Trials@uspto.gov
`571-272-7822
`
` Paper No. 7
`
`Date: May 29, 2020
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`CUBIST PHARMACEUTICALS LLC,
`Patent Owner.
`____________
`
`IPR2020-00193
`Patent 9,138,456 B2
`____________
`
`
`
`Before SUSAN L. C. MITCHELL, TINA E. HULSE, and
`TIMOTHY G. MAJORS, Administrative Patent Judges.
`
`MAJORS, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`571-272-7822
`
` Paper No. 7
`
`Date: May 29, 2020
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`AMNEAL PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`CUBIST PHARMACEUTICALS LLC,
`Patent Owner.
`____________
`
`IPR2020-00193
`Patent 9,138,456 B2
`____________
`
`
`
`Before SUSAN L. C. MITCHELL, TINA E. HULSE, and
`TIMOTHY G. MAJORS, Administrative Patent Judges.
`
`MAJORS, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`IPR2020-00193
`Patent 9,138,456 B2
`
`INTRODUCTION
`I.
`Amneal Pharmaceuticals LLC (“Petitioner”),1 on November 27, 2019,
`filed a Petition to institute inter partes review of claims 1, 2, and 7–11 of
`U.S. Patent No. 9,138,456 B2 (Ex. 1001, “the ’456 patent”). Paper 2 (“Pet.”
`or “Petition”). Cubist Pharmaceuticals LLC (“Patent Owner”)2 filed a
`Preliminary Response to the Petition. Paper 6 (“Prelim. Resp.”).
`Under 35 U.S.C. § 314(a), inter partes review may not be instituted
`unless the Petition “shows that there is a reasonable likelihood that the
`petitioner would prevail with respect to at least 1 of the claims challenged in
`the petition.” Petitioner has not established a reasonable likelihood of
`prevailing on its assertion that claims 1, 2, and 7–11 are unpatentable based
`on the grounds advanced here. Thus, for reasons explained below, we do
`not institute inter partes review of claims 1, 2, and 7–11 of the ’456 patent.
`
` Related Patents & Proceedings
`The ’456 patent issued September 22, 2015, from U.S. Patent
`Application No. 14/096,346 (“the ’346 Application”), filed December 4,
`2013. Ex. 1001, (21), (22), (45). The ’346 Application is a division of U.S.
`Patent Application No. 13/511,246, which was filed November 23, 2010 and
`issued as U.S. Patent No. 8,835,382 B2. Id. at (62). The ’346 Application
`
`
`1 Petitioner identifies Amneal Pharmaceuticals LLC, Amneal
`Pharmaceuticals Company GmbH, Amneal Pharmaceuticals of NY LLC,
`and Amneal Pharmaceuticals Company (India) Private Limited as the real
`parties-in-interest. Pet. 1.
`2 Patent Owner identifies Cubist Pharmaceuticals LLC, Merck & Co., Inc.,
`and Merck Sharp & Dohme Corp. as the real parties-in-interest. Paper 4, 1.
`2
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`also claimed priority to U.S. Provisional Application No. 61/263,784, filed
`November 23, 2009 (“the ’784 Application”). Id. at (60).
`Petitioner identifies the following lawsuits involving the ’456 patent:
`Cubist Pharmaceuticals LLC v. Amneal Pharmaceuticals, LLC, No. 3:19-cv-
`15439, filed July 16, 2019, in the United States District Court for the District
`of New Jersey; and Cubist Pharmaceuticals LLC v. Cipla USA, Inc.,
`No. 3:19-cv-12920-BRM, filed May 25, 2019, in the United States District
`Court for the District of New Jersey. Pet. 1–2. Patent Owner states that
`those lawsuits have been consolidated. Paper 4, 1.
`
` Asserted Grounds of Unpatentability
`Petitioner asserts two grounds of unpatentability in this Petition
`(Pet. 3–4), which are provided in the table below:
`Claims Challenged
`35 U.S.C. §
`Reference(s)/Basis
`1, 2, 7–11
`103(a)3
`The Cubicin® label,4 Neururkar,5
`Mittal,6 Sawai7
`Inman,8 Neururkar, Mittal, Sawai
`
`1, 2, 7–11
`
`103(a)
`
`
`3 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”), amended 35 U.S.C. §§ 102 and 103. Based on the putative
`effective filing date of the ’456 patent, we refer to the pre-AIA versions of
`35 U.S.C. §§ 102 and 103 in this Decision.
`4 Cubicin® label (downloaded December 7, 2018, from
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-
`572_Cubicin_Prntlbl.pdf) (Ex. 1004, “The Cubicin® label”).
`5 Neururkar, US 6,136,783, issued Oct. 24, 2000 (Ex. 1005, “Neururkar”).
`6 Mittal, US 2010/0137197 A1, publ. June 3, 2010 (Ex. 1007, “Mittal”).
`7 Sawai, US 7,112,565 B2, issued Sept. 26, 2006 (Ex. 1006, “Sawai”).
`8 Inman, EP 0 386 951 A2, publ. Sept. 12, 1990 (Ex. 1008, “Inman”).
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`Petitioner also relies on the declaration of Raj Suryanarayanan, Ph.D.,
`among other evidence. Ex. 1003.
`
` The ’456 Patent
`According to the ’456 patent, the patent relates to “novel powder
`daptomycin formulations which have improved chemical stability and faster
`reconstitution times when in the solid state,” and exemplary formulations
`“comprise daptomycin and sucrose.” Ex. 1001, Abstr.
`The ’456 patent explains that “[d]aptomycin is a cyclic lipopeptide
`antibiotic indicated for the treatment of complicated skin and skin structure
`infections and bacteremia, including bacteremia with suspected or proven
`infective endocarditis.” Id. at 1:26–31 (describing treatment of infections
`caused by susceptible gram-positive bacteria including methicillin-resistant
`Staphylococus aureus (MRSA)). The ’456 patent notes, as background, that
`daptomycin is “supplied as a lyophilized powder that is reconstituted and
`compounded as a pharmaceutical composition for parenteral
`administration.” Id. at 1:33–37 (identifying “[d]aptomycin for injection
`(CUBICIN®, Cubist Pharmaceuticals, Inc., Lexington, Mass.), [which] is
`supplied as a lyophilized powder”).
`According to the ’456 patent, daptomycin “can be derived from the
`fermentation product of the microorganism Streptomyces roseosporus with a
`feed of n-decanoic acid.” Id. at 1:47–49. The ’456 patent explains,
`however, that other structurally similar components are also present in the
`fermentation product. Id. at 1:51–2:19 (describing degradation products
`including anhydro-daptomycin). One measure of chemical stability of
`
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`daptomycin in the lyophilized form is described in the ’456 patent as the
`amount of daptomycin present in the reconstituted composition relative to
`the amount of structurally similar degradation compounds. Id. at 2:20–26.
`The ’456 patent describes “a need for solid daptomycin compositions
`with improved chemical stability in the solid and/or reconstituted form (i.e.,
`higher total percent daptomycin purity over time), providing advantages of
`longer shelf life, increased tolerance for more varied storage conditions (e.g.,
`higher temperature or humidity) and increased chemical stability after
`reconstitution.” Id. at 2:51–58.
`The ’456 patent discloses that “[s]olid pharmaceutical daptomycin
`preparations can be obtained by converting an aqueous solution including
`daptomycin and a non-reducing sugar (e.g., 15-20% sucrose w/v in the
`solution) at a pH above the isoelectric point of daptomycin (e.g., a pH of
`about 3.7 or greater).” Id. at 4:33–39. The solid, lyophilized composition
`can later be reconstituted in a suitable diluent for injection. Id. at 3:1–4.
`Pharmaceutically-acceptable diluents “include sterile Water for Injection
`(sWFI), 0.9% sterile sodium chloride injection (sSCl), bacteriostatic water
`for injection (bWFI), and Ringer’s solution.” Id. at 8:16–21.
`The ’456 patent teaches that the time for reconstituting the solid
`daptomycin compositions can be “unexpectedly reduced” by increasing the
`pH of the aqueous solution (preferably to a pH of about 6.5–7.5, most
`preferably about 7.0) prior to lyophilizing the solution. Id. at 3:5–10. The
`’456 patent also teaches that “[t]he molar ratio of the lipopeptide to the total
`amount of glycine and/or one or more sugars can be selected to obtain solid
`compositions with more rapid reconstitution rates in aqueous solvents” with
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`daptomycin to sucrose molar ratios of 1.00:1.12 to about 1.00:8.98 being
`preferred. Id. at 7:1–7; see also id. at Fig. 6A (describing, for example, a
`reconstitution time of 0.3–3 minutes in a formulation including 10% sucrose
`versus 5 minutes in a control formulation without sucrose).
`Moreover, the ’456 patent describes improved stability of the
`lyophilized daptomycin formulations with the addition of certain sugars
`including, in particular, sucrose. See, e.g., id. at 17:54–19:55. The patent
`cites data showing, for example, that daptomycin in a solid composition
`containing 15.0% sucrose can provide a roughly 96% increase in chemical
`stability. Id. at 18:54–19:40 (Table 4); see also id. at Fig. 8A (Table 9)
`(showing daptomycin stability from 0–6 months for various formulations at
`40°C). In contrast, the patent discloses that “daptomycin was about 2-9
`times less stable in formulations comprising daptomycin and lactose,
`maltose, fructose, and/or dextrose.” Id. at 19:47–50.
`
` Challenged Claims
`The ’456 patent includes fifteen claims. Petitioner challenges one
`independent claim, claim 1, and dependent claims 2 and 7–11. Pet. 1.
`Claim 1 is illustrative and reads as follows:
`1. A solid pharmaceutical daptomycin composition, wherein
`said composition is prepared by lyophilizing an aqueous
`daptomycin solution comprising daptomycin and sucrose.
`Ex. 1001, 27:2–5. Claim 2 recites a range for the molar ratios of daptomycin
`to sucrose; claims 7–9 recite pH values/ranges for the lyophilized aqueous
`solution; and claims 10 and 11 add a pharmaceutically acceptable diluent
`(e.g., sterile water for injection). Id. at 27:6–8, 27:25–28:2.
`
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` Prosecution History
`Petitioner contends that the Cubicin® label and Inman were identified
`during prosecution, and that the claims of the ’456 patent were allowed after
`being amended to include sucrose in the aqueous composition. Pet. 60
`(noting that Inman was applied by the Examiner in a rejection during
`prosecution); see also id. at 8–10 (summarizing prosecution history).
`Ultimately, by a combination of claim amendment, argument, and
`citation to data in the Specification and in secondary references, Applicant
`persuaded the Examiner that the claims were allowable. Pet. 8–10; Ex. 1002
`(file history).9 In remarks that preceded allowance of the claims, Applicant
`argued the cited prior art did “not disclose the use of sucrose” in a
`lyophilized formulation of daptomycin, nor “teach the surprising stabilizing
`effect of sucrose on solid daptomycin as discovered by the instant inventors,
`as shown in Table 4 . . . and in Table 9 (Figure 8) of the application as
`filed.” Ex. 1002 (Remarks dated April 10, 2015, at 15–16). Applicant also
`argued the cited art did not “teach or suggest the surprising rapid
`reconstitution of solid daptomycin compositions comprising sucrose.” Id.
`Pointing, for example, to an “average reconstitution time for a 500 mg vial
`of lyophilized daptomycin for injection (CUBICIN®) powder [(no sucrose)]
`. . . [of] about 15 minutes” compared to “Tables 6 (Figure 5) and 7
`(Figure 6) of the application,” which showed “daptomycin solutions
`comprising sucrose reconstitute in less than 2 minutes, with most
`
`
`9 Exhibit 1002 does not add page numbers. We, accordingly, refer to the
`dates of the relevant prosecution history entries that appear in Exhibit 1002.
`7
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`reconstituting in less than 1 minute,” Applicant argued that the claims were
`nonobvious. Ex. 1002 (Remarks dated April 10, 2015, at 15–16).
`In allowing the claims, the Examiner reasoned that “a solid
`pharmaceutical daptomycin composition comprising daptomycin and
`sucrose . . . is free of prior art.” Ex. 1002 (Notice of Allowability dated May
`13, 2015, at 5). Also, the Examiner found that “Applicant has presented
`unexpected results of surprising rapid reconstitution of solid daptomycin
`compositions comprising sucrose and increased chemical stability of such
`composition,” which “unexpected results rebut any prima facie case of
`obviousness.” Id.
`
`II. ANALYSIS
` Principles of Law
`“In an [inter partes review], the petitioner has the burden from the
`onset to show with particularity why the patent it challenges is
`unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
`Cir. 2016) (citing 35 U.S.C. § 312(a)(3) (requiring inter partes review
`petitions to identify “with particularity . . . the evidence that supports the
`grounds for the challenge to each claim”)).
`A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
`between the subject matter sought to be patented and the prior art are such
`that the subject matter as a whole would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which that
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`
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`factual determinations including: (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of ordinary skill in the art; and (4) objective evidence of
`nonobviousness when presented. Graham v. John Deere Co., 383 U.S. 1,
`17–18 (1966).
`In analyzing the obviousness of a combination of prior art elements, it
`can be important to identify a reason that would have prompted one of skill
`in the art “to combine . . . known elements in the fashion claimed by the
`patent at issue.” KSR, 550 U.S. at 418. Indeed, a party who petitions the
`Board for a determination of unpatentability based on obviousness must
`show that “a skilled artisan would have been motivated to combine the
`teachings of the prior art references to achieve the claimed invention, and
`that the skilled artisan would have had a reasonable expectation of success in
`doing so.” In re Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed.
`Cir. 2016) (quotations and citations omitted).
`
` Person of Ordinary Skill in the Art (“POSA”)
`In determining the level of skill in the art, we consider the problems
`encountered in the art, the art’s solutions to those problems, the rapidity with
`which innovations are made, the sophistication of the technology, and the
`educational level of active workers in the field. Custom Accessories, Inc. v.
`Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed. Cir. 1986).
`Petitioner contends:
`[A] POSA in the relevant field at that time would have had at
`least a bachelor of science degree in one of the pharmaceutical
`sciences,
`including
`pharmaceutical
`chemistry
`and/or
`
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`pharmaceutics, or a related technical field, and either an
`advanced degree (such as a masters or doctorate) or an equivalent
`amount of work experience, i.e. 3-5 years, in an area relating to
`lyophilized pharmaceutical formulations.
`Pet. 11 (citing Ex. 1003 ¶ 57). Patent Owner does not oppose this
`description of the POSA’s qualifications. Prelim. Resp. 21.
`Because Petitioner’s proposal on the level of ordinary skill in the art is
`unopposed and is not inconsistent with the cited prior art, we adopt it for the
`purposes of this Decision. Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed.
`Cir. 2001) (explaining that specific findings regarding ordinary skill level
`are not required “where the prior art itself reflects an appropriate level and a
`need for testimony is not shown”) (quoting Litton Indus. Prods., Inc. v. Solid
`State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985)).
`
` Claim Construction
`We interpret a claim “using the same claim construction standard that
`would be used to construe the claim in a civil action under 35 U.S.C.
`282(b).” 37 C.F.R. § 42.100(b) (2019). Under this standard, we construe
`the claim “in accordance with the ordinary and customary meaning of such
`claim as understood by one of ordinary skill in the art and the prosecution
`history pertaining to the patent.” Id. “[W]e need only construe terms ‘that
`are in controversy, and only to the extent necessary to resolve the
`controversy.’” See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor
`Co. Ltd., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (quoting Vivid Techs., Inc. v.
`Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`10
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`“about” (claims 2, 7–9)
`Claims 2 and 7–9 include the term “about” in modifying the
`numerical limitations in those claims. See, e.g., Ex. 1001, 27:25–27
`(reciting a “pH of about 4.5 to about 8.0”). Petitioner argues “about” is not
`defined in the ’456 patent. Pet. 11. Petitioner asserts that “about” should
`“be construed according to its plain and ordinary meaning as understood by
`a POSA,” which Petitioner contends is generally accepted to be
`“approximately.” Id. at 12 (citing Ex. 1003 ¶¶ 60–61). Patent Owner
`“stipulates that no term, including ‘about’ (claims 2, 7-9) in the challenged
`claims requires construction.” Prelim. Resp. 21.
`We do not, on this record, perceive a material difference between
`“about,” as recited in the claims, and “approximately,” as proposed by
`Petitioner. Both terms reflect a degree of imprecision related to the claimed
`values, yet Petitioner does not explain how “about” is narrower than
`“approximately”—or vice versa. It is clear, however, that Petitioner
`interprets “about” or “approximately” as embracing values ±10% of the
`particular numerical limitations in the claims. See, e.g., Pet. 40 (“The
`claimed value of ‘about 7’ in the ‘456 Patent would likewise be understood
`by a POSA to include any pH in the range of 6.3 to 7.7”). Patent Owner
`does not specifically oppose Petitioner’s arguments about the breadth of the
`term “about.” Solely for purposes of assessing Petitioner’s challenge to the
`dependent claims here, we interpret “about” as “approximately,” as proposed
`by Petitioner.
`
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` Obviousness over the Cubicin® label and Neururkar, Mittal, or Sawai
`Petitioner asserts that claims 1, 2, and 7–11 are unpatentable as
`obvious over the Cubicin® label and any one of Neururkar, Sawai, or Mittal.
`Pet. 12–45; see id. at 12–27 (claim 1), 27–45 (dependent claims).
`We provide an overview of the asserted references, followed by
`analysis of Petitioner’s obviousness challenge.
`
`The Cubicin® label (Exhibit 1004)
`1.
`The Cubicin® label discloses that “Cubicin contains daptomycin, a
`cyclic lipopeptide antibacterial agent derived from the fermentation of
`Streptomyces roseosporus” and “Cubicin is supplied as a sterile,
`preservative-free . . . lyophilized cake containing approximately 900 mg/g of
`daptomycin for intravenous use following reconstitution.” Ex. 1004, ll. 9–
`10, 14–17. The Cubicin® label further discloses that the only inactive
`ingredient is sodium hydroxide, which is used in minimal quantities for pH
`adjustment. Id. at ll. 17–18.
`The chemical structure of daptomycin is shown below:
`
`
`
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`Id. at ll. 12–13. The chemical name of the above-depicted structure is N-
`decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-L-
`ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-
`glutamyl-3-anthraniloyl-L-alanine ε1-lactone. Id. at ll. 10–12.
`The Cubicin® label explains that “Cubicin is supplied in single-use
`vials containing either 250 or 500 mg daptomycin as a sterile, lyophilized
`powder” and the contents of the vials should be reconstituted with a sodium
`chloride solution for injection. Id. at ll. 485–490. The Cubicin® label
`teaches to “[s]tore original packages [of the lyophilized product] at
`refrigerated temperatures 2 to 8°C (36 to 46°F)” and to “avoid excessive
`heat.” Id. at ll. 514–515.10
`
`Neururkar (Exhibit 1005)
`2.
`Neururkar discloses “compositions for treating and/or preventing
`fungal infections.” Ex. 1005 at 1:7–8, 27–30 (describing use in treating, for
`example, Pneumocystis carinii pneumonia).11 Neururkar states that its
`compositions “are safe, stable, lyophilized dosage forms for reconstitution
`which are particularly useful for delivering antifungal agents to patients in
`need of such agents.” Id. at 1:31–34. According to Neururkar, its
`formulations provide enhanced stability and shelf life. Id. at 2:20–23.
`
`10 Patent Owner cites, among other things, a European Medicines Agency
`Annex related to Cubicin®, describing the shelf-life of the lyophilized,
`refrigerated product as 3 years. Prelim. Resp. 7, 12, 27; Ex. 2001, 18;
`Ex. 1004, ll. 514–515; Ex. 1016, 4.
`11 Patent Owner states that Neururkar is an Orange Book-listed patent for the
`antifungal product Cancidas®. Prelim. Resp. 13; see also Ex. 1010 (label
`for Cancidas® (caspofungin acetate)).
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`Neururkar describes, in particular, a pharmaceutical composition
`including a pharmaceutically effective amount of a compound of formula I:
`
`
`or pharmaceutically acceptable salts thereof, “a pharmaceutically acceptable
`amount of an acetate buffer effective to provide a pH of between about 4 and
`7,” and “a pharmaceutically acceptable amount of an excipient such as a
`sucrose/mannitol mixture to form a lyophilized cake.” Id. at 1:36–2:3.
`Neururkar discloses that compounds of formula I “are significantly
`more stable on storage when formulated in the presence of an acetate
`buffer.” Id. at 2:29–55. According to Neururkar, by switching to an acetate
`buffer, the lyophilized product is “more stable, contains less of unwanted
`degradates while extending the shelf life of the composition.” Id. at 2:66–
`3:1; see also id. at 8:44–67 (describing formulations in “Table 1” and
`disclosing that “[i]t was surprisingly found that Formulations 1, 5, 7, and 8
`[(formulations with acetate)] were significantly more stable and showed
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`significantly less of the unwanted degradates than the other formulations
`[(formulations without acetate)]”).
`Neururkar also discloses that “[e]xcipients such as bulking agents, i.e.,
`excipient sugars, are used to provide an aesthetically suitable lyophilized
`cake.” Id. at 3:20–22. More specifically, Neururkar discloses that “[s]ugars
`useful in the invention include sucrose, lactose, mannitol or combinations
`thereof” and “[i]t has been found that sucrose and mannitol provide a more
`stable formulation and form a pharmaceutically elegant cake for the
`composition.” Id. at 3:23–27.
`In describing “formulations suitable for long-terms storage,”
`Neururkar teaches a preparation of the lyophilized formulations including,
`inter alia, a bulking agent in water, acetic acid, and compound I, forming a
`pH-adjusted solution which is then filtered and freeze dried over multiple
`days. Id. at 3:33–48. Neururkar teaches that the lyophilized formulations
`prepared as above are “stored at about 5°C.” Id. at 3:49–50; see also id. at
`8:44–61 (describing various formulations in “Table 1” and disclosing that
`“[t]he formulations were stored in the lyophilized state at 5° C. and tested at
`about 4 week intervals for stability”).
`
`3. Mittal (Exhibit 1007)
`Mittal, like Neururkar, “is directed to caspofungin-containing
`pharmaceutical compositions useful for treating and/or preventing fungal
`infections.” Ex. 1007 ¶ 1. Mittal discloses that “[c]aspofungin is a
`macrocyclic lipopeptide echinocandin” and “[c]aspofungin is typically
`employed in a lyophilized composition that is reconstituted for intravenous
`infusion.” Id. ¶¶ 2–3 (citing, e.g., Neururkar). Mittal explains that
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`“[c]aspofungin is an inhibitor of the synthesis of β-(1,3)-D-glucan, which is
`an integral part of the fungal cell wall” and is “useful for the control of both
`filamentous fungi and yeast.” Id. ¶ 2 (describing, for example, treatment of
`Pneumocystis carinii pneumonia).
`Mittal discloses that “[l]yophilized, acetate-buffered, caspofungin
`products such as CANCIDAS are characterized by good storage stability at
`low temperature (e.g., 2° C. to 8° C.)” but “lyophilized caspofungin-
`containing products with improved storage stability at low temperatures
`and/or satisfactory storage stability at higher temperatures is desirable.” Id.
`¶ 4 (teaching that existing caspofungin products “can be stored at low
`temperature (e.g., 5°C) for many months with minimal formation of
`degradates”). According to Mittal, “[s]atisfactory storage stability at room
`temperature would eliminate the need for refrigeration and the special
`handling and extra costs associated therewith.” Id.
`Mittal describes a lyophilized composition that includes caspofungin
`and “one or more non-reducing sugars having a glass transition temperature
`Tg(s) of at least about 90° C,” and “an acetate buffer in an amount effective
`to provide a pH in a range of from about 5 to about 7.” Id. ¶¶ 5–8; see also
`id. ¶ 60 (“The Tg(s) value of the one or more non-reducing sugars used in the
`present invention is at least about 90° C.”), ¶ 61 (“When more than one non-
`reducing sugar is employed, it is the Tg(s) value of the sugars together in a
`mixture (after lyophilization) that must be at least about 90° C. . . .
`Typically, however, each of the non-reducing sugars employed in the
`lyophilized composition has an individual glass transition temperature of at
`least about 90° C.”).
`
`16
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`IPR2020-00193
`Patent 9,138,456 B2
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`According to Mittal, the lyophilized composition includes “one or
`more non-reducing sugars . . . selected from the group consisting of
`trehalose, sucrose, raffinose, sorbitol and combinations thereof.” Id. ¶ 15.
`More specifically, Mittal teaches “[s]uitable combinations include any two
`of the sugars (e.g., trehalose and sucrose), any three of the sugars (e.g.,
`trehalose, sucrose, and sorbitol), or all four of the sugars.” Id. Further,
`Mittal discloses that “[i]n an aspect of this embodiment, the one or more
`non-reducing sugars is trehalose or a mixture of trehalose with any one of
`sucrose, raffinose and sorbitol.” Id. (“In a feature of this aspect, the non-
`reducing sugar is trehalose or a major amount of trehalose.”).
`Mittal further teaches “a process for preparing a lyophilized anti-
`fungal composition with a moisture content of less than about 0.8 wt. %.”
`Id. ¶ 67. The process includes preparing an aqueous solution with a pH “in a
`range of from about 5 to about 7 and comprising an effective amount of
`caspofungin . . . , one or more non-reducing sugars having a glass transition
`temperature Tg(s) of at least about 90° C., and an acetate buffer,” and freeze-
`drying the solution to provide a lyophilized composition. Id. ¶¶ 68–69.
`Mittal discloses that “[t]he lyophilized anti-fungal composition of the
`present invention has good chemical and storage stability at and below room
`temperature (i.e., at or below about 30° C.)” and the stability of the
`composition exceeds “that of known lyophilized caspofungin-containing
`compositions which employ sucrose and mannitol and have a Tg(c) in a
`range of from about 40° C. to about 45° C.” Id. ¶ 13; see also id. ¶¶ 100–
`111 (Example 1 (with trehalose as the only sugar)), 112–118 (Example 2
`(identifying various other lyophilized compositions (e.g., Nos. 2-1 and 2-2,
`17
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`IPR2020-00193
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`
`sucrose/mannitol combinations))); Example 3 (identifying results of stability
`tests for example compositions).
`
`Sawai (Exhibit 1006)
`4.
`Sawai discloses “a stabilized pharmaceutical composition in
`lyophilized form containing a cyclic polypeptide compound or its
`pharmaceutically acceptable salt and a stabilizer.” Ex. 1006, 1:13–17. The
`compound of Sawai is represented by formula I:
`
`
`“wherein R1 is a hydrogen atom or an acyl group and R2 and R3 are, the
`same or different, a hydrogen atom or a hydroxyl group.” Id. at 1:18–49.
`Sawai teaches that this compound has “an antifungal activity and a β-1,3-
`glucan synthase inhibiting action, and is useful for preventing and treating
`
`18
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`IPR2020-00193
`Patent 9,138,456 B2
`
`various kinds of infectious diseases including Pneumocystis carinii
`infection, e.g., carinii pneumonia.” Id. at 1:48–52.12
`Sawai discloses that a lyophilized composition may be prepared from
`an aqueous solution that includes compound (I) (or its salt) and a stabilizer.
`Id. at 10:34–37. A pH adjustor may be added and the solution is lyophilized
`in a conventional way. Id. at 10:37–41.
`For the stabilizer, Sawai teaches that, “[a]ccording to the present
`invention, provided is a composition in lyophilized form in which the cyclic
`polypeptide compound (I) or its pharmaceutically acceptable salt are
`stabilized by a stabilizer such as polysaccharide, disaccharide and sodium
`chloride.” Id. at 15:53–57. Sawai discloses “[a]s the stabilizer, may be
`mentioned polysaccharides, disaccharides, sodium chloride and a
`combination thereof,” and Sawai identifies polysaccharides such as
`“dextran, starch, cellulose and hyaluronic acid” and disaccharides such as
`“lactose, maltose and sucrose.” Id. at 9:34–38. Sawai also teaches “[t]he
`polysaccharide or disaccharide contained in the pharmaceutical composition
`of the present invention may be α-monohydrate, α-anhydride, β-anhydride or
`a combination thereof.” Id. at 9:38–41; see also id. at 12:16–13:15
`(describing stability results for various lyophilized compositions).
`
`
`
`
`12 As Patent Owner points out, Sawai’s compounds appear to be sulfate
`substituted derivatives of caspofungin. Prelim. Resp. 18, 36.
`19
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`IPR2020-00193
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`Analysis of Alleged Obviousness
`
`5.
`Claim 1
`Petitioner contends that the Cubicin® label discloses a lyophilized
`formulation of daptomycin that must be stored at refrigerated temperatures
`(i.e., 2 to 8° C). Pet. 12–13. Because “[t]he Cubicin® label does not,
`however, disclose that the [lyophilized] cake is prepared by lyophilizing an
`aqueous solution of daptomycin and sucrose,” as recited in claim 1,
`Petitioner turns to Neururkar, Mittal, and Sawai. Id. at 13; Ex. 1003 ¶ 64.
`According to Petitioner, Neururkar and Mittal disclose improved
`stability and shelf-life with lyophilized pharmaceutical products, particularly
`those including the active agent, caspofungin. Pet. 13–17. For example,
`Petitioner cites Neururkar’s teaching of lyophilized caspofungin
`formulations that include “sucrose and mannitol,” which Neururkar
`describes as “provid[ing] a more stable formulation and form[ing] a
`pharmaceutically elegant cake for the composition.” Pet. 14–15 (citing
`Ex. 1005, 3:20–26) (emphasis omitted). Petitioner acknowledges that
`Neururkar does not describe daptomycin. Pet. 15.
`Petitioner cites Mittal’s teaching of a need for “[s]atisfactory storage
`stability at room temperature [(for a caspofungin/Cancidas® lyophilized
`formulation)]” as that “would eliminate the need for refrigeration and the
`special handling and extra costs associated therewith.” Pet. 16 (citing
`Ex. 1007 ¶ 4) (emphasis omitted). Petitioner further cites Mittal’s teaching
`of the use of “one or more non-reducing sugars . . . selected from the
`group consisting of trehalose, sucrose, raffinose, sorbitol and combinations
`thereof” and the preparation of lyophilized compositions with caspofungin
`20
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`IPR2020-00193
`Patent 9,138,456 B2
`
`and “one or more non-reducing sugars having a glass transition
`temperature Tg(s) of at least about 90°C.” Pet. 17 (quoting Ex. 1007
`¶¶ 15, 68–69) (emphasis added by Petitioner). And Petitioner cites Mittal’s
`teaching of lyophilized anti-fungal compositions with “good chemical and
`storage stability at and below room temperature (i.e., at or below about
`30°C).” Id. at 16 (citing Ex. 1007 ¶ 13); Ex. 1003 ¶ 75. As with Neururkar,
`Petitioner notes that Mittal does not disclose daptomycin. Pet. 17.
`Turning to Sawai, Petitioner contends that, “although not expressly
`stating the benefits . . . like Neururkar and Mittal,” Sawai describes
`stabilized lyophilized formulations. Pet. 18. Petitioner cites Sawai’s
`disclosure of “a composition in lyophilized form in which the cyclic
`polypeptide compound (I) . . . [is] stabilized by a stabilizer such as
`polysaccharide, disaccharide and sodium chloride.” Id. (citing Ex. 1005,
`15:54–65) (emphasis omitted). Petitioner also cites Sawai’s disclosure of
`“examples of the disaccharide are lactose, maltose and sucrose.” Id. at 19
`(citing Ex. 1006, 9:34–41) (emphasis added by Petitioner); Ex. 1003 ¶ 79.
`Petitioner acknowledges that the active compound in Sawai is not
`daptomycin. Pet. 19.
`From Neururkar,
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