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` Paper No. 24
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` Entered: October 15, 2018
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`
`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 U.S.C. § 314
`
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`IPR2018-00892
`Patent 9,326,945 B2
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`I.
`
`INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Petitioner”), filed a Petition requesting
`an inter partes review of claims 1–38 of U.S. 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 μm, and a
`pharmaceutically acceptable carrier.” Ex. 1001, Abstract. The compositions
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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 (40 μg/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:
`Surprisingly and unexpectedly, it has been found that
`compositions for tablets comprising up to 5 mg, apixaban
`particles having a D90 (90% of the volume) less than 89 microns
`(μm) 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 1:64–2:3.
`The ’945 patent discloses the need for the use of a surfactant in the
`composition as follows:
`the pharmaceutical
`The
`invention further provides
`composition further comprising a surfactant from 0.25% to 2%
`by weight, preferably from 1% to 2% by weight. As regards the
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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.
` The ’945 patent further discloses how to perform certain dissolution
`rate tests. Id. at 3:1–19; 6:24–41.
`
`
`
`C. Illustrative Claims
`Independent claims 1 and 12, reproduced below, are illustrative:
`1. A
`solid pharmaceutical composition comprising a
`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 μm, 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.
`
`12. A solid pharmaceutical composition comprising a
`therapeutically
`effective
`amount of
`apixaban
`and
`a
`pharmaceutically acceptable diluent or carrier,
`wherein apixaban comprises crystalline apixaban
`particles,
`wherein the crystalline apixaban particles have a D90 equal
`to or less than about 89 μm, 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
`phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.
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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, U.S. Patent No. 6,967,208 B2 to Pinto et al., issued Nov. 22, 2005
`(“Pinto”).
`Ex. 1008, U.S. 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 C.T. 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,” U.S. 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):
`
`Ground Claims
`
`1
`
`2
`
`1–38
`
`1–38
`
`References
`Basis
`§ 103(a) Carreiro, Wei, and
`FDA Dissolution Guidance
`§ 103(a) Carreiro, Wei, Rudnic, and
`FDA Dissolution Guidance
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`Ground Claims
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`3
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`4
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`1–38
`
`1–38
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`References
`Basis
`§ 103(a) Pinto, Wei, and
`FDA Dissolution Guidance
`§ 103(a) Pinto, Wei, Rudnic, and
`FDA Dissolution Guidance
`
`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,
`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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`B. Discretion Whether to Institute Under 35 U.S.C. § 325(d)
`Section 325(d) provides: “[i]n 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’s 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.
`at 16, 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
`
`
`1 Ex. 2011, Nause, Richard G., U.S. Patent Application Publication No.
`2012/0087978 A1, published Apr. 12, 2012 (“Nause”).
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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 of Relevant 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 III 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 438 (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 μm,
`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 III drug, but provides insufficient evidence to support this position.
`Prelim. Resp. 7, 9.
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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 ¶ 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.
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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 of Asserted 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 ¶¶ 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 154:65–155:3. 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 270:5–9 (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. ¶ 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. ¶ 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. ¶ 20. Large and
`small crystals are described as follows:
`Generally, large crystals have a particle size D[90] greater than
`about 100 μm, and small crystals have a particle size D[90] less
`than about 30 μm. In addition, large crystals can have a particle
`size D[90] greater than about 60 μm, and small crystals can have
`a particle size D[90] less than about 50 μm.
`
`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. ¶ 41. In
`Example 1, Wei produces “small, granular crystals which have a particle
`size D[90] less than about 20 μm.” Id. ¶ 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
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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 ¶¶ 160–62); see also Ex. 1004, 1940 (apixaban shows a
`“pharmacokinetic profile . . . consistent with rapid oral absorption and
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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 ¶¶ 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-1 disclosed in the examples of Wei.” Id. at 40–41 (citing Ex. 1008
`¶¶ 6–8, 20, 41–46; Ex. 1002 ¶ 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
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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 ¶¶ 3, 41–46). See also id. at 36 (citing
`Ex. 1002 ¶¶ 26, 135, 163–164, 173, 176); Ex. 1008 ¶ 20 (defining “small
`crystals” as having a D90 of less than 30 μm). 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, ¶¶ 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 that, “[t]o test the optimization of the dissolution and
`solubility of the apixaban formulation, a POSA would have consulted the
`published FDA guidance, including the FDA Dissolution Guidance, which
`teaches the use of routine dissolution testing.” Id. at 55; Ex. 1015, A-1.
`Furthermore, in its discussion of the reasonable expectation of
`success, Petitioner contends as follows:
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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, ¶¶ 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, ¶¶ 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-1).
`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 ¶¶ 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
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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-1.) 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
`
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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, ¶169.)
`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, ¶¶166-171.)
`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 capsu