Filed on behalf of Patent Owners Bristol-Myers Squibb Company and Pfizer Inc.
`
`By: Heather M. Petruzzi, Reg. No. 71,270 (Lead Counsel)
`
`Timothy A. Cook, Reg. No. 74,073 (Back-up Counsel)
`
`Amy K. Wigmore (Pro Hac Vice)
`
`Kevin S. Prussia (Pro Hac Vice)
` WILMER CUTLER PICKERING HALE AND DORR LLP
`
`1875 Pennsylvania Avenue NW
` Washington, DC 20006
`
`Tel: (202) 663-6028
`
`Email: Heather.Petruzzi@wilmerhale.com
`
`
`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
`
`Patent No. 9,326,945
`
`
`PATENT OWNERS’ PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`
`
`By: Heather M. Petruzzi, Reg. No. 71,270 (Lead Counsel)
`
`Timothy A. Cook, Reg. No. 74,073 (Back-up Counsel)
`
`Amy K. Wigmore (Pro Hac Vice)
`
`Kevin S. Prussia (Pro Hac Vice)
` WILMER CUTLER PICKERING HALE AND DORR LLP
`
`1875 Pennsylvania Avenue NW
` Washington, DC 20006
`
`Tel: (202) 663-6028
`
`Email: Heather.Petruzzi@wilmerhale.com
`
`
`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
`
`Patent No. 9,326,945
`
`
`PATENT OWNERS’ PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I. Introduction ........................................................................................... 1
`
`II. Background ........................................................................................... 4
`
`A. Anticoagulants and the Development of Apixaban .............. 4
`
`B. The ’945 Patent ..................................................................... 6
`
`C. The Relevant Prosecution History ........................................ 7
`
`1. Rejections Over Nause and Wei .................................... 7
`
`2.
`
`Interview and Response ................................................. 9
`
`3. Notice of Allowance .................................................... 10
`
`D. Asserted Prior Art ............................................................... 10
`
`1. Wei (Ex. 1008) ............................................................ 10
`
`2. Carreiro (Ex. 1004) ...................................................... 11
`
`3. The ’208 Patent (Ex. 1007) ......................................... 12
`
`4. Rudnic (Ex. 1010) ....................................................... 13
`
`5. FDA Dissolution Guidance (Ex. 1015) ....................... 13
`
`III. The Level of Ordinary Skill in the Art and Claim Construction ........ 14
`
`IV.
`
`The Board Should Deny Institution Pursuant to § 325(d) ........... 15
`
`A. Legal Standard .................................................................... 17
`
`B. The Balance of Interests Favors Denial of Institution ........ 18
`
`1. The Examiner already considered and applied the
`same or substantially the same prior art ...................... 19
`
`– ii –
`
`
`
`2. The Petition fails to provide any reason why the
`Examiner was wrong ................................................... 25
`
`3. No additional evidence in the Petition or Park
`Declaration warrants reconsideration .......................... 28
`
`4. Patent Owners’ interest in repose outweighs
`Petitioner’s competing interest .................................... 30
`
`V. The Petition Fails to Establish a Motivation to Combine the
`References ................................................................................... 32
`
`A. Legal Standard .................................................................... 33
`
`B. The Petition Relies on Two Generalized Conclusory
`Assumptions that Are Not Supported in the Record .......... 34
`
`1. The Petition assumes that low solubility equates
`to low bioavailability ................................................... 34
`
`2. The Petition assumes that increasing the
`dissolution rate of a compound improves
`bioavailability .............................................................. 38
`
`VI.
`
`The Petition Fails to Establish that Carreiro, FDA
`Dissolution Guidance, and Rudnic are Printed Publications ...... 40
`
`A. Rudnic ................................................................................. 42
`
`B. FDA Dissolution Guidance ................................................. 43
`
`C. Carreiro ............................................................................... 44
`
`VII. Petitioner Fails to Name All of the Real Parties in Interest ......... 45
`
`VIII. Conclusion .................................................................................... 50
`
`
`
`
`
`– iii –
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`10X Genomics, Inc. v. Bio-Rad Laboratories, Inc.,
`IPR2018-00301, 2018 WL 3019915 (June 15, 2018) ........................................ 38
`Align Technology, Inc. v. 3Shape A/S,
`IPR2018-00198, Paper 7 (May 30, 2018) ..................................................... 17, 26
`Amazon.com, Inc. v. Appistry, Inc.,
`IPR2015-00480, 2015 WL 4467407 (July 13, 2015) ......................................... 48
`Applications in Internet Time, LLC v. RPX Corp.,
`No. 2017-1698 (Fed. Cir. July 9, 2018) .............................................................. 47
`Atlanta Gas Light Co. v. Bennett Regulator Guards, Inc.,
`IPR2013-00453, Paper 88 (Jan. 6, 2015) ...................................................... 48, 49
`Becton, Dickinson, and Co. v. B. Braun Melsungen AG,
`IPR2017-01586, 2017 WL 6405100 (Dec. 15, 2017) .................................. 17, 18
`Bristol-Myers Squibb Co. v. Aurobindo Pharma USA Inc.,
`No. 17-cv-374-LPS, D.I. 182-1 (D. Del. May 18, 2018) ................................... 15
`Celltrion, Inc. v. Biogen, Inc.,
`IPR2016-01614, 2018 WL 1037223 (Feb. 21, 2018) ............................. 14, 43, 44
`Cultec, Inc. v. Stormtech LLC,
`IPR2017-00777, 2017 WL 3635100 (Aug. 22, 2017) .................................. 17, 20
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268, 1279 (Fed. Cir. 2015) ................................................................ 15
`Dole Food Co. v. Patrickson,
`538 U.S. 468 (2003) ............................................................................................ 48
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ...................................................................... 3, 41
`Fox Factory, Inc. v. SRAM, LLC,
`IPR2016-01876, 2017 WL 1240081 (Apr. 3, 2017) ........................................... 30
`
`– iv –
`
`
`
`Gen. Elec. Co. v. Joiner,
`522 U.S. 136 (1997) ...................................................................................... 37, 40
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00739, 2017 WL 3209157 (July 27, 2017) ................................... 17, 30
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .......................................................................... 33
`Kayak Software Corp. v. Int’l Business Machines Corp.,
`CBM2016-00075, 2016 WL 11034653 (Dec. 15, 2016) .................................... 22
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) .......................................................................... 41
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 33
`In re Lister,
`583 F.3d 1307 (Fed. Cir. 2009) .................................................................... 41, 44
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) .......................................................................... 34
`Microsoft Corp. v. Corel Software, Inc.,
`IPR2016-01300, 2017 WL 380951 (Jan. 4, 2017) ....................................... 44, 45
`Mylan Pharm. Inc. v. Boehringer Ingelheim Int’l GmbH,
`IPR2016–01563, 2017 WL 506756 (Feb. 3, 2017) ............................................ 44
`Mylan Pharms. Inc. v. Anacor Pharms., Inc.,
`IPR2018-01358, Paper 2 (July 6, 2018) ............................................................. 49
`In re Nuvasive, Inc.,
`842 F.3d 1376 (Fed. Cir. 2016) .......................................................................... 34
`Samsung Elecs. Co., Ltd. v. Imperium (IP) Holdings,
`IPR2015-01233, 2015 WL 9599164 (Dec. 1, 2015) .................................... 37, 40
`Samsung Electronics Co. v. Arendi S.A.R.L.,
`IPR2014-00214, 2014 WL 2447197 (May 28, 2014) ........................................ 28
`
`– v –
`
`
`
`Sandoz Inc. v. AbbVie Biotechnology Ltd.,
`IPR2018-00002, 2018 WL 2087129 (May 3, 2018) .......................................... 43
`Sandoz, Inc. v. AbbVie Biotechnology Ltd.,
`IPR2018-00156, 2018 WL 2735468 (June 5, 2018) .......................................... 41
`SAS Institute Inc. v. Iancu,
`138 S. Ct. 1348 (2018) ........................................................................................ 17
`SRI Int’l, Inc. v. Internet Sec. Sys., Inc.,
`511 F.3d 1186 (Fed. Cir. 2008) .......................................................................... 41
`Symantec Corp. v. Trs. of Columbia Univ.,
`IPR2015-00371, 2015 WL 4036014 (June 17, 2015) ........................................ 42
`Unified Patents, Inc. v. Berman,
`IPR2016-01571, 2016 WL 10033540 (Dec. 14, 2016) .......................... 17, 25, 28
`
`
`
`
`– vi –
`
`
`
`PATENT OWNERS’ EXHIBIT LIST
`
`Exhibit No.
`
`Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`Declaration of Kevin S. Prussia in Support of Motion for
`Admission Pro Hac Vice
`
`Declaration of Amy K. Wigmore in Support of Motion for
`Admission Pro Hac Vice
`
`Sumeet S. Chugh et al., Worldwide Epidemiology of Atrial
`Fibrillation: A Global Burden of Disease 2010 Study, 129
`Circulation 837 (2014)
`
`John A. Heit, Epidemiology of venous thromboembolism, 12
`Nature Rev. Cardiology 464 (2015)
`
`Jeffrey Weitz, The 50-year quest to replace warfarin (2011),
`Nature Reviews Drug Discovery,
`http://www.nature.com/nrd/posters/warfarin (last visited Jul. 11,
`2018)
`
`Larry Husten, Pfizer and Bristol’s ARISTOTLE Study Finds the
`Golden Mean of Anticoagulation, Forbes (Aug. 28, 2011, 2:08
`AM), https://www.forbes.com/sites/larryhusten/2011/08/28/pfizer-
`and-bristols-aristotle-study-finds-the-golden-mean-of-
`anticoagulation-2/#3fb534ac706a
`
`Alpesh Amin et al., Effectiveness and Safety of Apixaban,
`Dabigatran, and Rivaroxaban Compared to Warfarin Among Non-
`Valvular Atrial Fibrillation Patients in the US Medicare
`Population, 69 J. Am. Coll. Cardiology (Supplement) 316 (2017)
`
`Ergene Oktay, Will NOACs become the new standard of care in
`anticoagulation therapy?, 1 Int’l J. Cardiovascular Acad. 1 (2015)
`
`Pancras C. Wong et al., Preclinical discovery of apixaban, a direct
`and orally bioavailable factor Xa inhibitor, 31 J. Thrombosis &
`Thrombolysis 478 (2011)
`
`– vii –
`
`
`
`Exhibit No.
`
`Description
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`Coal. for Affordable Drugs IX LLC v. Bristol-Myers Squibb Co.,
`Decision Denying Institution of Inter Partes Review, IPR2015-
`01723, 2016 WL 1082935 (Feb. 22, 2016)
`
`U.S. Patent Application Publication No. 2012/0087978 to Richard
`G. Nause (published Apr. 12, 2012)
`
`The Merck Index: An Encyclopedia of Chemicals, Drugs, and
`Biologicals, at 1582 (Maryadele J. O’Neil et al. eds., 13th ed.
`2001)
`
`TRENTAL® (pentoxifylline) Package Insert (July 2010)
`
`COPEGUS® (ribavirin) Package Insert (August 2015)
`
`EPIVIR® (lamivudine) Package Insert (April 2018)
`
`HIVID® (zalcitabine) Package Insert (September 2001)
`
`ZERIT® (stavudine) Package Insert (December 2017)
`
`ELIQUIS® (apixaban) Package Insert (June 2018)
`
`Modern Pharmaceutics, Table of Contents (Gilbert S. Banker &
`Christopher T. Rhodes Eds., 4th ed. 2002)
`
`– viii –
`
`
`
`I.
`
`Introduction
`
`In 2016, the United States Patent Office issued U.S. Patent No. 9,326,945
`
`(“the ’945 patent”) to Patent Owners Bristol-Myers Squib Company and Pfizer,
`
`Inc., affirmatively finding that the inventions claimed in the ’945 patent were
`
`“unexpected” and that “it would not have been obvious” to arrive at them.
`
`Ex. 1003, at 498 (Notice of Allowability mailed Mar. 4, 2016).
`
`Now, Petitioner Mylan Pharmaceuticals, Inc. (“MPI”) tells the USPTO that
`
`it got it wrong. In doing so, Petitioner does not present a different theory of
`
`obviousness, identify any substantially different prior art, or present any evidence
`
`undermining the unexpected results presented in the ’945 patent specification.
`
`Rather, Petitioner presents the identical case for obviousness considered by the
`
`Examiner during prosecution; namely, that the claims are supposedly obvious
`
`because a person of ordinary skill would be motivated to use small, crystalline
`
`apixaban particles in a formulation to increase the drug dissolution rate, and
`
`thereby improve bioavailability.
`
`As the Examiner ultimately recognized in allowing the claims, such an
`
`argument relies on broad assumptions about low-solubility compounds that were
`
`not expected to apply to apixaban. Indeed, the Examiner withdrew the
`
`obviousness rejection based upon this theory in view of Patent Owners’ evidence
`
`that, due to apixaban’s profile under the Biopharmaceutics Classification System
`
`– 1 –
`
`
`
`(“BCS”), a person of ordinary skill would not have expected apixaban’s
`
`bioavailability to be limited by its dissolution rate, and therefore would not even
`
`consider reducing apixaban’s particle size to improve its bioavailability.
`
`In recycling the Examiner’s well-worn argument and repurposing it for the
`
`Petition, Petitioner does nothing to cast it in a new light. The Petition presents no
`
`new line of reasoning, describes no substantially different prior art, and identifies
`
`no errors in the Examiner’s analysis. The Petition simply repackages the
`
`Examiner’s since-overcome office action rejection. Because the Petition is nothing
`
`more than a rehash of material that the USPTO considered extensively during
`
`prosecution, inter partes review should be declined under § 325(d).
`
`Additionally, the Petition should be denied for failing to provide the
`
`requisite evidence of motivation to combine prior art necessary to establish a prima
`
`facie case of obviousness. To manufacture alleged motivation, Petitioner relies on
`
`generalized assumptions regarding the relationship between solubility of a
`
`compound, its dissolution rate, and its bioavailability—assumptions that not only
`
`are incorrect and untethered to what was actually known about apixaban, but are
`
`contradicted by the very references cited in the Petition.
`
`Further, the Petition fails to establish that three of the four asserted prior art
`
`references are “printed publications.” Indeed, aside from the documents
`
`themselves, Petitioner does not offer any evidence in support of their status as
`
`– 2 –
`
`
`
`printed publications. But the Board has held time and again, that printed
`
`publication status cannot be assumed and that it is Petitioner’s burden to establish a
`
`document’s printed publication status. See Dynamic Drinkware, LLC v. Nat’l
`
`Graphics, Inc., 800 F.3d 1375, 1379 (Fed. Cir. 2015) (citing Tech. Licensing Corp.
`
`v. Videotek, Inc., 545 F.3d 1316, 1327 (Fed. Cir. 2008)). Here, Petitioner relies on
`
`documents that, in some instances, have internal markings calling into question
`
`whether they were accessible to persons of skill in the art before the priority date;
`
`and, in other instances, are of a type similar to other documents that the Board has
`
`previously required something more to show printed publication status (e.g., FDA
`
`regulatory documents).
`
`Finally, Petitioner has failed to name all the real-parties-in-interest (“RPIs”).
`
`The Petition discloses Petitioner MPI, its immediate parent company, Mylan Inc.,
`
`and its ultimate parent company, Mylan N.V., as RPIs. This was no accident.
`
`Petitioner has named the same two parties as RPIs in several other IPRs. But
`
`Mylan N.V. indirectly holds Mylan Inc. through at least two other companies,
`
`Mylan Holdings Ltd. and Mylan Holdings Inc., which the Petition fails to disclose
`
`as RPIs. Mylan N.V. can only effectuate its desire for the ’945 Patent to be
`
`reviewed via these undisclosed intermediaries. The Petition’s RPI disclosure is
`
`therefore incomplete, so the Petition should not be accorded its current filing date.
`
`And because Patent Owners served Petitioner with a complaint for infringement of
`
`– 3 –
`
`
`
`the ’945 Patent’s claims over a year ago, the Petition is now time-barred under 35
`
`U.S.C. § 315(b).
`
`II. Background
`A. Anticoagulants and the Development of Apixaban
`
`Anticoagulants are used to treat cardiovascular medical conditions affecting
`
`tens of millions of people worldwide. Ex. 2003, Chugh at 837; Ex. 2004, Heit at
`
`464. They are used to prevent or treat thrombosis, which is the formation of blood
`
`clots. Ex. 2009, Wong at 478-79; Ex. 2018, Eliquis® (apixaban) Label, at 1, 4, 41.
`
`To treat or prevent thrombosis, patients generally need to take anticoagulants for
`
`long periods of their lives. Finding the right balance between a drug’s
`
`anticoagulant effects and the risk of additional bleeding is key to developing a
`
`useful anticoagulant. But finding this balance has been extremely difficult.
`
`Until recently, warfarin was the leading oral anticoagulant. But warfarin has
`
`several significant limitations. For example, warfarin has a narrow therapeutic
`
`index—that is, the window between a therapeutically effective dose and the dose
`
`that causes side effects (e.g., bleeding) is very small. It also has nonlinear
`
`intra-patient pharmacokinetics and high interpatient variability in its dose-response
`
`relationship. Warfarin is also limited by a slow onset of action, and drug-drug and
`
`drug-food interactions. Warfarin’s variable response requires regular monitoring
`
`for dose adjustment to confirm that a safe and effective level of anticoagulant
`
`– 4 –
`
`
`
`effect is achieved and maintained. Ex. 2005, Weitz at 1.
`
`Despite warfarin’s limitations and the great incentive to provide an
`
`improved oral anticoagulant to a significant patient population, no new oral
`
`anticoagulants received regulatory approval for more than 50 years.
`
`After many years of development and failures by various pharmaceutical
`
`companies, a handful of novel oral anticoagulants have recently received
`
`regulatory approval. Apixaban is the only one of these three new drugs to show a
`
`significant improvement in mortality over warfarin. Ex. 2006, Husten at 2; see
`
`also Ex. 2007, Amin at 1. Apixaban features an improved pharmacokinetic
`
`profile, does not require anticoagulation monitoring, and has limited food and drug
`
`interactions. See Ex. 2008, Oktay at 2.
`
`The challenge in developing apixaban was not only to find a compound with
`
`the right mix of potency and pharmacokinetic properties, but also to find a
`
`formulation that would allow patients to take advantage of the compound’s
`
`breakthrough properties (e.g., potent anticoagulation combined with a low risk of
`
`bleeding). Ex. 2009, Wong at 479.
`
`The first issue was addressed by U.S. Patent No. 6,967,208, which is titled
`
`“Lactam-Containing Compounds and Derivatives Thereof as Factor Xa Inhibitors”
`
`and is directed to “lactam-containing compounds . . . that are useful as factor Xa
`
`inhibitors” and “pharmaceutically acceptable salts or prodrugs” of those
`
`– 5 –
`
`
`
`compounds. Ex. 1007, Pinto at 5:53-56. The ’208 patent was previously
`
`challenged in IPR2015-01723, but the Board declined to institute the proceedings.
`
`Ex. 2010, IPR2015-01723 at 18. The ’945 patent claims at issue here address the
`
`second issue.
`
`B.
`
`The ’945 Patent
`
`The ’945 patent discloses and claims apixaban pharmaceutical formulations
`
`with improved bioavailability and their use in the treatment and/or prophylaxis of
`
`thromboembolic disorders. The claimed formulations comprise crystalline
`
`apixaban having a maximum particle size and exhibiting specified dissolution
`
`criteria. Claims 1 and 9 are set forth below as an example:
`
`a
`comprising
`composition
`pharmaceutical
`solid
`A
`1.
`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.
`
`the
`in claim 1, wherein
`The composition as defined
`9.
`pharmaceutical composition comprises from about 2.5 mg to about 5
`mg of apixaban.
`
`The inventions are the result of the surprising and unexpected discovery that
`
`– 6 –
`
`
`
`the bioavailability of apixaban—a highly soluble compound under the BCS
`
`classification system—is improved by increasing the dissolution rate of the drug.
`
`See, e.g., Ex. 1001, ’945 patent cols. 1:46-60, 1:64-2:5, 2:44-57. At the time of the
`
`invention, the bioavailability of a drug with such a profile (BCS Class III), was not
`
`predicted based on the rate of dissolution, so reducing particle size to improve the
`
`dissolution rate was not thought to affect bioavailability. The inventors of the ’945
`
`patent discovered that this accepted principle was not applicable to apixaban.
`
`C. The Relevant Prosecution History
`
`The ’945 patent issued on May 3, 2016 from U.S. Application No.
`
`13/579,796 (“’796 application”). The ’796 application is the U.S. National Stage
`
`of International Application PCT/US2011/025994, filed February 24, 2011, which
`
`claims priority to U.S. Provisional Application No. 61/308,056, filed February 25,
`
`2010.
`
`1.
`
`Rejections Over Nause and Wei
`
`During prosecution, the claims were examined extensively over Wei (Ex.
`
`1008) and Nause (Ex. 2011).1 The Examiner rejected the pending claims in view
`
`of Wei and Nause in Office Actions dated February 28, 2014 and July 18, 2014.
`
`
`1 Although the Examiner treated Nause as prior art, Patent Owners do not concede
`
`that Nause is prior art.
`
`– 7 –
`
`
`
`Ex. 1003, at 203-04 (Office Action mailed Feb. 28, 2014), 263-64 (Office Action
`
`mailed Jul. 18, 2014). In a Non-Final Office Action dated August 13, 2015, the
`
`Examiner withdrew this rejection, but then rejected the claims as obvious over
`
`Nause in view of Wei. Ex. 1003, at 397-99 (Non-Final Office Action mailed Aug.
`
`13, 2015).
`
`The Examiner found that the Nause “teaches a factor Xa inhibitor dosage
`
`form comprising apixaban in a solubility-improved form,” including crystalline
`
`forms, as well as “[d]esired dosages (which constitute therapeutically effective
`
`amounts).” Id. at 397. According to the Examiner, “Nause teaches in most cases
`
`apixaban is sufficiently insoluble in aqueous media that a surfactant such as SLS
`
`may be added to raise the solubility of the drug.” Id. at 400.
`
`As to Wei, the Examiner explained that it “generally teaches that it is well
`
`known in the pharmaceutical industry 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 398. The Examiner further noted that “Wei
`
`teaches a robust crystallization that [sic] process that can produce small and
`
`uniform crystals with high purity, high stability, and high surface area, without the
`
`necessity of post-crystallization milling, thus producing apixaban particles which
`
`are crystalline and have a D90 of less than about 20 microns.” Id.
`
`– 8 –
`
`
`
`The Examiner found that it would have been obvious “to combine Wei with
`
`Nause and utilize the crystalline apixaban particles of Wei in the composition of
`
`Nause.” Id.
`
`As will be discussed further below, the arguments presented in the Petition
`
`are a near carbon-copy of the Office Action rejections, just with cumulative
`
`references substituted for Nause in an effort to mask the nearly identical
`
`arguments.
`
`2.
`
`Interview and Response
`
`Following the Office Action rejections, the Applicants, including one of the
`
`’945 patent inventors, Jatin Patel, conducted an interview with the Examiner.
`
`Applicants explained that a person of ordinary skill in the art would not have
`
`expected apixaban’s particle size and dissolution rate to have influenced its in vivo
`
`exposure because apixaban is a BCS Class III drug, which is highly soluble. Ex.
`
`1003, at 438 (PTO Interview Summary dated Sept. 17, 2015), 468-70 (Amendment
`
`and Statement of the Substance of the Interview dated Nov. 30, 2015). The
`
`Applicants further explained that Wei (Ex. 1008) does not teach a pharmaceutical
`
`composition at all, and it does not teach a composition that includes apixaban with
`
`a specific particle size. Id. at 467-68 (Amendment and Statement of the Substance
`
`of the Interview dated Nov. 30, 2015).
`
`In the subsequent Response, the Applicants explained the BCS
`
`– 9 –
`
`
`
`Classification system, and noted that apixaban is recognized as a BCS Class III
`
`drug, which means it is highly soluble as defined by the BCS. Id. at 469.
`
`Therefore, a person of ordinary skill in the art would not have expected the
`
`absorption of apixaban to be limited by its dissolution rate. Id. at 470. Thus, there
`
`would have been no reason to control apixaban’s particle size to increase its
`
`dissolution rate for achieving consistent exposure. Id.
`
`3.
`
`Notice of Allowance
`
`The Examiner issued a Notice of Allowance on March 4, 2016, noting the
`
`criticality of the claimed size range and stating that “it would not have been
`
`obvious to a person having ordinary skill in the art at the time the invention was
`
`made to formulate solid apixaban pharmaceutical formulations according to the
`
`specific limitations of size and dissolution claimed, with the results of
`
`unexpectedly improved bioequivalence within said ranges as demonstrated in the
`
`specification.” Id. at 497-98 (Notice of Allowability mailed Mar. 4, 2016)
`
`(emphasis added).
`
`D. Asserted Prior Art
`
`The Petition contains the following prior art in its four obviousness Grounds.
`
`1. Wei (Ex. 1008)
`
`Wei (Grounds I-IV) is the same Wei reference considered during
`
`prosecution. Wei relates to a process for preparing crystals of organic chemical
`
`– 10 –
`
`
`
`materials. In particular it discloses a process for transforming a first polymorph of
`
`a chemical material into a second polymorph of the same chemical material
`
`utilizing an apparatus comprising a vessel connected to a re-circulation system.
`
`Ex. 1008 at ¶ [0012].
`
`Wei contains three examples wherein different amounts of apixaban were
`
`dissolved in slurries and subjected to the polymorph process described in the
`
`publication. Needle-shaped crystals having a particle size of less than about 20
`
`microns were obtained.
`
`Wei does not disclose a pharmaceutical composition containing the
`
`crystalline compounds. Nor does Wei disclose a composition that includes
`
`apixaban with a specific particle size.
`
`Wei does not describe any issues with the bioavailability or solubility of
`
`apixaban. The “Background” section of Wei provides a possible application for its
`
`process, stating that “[i]t is well known in the pharmaceutical industry 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.” Ex. 1008 at
`
`¶ [0003]. However, Wei never states that these assumptions apply to apixaban.
`
`2.
`
`Carreiro (Ex. 1004)
`
`Carreiro (Grounds I-II) is a “review article” discussing the “discovery,
`
`– 11 –
`
`
`
`pharmacokinetics, attributes, and current clinical trials of emerging drugs.” Ex.
`
`1004, Carreiro at 1937.2 Carreiro describes apixaban as a “potent, selective,
`
`reversible, and orally bioavailable [Factor Xa] inhibitor that demonstrates
`
`antithrombotic efficacy, with a favorable pharmacokinetic profile.” Id. Further,
`
`Carreiro reports that apixaban “is being evaluated in Phase II and Phase III trials,
`
`involving nearly 25,000 patients,” and “trials are underway involving 47,000”
`
`patients overall. Id., at 1937, 1938. Carreiro reports the apixaban doses involved
`
`in those trials, including 2.5 mg and 5 mg doses. (Id. at Table 1, 1941-1943.)
`
`Carreiro does not describe any bioavailability issues with apixaban. To the
`
`contrary, Carreiro reports that “[t]he pharmacokinetic profile of apixaban is
`
`consistent with rapid oral absorption and bioavailability.” Id. at 1940.
`
`3.
`
`The ’208 Patent (Ex. 1007)
`
`The ’208 patent (Grounds III-IV) discloses lactam-containing compounds
`
`and pharmaceutical compositions comprising the lactam-containing compounds
`
`
`2 As explained further below, Petitioner has not established that Carreiro is a
`
`“printed publication” under 35 U.S.C. §102(b). 35 U.S.C. § 311(b). Although the
`
`Exhibit includes a citation format in the footer, the Exhibit bears no library stamp
`
`and the face of the Exhibit identifies that it was downloaded from the internet in
`
`August 2017, i.e., more than seven years after the priority date. Ex. 1004 at 1.
`
`– 12 –
`
`
`
`characterized by Formula I, including apixaban. The patent teaches that the
`
`compounds are useful as factor Xa inhibitors, and describes possible dosages and
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`dosage forms. Ex. 1007, Patel at 154:65-155:28.
`
`4.
`
`Rudnic (Ex. 1010)
`
`Rudnic (Grounds II, IV) is a book chapter discussing tablet dosage forms
`
`and describes several raw material properties that may influence tablet design and
`
`formulation, including purity, variability, moisture content, particle size, and
`
`polymorphism. Ex. 1010, Rudnic at 335-340.3 Rudnic describes the use of sodium
`
`lauryl sulfacte as a lubricant that can be used in tablets. Id. at 354.
`
`Rudnic does not discuss apixaban.
`
`5.
`
`FDA Dissolution Guidance (Ex. 1015)
`
`FDA Dissolution Guidance (Grounds I-IV) describes in vitro dissolution
`
`
`3 As explained further below, Petitioner has not established that Rudnic is a
`
`“printed publication” under 35 U.S.C. §102(b), or, if it is, that the version of
`
`Rudnic in Exhibit 1010 is authentic. The Exhibit bears no library stamp, the cover
`
`page of the Exhibit does not appear to be a photocopy of a hardcopy textbook,
`
`nothing in the Exhibit associates the Rudnic chapter to the specific version of the
`
`textbook, and inconsistent markings within the Exhibit suggest that it is a
`
`compilation of multiple documents pieced together by Petitioner.
`
`– 13 –
`
`
`
`testing of immediate release solid oral dosage forms.4 The document reports that
`
`the BCS “is recommended in the literature” and specifically describes BCS “Case
`
`3” drugs as having “High Solubility – Low Permeability.” The document explains
`
`the “classification can be used as a basis for setting in vitro dissolution
`
`specifications and can also provide a basis for predicting the likelihood of
`
`achieving a successful in vivo-in vitro correlation (IVIVC).” FDA Dissolution
`
`Guidance further reports that “[i]n the case of high solubility/low permeability
`
`drugs (case 3), permeability is the rate controlling step . . . .” Ex. 1015, at 3. It
`
`also provides dissolution testing conditions. Id. at Appendix A.
`
`FDA Dissolution Guidance does not report on apixaban.
`
`III. The Level of Ordinary Skill in the Art and Claim Construction
`
`The Petition proposes a definition of a person of ordinary skill in the art
`
`(“POSA”), (Pet. at 8), and states that none of the claim terms needs to be
`
`construed, (Pet. at 16). For the purpose of this preliminary response, Patent
`
`
`4 Petitioner has not established that FDA Dissolution Guidance is a “printed
`
`publication” under 35 U.S.C. §102(b). The mere fact that the document purports to
`
`be a FDA document is not enough to establish it as a printed publication. See, e.g.,
`
`Celltrion, Inc. v. Biogen, Inc., IPR2016-01614, 2018 WL 1037223, at *7 (Feb. 21,
`
`2018).
`
`– 14 –
`
`
`
`Owners do not contest the definition of a POSA set forth in the Petition and do not
`
`set forth any terms for construction at this time.5
`
`IV. The Board Should Deny Institution Pursuant to § 325(d)
`
`The Board should deny institution because Petition relies on the same theory
`
`of obviousness overcome by Patent Owners during prosecution.
`
`As an initial matter, Petitioner relies on the same or substantially the same
`
`references applied by the Examiner during prosecution. The Wei reference
`
`
`5 When construing claims in inter partes review, the Board adopts a “broadest
`
`reasonable interpretation” standard. In re Cuozzo Speed Techs., LLC, 793 F.3d
`
`1268, 1279 (Fed. Cir. 2015). On May 8, 2018, the USPTO proposed rulemaking
`
`that would use the Phillips standard in construing claims. Patent Owners are not
`
`aware of any difference in how
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