Trials@uspto. gov
`571-272-7822
`
`Paper No. 24
`Entered: October 15, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`BRISTOL-MYERS SQUIBB COMPANY and PFIZER INC,
`Patent Owners.
`
`Case IPR2018-00892
`
`Patent 9,326,945 B2
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`DECISION
`
`Institution of Inter Partes Review
`
`35 US. C. § 314
`
`
`571-272-7822
`
`Paper No. 24
`Entered: October 15, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`
`Petitioner,
`
`V.
`
`BRISTOL-MYERS SQUIBB COMPANY and PFIZER INC,
`Patent Owners.
`
`Case IPR2018-00892
`
`Patent 9,326,945 B2
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`KRISTI L. R. SAWERT, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`DECISION
`
`Institution of Inter Partes Review
`
`35 US. C. § 314
`
`
`
`IPR2018-00892
`
`Patent 9,326,945 B2
`
`I.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”), filed a Petition requesting
`
`an inter partes review of claims 1—38 of US. Patent No. 9,326,945 B2
`
`(Ex. 1001, “the ’945 patent”). Paper 2 (“Pet”). Bristol-Myers Squibb
`
`Company and Pfizer, Inc. (collectively, “Patent Owner”) filed a Preliminary
`
`Response. Paper 18 (“Prelim Resp”).
`
`We have authority to determine whether to institute an inter partes
`
`review under 35 U.S.C. § 314, which provides that an inter partes review
`
`may not be instituted unless the information presented in 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.” See also
`
`37 C.F.R. § 42.4 (a). Upon consideration of the Petition and the Preliminary
`
`Response, and for the reasons explained below, we determine that Petitioner
`
`has established a reasonable likelihood that it would prevail with respect to
`
`at least one challenged claim. We thus grant Petitioner’s request to institute
`
`an inter partes review of the challenged claims on all grounds set forth in the
`
`Petition.
`
`A. Related Matters
`
`The parties provide a list of numerous litigations involving the ’945
`
`patent. Pet. 1—3; Paper 7, 1—3.
`
`B. The ’945 patent
`
`The ’945 patent describes “[c]ompositions comprising crystalline
`
`apixaban particles having a D90 equal to or less than 89 um, and a
`
`pharmaceutically acceptable carrier.” Ex. 1Q01, Abstract. The compositions
`
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`IPR2018-00892
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`Patent 9,326,945 B2
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`can be used for the treatment and/or prophylaxis of thromboembolic
`
`disorders. Id.
`
`The ’945 patent discloses as follows:
`
`The aqueous solubility (4O ug/mL at all physiological pH)
`of apixaban suggests that the tablets with less than 10 mg
`apixaban (dose/solubility ratio=250 mL) should not demonstrate
`dissolution rate
`limited absorption since dissolution rate
`limitations are only expected when the dose/solubility ratio is
`greater
`than 250 mL. Based on this dose and solubility
`consideration, the particle size of the compound should not be
`critical for achieving consistent plasma profiles, according to the
`prediction based on the Biopharmaceutics Classification System
`(BCS; Amidon, G. L. et al., Pharmaceutical Research, 12: 413—
`420 (1995)). However, it was determined that formulations that
`were made using a wet granulation process as well as those using
`large particles of apixaban drug substance resulted in less than
`optimal exposures, which can present quality control challenges.
`
`Id. at 1:46—60.
`
`The ’945 patent discloses as follows:
`
`it has been found that
`Surprisingly and unexpectedly,
`compositions for tablets comprising up to 5 mg, apixaban
`particles having a D90 (90% of the volume) less than 89 microns
`(um)
`lead to consistent
`in—vivo dissolution in humans (at
`physiologic pH), hence, consistent exposure and consistent
`Factor Xa inhibition that will lead to consistency in therapeutic
`effect.
`
`Id. at 1:64—23.
`
`The ’945 patent discloses the need for the use of a surfactant in the
`
`composition as follows:
`
`the pharmaceutical
`invention further provides
`The
`composition further comprising a surfactant from 0.25% to 2%
`by weight, preferably from 1% to 2% by weight. As regards the
`
`3
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`Patent 9,326,945 B2
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`surfactant, it is generally used to aid in wetting of a hydrophobic
`drug in a tablet formulation to ensure efficient dissolution of the
`drug,
`for example, sodium lauryl sulfate, sodium stearate,
`polysorbate 80 and poloxamers, preferably sodium lauryl sulfate.
`
`Id. at 2:24—31.
`
`I
`
`The ’945 patent further discloses how to perform certain dissolution
`
`rate tests. Id. at 321—19; 6:24—41.
`
`C. Illustrative Claims
`
`Independent claims 1 and 12, reproduced below, are illustrative:
`
`a
`comprising
`composition
`pharmaceutical
`1. A solid
`therapeutically effective amount of crystalline apixaban particles
`and a pharmaceutically acceptable diluent or carrier,
`
`wherein the crystalline apixaban particles have a D90 equal
`to or less than about 89 um, and
`
`wherein at least 77 wt % of apixaban dissolves within 30
`minutes in a pH 6.8 phosphate buffer containing 0.05% sodium
`lauryl sulfate.
`
`comprising
`composition
`12. A solid pharmaceutical
`therapeutically
`effective
`amount
`of
`apixaban
`and
`pharmaceutically acceptable diluent or carrier,
`
`a
`a
`
`wherein
`particles,
`
`apixaban
`
`comprises
`
`crystalline
`
`apixaban
`
`wherein the crystalline apixaban particles have a D90 equal
`to or less than about 89 um, and
`
`wherein, as measured using a USP Apparatus 2 at a paddle
`rotation speed of 75 rpm in 900 mL, of a dissolution medium at
`37° C., at
`least 77 wt % of apixaban in the pharmaceutical
`composition dissolves within 30 minutes in the dissolution
`medium, and the dissolution medium is 0.05 M sodium r
`phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.
`
`4
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`Patent 9,326,945 B2
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`Ex. 1001, 9:49—57; 10:13—27.
`
`D. Evidence Relied Upon
`
`Petitioner relies upon the following prior art references:
`
`Ex. 1004, Carreiro et al., “Apixaban, an oral direct Factor Xa inhibitor:
`awaiting the verdict,” Expert Opin. Investig. Drugs, 17(12):1937—1945
`(2008) (“Carreiro”).
`
`Ex. 1007, US. Patent No. 6,967,20891B2 to Pinto et al., issued Nov. 22, 2005
`(“Pinto”).
`
`Ex. 1008, US. Patent Publication No. 2006/0160841 A1 by Chenkou Wei et
`al., published Jul. 20, 2006 (“Wei”).
`
`Ex. 1010, Rudnic et al., “Tablet Dosage Forms,” in Modern Pharmaceutics,
`4th ed., G.S. Banker and GT. Rhodes, eds., Taylor & Francis Group, Boca
`Raton, FL, pp. 333—359 (2002) (“Rudnic”).
`
`Ex. 1015, “Guidance for Industry: Dissolution Testing of Immediate Release
`Solid Oral Dosage Forms,” US. Department of Health and Human Services,
`Food and Drug Administration, Center for Drug Evaluation and Research
`(CDER) (Aug. 1997) (“FDA Dissolution Guidance”).
`
`Petitioner also relies upon the Declaration of Kinam Park, Ph.D. (Ex.
`
`1002) to support its contentions.
`
`E. Asserted Grounds of Unpatentability
`
`Petitioner asserts the following grounds of unpatentability (Pet. 4—5):
`
`“—m
`
`
`
`
`
`
`
`
`Carreiro, Wei, and
`FDA Dissolution Guidance
`Carreiro, Wei, Rudnic, and
`FDA Dissolution Guidance
`
`'
`
`§ 103(a)
`
`§ 103(a)
`
`
`
`IPR2018-00892
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`Patent 9,326,945 B2
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`“—m
`
`
`
`
`
`
`
`
`’ Pinto, Wei, and
`FDA Dissolution Guidance
`Pinto, Wei, Rudnic, and
`FDA Dissolution Guidance
`
`§ 103(a)
`
`§ 103(a)
`
`II. ANALYSIS
`
`A. Claim Construction
`
`In an inter partes review, the Board interprets claim terms in an
`
`unexpired patent according to the broadest reasonable construction in light
`
`of the specification of the patent in which they appear. 37 C.F.R.
`
`§42.100(b); Cuozzo Speed Techs, LLC v. Lee, 136 S. Ct. 2131, 2142 (2016)
`
`(affirming applicability of broadest reasonable construction standard to inter
`
`partes review proceedings). Under that standard, and absent any special
`
`definitions, we give claim terms their ordinary and customary meaning, as
`
`would be understood by one of ordinary skill in the art at the time of the
`
`invention, in the context of the entire disclosure. In re Translogic Tech,
`
`Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions for
`
`claim terms must be set forth with reasonable clarity, deliberateness, and
`
`precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`We determine that no explicit construction of any claim term is
`
`necessary to determine whether to institute a trial in this case. See Nidec
`
`Motor Corp. v. Zhongshan Broad Ocean Motor Co., 868 F.3d 1013, 1017
`
`(Fed. Cir. 2017) (“[W]e need only construe terms ‘that are in controversy,
`9”
`
`and only to the extent necessary to resolve the controversy.
`
`(quoting Vivid
`
`Techs, Inc. v. Am. Sci. & Eng ’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999))).
`
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`IPR2018-00892
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`Patent 9,326,945 B2
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`B. Discretion Whether to Institute Under 35 US. C. § 325(d)
`
`Section 325(d) provides: “[iJn determining whether to institute .
`
`.
`
`. a
`
`proceeding .
`
`.
`
`.
`
`, the Director may take into account whether, and reject the
`
`petition or request because, the same or substantially the same prior art or
`
`arguments previously were presented to the Office.” Thus, before we decide
`
`whether we should exercise our discretion to deny institution for one or
`
`more grounds, we first must determine whether any of the grounds asserted
`
`in this Petition present the “same or substantially the same prior art or
`
`arguments” as those previously presented to the Office.
`
`1. Patent Owner ’5 Contentions
`
`Patent Owner contends that we should exercise our discretion to deny
`
`institution on all grounds because “Petitioner relies on the same or
`
`substantially the same references applied by the Examiner during
`
`prosecution.” Prelim. Resp. 15, 21. Specifically, Patent Owner asserts that
`
`“the portions of Wei relied upon by Petitioner are identical to the portions of
`
`Wei that were cited by the Examiner” and that “the portions of the Carreiro
`
`reference and [Pinto] asserted in the Grounds are cumulative to the Nause1
`
`reference cited by the Examiner for substantially the same information.” Id.
`
`at16, 19.
`
`Regarding Petitioner’s reliance on Rudnic and FDA Dissolution
`
`Guidance in the Grounds set forth in the Petition, Patent Owner contends
`
`that these references
`
`‘ Ex. 2011, Nause, Richard G., US. Patent Application Publication No.
`2012/0087978 A1, published Apr. 12, 2012 (“Nause”).
`7
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`Patent 9,326,945 B2
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`add nothing new. The Examiner relied on Nause for the same
`material allegedly taught by Rudnic, which is only cited for
`certain dependent claims. As for the FDA Dissolution Guidance,
`the Petition uses it to describe information ancillary to the
`
`reasons for allowance.
`
`Id. at 16, 22—23.
`
`Lastly, Patent Owner contends that the Park Declaration “largely
`
`parrots the Petition” and “contains no new analysis or anything above the
`
`attorney argument presented in the Petition.” Id. at 16.
`
`2. Summary ofRelevant Prosecution History
`
`During prosecution of the ’945 patent, the examiner rejected the
`
`claims as being unpatentable as obvious over the combination of Nause and
`
`Wei. Ex. 1003, 397—98 (Non-Final Office Action mailed Aug. 13, 2015).
`
`Subsequently, applicants initiated an interview with the examiner and the
`
`examiner entered an Applicant-Initiated Interview Summary (Sept. 17,
`
`2015), where the examiner stated the following:
`
`Applicants discussed different properties observed with claimed
`invention, including dissolution rate, and stated .
`.
`. one skilled
`in the art would not have expected particle size to have made a
`difference in in vivo data, since apixaban is a BCS Class 111 drug
`(highly soluble)[.] Applicants stated the dosage form of Nause
`is directed controlled release, while the claimed invention is
`directed to immediate release, noting dissolution property
`recited in [now independent claim 1]. Applicants discussed
`[that] Wei is directed to making specific polymorphs, rather than
`therapeutic properties of apixaban.
`
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`Id. at 4318 (emphasis added).2
`
`After the interview, applicants entered an amendment and traversed
`
`the rejection set forth in the Non-Final Office Action mailed Aug. 13, 2015.
`
`Id. at 456—74 (Amendment entered Nov. 30, 2015). In that Amendment,
`
`applicants distinguished Nause from the claimed subject matter on the basis
`
`that Nause is directed to controlled release dosage forms, which is
`
`“differen[t] from a composition of the present invention, as is evident from,
`
`for example, the rate of dissolution recited in [the claims].” Id. at 465; see
`
`also id. at 466—67 (further distinguishing the dissolution rate of the
`
`controlled release dosage forms disclosed in Nause from the claimed dosage
`
`forms).
`
`Next, the examiner issued a Notice of Allowance (mailed Mar. 4,
`
`2016). Id. at 492—499. In that paper, the examiner stated the following
`
`reasons for allowance:
`
`Applicant’s data in the specification demonstrates the criticality
`of the particular size range claimed, wherein the crystalline
`apixaban particles have a D90 equal to or less than about 89 um,
`and the resulting dissolution property, wherein at least 77wt% of
`apixaban dissolves within 30 minutes in a pH 6.8 phosphate
`buffer containing 0.05% sodium lauryl sulfate, for establishing
`bioequivalence of solid apixaban formulations with a solution
`(see paragraphs [0035]—[0038] of the Specification).
`It is also
`noted that Nause teaches ‘controlled release’ formulations of
`apixaban, which Nause distinguishes from ‘immediate release’
`
`2 We note that Patent Owner contends that apixaban was known as a BCS
`Class 111 drug, but provides insufficient evidence to support this position.
`Prelim. Resp. 7, 9.
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`9
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`IPR2018-00892
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`Patent 9,326,945 B2
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`formulations having similar dissolution rates to those of the
`claimed invention (see Nause, paragraph [0032]).
`
`Id at 497—498 (emphasis added).
`
`3. Analysis
`
`Having considered Patent Owner’s arguments and the prosecution
`
`history of the ’945 patent, we are not persuaded to exercise our discretion
`
`under § 325(d) to deny the Petition. We agree with Patent Owner that Wei
`
`was considered and relied on by the examiner during prosecution, however,
`
`we are not persuaded that Carreiro and Pinto are cumulative of Nause. As
`
`noted during prosecution, Nause is limited to controlled release dosage
`
`forms having a specific dissolution profile. Ex. 2011 11 32. In contrast, the
`
`dosage forms disclosed in Carreiro and Pinto do not appear to be limited to
`
`controlled release dosage forms. While we acknowledge that Pinto is cited
`
`in the ’945 patent, we note that the examiner did not raise any ground of
`
`rejection involving the combination of Pinto and Wei, and thus, it is unclear
`
`whether this combination of references was fully evaluated by the examiner.
`
`In addition, Carreiro, FDA Dissolution Guidance, and Rudnic were
`
`not cited by the Examiner during prosecution and none are cited on the face
`
`of the patent. FDA Dissolution Guidance, for example, discloses routine
`
`tests for dissolution testing that are specifically relevant to the claim
`
`elements added during prosecution to overcome the examiner’s rejection
`
`over Nause and Wei. In this regard, we do not agree with Patent Owner that
`
`FDA Dissolution Guidance merely provides “information ancillary to the
`
`reasons for allowance.” Prelim. Resp. 16.
`
`10
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`Patent 9,326,945 B2
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`Thus, with the exception of Wei, it is unclear to the extent that the
`
`examiner considered the subject matter disclosed in any of Carreiro, Pinto,
`
`FDA Dissolution Guidance, and Rudnic and relied upon by Petitioner in
`
`Grounds 1—4 of the Petition. Accordingly, based on our evaluation of the
`
`entirety of the record before us, we are unable to determine that any of the
`
`grounds asserted in this Petition present the “same or substantially the same
`
`prior art or arguments” as those previously presented to the Office.
`
`C. Whether to Institute Based on Information Presented in the Petition
`
`1 . Summary ofAsserted Prior Art
`
`a. Carreiro
`
`Carreiro is a “review article discuss[ing] the discovery,
`
`pharmacokinetics, attributes, and current clinical trials of [apixaban].” Ex.
`
`1004, Abstract. Carreiro discloses apixaban as “a potent, selective,
`
`reversible, and orally bioavailable FXa inhibitor that demonstrates
`
`antithrombotic efficacy with a favorable pharmacokinetic profile.” Id. at
`
`1938.
`
`Carreiro further discloses the results of the APROPOS Phase II trial,
`
`examining the efficacy of apixaban in preventing deep vein thrombosis
`
`(DVT) and pulmonary embolism (PE) in patients undergoing total knee
`
`replacements (TKR). Id. at 1941. Carreiro teaches that “the optimal dose of
`
`apixaban was determined to be either 2.5 mg twice daily or 5 mg once daily,
`
`both of which had a promising benefit—risk profile compared with the
`
`current standards of care following TKR.” Id.
`
`Carreiro also discloses that “[a]pixaban has no ionizable groups and
`
`therefore does not exhibit pH-dependent aqueous solubility,” which
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`Petitioner contends is an indication to a person of ordinary skill in the art the
`
`drug would have had poor solubility. Id. at 1940; Ex. 1002 1111 120, 163,
`
`173.
`
`' b. Pinto
`
`Pinto discloses a class of compound inhibitors of trypsin-like serine
`
`protease enzymes, especially Factor Xa, useful for the prevention and
`
`treatment of thromboembolic diseases. Ex. 1005, Abstract, 1:19—22. Pinto
`
`discloses that the compounds of the invention can be administered in oral
`
`dosage forms, including tablets or capsules. Id. at 154:65—15523. Pinto
`
`further provides that the daily oral dosage of the compounds of the invention
`
`“will range between about 0.001 to 1000 mg/kg of body weight, preferably
`
`between about 0.01 to 100 mg/kg of body weight per day, and most
`
`preferably between about 1.0 to 20 mg/kg/day.” Id. at 155:23—28.
`
`Pinto identifies apixaban (“1-(4-methoxyphenyl)-.7-oxo-6-[4-(2-oxo-l-
`
`piperidinyl) phenyl-4,5,6,7—tetrahydro-1H—pyrazole-[3,4—c] pyridine-3-
`
`carboxamide”) as a member of the disclosed class of compounds. Id. at
`
`269:1—6 (claim 13). Pinto discloses a pharmaceutical comprising apixaban
`
`(id. at 27015—9 (claim 27)) and further discloses apixaban in crystalline form
`
`(id. at Certificate of Correction, page 11 (claim 104)).
`
`c. Wei
`
`Wei discloses “a process or apparatus for transforming a first
`
`polymorph of a chemical material into a second polymorph of the same
`
`chemical material.” Ex. 1008, Abstract. Wei discloses that .“[i]t is well
`
`known'in the pharmaceutical industry that the bioavailability of a sparingly
`
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`soluble organic compound is often enhanced when the compound is very
`
`pure and the molecules of the compound have a small, uniform particle size,
`
`high surface area, and short dissolution time.” Id. Tl 3. Thus, one object of
`
`the process of Wei is to “provide crystalline particles of high surface area,
`
`high chemical purity, and high stability, without the need for post-
`
`crystallization milling.” Id. fl 5.
`
`Wei discloses that “the present invention can be especially effective
`for transforming a first polymorph which consists of large crystals into a
`
`second polymorph which consists of small crystals.” Id. fl 20. Large and
`
`small crystals are described as follows:
`
`Generally, large crystals have a particle size D[90] greater than
`about 100 um, and small crystals have a particle size D[90] less
`than about 30 um. In addition, large crystals can have a particle
`size D[90] greater than about 60 um, and small crystals can have
`a particle size D[90] less than about 50 um.
`
`Id.
`
`Example 1 of Wei discloses the preparation of small crystals of
`
`apixaban (1-(4—methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidine-1-yl)phenyl)-
`
`4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide). Id. fil41. In
`Example 1, Wei produces “small, granular crystals which have a particle
`
`size D[9o] less than about 20 um.” Id. 11 42.
`
`d. FDA Dissolution Guidance
`
`The FDA Dissolution Guidance was prepared by the Immediate
`
`Release Expert Working Group of the Biopharmaceutics Coordinating
`
`Committee in the Center for Drug Evaluation and Research (CDER) at the
`
`Food and Drug Administration and is an industry guidance document
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`developed for immediate release (IR) dosage forms and is
`intended to provide (1) general recommendations for dissolution
`testing;
`(2) approaches for setting dissolution specifications
`related to the biopharmaceutic characteristics of the drug
`substance; (3) statistical methods for comparing dissolution
`profiles; and (4) a process to help determine when dissolution
`testing is
`sufficient
`to grant a waiver
`for
`an in vivo
`bioequivalence study.
`
`Ex. 1015, 1.
`
`FDA Dissolution Guidance discloses the Biopharmaceutics
`
`Classification System, which classifies drugs into 4 categories based on drug
`
`solubility and permeability, as follows:
`
`Case 1:
`
`High Solubility - High Permeability Drugs
`
`Case 2:
`
`Low Solubility - High Permeability Drugs
`
`Case 3:
`
`High Solubility - Low Permeability Drugs
`
`Case 4:
`
`Low Solubility - Low Permeability Drugs
`
`‘
`
`Id. at 2—3.
`
`FDA Dissolution Guidance discloses that a drug substance is
`
`considered to be highly soluble under the BCS when the dose/solubility
`
`volume of solution are less than or equal to 250 mL. Id. A drug substance is
`
`considered to be highly permeable with an extent of absorption that is
`
`greater than 90% in the absence of documented instability in the GI tract or
`
`those whose permeability have been determined experimentally. Id.
`
`FDA Dissolution Guidance provides the following guidance with
`
`regard to Case 2 and Case 3 drugs:
`
`In the case of low solubility/high permeability drugs (case 2),
`drug dissolution may be the rate limiting step for drug absorption
`and an IVIVC may be expected. A dissolution profile in multiple
`
`l4
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`Patent 9,326,945 B2
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`media is recommended for drug products in this category. In the
`case of high solubility/low permeability drugs
`(case 3),
`permeability is the rate controlling step and a limited IVIVC may
`be possible, depending on the relative rates of dissolution and
`intestinal transit.
`
`Id. at 3. FDA Dissolution Guidance further provides that “for high
`
`solubility, high permeability (case 1) drugs and in some instances for high
`
`solubility, low permeability (case 3) drugs, 85% dissolution in 0.1N HCl in
`
`15 minutes can ensure that the bioavailability of the drug is not limited by
`
`dissolution.” Id.
`
`2. Petitioner ’s Ground 1: Obviousness over the Combination of
`
`Carreiro, Wei, and FDA Dissolution Guidance
`
`Petitioner asserts that claims 1—38 are unpatentable under § 103 as
`
`obvious over the combination of Carreiro, Wei, and FDA Dissolution
`
`Guidance. Pet. 33—40. In support of its assertion that the combination of
`
`Carreiro, Wei, and FDA Dissolution Guidance renders claims 1—38 obvious,
`
`Petitioner sets forth the foregoing teachings of Carreiro, Wei, and FDA
`
`Dissolution Guidance and provides a detailed discussion explaining how
`
`each claim limitation is disclosed in the combination of references. Id.
`
`For the elements of independent claim 1, Petitioner contends that
`
`Carreiro discloses the development of 'oral dosage forms of apixaban for
`
`treatment and prophylaxis of thromboembolic disorders, and therefore, a
`
`person of ordinary skill in the art would have been motivated .to optimize
`known oral apixaban dosages based on clinical results. Pet. 34—35 (citing
`
`Ex. 1002 W 160—62); see also Ex. 1004, 1940 (apixaban shows a
`
`“pharmacokinetic profile .
`
`.
`
`. consistent with rapid oral absorption and
`
`15
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`Patent 9,326,945 B2
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`bioavailability”). Also, on this issue, Dr. Park states that optimal dissolution
`
`is important for drugs like apixaban because “the drug is being developed
`
`for treating thromboembolic disorders and events, which often require
`
`immediate action of the drug to help treat or prevent clotting in an
`
`emergency situation.” Ex. 1002 W 161—62.
`
`Emphasizing apixaban’s solubility profile, Petitioner contends that a
`person of ordinary skill in the art would have understood that the drug’s poor
`
`solubility “could pose a challenge to developing a bioavailable oral
`
`pharmaceutical dosage formulation, and would thus be motivated to improve
`
`the dissolution rate of apixaban.” Pet. 36. Petitioner contends also that
`
`a POSA, in view of the potential clinical usefulness of an oral
`dosage form of apixaban as disclosed by Carreiro, and the
`solubility and dissolution issues associated with apixaban as
`disclosed by Wei, would have been motivated to optimize the
`solubility and dissolution of apixaban by reducing the crystalline
`apixaban’s particle size as taught by Wei to provide a quick-
`acting immediate release formulation of apixaban with increased
`solubility,
`and
`consequently,
`better
`dissolution
`and
`bioavailability.
`
`Id. (emphasis added). Such a desire to improve the dissolution rate of
`
`apixaban would have lead a person of ordinary skill in the art “to apply the
`
`Wei process to the oral dosage forms being clinically tested as disclosed by
`
`Carreiro to optimize a smaller particle size, such as the crystalline apixaban,
`
`form N-l disclosed in the examples of Wei.” Id. at 40—41 (citing Ex. 1008
`
`111] 6—8, 20, 41—46; Ex. 1002 1] 173). Petitioner further contends that, “in an
`
`effort to improve dissolution and solubility, and consequently, the
`
`bioavailability of apixaban .
`
`.
`
`. a POSA would seek to apply the Wei process
`
`16
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`IPR2018-00892
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`Patent 9,326,945 B2
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`to the oral dosage forms being clinically tested as disclosed by Carreiro.” Id.
`
`at 40.
`
`To support its argument that apixaban was known to be poorly
`
`soluble, Petitioner relies on Wei and contends that Wei discloses apixaban as
`
`an example of a “sparingly soluble” molecule and that the bioavailability of
`
`a “sparingly soluble organic compound is often enhanced when the
`
`compound is very pure and the molecules of the compound have a small,
`
`uniform particle size, high surface area, and short dissolution time.” Id. at
`
`26 (emphasis added) (citing Ex. 1008 1111 3, 41—46). See also id. at 36 (citing
`
`Ex. 1002 1111 26, 135, 163—164, 173, 176); Ex. 1008 ‘H 20 (defining “small
`
`crystals” as having a D90 of less than 30 pm). Petitioner further contends
`
`that Carreiro’s disclosure that apixaban has no ionizable groups and
`
`therefore does not exhibit pH—dependent aqueous solubility would inform a
`
`person of ordinary skill in the art that “the drug may have poor solubility.”
`
`Pet. 35—36 (citing Ex. 1004, 1940; Ex. 1002, W 120, 163, 173; Ex. 1011,
`
`252).
`
`Thus, Petitioner contends that a person of ordinary skill in the art
`
`would have sought to optimize or improve the dissolution rate of apixaban
`
`due to the drug’s solubility profile. Id. at 35—36. In this regard, Petitioner
`
`further contends tha , “[t]o test the optimization of the dissolution and
`
`solubility of the apixaban formulation, a POSA would have consulted the
`
`published FDA guidance, includingthe FDA Dissolution Guidance, which
`
`teaches the use of routine dissolution testing.” Id. at 55; Ex. 1015, A-l.
`
`Furthermore, in its discussion of the reasonable expectation of
`
`success, Petitioner contends as follows:
`
`17
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`Patent 9,326,945 B2
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`The general state of the art during the time frame leading
`up to the priority date of the ’945 patent made clear to a POSA
`that two of the most common ways for improving solubility of a
`drug were: (1) to decrease the particle size of the drug; and (2)
`add a surfactant. Therefore, the prior art provided a POSA
`seeking to develop an immediate release apixaban formulation
`with a reasonable expectation of success that a reduction in
`particle size, along with the addition of a surfactant, would result
`in increased dissolution and solubility, and consequently,
`bioavailability. (See Exs. 1009 and 1010; Ex. 1002, 1111 166—170,
`226, 264.)
`
`Finally, a POSA seeking FDA approval for an immediate
`release formulation would look to known industry standard
`dissolution methods,
`including the FDA Guidance
`for
`recommendations on the routine equipment and methods for
`dissolution testing and follow those recommendations.
`(See
`generally Ex. 1015; Ex. 1002, 111] 154, 161, 170.) As discussed
`below, the FDA Guidance teaches to a POSA each of the claim
`limitations for dissolution testing. (Id)
`
`Pet. 37—39.
`
`Petitioner contends that “FDA Dissolution Guidance recommends that
`
`for sparingly soluble drugs, such as apixaban, sodium lauryl sulfate should
`
`be used in the dissolution medium.” Id. at 43 (citing Ex. 1015, A-l).
`
`Petitioner contends that “a POSA would also understand that the 77%
`
`wt dissolution after 30 minutes to be the inherent result of the claimed
`
`‘crystalline apixaban particles’ from a well-known and routine dissolution
`
`test.” Id. (citing Ex. 1002 1111 178—180 (“[T]he percent of apixaban dissolved
`
`in the dissolution medium chosen after a certain period of time is an inherent
`
`characteristic of the drug itself.”)). Thus, to meet the 77% wt dissolution
`
`after 30 minutes element of claim 1, Petitioner contends that “nothing more
`
`18
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`IPR2018-00892
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`Patent 9,326,945 B2
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`is required to achieve this dissolution profile than having apixaban with
`
`particle sizes as recited in the claims.” Id.
`
`Independent claim 12 contains the same limitations as claim 1, but
`
`recites alternative dissolution test parameters, as follows: “wherein, as
`measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in
`
`900 mL, of a dissolution medium at 37° C., at least 77 wt % of apixaban in
`
`the pharmaceutical composition dissolves within 30 minutes in the
`
`dissolution medium, and the dissolution medium is 0.05 M sodium
`
`phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.” Ex. 1001,
`
`10:21—27. For this claim element, Petitioner contends as follows:
`
`[A] POSA would have been motivated to look to the FDA’s
`guidance on routine dissolution testing provided in the FDA
`Dissolution Guidance.
`(Ex. 1015.) The FDA Dissolution
`Guidance teaches that the most commonly employed dissolution
`test methods are (1) the basket method (Apparatus 1); and (2) the
`paddle method (Apparatus 2), which should be used unless
`shown to be unsatisfactory.
`(Id., A-l.) As the paddle method
`recommended by the FDA Dissolution Guidance is the same as
`that in claim 12, a POSA would consider claim 12 to be obvious
`for the same reasons as claim 1.
`
`Pet. 45.
`
`3. Petitioner’s Ground 2: Obviousness over the Combination of
`Carreiro, Wei, Rudnic, and FDA Dissolution Guidance
`
`For substantially similar reasons, Petitioner contends that claims 1—38
`
`are unpatentable under § 103 as obvious in View of the combination of
`
`Carreiro, Wei, Rudnic, and FDA Dissolution Guidance. Pet. 49—54. For
`
`this ground, Petitioner adds Rudnic because the reference allegedly provides
`
`“additional motivation to a POSA to utilize the common lubricant and
`
`19
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`surfactant sodium lauryl sulfate in the claimed formulation at the claimed
`
`concentrations,” which is allegedly relevant to challenged claims 7, 8, 18,
`
`and 19. Id. at 49—50. In particular, Petitioner contends that
`
`Rudnic discloses the design and formulation of compressed
`tablets for oral dosage, and teaches use of the well-known
`surfactant sodium lauryl sulfate as a lubricant and a wetting agent
`to improve solubility.
`(Ex. 1010, 354-355, 30; Ex. 1002, 11169.)
`Accordingly, a POSA would have a reasonable expectation of
`success that the combination of prior art references discussed
`herein would result in a crystalline apixaban formulation with an
`increased solubility and dissolution properties as claimed in the
`’945 patent.
`(Ex. 1002,1[11166-171.)
`
`Id. at 38.
`
`4. Petitioner ’s Ground 3: Obviousness over the Combination of
`
`Pinto, Wei, and FDA Dissolution Guidance
`
`Ground 3 is substantially similar to Ground 1. For this ground,
`
`Petitioner substitutes Pinto for Carreiro for, inter alia, its disclosure of oral
`
`dosage forms of Factor Xa inhibitors, including apixaban. Pet. 52—54. In
`
`particular, Petitioner contends as follows:
`
`Claim 13 of [Pinto] recites apixaban by its known chemical
`name. (Ex. 1007, 269: 1-6.) Claim 27 depends from claim 13 and
`claims
`a
`pharmaceutical
`composition
`comprising
`a
`therapeutically
`effective
`amount
`of
`apixaban
`and
`a
`pharmaceutically acceptable carrier. (Id, 270:5-9.)
`[Pinto]
`further discloses that the compounds disclosed therein, including
`apixaban, could be administered in oral dosage forms such as
`tablets and capsules.
`(Id, 154165-1553.) Claim 104 also
`depends from claim 13 adding the limitation that the “compound
`according to claim 13 is a crystalline compound.” (Id, 276:31.)
`
`20
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`IPR2018-00892
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`Thus, [Pinto] clearly contemplated formulating crystalline
`apixaban, disclosing both tablet and capsule formulations that
`included apixaban and an inert carrier.
`
`Pet. 53—54.
`
`As in Ground 1, Petitioner relies on Wei for its disclosure that
`
`“apixaban is a sparingly soluble molecule, and that the bioavailability of
`
`such a compound can be increased by decreasing the particle size, resulting
`
`in very pure molecules of the compound with a small, uniform particle size,
`
`high surface area, and short dissolution time.” Id. at 52—53 (citing Ex. 1008
`
`1111 3, 41—46). Pet
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