Filed on behalf of: Mylan Pharmaceuticals Inc.
`By: Steven W. Parmelee
`
`Michael T. Rosato
`Jad A. Mills
`WILSON SONSINI GOODRICH & ROSATI
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BAYER Intellectual Property GmbH,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2017-00041
`Patent No. 7,157,456
`_____________________________
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 7,157,456
`
`
`

`
`Table of Contents
`
`I.
`
`INTRODUCTION .............................................................................................. 1
`
`A.
`
`Brief Overview of the ’456 Patent....................................................... 5
`
`B.
`
`C.
`
`Brief Overview of the Prosecution History ......................................... 6
`
`Brief Overview of the Scope and Content of the Prior Art .................. 7
`
`D.
`
`Brief Overview of the Level of Skill in the Art ................................. 17
`
`II.
`
`GROUNDS FOR STANDING ............................................................................. 20
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ........................................... 20
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED ......................................... 22
`
`V.
`
`CLAIM CONSTRUCTION ................................................................................ 22
`
`VI. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO DECEMBER 24, 1999 ....... 23
`
`VII. DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY ................... 31
`
`A.
`
`[Ground 1] Claims 1-6, 8, 10, 13-14, 16-19, 24, 26-28 and 30
`are Obvious Under 35 U.S.C. § 103 Over Ewing, Riedl, the
`’111 Publication and Chiba. .............................................................. 31
`
`i.
`
`ii.
`
`Claim 16 ................................................................................. 32
`
`Claims 1-6 and 10 ................................................................... 45
`
`iii. Claims 14 and 27 .................................................................... 53
`
`iv.
`
`Claims 8, 17-19, 28 ................................................................. 55
`
`v.
`
`Claims 13, 24, 26, and 30 ........................................................ 56
`
`B.
`
`[Ground 2] Claims 7, 11-12, and 20-22 are Obvious under 35
`U.S.C. § 103 over Ewing, Riedl, the ’111 Publication, Chiba,
`the ’630 Publication, and the ’671 patent. ......................................... 61
`
`VIII. CONCLUSION ............................................................................................... 73
`
`
`
`1
`
`

`
`IX. CERTIFICATE OF COMPLIANCE ...................................................................... 75
`IX.
`CERTIFICATE OF COMPLIANCE .................................................................... ..75
`
`X.
`X.
`
`PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ...................... 76
`PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 .................... ..76
`
`XI. APPENDIX – LIST OF EXHIBITS...................................................................... 77
`XI.
`APPENDIX — LIST OF EXHIBITS .................................................................... ..77
`
`
`
`
`2
`
`

`
`I.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) requests inter partes review of
`
`U.S. Patent No. 7,157,456 to Straub et al. (“the ’456 patent,” EX1001), which
`
`issued on January 2, 2007. PTO records indicate the ’456 patent is assigned to
`
`Bayer Intellectual Property GmbH (“Patent Owner”). This Petition demonstrates
`
`there is a reasonable likelihood that claims 1-8, 10-14, 16-22, 24, 26-28, and 30 of
`
`the ’456 patent are unpatentable over prior art. Additional Petitions are being filed
`
`to address related patents that are terminally disclaimed over the ’456 patent.
`
`Multiple enzymes are involved in the blood clotting cascade, but one protein
`
`known as “factor X,” via its active form, “Xa,” is called upon at an essential point
`
`in both the intrinsic and extrinsic coagulation pathways. EX1014 at 6630. The
`
`ʼ456 patent is directed to a class of compounds that bind to and inhibit “factor Xa.”
`
`Because the crystal structure of factor Xa was known, the art had established the
`
`presence of dual binding pockets for inhibitors, termed the S1 and S4 pockets. Id.;
`
`see also EX1015 at 390. The S1 pocket was recognized as a narrow cleft that
`
`bound planar aromatic groups, while the S4 pocket was less selective, binding not
`
`only planar aromatic groups but also non-aromatic rings with heteroatoms, such as
`
`nitrogen and oxygen. Id.
`
`Based on the detailed knowledge of the factor Xa binding pockets, the art
`
`had designed dozens of compounds which fit into these pockets and showed potent
`
`
`
`1
`
`

`
`inhibition of factor Xa. See generally, Ewing, EX1007. What these compounds
`
`lacked was not potency, but favorable pharmacokinetic profiles. Id. Oral
`
`bioavailability was especially sought after, as the art needed new, safe and
`
`effective, orally-active anticoagulants. Many viewed factor Xa inhibitors as
`
`attractive drug targets for developing effective oral anticoagulants. Id.
`
`Oxazolidinones are a class of compounds comprising a
`
`5-membered heterocycle (shown), and had long been known
`
`in the art to have various pharmacologic activities. EX1008.
`
`O
`
`R
`
`N
`
`O
`
`The art described oxazolidinone compounds that inhibited platelet aggregation, and
`
`were said to be useful in the treatment of thrombosis and myocardial infarction. Id.
`
`The “most advanced” oxazolidinone compound, linezolid, was known to have very
`
`desirable pharmacokinetic and pharmacologic properties, including high oral
`
`bioavailability and patient tolerability. Id. at 626-27. Linezolid was safe in humans
`
`and had entered Phase III human clinical trials for antimicrobial uses.
`
`It was known that oxazolidinone-based antibiotics could have dual uses for
`
`other indications, and that they could be optimized for other therapeutic activities,
`
`including as anti-depressants or as anticoagulants. EX1008 at 630; EX1018 at 136.
`
`Linezolid’s 4’-morpholinophenyl arm was a known factor Xa binding moiety, and
`
`was present on a factor Xa inhibitor disclosed in Example 1 of PCT WO 00/39111
`
`(the ʼ111 publication, EX1009). This binding moiety is structurally similar to the
`
`
`
`2
`
`

`
`4’-cyclohexyl phenyl moiety found on Ewing’s Compound 49, also a factor Xa
`
`inhibitor. EX1007 at 782. Linezolid, Ewing Compound 49, and Examples 1 and 7
`
`of the ʼ111 publication (shown below), have a two-arm shape and structure
`
`consistent with providing a binding moiety for each of the two known binding
`
`pockets of factor Xa. Id.; EX1008 at 626 (Compound 1); EX1009, 39:1-5;
`
`O
`
`CH3
`
`NH
`
`O
`
`O
`
`N
`
`N
`
`N
`
`N
`
`F
`
`O
`
`OCH3
`
`Cl
`
`S
`
`O
`
`NH
`
`NH
`
`N
`
`N
`
`O
`
`NH
`
`NH
`
`O
`
`EX1010, 0043:1-5.
`
`NH
`
`NH2
`
`HN
`
`O
`
`HN
`
`Ewing, EX1007
`Compound 49
`
`T he '111 Publication; EX1009
`Example 1
`
`T he '111 Publication; EX1009
`Example 7
`
`Riedl, EX1008
`Linezolid
`
`
`
`Given linezolid’s general shape, its 4’-morpholinophenyl arm that was
`
`already a known factor Xa binding moiety (supra, EX1009), and its excellent
`
`pharmacokinetic properties (supra, EX1008), the skilled artisan would have been
`
`motivated to exchange the terminal methyl group on the amide arm of linezolid for
`
`a known factor Xa binding moiety to optimize its factor Xa binding affinity. In
`
`keeping with the known preference for aromatic moieties in the binding pockets of
`
`factor Xa, the ’111 publication identifies a set of six terminal moieties on the
`
`amide-end of a series of compounds that are suitable for factor Xa binding and
`
`
`
`3
`
`

`
`inhibition. Four of these terminal moieties are attached through the exact same
`
`amide linkage that is present in linezolid, and among these four is 5-
`
`chlorothiophene, the same moiety found in rivaroxaban. EX1009, 47:14-25. Thus,
`
`evaluation of each of these four moieties, including 5-chlorothiophene, on the
`
`amide arm of linezolid would have been an apparent choice by the skilled artisan
`
`working to optimize factor Xa inhibition activity.
`
`None of the comparable factor Xa inhibitors taught by the ʼ111 publication
`
`had a fluorine atom on the 4’-morpholinophenyl arm as found in linezolid. For this
`
`reason, the skilled artisan would have been motivated to leave out linezolid’s
`
`fluorine atom. This would also have made it possible to use a simpler and less
`
`expensive synthetic precursor.
`
`The assessment of known metabolites of a compound intended for
`
`pharmaceutical use is considered routine in the art. An assessment of a factor Xa
`
`inhibitor compound based on the structure of linezolid would have identified
`
`morpholine ring-opened metabolites, as were noted in Chiba (EX1011). The
`
`skilled artisan would have been motivated to block that metabolism by installing a
`
`carbonyl adjacent to the nitrogen in the morpholine ring so as to block or slow its
`
`degradation into a ring-opened metabolite. This would directly result in the
`
`compound now known as rivaroxaban.
`
`
`
`4
`
`

`
`As factor Xa inhibitors were known to be useful in the treatment of
`
`thromboembolic disorders, the methods of treatment using a compound such as
`
`rivaroxaban for myocardial infarct, pulmonary embolism, or deep venous
`
`thrombosis would have likewise been readily apparent and obvious uses. Further,
`
`synthetic routes and formulations for linezolid were already well established in the
`
`art, and these could have been easily applied to the synthesis and formulation of
`
`rivaroxaban, making obvious the pharmaceutical compositions and synthetic routes
`
`recited in the remaining claims.
`
`Evidence in support of the forgoing analysis is presented and discussed in
`
`detail below.
`
`A. Brief Overview of the ’456 Patent
`
`The ’456 patent is entitled “Substituted Oxazolidinones and their Use in the
`
`Field of Blood Coagulation.” The ’456 patent is directed to rivaroxaban, genuses
`
`of oxazoldidinones that include rivaroxaban, and methods of formulation,
`
`processes to make them, and methods to administer them to patients with various
`
`thromboembolic disorders. The patent describes these compounds as factor Xa
`
`inhibitors. Claims 6 and 16 are directed to rivaroxaban (structure shown below), or
`
`pharmaceutically acceptable salts or hydrates thereof:
`
`
`
`5
`
`

`
`O
`
`N
`
`O
`
`O
`
`N
`
`O
`
`NH
`
`S
`
`O
`
`Cl
`
`
`
`Claims 1-5 and 10 recite genuses of oxazolidinones that include rivaroxaban.
`
`Claim 7 is directed to two different proccess alternatives (A and B) for
`
`synthesizing these compounds. Claims 11, 12, and 20-22 depend directly or
`
`indirectly from claim 7 and recite various process specifics.
`
`Claims 8, 17, 18, and 19 recite pharmaceutical compositions comprising a
`
`compound of claims 1, 6, 14, and 16, respectively. Claims 27 and 28 recite
`
`pharmaceutical composition of enantiomerically pure rivaroxaban.
`
`Claims 13, 24, 26, and 30 recite methods of treating myocardial infarct,
`
`pulmonary embolism, or deep venous thrombosis, by administering to a patient in
`
`need thereof an effective amount of the compounds or compositions recited in
`
`claims 1, 17, 18, or 28, respectively.
`
`B.
`
`Brief Overview of the Prosecution History
`
`U.S. Patent Application 10/181,051 (“the ’051 application”) was filed on
`
`June 24, 2002 as a national stage entry of PCT/EP00/12492, filed on December 11,
`
`2000, and claims priority to German Application No. 199 62 924, filed on
`
`
`
`6
`
`

`
`December 24, 1999. The ’051 application issued on January 2, 2007 as the ’456
`
`patent.
`
`Following a restriction requirement and a subsequent election of a subset of
`
`oxazolidinones comprising a phenylmorpholinone subunit (EX1006 at 3463-64),
`
`the Office made no rejections over the prior art. Instead, prosecution was primarily
`
`directed to issues arising under 35 U.S.C. § 112, first and second paragraphs. In the
`
`Notice of Allowability, the Office stated that the closest prior art of record was
`
`Hutchinson et al., WO 97/09328, a reference not relied upon in the present
`
`Petition. Id. at 0693-0694. Hutchinson discloses a genus of oxazolidinone
`
`compounds. The examiner discussed Hutchinson only as a single reference, and
`
`only in terms of structural similarity to the claimed genus.
`
`C. Brief Overview of the Scope and Content of the Prior Art
`
`In obviousness cases, Graham v. John Deere Co. of Kansas City requires an
`
`evaluation of any differences between the claimed subject matter and the asserted
`
`prior art. 383 U.S. 1, 17-18 (1966). As noted in KSR Int’l Co. v. Teleflex Inc., the
`
`obviousness inquiry may account for inferences that would be employed by a
`
`person of ordinary skill in the art. 550 U.S. 398, 418 (2007).
`
`1)
`
`Ewing, W. R., et al., Progress in the design of inhibitors of
`
`coagulation factor Xa, 24 DRUGS OF THE FUTURE 771-87 (1999)
`
`(“Ewing,” EX1007).
`
`
`
`7
`
`

`
`Ewing was published in July 1999 and is prior art to the claims of the ’456
`
`patent under 35 U.S.C. § 102(b). Ewing teaches using anticoagulants for the
`
`treatment and prevention of thromboembolic disorders. EX1007 at 771; EX1002,
`
`¶49; EX1003, ¶35. Ewing teaches, “The formation of an occlusive thrombus is
`
`causally related to the pathology of” myocardial infarction, stroke, deep vein
`
`thrombosis, and pulmonary embolism, and that, “[a]s such, antithrombotic therapy
`
`is a crucial component in both acute intervention procedures and chronic
`
`prevention strategies for treatment and management of these diseases.” Id. Ewing
`
`teaches that antithrombotic therapy includes an anticoagulant. Id.
`
`Ewing teaches that developing “safe and effective oral anticoagulants to
`
`replace warfarin” with strong pharmacokinetic profiles “may be particularly
`
`important since clinical data suggest that long-term and/or prophylactic
`
`anticoagulant therapy can provide a significant benefit over current standard
`
`treatment.” Id. at 774; EX1003, ¶36. Ewing identifies several advantages of using
`
`factor Xa inhibitors as anticoagulants, including the advantage of increased
`
`efficiency by “[i]nhibiting the source of thrombin generation rather than its
`
`catalytic activity.” Id. Additionally, Ewing states that “the risk of bleeding
`
`complications might be minimized” by using factor Xa inhibitors. Id; EX1002,
`
`¶50; EX1003, ¶37. Ewing states “[t]he risk of provoking prothrombotic rebound
`
`episodes observed with heparin and thrombin inhibitors would be minimized as
`
`
`
`8
`
`

`
`well.” Id. Ewing thus teaches that “direct inhibition of factor Xa activity should
`
`provide a potent anticoagulant devoid of the potentially limiting side effects
`
`observed with thrombin inhibitors.” Id.; EX1002, ¶51.
`
`Ewing identifies two main binding pockets for factor Xa, “[t]he specificity
`
`or S1 binding pocket” and “[t]he aromatic or S4 binding pocket.” Id. at 775. Ewing
`
`describes factor Xa inhibitors that generally have two arms connected via various
`
`linkers. Many of these factor Xa inhibitors have aryl rings or heteroaryl rings at
`
`one terminal end, and aryl rings or saturated heterocyclic or cycloalkane moieties
`
`at the opposing end. Id. at 777-83 (Compounds 11-57); EX1002, ¶¶52-53. Ewing
`
`also notes that “The discovery of factor Xa inhibitors which lack highly basic
`
`functions (i.e., amidines) holds considerable promise for future design since similar
`
`advances in the thrombin inhibitor field is what ultimately led to the discovery of
`
`orally effective factor IIa [thrombin] inhibitors.” Id. at 783. Regarding thrombin
`
`inhibitors, Ewing states that “[m]any highly potent and selective inhibitors have
`
`been described,” but that it had been difficult to combine potency and selectivity
`
`“with strong oral pharmacokinetic properties.” Id. at 773-74; EX1002, ¶54;
`
`EX1003, ¶38. Ewing was not of record during examination of the ’456 patent.
`
`2)
`
`Riedl, B. et al., Recent Developments with Oxazolidinone
`
`Antibiotics, 9 EXP. OPIN. THER. PATENTS 625-633 (1999) (“Riedl,”
`
`EX1008).
`
`
`
`9
`
`

`
`Riedl was published in May 1999 and is prior art to the claims of the ’456
`
`patent under 35 U.S.C. § 102(b). Riedl discloses an oxazolidinone compound
`
`called linezolid:
`
`F
`
`O
`
`O
`
`N
`
`N
`
`O
`
`linezolid
`(U-100766)
`
`NH
`
`O
`
`CH3
`
`
`
`Riedl teaches linezolid as “[t]he most promising representative” of an
`
`antibacterial oxazolidinone series due to its “advantageous pharmacokinetic
`
`profile” and “favourable safety profile,” making it notably “well-tolerated in
`
`humans at clinically relevant doses,” and allowing for its advancement into Phase
`
`III clinical trials. EX1008 at 626; EX1002, ¶56; EX1003, ¶45. Riedl notes: “In
`
`addition to the antimicrobial activity, other pharmacological activities of the
`
`oxazolidinones have been reported,” noting “[n]ovel oxazolidinone derivatives
`
`which inhibit platelet aggregation . . . and may be useful in the treatment of
`
`thrombosis and myocardial infarction.” EX1008 at 630, 633; EX1002, ¶57.
`
`Riedl teaches that the antibacterial activity of oxazolidinones, including
`
`linezolid, was significantly affected by the terminal moiety of the methylamino
`
`acyl arm: “The SAR of the methylamino acyl group in the 5-position of the
`
`oxazolidinone seemed to be narrowed down to acetyl amino methyl in this
`
`
`
`10
`
`

`
`position.” Id. at 629; EX1002, ¶58. Riedl notes that most compounds “in the field
`
`of oxazolidinones with antibacterial activity, use this substituent preferentially,” or
`
`else use groups that are similarly “unpolar and rather small.” Id. at 629. Riedl
`
`additionally notes the availability of pharmaceutical compositions for both oral and
`
`intravenous administration of linezolid. Id. at 627; EX1002, ¶59; EX1003, ¶46.
`
`Riedl was not substantively discussed during examination of the ’456 patent.
`
`3)
`
`International Patent Publication No. WO 00/39111 to Beight et
`
`al. (“the ’111 publication,” EX1009).
`
`The ’111 publication published in English on July 6, 2000 based on
`
`International Application No. PCT/US99/29832, filed on December 15, 1999.
`
`EX1009 at cover. The ’111 publication claims priority to U.S. Provisional
`
`Application No. 60/113,778 (“the ’778 application,” EX1010), filed December 23,
`
`1998. EX1009.
`
`Subject matter “carried forward” from the ’778 application into the ’111
`
`publication is entitled to the benefit of the December 23, 1998 priority date of the
`
`’778 application. See In re Giacomini, 612 F.3d 1380, 1382-83 (2010) (Under pre-
`
`AIA 35 U.S.C. § 102(e)(2), “an applicant is not entitled to a patent if another’s
`
`patent discloses the same invention, which was carried forward from an earlier
`
`U.S. provisional application[.]”). Throughout this Petition the teachings of the ’111
`
`
`
`11
`
`

`
`publication are supported by concurrent citations to both the ’111 publication and
`
`the ’778 application.
`
`The ’111 publication is also entitled to the December 23, 1998 priority date
`
`because at least one of its claims has adequate written description in the ’778
`
`application under pre-AIA 35 U.S.C. § 112, ¶1. See Benitec Biopharma Limited v.
`
`Cold Spring Harbor Laboratory, IPR2016-00016, Paper 8, at 7 (March 31, 2016)
`
`(priority claim of an issued patent to a U.S. provisional application as prior art
`
`under 35 U.S.C. § 102(e)(2) is established if petitioner demonstrates that the
`
`provisional “provide[s] written descriptive support for at least one claim of the
`
`[issued] patent.”) (citing Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800
`
`F.3d 1375, 1381 (Fed. Cir. 2015)).
`
`As explained by Dr. Lepore, the ’778 application provides written
`
`description support for at least one claim of the ’111 publication. EX1002, ¶¶66-68
`
`For example, claim 13 of the ’111 publication is identical to claim 13 of the ’778
`
`application, and provides:
`
`Claim 13 of the ’778 Application
`and the ’111 Publication
`13. A novel compound of
`formula I substantially as herein before
`described with reference to any of the
`examples.
`
`EX1009, 74:15-19; EX1010, 0078:15-19; EX1002, ¶66.
`
`
`
`12
`
`

`
`Example 1 of the ’111 publication is identical to Example 1 of the ’778
`
`application, and is shown below:
`
`OCH3
`
`N
`
`O
`
`NH
`
`NH
`
`O
`
`Example 1
`The '111 Publication; EX1009
`and the '778 Application; EX1010
`
`
`
`EX1009, 39:1-5; EX1010, 0043:1-5. Formula 1 of the ’111 publication is also
`
`identical to Formula 1 of the ’778 application, and is shown below:
`
`Q1
`L1
`
`A6
`
`A3
`
`R2
`
`A5
`A4
`
`Formula 1
`The '111 Publication; EX1009
`and the '778 App lication; EX1010
`
`EX1009, 3:5-9; EX1010, 0007:5-9. Example 1 is a compound of formula I, shown
`
`above, when A3, A4, A5 and A6 are CR3, CR4, CR5, and CR6, respectively, wherein
`
`R3, R4, R5, and R6 are all identically hydrogen, L1 is NHCO, Q1 is phenyl, wherein
`
`the phenyl bears a 4-methoxy group, and R2 is NHCH2Q2, wherein Q2 is Q2B, and
`
`Q2B is as shown below (also showing the methylene unit to which Q2B is attached):
`
`
`
`13
`
`

`
`
`
`wherein Ro is hydrogen and Rp is a 4-morpholino group. EX1009, 3:5-6:10;
`
`EX1010, 0007:5-0010:10; EX1002, ¶67. Likewise, Examples 2-15 of the ’111
`
`publication are identical to Examples 2-15 of the ’778 application and each is a
`
`compound of formula I. EX1009, 39:1-65:5; EX1010, 0043:1-0069:5; EX1002,
`
`¶67. Thus, the ’778 application provides written description support for at least
`
`one claim of the ’111 publication. EX1002, ¶68.
`
`The ’111 publication teaches the role of factor Xa in the blood coagulation
`
`cascade, noting it as a target for anticoagulant therapy. EX1002, ¶62; EX1003, ¶41.
`
`The ’111 publication teaches factor Xa inhibitors for administration “as
`
`anticoagulants for prophylaxis and treatment of thromboembolic disorders such as
`
`venous thrombosis, pulmonary embolism, arterial thrombosis, in particular
`
`myocardial ischemia, myocardial infarction and cerebral thrombosis.” EX1009,
`
`1:16-20; EX1010, 0005:12-16; EX1002, ¶61; EX1003, ¶¶40, 42. The ’111
`
`publication discloses 15 specific direct factor Xa inhibitors, each comprising one
`
`of three modules (e.g., 4’-morpholinophenyl, 4’-pyridinylpiperidinyl, or 4’-
`
`
`
`14
`
`

`
`isopropylpiperidinyl) on one arm and one of a small set of terminal moieties on the
`
`other arm. EX1009, 39:1-65:5; EX1010, 0043:1-0069:5; EX1002, ¶¶63-64.
`
`OCH3
`
`Cl
`
`S
`
`Terminal Moieties
`
`OCH3
`
`S
`
`Cl
`
`Cl
`
`N
`
`HN
`
`X
`
`X = F or H
`
`N
`
`N
`
`O
`
`NH
`
`NH
`
`N
`
`N
`
`O
`
`NH
`
`NH
`
`O
`
`4'-morpholinophenyl
`
`4'-pyridinylpiperidinyl
`
`Example 1
`The '111 Publication; EX1009
`
`Example 7
`The '111 Publication; EX1009
`
`Examples 1-15
`The '111 Publication; EX1009
`
`
`
`The ’111 publication states that these compounds may be prepared as single
`
`enantiomers when a source of chirality is present, and that they may be purified
`
`and formulated using methods known to those in the art. EX1009, 18:16-29; 21:31-
`
`22:2; EX1010, 0022:16-29; 0025:31-0026:2; EX1002, ¶65. The ’111 publication
`
`also describes assays commonly used to measure factor Xa activity. EX1009, 27:7;
`
`EX1010, 0031:7; EX1003, ¶43. The ’111 publication was not of record during
`
`examination of the ’456 patent.
`
`4)
`
`Chiba, K., et al., Absorption, Distribution, Metabolism, and
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`Excretion of the Oxazolidinone Antibiotic Linezolid (PNU-100766) in
`
`the Sprague Dawly Rat, ICAAC, SAN DIEGO, CA September 24-27,
`
`1998 (“Chiba,” EX1011).
`
`Chiba is prior art to the claims of the ’456 patent under 35 U.S.C. § 102(b).
`
`Chiba discloses pharmacokinetic properties of linezolid, including 100% oral
`
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`bioavailability. EX1011 at 39; EX1002, ¶71; EX1003, ¶48. Chiba highlights
`
`linezolid as being “bioavailable and widely distributed,” after which it is excreted
`
`“primary in urine as parent drug, or as carboxylic acid metabolites that have low
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`antibacterial potency.” Chiba teaches that these metabolites are formed via
`
`morpholine ring oxidation. Id.; EX1002, ¶71. Chiba was not of record during
`
`examination of the ’456 patent.
`
`5) WO 99/37630, to Gordeev et al., filed January 22, 1999 (“the
`
`’630 publication,” EX1012).
`
`The ’630 publication published on July 29, 1999 and qualifies as prior art
`
`under 35 U.S.C. 102(b). The ’630 publication teaches acylation of the free amine
`
`precursor of linezolid with a carbonyl chloride, as shown below:
`
`EX1012 at Figure 25, 0194; EX1002, ¶¶73-74.
`
`The ’630 publication also teaches that linezolid and its (S)-isomer may be
`
`synthesized via epoxidation of an alkene, followed by amine-based nucleophilic
`
`attack and subsequent cyclization with the phosgene equivalent CDI, as shown
`
`
`
`below:
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`
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`EX1012 at Figure 25, 0194; EX1002, ¶¶74-75.
`
`The ’630 publication was not substantively discussed during examination of the
`
`’456 patent.
`
`6)
`
`U.S. Patent No. 5,817,671 to Filla et al., filed November 14,
`
`1997 (“the ’671 patent,” EX1013).
`
`The ’671 patent issued on October 6, 1998 and qualifies as prior art under 35
`
`U.S.C. 102(b). The ’671 patent teaches the acylation of the free amine of a
`
`substituted 5-aminopyrrolo[3,2,-b]pyridine with 5-chloro-2-thiophenecarbonyl
`
`chloride, in pyridine, to yield the corresponding acylated derivative in high yield.
`
`EX1013 at 34:40-53; EX1002, ¶77. The ’671 patent was not of record during
`
`examination of the ’456 patent.
`
`D. Brief Overview of the Level of Skill in the Art
`
`At the time of the invention, a person having ordinary skill in the art of the
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`claims of the ’456 patent would include an individual or a team of individuals
`
`having some combination of the following skills and experience: (i) experience
`
`with the synthesis of organic compounds; (ii) experience designing pharmaceutical
`
`compounds; (iii) an understanding of general principles of drug design and
`
`delivery, including pharmacology, pharmacokinetics, toxicology, and formulation;
`
`(iv) an understanding of the role of anticoagulants, including factor Xa inhibitors,
`
`in the treatment and prevention of thromboembolism disorders; and (v) the ability
`
`to understand work presented or published by others in the field, including the
`
`publications discussed in this petition. EX1002, ¶¶23-24; EX1003, ¶¶22-23.
`
`Typically, a person of ordinary skill in the relevant field as of the earliest
`
`alleged priority date, i.e., December 24, 1999, would have, or be a member of a
`
`team with a member having, an advanced degree (e.g., a Ph.D.) in organic
`
`chemistry, medicinal chemistry, or a related field. The skilled artisan may also
`
`have, or be a member of a team having, a medical degree (e.g., an M.D.) with
`
`experience treating thromboembolism disorders using anticoagulants.
`
`Alternatively, a person of ordinary skill in the relevant field might have less
`
`education but considerable professional experience in one or more of these fields.
`
`EX1004; EX1005.
`
`Dr. Salvatore Lepore is a medicinal chemist who began his career in
`
`pharmaceutical research and drug development nearly 20 years ago, and worked in
`
`
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`18
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`the development of factor Xa inhibitors in the late 1990s and early 2000s. EX1002,
`
`¶¶1-2. Dr. Lepore is currently a Professor of Chemistry and Biochemistry at
`
`Florida Atlantic University where he teaches courses on organic chemical reactions
`
`and drug design, and leads research efforts focused on the development of new
`
`synthetic organic reaction methodology and their application to the total synthesis
`
`of compounds of therapeutic interest. EX1002, ¶3. Dr. Lepore earned his Ph.D. in
`
`1997 from Purdue University, after which he conducted research as a postdoctoral
`
`fellow at Eli Lilly and Company. EX1002, ¶2. Dr. Lepore has authored or co-
`
`authored many peer-reviewed journal articles and book chapters and has been the
`
`recipient of numerous awards. Id. at ¶5. A summary of his education, experience,
`
`awards and honors, patents, publications, and presentations is provided in his CV,
`
`submitted as EX1004. See also, EX1002, ¶¶ 1-6.
`
`Dr. Lepore is a well-qualified expert in the field of drug design and
`
`possesses the expertise necessary to determine and explain the level of ordinary
`
`skill in the art during the relevant time frame, i.e., prior to December 24, 1999.
`
`EX1002, ¶¶1-6; see also EX1004.
`
`Dr. Jack Hirsh has over 50 years of experience in the field of treating blood
`
`coagulation disorders. EX1003, ¶1. Dr. Hirsh is currently a Professor Emeritus in
`
`the Department of Medicine at McMaster University in Ontario, Canada. EX1003,
`
`¶3. Dr. Hirsh received a Bachelor of Medicine, Bachelor of Surgery degree, and a
`
`
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`subsequent M.D. from Melbourne University in 1958 and 1962, respectively. Id. at
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`¶2. Dr. Hirsh has authored or co-authored many peer-reviewed journal articles and
`
`book chapters and has been the recipient of numerous awards. Id. at ¶5. A
`
`summary of his education, experience, awards and honors, publications, and
`
`presentations is provided in his CV, submitted as EX1005; see also, EX1003, ¶¶ 1-
`
`6.
`
`Dr. Hirsh is a well-qualified expert in the field of blood coagulation
`
`disorders, possessing the necessary scientific, technical, and other specialized
`
`knowledge to assist in an understanding of the evidence presented herein, as well
`
`as possessing the expertise necessary to determine and explain the level of ordinary
`
`skill in the art during the relevant time frame, i.e., prior to December 24, 1999.
`
`EX1005; see also, EX1003, ¶¶1-6.
`
`II. GROUNDS FOR STANDING
`
`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’456 patent is
`
`available for inter partes review, and Petitioner is not barred or estopped from
`
`requesting inter partes review of the ’456 patent on the grounds identified.
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`Real Party-in-Interest (37 C.F.R. § 42.8(b)(1)): The following real parties-in-
`
`interest are identified: Mylan Pharmaceuticals, Inc., which is the Petitioner in this
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`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.
`
`Related Matters (37 C.F.R. § 42.8(b)(2)):
`
`IPR petitions for related 7,585,860 and 7,592,339 are being been filed by the
`
`present Petitioner as IPR2017-00042 and IPR2017-00043, respectively.
`
`Petitioner and other entities are involved in litigation over the ’456 patent
`
`and related patents in the action styled CA No. 1:15-cv-00902-SLR, filed by Bayer
`
`Intellectual Property GmbH et al. in the District of Delaware. (EX1016). A
`
`complaint asserting the ’456 patent against Petitioner was served no earlier than
`
`October 9, 2015. Petitioner also identifies the following pending actions involving
`
`the ’456 patent: Bayer GmbH v. Breckenridge Pharmaceutical, Inc., No. 1:16-cv-
`
`00628, in the District of Delaware; and Bayer GmbH v. InvaGen Pharmaceutical
`
`Inc., No. 1:16-cv-00064, in the District of Delaware.
`
`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b) (3)):
`
`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
`
`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
`
`Back-Up Counsel: Jad A. Mills (Reg. No. 63,344)
`
`Service Information (37 C.F.R. § 42.8(b) (4)):
`
`Petitioner hereby consents to electronic service.
`
`Email: sparmelee@wsgr.com; mrosato@wsgr.com; jmills@wsgr.com
`
`
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`Post: WILSON SONSINI GOODRICH & ROSATI
`
`701 Fifth Avenue, Suite 5100, Seattle, WA 98104-7036
`
`Tel.: 206-883-2542 Fax: 206-883-2699
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED
`
`Petitioners request review of claims 1-8, 10-14, 16-22, 24, 26-28, and 30 of
`
`the ’456 patent under 35 U.S.C. § 311 and AIA § 6 and that each of the claims be
`
`canceled as unpatentable:
`
`Ground
`
`Claims
`
`Obvious under §103 over
`
`1
`
`2
`
`1-6, 8, 10, 13-14, 16-19, 24,
`26-28, and 30
`
`Ewing, Riedl, the ’111 publication,
`and Chiba
`
`7, 11-12, and 20-22
`
`Ewing, Riedl, the ’111 publication,
`Chiba, the ’630 publication, and the
`’671 patent
`
`V. CLAIM CONSTRUCTION
`
`In an inter partes review, a claim in an unexpired patent is given its broadest
`
`reasonable construction in light of the specification. 37 C.F.R. § 42.100(b);
`
`Cuozzo Speed Techs., LLC v. Lee, 15-446, slip op. at 2 (U.S. June 20, 2016).
`
`Claims terms are also “generally given their ordinary and customary meaning,”
`
`which is the meaning that the term would have to a person of ordinary skill in the
`
`art at the time of the invention in view of the specification. In re Translogic Tech.,
`
`Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); EX1002, ¶25; EX1003, ¶24. Under
`
`
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`22
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`

`
`either standard, there is a reasonable likelihood that Petitioner will prevail with
`
`respect to the challenged claims. No terms are believed to require special
`
`construction for the purposes of this inter partes review proceeding.
`
`VI. BACKGROUND KNOWLEDGE IN THE ART P