`
`Paper No. _____
`Filed: April 5, 2018
`
`Filed on behalf of: Mylan Pharmaceuticals Inc.
`
`By: Robert L. Florence (robertflorence@parkerpoe.com)
`Karen L. Carroll (karencarroll@parkerpoe.com)
`Micheal L. Binns (michealbinns@parkerpoe.com)
`Sharad K. Bijanki (sharadbijanki@parkerpoe.com)
`Parker Poe Adams & Bernstein LLP
`
`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.
`
`
`IPR2018-00892
`U.S. Patent No. 9,326,945 to Patel et al.
`Issue Date: May 3, 2016
`Title: Apixaban Formulations
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,326,945
`
` 
`
`

`

` 
`
`TABLE OF CONTENTS
`
`INTRODUCTION ......................................................................................... 1 
`I. 
`II.  MANDATORY NOTICES ........................................................................... 1 
`REAL PARTIES-IN-INTEREST UNDER 37 C.F.R. § 42.8(B)(1) ................. 1 
`A. 
`RELATED MATTERS UNDER 37 C.F.R. § 42.8(B)(2) .............................. 1 
`B. 
`LEAD AND BACK-UP COUNSEL UNDER 37 C.F.R. § 42.8(B)(3) ............. 3 
`C. 
`SERVICE INFORMATION UNDER 37 C.F.R. § 42.8(B)(4) ......................... 4 
`D. 
`III.  GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(A) ................ 4 
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF
`IV. 
`THE PRECISE RELIEF REQUESTED (37 C.F.R. § 42.22(A) AND
`37 C.F.R. § 42.104(B)) ................................................................................... 4 
`THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ...... 5 
`V. 
`VI.  STATEMENT OF REASONS FOR THE RELIEF REQUESTED ......... 5 
`A. 
`SUMMARY OF THE ARGUMENT .............................................................. 5 
`LEVEL OF ORDINARY SKILL IN THE ART ............................................... 8 
`B. 
`THE ’945 PATENT AND ITS PROSECUTION HISTORY .............................. 8 
`C. 
`1. 
`The ’945 Patent ......................................................................... 8 
`2. 
`The Disclosure of the ’945 Patent ........................................... 11 
`3. 
`The Prosecution History of the ’945 Patent ............................. 13 
`a. 
`Office Action (February 28, 2014) ................................ 13 
`b. 
`August 13, 2015 Office Action ..................................... 14 
`c. 
`Interview/Response ....................................................... 15 
`d. 
`Notice of Allowance/Notice of Allowability ................. 16 
`CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) ................... 16 
`THE PRIOR ART CITED IN THIS PETITION IS NOT REDUNDANT TO
`PRIOR ART CONSIDERED DURING PROSECUTION ................................ 17 
`SCOPE AND CONTENT OF THE PRIOR ART ............................................ 17 
`The Use of Anti-Coagulant Agents to Treat
`1. 
`Thromboembolic Disease ........................................................ 17 
`Apixaban Was a Well-Known Anticoagulant.......................... 18 
`a. 
`The ’208 Patent ............................................................. 19 
`Apixaban Was Known to Have Poor Solubility ...................... 20 
`a. 
`Carreiro ......................................................................... 23 
`b. 
`Pinto .............................................................................. 24 
`c. 
`Nause ............................................................................. 25 
`
`D. 
`E. 
`
`F. 
`
`2. 
`
`3. 
`
`i
`
`

`

` 
`
`4. 
`
`d.  Wei ................................................................................ 26 
`Routine Techniques for Optimizing the Solubility of a
`Compound Were Well-Known and Included Reducing
`Particle Size and Adding a Surfactant ..................................... 27 
`a. 
`Ashford .......................................................................... 27 
`b. 
`Rudnic ........................................................................... 28 
`c. 
`Stegemann ..................................................................... 29 
`d. 
`The ’506 Patent ............................................................. 30 
`e. 
`FDA Dissolution Guidance ........................................... 31 
`G.  GROUND 1: CARREIRO IN VIEW OF WEI AND THE FDA
`DISSOLUTION GUIDANCE RENDER CLAIMS 1-38 OF THE ’945
`PATENT OBVIOUS UNDER 35 U.S.C. § 103(A) ..................................... 33 
`1.  Motivation to Combine ............................................................ 34 
`2. 
`Reasonable Expectation of Success ......................................... 37 
`3. 
`Carreiro combined with Wei and the FDA Dissolution
`Guidance Rendered Claim 1 Obvious ..................................... 39 
`Limitation 1(a): “A solid pharmaceutical
`a. 
`composition comprising a therapeutically effective
`amount of crystalline apixaban particles.” .................... 39 
`Limitation 1(b): “a pharmaceutically acceptable
`diluent or carrier” .......................................................... 41 
`Limitation 1(c): “wherein the crystalline apixaban
`particles have a D90 equal to or less than about 89
`µm,” .............................................................................. 42 
`Limitation 1(d): “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.” ......................................................................... 42 
`Independent Claim 12: “A solid pharmaceutical
`composition comprising … [d] 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.” ................................ 44 
`Claims 2 and 13: “The composition as defined in claim[s 1
`or 12], wherein said composition comprises Form N-1 of
`apixaban.” ................................................................................ 45 
`
`b. 
`
`c. 
`
`d. 
`
`4. 
`
`5. 
`
`ii
`
`

`

` 
`
`7. 
`
`8. 
`
`9. 
`
`6. 
`
`Claims 3 and 14: “The composition as defined in claim[s 1
`or 12], wherein the D90 is equal to or less than 85 µm.” .......... 45 
`Claims 4 and 15: “The composition as defined in claim[1 or
`12], wherein the D90 is equal to or less than 50 µm.” .............. 45 
`Claims 5 and 16: “The composition as defined in claim[s 1
`or 12], wherein the D90 is equal to or less than 30 µm.” .......... 45 
`Claims 6 and 17: “The composition as defined in claim[s 1
`or 12], wherein the D90 is equal to or less than 25 µm.” .......... 46 
`10.  Claims 7 and 18: “The composition as defined in claim[s 1
`or 12], further comprising: from 1% to 2% by weight of a
`surfactant.” .............................................................................. 46 
`11.  Claims 8 and 19: “The composition as defined in claim[s 7
`and 18], wherein the surfactant is sodium lauryl sulfate.” ....... 47 
`12.  Claims 9-11 and 20-22: “The composition as defined in
`claim[s 1 or 12], wherein the pharmaceutical composition
`comprises [between 2.5 and 5 mg] of apixaban.” .................... 48 
`13.  Claims 23, 25, 27, 29, 31, 33, 35 and 37: “The composition
`as defined in claim[s 1, 9-12, and 20-22], which is a tablet.” .. 48 
`14.  Claims 24, 26, 28, 30, 32, 34, 36 and 38: “The composition
`as defined in claim[s 1, 9-12, 20-22], which is a capsule.”...... 49 
`H.  GROUND 2: CARREIRO AND WEI, IN VIEW OF RUDNIC AND FDA
`DISSOLUTION GUIDANCE RENDER CLAIMS 1-38 OF THE ’945 PATENT
`OBVIOUS UNDER 35 U.S.C. § 103(A.) .................................................. 49 
`1.  Motivation to Combine References and Reasonable
`Expectation of Success ............................................................ 49 
`a. 
`Claims 1, 3-6, 12 and 13-17 .......................................... 50 
`b. 
`Claims 7-8 and 18-19 .................................................... 50 
`c. 
`Claims 9-11, 20-38 ........................................................ 51 
`GROUND 3: THE ’208 PATENT AND WEI, IN VIEW OF THE FDA
`DISSOLUTION GUIDANCE RENDER CLAIMS 1-38 OF THE ’945 PATENT
`OBVIOUS UNDER 35 U.S.C. § 103(A.) .................................................. 51 
`1.  Motivation to Combine References and Reasonable
`Expectation of Success ............................................................ 52 
`Claim 1 .................................................................................... 53 
`a. 
`Limitations 1(a)-(b) ....................................................... 53 
`b. 
`Limitation 1(c) .............................................................. 54 
`c. 
`Limitation 1(d) .............................................................. 55 
`Claim 12 .................................................................................. 56 
`
`I. 
`
`2. 
`
`3. 
`
`iii
`
`

`

` 
`
`J. 
`
`Claims 2 and 13 ....................................................................... 56 
`4. 
`Claims 3-6 and 14-17 .............................................................. 57 
`5. 
`Claims 7-8 and 18-19 .............................................................. 57 
`6. 
`Claims 9-11 and 20-22 ............................................................ 58 
`7. 
`Claims 23-38 ........................................................................... 58 
`8. 
`GROUND 4: THE ’208 PATENT AND WEI, IN VIEW OF RUDNIC AND
`THE FDA DISSOLUTION GUIDANCE RENDER CLAIMS 1-38 OF THE
`’945 PATENT OBVIOUS UNDER 35 U.S.C. § 103(A.) ............................. 59 
`1.  Motivation to Combine References and Reasonable
`Expectation of Success ............................................................ 59 
`a. 
`Claims 1, 3-6, 12, and 13-17 ......................................... 59 
`b. 
`Claims 7-8 and 18-19 .................................................... 60 
`c. 
`Claims 9-11 and 20-38 .................................................. 61 
`K.  NO SECONDARY CONSIDERATIONS SUPPORT NONOBVIOUSNESS ......... 61 
`1. 
`There Are No Unexpected Results .......................................... 62 
`2. 
`The ’945 Patent Did Not Satisfy Any Long-Felt But Unmet
`Need ........................................................................................ 64 
`There Was No Industry Skepticism ......................................... 65 
`3. 
`There is No Evidence of Commercial Success ........................ 65 
`4. 
`Copying by Generic Drug Makers is Irrelevant ....................... 67 
`5. 
`VII.  CONCLUSION ............................................................................................ 67 
`
`
`
`iv
`
`

`

` 
`
`TABLE OF AUTHORITIES
`
`
`Cases
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.
` 713 F.3d 1369 (Fed. Cir. 2013.) ......................................................................... 67
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.
` 246 F.3d 1368 (Fed. Cir. 2001.) ......................................................................... 43
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.
` 752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 64
`Eli Lilly & Co. v. Barr Labs., Inc.
` 251 F.3d 955 (Fed. Cir. 2001.) ........................................................................... 44
`Galderma Labs., L.P. v. Tolmar
` 737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 66
`In re Huang
` 100 F.3d 135 (Fed Cir. 1996.) ............................................................................ 66
`Merck & Co., Inc. v. Teva Pharm. USA, Inc.
` 395 F.3d 1364 (Fed Cir 2005.) ........................................................................... 66
`Ormco Corp. v. Align Tech., Inc.
` 563 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 66
`Pfizer, Inc. v. Apotex, Inc.
` 480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 62
`
`
`P.T.A.B. Cases
` Ex Parte Smith, No. 2009-014595 (B.P.A.I. Aug. 17, 2010) ................................. 13
`Unified Patents Inc. v. Berman,
` IPR2016-01571, Paper 10 (PTAB Dec. 14, 2016) ............................................. 17
`
`
`Statutes
`35 U.S.C. § 102(a ..................................................................................................... 25
`35 U.S.C. § 102(b) ................................................................................................... 26
`35 U.S.C. § 102(b.) .................................................................................................. 59
`35 U.S.C. § 103(a.) .................................................................................................. 59
`35 U.S.C. § 314(a.) .................................................................................................... 5
`35 U.S.C. §§ 311-319 ................................................................................................ 1
`
`Regulations
`37 C.F.R. § 42.104(A)................................................................................................ 4
`37 C.F.R. § 42.8 ......................................................................................................... 3
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 4
`
`v
`
`

`

` 
`
`37 C.F.R. Part 42 ....................................................................................................1, 4
`
`37 CPR. Part 42 .................................................................................................... 1, 437 C.F.R. Part 42 .................................................................................................... 1, 4
`
`
`vi
`
`
`
`ViVi
`
`

`

` 
`
`I.
`
`INTRODUCTION
`Mylan Pharmaceuticals Inc. (“Petitioner”) petitions for Inter Partes Review
`
`of claims 1-38 of U.S. Patent No. 9,326,945 (“the ’945 patent,” Ex. 1001), issued
`
`on May 3, 2016, and assigned to Bristol-Myers Squibb Company of Princeton,
`
`New Jersey and Pfizer Inc. of New York, New York (“Patent Owners”), under 35
`
`U.S.C. §§ 311-319 and 37 C.F.R. Part 42, and seeks determination that claims 1-38
`
`of the ’945 patent be canceled as unpatentable.
`
`This Petition is filed in accordance with 37 C.F.R. § 42.106(a). Filed
`
`herewith is a power of attorney and exhibit list per § 42.10(b) and § 42.63(e).
`
`Pursuant to 37 C.F.R. § 42.103, the fee set forth in § 42.15(a) accompanies this
`
`Petition.
`
`II. MANDATORY NOTICES
`A. Real Parties-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`The real parties-in-interest are Mylan Pharmaceuticals Inc., the Petitioner in
`
`this matter and a wholly owned subsidiary of Mylan Inc.; Mylan Inc., which is an
`
`indirectly wholly owned subsidiary of Mylan N.V.; and Mylan N.V.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`The following litigations related to the ’945 patent are pending: Bristol-
`
`Myers Squibb Co. et al. v. Aurobindo Pharma USA Inc., 1:17-cv-00374-LPS (D.
`
`Del.); Bristol-Myers Squibb Co. et al. v. Breckenridge Pharmaceutical, Inc., 1:17-
`
`cv-00375-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v. Hetero USA Inc., 1:17-
`
`1
`
`

`

` 
`
`cv-00376-LPS
`
`(D. Del.); Bristol-Myers Squibb Co. et al. v.
`
`InvaGen
`
`Pharmaceuticals, Inc., 1:17-cv-00377-LPS (D. Del.); Bristol-Myers Squibb Co. et
`
`al. v. Lupin Ltd., 1:17-cv-00378-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v.
`
`Mylan Pharmaceuticals Inc., 1:17-cv-00379-LPS (D. Del.); Bristol-Myers Squibb
`
`Co. et al. v. Sunshine Lake Pharma Co., Ltd. et al., 1:17-cv-00380-LPS (D. Del.);
`
`Bristol-Myers Squibb Co. et al. v. Torrent Pharmaceuticals Ltd., 1:17-cv-00381-
`
`LPS (D. Del.); Bristol-Myers Squibb Co. et al. v. Unichem Laboratories, Ltd.,
`
`1:17-cv-00382-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v. Accord
`
`Healthcare Inc., 1:17-cv-00398-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v.
`
`Apotex, Inc. et al., 1:17-cv-00399-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v.
`
`Bionpharma Inc., 1:17-cv-00400-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v.
`
`Dr. Reddy’s Laboratories, Ltd. et al., 1:17-cv-00401-LPS (D. Del.); Bristol-Myers
`
`Squibb Co. et al. v. Emcure Pharmaceuticals Ltd., 1:17-cv-00402-LPS (D. Del.);
`
`Bristol-Myers Squibb Co. et al. v. Impax Laboratories, Inc., 1:17-cv-00403-LPS
`
`(D. Del.); Bristol-Myers Squibb Co. et al. v. Indoco Remedies Ltd., 1:17-cv-00404-
`
`LPS (D. Del.); Bristol-Myers Squibb Co. et al. v. Macleods Pharmaceuticals Ltd.,
`
`1:17-cv-00405-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v. Micro Labs USA
`
`Inc. et al., 1:17-cv-00406-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v. Sandoz
`
`Inc., 1:17-cv-00407-LPS (D. Del); Bristol-Myers Squibb Co. et al. v. Sigmapharm
`
`Laboratories, LLC, 1:17-cv-00408-LPS (D. Del.); Bristol-Myers Squibb Co. et al.
`
`2
`
`

`

` 
`
`v. Sun Pharmaceutical Industries, Inc. et al., 1:17-cv-00409-LPS (D. Del.);
`
`Bristol-Myers Squibb Co. et al. v. Teva Pharmaceuticals USA, Inc., 1:17-cv-
`
`00410-LPS (D. Del); Bristol-Myers Squibb Co. et al. v. Zydus Pharmaceuticals
`
`(USA) Inc., 1:17-cv-00412-LPS (D. Del.); Bristol-Myers Squibb Co. et al. v.
`
`Prinston Pharmaceutical Inc., 1:17-cv-00426-LPS (D. Del); and Bristol-Myers
`
`Squibb Co. et al. v. Wockhardt Bio AG et al., 1:17-cv-00411-LPS (D. Del.), each
`
`consolidated (1:17-cv-00374-LPS (D. Del.) and Bristol-Myers Squibb Co. et al. v.
`
`Mylan Pharmaceuticals Inc., 1:17-cv-00055-IMK (N.D.W. Va.)
`
`C. Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`
`Lead Counsel
`Robert L. Florence (Reg. No. 54,933)
`Parker Poe Adams & Bernstein
`1180 Peachtree Street, N.E.
`Suite 3300
`Atlanta, GA 30309
`Telephone: (678) 690-5701
`Facsimile: (404) 869-6972
`robertflorence@parkerpoe.com
`Back-Up Counsel
`Sharad K. Bijanki (Reg. No. 73,400)
`Parker Poe Adams & Bernstein
`1180 Peachtree Street, N.E.
`Suite 3300
`Atlanta, GA 30309
`Telephone: (678) 690-5713
`Facsimile: (404) 869-6972
`sharadbijanki@parkerpoe.com
`
`Back-Up Counsel
`Karen L. Carroll (Reg. No. 50,748)
`Parker Poe Adams & Bernstein
`1180 Peachtree Street, N.E.
`Suite 3300
`Atlanta, GA 30309
`Telephone: (678) 690-5704
`Facsimile: (404) 869-6972
`karencarroll@parkerpoe.com
`Back-Up Counsel
`Micheal L. Binns (Reg. No. 65,836)
`Parker Poe Adams & Bernstein
`1180 Peachtree Street, N.E.
`Suite 3300
`Atlanta, GA 30309
`Telephone: (678) 690-5703
`Facsimile: (404) 869-6972
`michealbinns@parkerpoe.com
`
`3
`
`

`

` 
`
`Service Information Under 37 C.F.R. § 42.8(b)(4)
`
`D.
`Please direct all correspondence to lead counsel and back-up counsel at the
`
`contact information above. Petitioner consents to electronic service by e-mail at
`
`the following email addresses:
`
` robertflorence@parkerpoe.com
`
` karencarroll@parkerpoe.com
`
` michealbinns@parkerpoe.com
`
` sharadbijanki@parkerpoe.com
`
` crystalregan@parkerpoe.com
`
`III. GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a)
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’945 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’945 patent on the grounds identified.
`
`IV.
`
`IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE
`PRECISE RELIEF REQUESTED (37 C.F.R. § 42.22(a) AND 37 C.F.R.
`§ 42.104(b))
`Petitioner respectfully requests inter partes review and cancellation of
`
`claims 1-38 on grounds set forth below.
`
`Ground 1: Claims 1-38 are unpatentable as obvious under 35 U.S.C.
`§ 103(a) over Carreiro and Wei, in view of the FDA
`Dissolution Guidance.
`
`4
`
`

`

` 
`
`Ground 2: Claims 1-38 are unpatentable as obvious under 35 U.S.C.
`§ 103(a) over Carreiro and Wei, in view of Rudnic and the FDA
`Dissolution Guidance.
`
`Ground 3: Claims 1-38 are unpatentable as obvious under 35 U.S.C.
`§ 103(a) over the ’208 patent and Wei, in view of the FDA
`Dissolution Guidance.
`
`Ground 4: Claims 1-38 are unpatentable as obvious under 35 U.S.C.
`§ 103(a) over the ’208 patent and Wei, in view of Rudnic and
`the FDA Dissolution Guidance.
`
`V. THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW
`A petition for inter partes review must demonstrate “a reasonable likelihood
`
`that the petitioner would prevail with respect to at least 1 of the claims challenged
`
`in the petition.” 35 U.S.C. § 314(a.) This Petition clears that threshold. There is a
`
`reasonable likelihood that Petitioner will prevail with respect to at least one of the
`
`challenged claims.
`
`VI. STATEMENT OF REASONS FOR THE RELIEF REQUESTED
`A.
`Summary of the Argument
`By the priority date, apixaban was a well-known Factor Xa inhibitor.
`
`Compounds that inhibited Factor Xa were desirable as anticoagulants, particularly
`
`for treating thromboembolic diseases. The ’945 patent itself acknowledges
`
`apixaban’s utility as a Factor Xa inhibitor-type anticoagulant. (Ex. 1001, 1: 40-
`
`45).
`
`5
`
`

`

` 
`
`By the priority date, the prior art had (1) established apixaban’s
`
`demonstrated efficacy, (2) recognized apixaban as a promising candidate to expand
`
`the armamentarium of available anticoagulants; (3) classified apixaban as
`
`“practically insoluble” under established United States Pharmacopeia criteria; and
`
`(4) developed well-known
`
`techniques for
`
`improving solubility of poorly
`
`soluble/sparingly soluble drugs. By the priority date, human clinical trial data
`
`demonstrated apixaban’s efficacy in treating clotting disorders. (See, e.g., Ex.
`
`1004, 1937-1938.) However, sparingly soluble drugs, such as apixaban, are slow
`
`to absorb in the body, have lower bioavailability (possibly necessitating
`
`administering higher doses to achieve a desired plasma concentration), and are
`
`slower to achieve the desired therapeutic benefit. Because of the nature of the
`
`diseases they treat, anticoagulants require fast action, and skilled artisans would be
`
`motivated to increase apixaban’s solubility to maximize and optimize its benefits
`
`as a therapeutic drug.
`
`Fortunately, the prior art taught skilled artisans myriad techniques to
`
`increase a compound’s solubility. Leading texts taught that when solubility or
`
`dissolution of a drug substance is identified as a problem, “[p]article size reduction
`
`is one of the first strategies investigated.” (Ex. 1011, 255.) Reduced particle size
`
`increases “the effective surface area exhibited by a given mass of drug and the
`
`higher the dissolution rate.” (Ex. 1009, 288.) This is because as the surface area of
`
`6
`
`

`

` 
`
`the drug increases, there is a corresponding increase in the amount of contact with
`
`the solvent, resulting in increased solubility. The skilled artisan would have had no
`
`reason to doubt that small particle size could successfully be achieved with
`
`apixaban at least because the prior art already disclosed apixaban falling within the
`
`particle size limitations claimed in the ’945 patent.
`
`The ’945 patent claims solid pharmaceutical compositions of 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,1 and a
`
`specific dissolution profile. The ’945 patent is the classic follow-on patent
`
`claiming conventional modifications to a previously patented invention to extend a
`
`drug’s monopoly. But the prior art disclosed apixaban—including its poor
`
`solubility profile—thus the art already recognized a need to increase the solubility
`
`of apixaban to achieve fast-acting efficacy in critically-ill patients (and skilled
`
`artisans already knew how to achieve that goal). Given these prior disclosures and
`
`teachings, the ’945 patent claims recite nothing more than the results of routine
`
`formulation parameters which skilled artisans would be motivated, if not
`
`                                                            
`1 D90 is a common unit to denote particle size. For example, a D90 less than or
`
`equal to 89 µm means that 90% of the particles have a diameter of less than 89 µm.
`
`(Ex. 1002. ¶58.)
`
`7
`
`

`

` 
`
`mandated, to achieve by the prior art and which they would have expected would
`
`work.
`
`For
`
`the reasons discussed herein,
`
`this Petition demonstrates by a
`
`preponderance of the evidence that there is a reasonable likelihood that at least one
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`of claims 1-38 of the ’945 patent are unpatentable for failing to distinguish over
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`prior art and should be canceled.
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`Level of Ordinary Skill in the Art
`
`B.
`A person of ordinary skill in the art (a “POSA”) in the relevant field as of
`
`the date of alleged invention of the ’945 patent, would be a Ph.D.-level (degree or
`
`experience) pharmaceutical scientist, with two or more years of experience or a
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`person with a Master’s degree with five or more years of experience, who iswell
`
`versed in the design and release of pharmaceutical dosage forms, drug delivery,
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`and has a working understanding of the factors relevant to achieving appropriate
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`bioavailability of an active pharmaceutical ingredient, particularly a substance
`
`known to have solubility issues. (Ex. 1002, ¶21.) However, in view of the clear
`
`teachings of the prior art, the claims of the ’945 patent are unpatenable under any
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`reasonable definition of the POSA.
`
`C. The ’945 Patent and Its Prosecution History
`1.
`The ’945 Patent
`The ’945 patent issued May 3, 2016, and claims priority back through a
`
`series of applications dating to February 25, 2010. (Ex. 1001.) However, as
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`detailed in Section VI.C.3, at least claims 1-2, 7-13, and 18-38 are not entitled to
`
`the priority date of the earlier provisional application. These claims are entitled to
`
`a priority date no earlier than February 24, 2011, which is the filing date of the
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`PCT application that gave rise to the ’796 application. The priority date for claims
`
`3-6 and 14-17 might be as early as February 25, 2010, the filing date of the U.S.
`
`Provisional Application. However, for purposes of this Petition, the Board need
`
`not address the priority date on a claim-by-claim basis because all prior art
`
`references relied on in Grounds 1-4 qualify as prior art under the earliest possible
`
`priority date.
`
`The ’945 patent discloses apixaban pharmaceutical formulations comprising
`
`crystalline apixaban particles having a maximum particle size threshold and a
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`corresponding dissolution profile, and methods of using the disclosed formulations,
`
`such as for the treatment or prophylaxis of thromboembolic disorders. (See, e.g.,
`
`Ex. 1001, 1:10-14.) The claims, however, are limited to specific compositions of
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`apixaban. Of the ’945 patent’s 38 claims, only claims 1 and 12 are independent.
`
`Independent claim 1 recites:
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`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
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`wherein at least 77 wt % of apixaban dissolves within 30 minutes in a
`pH 6.8 phosphate buffer containing 0.05% sodium lauryl sulfate.
`
`(Id., 9:50-57.)
`
`Dependent claims 2-11 and 22-28 depend directly or indirectly from claim 1.
`
`Claim 2 recites the crystalline form of apixaban as N-1. Claims 3-6 further limit
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`the D90 value of the apixaban particles to: 85 μm; 50 μm; 30 μm; and 25 μm
`
`respectively. Claim 7 adds the inclusion of 1% to 2% of a surfactant to the claimed
`
`composition and claim 8 limits the surfactant to sodium lauryl sulfate. Claims 9-
`
`11 limit the amount of apixaban in the claimed composition to: 2.5 mg to about 5
`
`mg; 2.5 mg; and 5 mg respectively. Claims 23, 25, 27 and 29 limit the claimed
`
`composition to a tablet, while claims 22, 24, 26 and 28 limit the claimed
`
`composition to a capsule.
`
`Independent claim 12 reads:
`
`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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`(Id., 10:13-26.)
`
`Thus, independent claim 12 contains the same limitations as claim 1, but
`
`recites further details of the dissolution testing parameters and apparatus.
`
`Dependent claims 13-22 and 31-38 depend directly or indirectly from claim
`
`12 and possess parallel content, as recited above, to those claims depending from
`
`claim 1. For example, claim 13 recites the crystalline form of apixaban as N-1,
`
`and claims 14-17 further limit the D90 value of the apixaban particles to: 85 μm; 50
`
`μm; 30 μm; and 25 μm respectively. Claim 18 adds the inclusion of 1% to 2% of a
`
`surfactant to the claimed composition and claim 19 limits the surfactant to sodium
`
`lauryl sulfate. Claims 21-22 limit the amount of apixaban in the claimed
`
`composition to: 2.5 mg to about 5 mg; 2.5 mg; and 5 mg respectively. Claims 31,
`
`33, 35 and 37 limit the claimed composition to a tablet, while claims 32, 34, 36 and
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`38 limit the claimed composition to a capsule.
`
`The Disclosure of the ’945 Patent
`
`2.
`The ’945 patent acknowledges that apixaban, its utility as a Factor Xa
`
`inhibitor, and its development for oral administration as an antithrombotic agent
`
`were well-known and disclosed in U.S. Patent No. 6,967,208 (“the ’208 patent”).
`
`(Id., 1:40-45.)
`
`The patent also explains that apixaban particles having a D90 of less than
`
`about 89 microns as claimed, “lead[s] to consistent in-vivo dissolution in humans
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`(at physiologic pH), hence, consistent exposure and consistent Factor Xa inhibition
`
`that will lead to consistency in therapeutic effect.” (Id., 1:64-2:3.) As further
`
`explained in the patent, “D90” is a metric employed in the pharmaceutical arts
`
`meaning that 90% of the volume of particles have a size less than the recited
`
`amount: here, about 89 μm. (Id., 2:15-17.) The ’945 patent discloses that
`
`“apixaban in any form which will crystallize can be used in this invention” (Id.,
`
`4:37-38) and specifically recites Form N-1 (neat) and Form H2-2 (hydrate) of
`
`apixaban as known (Id., 4:43-45).
`
`Without citation to any support, the patent states that apixaban has an
`
`aqueous solubility of 40 µg/mL. (Id., 1:46.) The patent also alleges that the
`
`consistent human in-vivo dissolution achieved by the claimed compositions is
`
`surprising because “one would expect dissolution rate for a drug that has high
`
`solubility (as defined by the Biopharmaceutical Classification System) would not
`
`be limited by the particle size.” (Id., 2:44-52.) The patent goes on to state that “[i]t
`
`has surprisingly been found, however, that the particle size that impacts apixaban
`
`absorption rate is about a D90 of 89 µm.” (Id., 2:52-54.) However, these
`
`statements, for all the reasons set forth in this Petition, are inconsistent with the
`
`teachings of the prior art regarding the effect of particle size on solubility in
`
`general, and more specifically, the prior art teachings regarding the solubility of
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`apixaban. Instead, what is claimed in the ’945 patent is exactly what a POSA
`
`would have known and expected, making all the claims obvious.
`
`The Prosecution History of the ’945 Patent
`
`3.
`Relevant portions of the prosecution history of the ’945 patent are discussed
`
`below.
`
`a. Office Action (February 28, 2014)
`Following a restriction requirement, the Examiner rejected the pending
`
`claims under 35 U.S.C. § 112, ¶ 1 for failing to find support in the earliest claimed
`
`priority application. (Ex. 1003, [Office Action (Feb. 28, 2014)], 3-4.) The
`
`Examiner asserted the provisional application to which the ’796 application
`
`claimed priority did not support or enable the limitation “D90 equal to or less than
`
`about 89 μm” as recited in then-pending claim 1 (and in the issued claims.) (Id.)
`
`Instead, the provisional application only recited formulations containing apixaban
`
`particles having a D90 of 85 μm or less. (See Ex. 1017.) By not challenging this
`
`rejection, the Applicants acquiesced to the Examiner’s position. (Id., [Amendment
`
`(Jun. 24, 2014)]); see Ex Parte Smith, No. 2009-014595 (B.P.A.I. Aug. 17, 2010)
`
`(applying administrative estoppel where applicant remained silent regarding
`
`Examiner’s priority