 U.S.C. §
`
`102(b). Pet. 12. Lakey discloses that daptomycin (LY146032) may exist in
`
`either monomeric or aggregate form, with aggregation of daptomycin
`
`occurring at “concentrations higher than 10-3 M.” Ex. 1033, 4643; Ex. 1005
`
`¶ 104. Dr. Tarantino testifies that one of ordinary skill in the art would
`
`understand the aggregates reported in Lakey “were in fact micelles.” Ex.
`
`1005 ¶ 104.
`
`
`
`
`
`6. Analysis
`
`Claim 91 requires, inter alia, a daptomycin composition that is
`
`essentially free of each of impurities 1 to 14 defined by peaks 1–14 shown
`
`in Figure 12 of the ’238 patent. Ex. 1001, 40:33–37, 42:54–56, 43:4–6. The
`
`’238 patent indicates that daptomycin is “essentially free” of another
`
`compound “when the other compound is present in an amount that is no
`
`more than 0.5% of the amount of the daptomycin” lipopeptide preparation.
`
`Id. at 7:52–56; Pet. 6; Prelim. Resp. 8.
`
`Petitioner contends it would have been obvious to obtain a
`
`daptomycin composition that is “essentially free” of impurities 1 to 14 in
`
`view of the disclosures of the ’843 patent, the ’226 patent, Mulligan, Lin II,
`
`and Lakey. Pet. 15–31. In support of this argument, Petitioner notes that
`
`daptomycin, or LY146032, is an antibiotic intended for therapeutic use. Pet.
`
`19; Ex. 1007, 1:5–8, 1:36–38; Ex. 1005 ¶ 137. Given this therapeutic
`
`application, Petitioner contends a person of ordinary skill in the art would
`
`have been motivated to increase the purity of daptomycin compositions “as
`
`high as possible.” Pet. 24; Ex. 1005 ¶¶ 75 (asserting that high levels of
`
`
`
`8
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`purity for pharmaceutical preparations of antimicrobial agents would have
`
`been a target goal for one of ordinary skill in the art), 137.
`
`To achieve this goal, Petitioner contends a person of ordinary skill in
`
`the art would have accessed the “extensive tool-box” known in the art for
`
`purifying lipopeptide biosurfactants. Pet. 16–17, 23. In particular,
`
`Petitioner contends that one of ordinary skill in the art would have
`
`understood that the methods disclosed in the ’843 patent, the ’226 patent,
`
`Lakey, Mulligan, and Lin II could be used to obtain a daptomycin
`
`composition with a purity level exceeding 99%. Pet. 17–18, 20.
`
`
`
`Patent Owner contends Petitioner does not explain why the proposed
`
`combination of references would result in a daptomycin composition that is
`
`“essentially free” of impurities 1-14. Prelim. Resp. 8–9. According to
`
`Patent Owner, Petitioner provides only general statements regarding the
`
`disclosures of the prior art references, and the claim chart for claim 91
`
`“includes no citation or support” for obtaining daptomycin that is
`
`“essentially free” of impurities 1–14. Id. at 8.
`
`
`
`We agree with Patent Owner that Petitioner does not provide
`
`sufficient argument or evidence to demonstrate that the purification methods
`
`set forth in the ’843 patent, the ’226 patent, Mulligan, and Lin II would
`
`result in a daptomycin composition having no more than 0.5% of each of
`
`impurities 1–14. As noted by Patent Owner, the Petition does not address
`
`directly the limitations of claim 91. See, e.g., Pet. 26–27, 31. For example,
`
`the claim chart for claim 91 merely states “See claim 85,” and the claim
`
`charts for claims 49 and 85 do not indicate that the methods set forth in the
`
`’843 patent, Mulligan, and Lin II would result in a daptomycin composition
`
`that is “essentially free” of impurities 1–14. Id. at 26–27, 30.
`
`
`
`9
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`
`The Petition does state that compositions purified using the disclosed
`
`methods “would have at least approached and likely exceeded 99% purity
`
`levels with respect to all impurities present.” Id. at 20 (citing Ex. 1005
`
`¶ 148). A 99% purity level, however, would still allow for at least one of the
`
`fourteen impurities to be present in the daptomycin composition at a level
`
`greater than 0.5%. Thus, we are not persuaded that this evidence
`
`demonstrates that the purification methods of the ’843 patent, the ’226
`
`patent, Mulligan, and Lin II would result in a daptomycin composition that
`
`is “essentially free of each of impurities 1 to 14,” as recited in claim 91.
`
`
`
`In the claim chart for claim 49, the Petition cites to the declaration
`
`testimony of Dr. Tarantino, who testifies that the purification methods
`
`disclosed in the ’843 patent, the ’226 patent, Mulligan, and Lin II would
`
`have achieved daptomycin compositions approaching “homogeneity” that
`
`satisfy the purity limitations of claims 91. Pet. 26-27; Ex. 1005 ¶¶ 146, 161.
`
`Dr. Tarantino does not define the term “homogenous,” however, and the
`
`Petition indicates “homogeneous” compositions have a purity level
`
`“approaching at least 99%,” which would not necessarily satisfy the
`
`requirements of claim 91. See Pet. 17–18 (noting that the purification
`
`process of Lin II could be used to “obtain homogeneous biosurfactant
`
`preparations, i.e., preparations approaching at least 99% purity”) (emphasis
`
`added); Ex. 1005 ¶ 146 (asserting that “additional chromatographic
`
`purification” methods applied to the daptomycin produced in the ’843 patent
`
`“would have at least approached and likely exceeded 99% purity levels with
`
`respect to all impurities present”) (emphasis added). As such, we are not
`
`persuaded that Petitioner and Dr. Tarantino provide sufficient argument or
`
`evidence to demonstrate a reasonable likelihood that the purification
`
`
`
`10
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`methods disclosed in the ’843 patent, the ’226 patent, Mulligan, and Lin II
`
`would achieve a daptomycin composition within the purity limitations set
`
`forth in claim 91.
`
`III. ORDER
`
`
`
`In consideration of the foregoing, it is ORDERED that no inter partes
`
`review is instituted.
`
`
`
`11
`
`
`
`IPR2015-01572
`Patent 8,058,238 B2
`
`PETITIONER:
`
`Elizabeth J. Holland
`eholland@goodwinprocter.com
`
`
`Robert V. Cerwinski
`rcerwinski@goodwinprocter.com
`
`
`Cynthia L. Hardman
`chardman@goodwinprocter.com
`
`
`Goodwin Procter LLP
`
`
`
`
`PATENT OWNER:
`
`Emily R. Whelan
`Emily.Whelan@wilmerhale.com
`
`Andrej Barbic
`Andrej.Barbic@wilmerhale.com
`
`Gerard M. Devlin, Jr.
`Gerard.Devlin@merck.com
`
`Lisa A. Jakob
`Lisa.Jakob@merck.com
`
`
`Wilmer Cutler Pickering Hale and Dorr LLP
`
`
`
`
`12
`
`
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