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. IPR2017-00042
`Patent No. 7,585,860
`_____________________________
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 7,585,860
`
`
`
`
`
`
`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. IPR2017-00042
`Patent No. 7,585,860
`_____________________________
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 7,585,860
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.INTRODUCTION .......................................................................................................... 1
`
`A.
`
`BRIEF OVERVIEW OF THE ’860 PATENT .................................................... 1
`
`B.
`
`BRIEF OVERVIEW OF THE PROSECUTION HISTORY .................................... 6
`
`C.
`
`BRIEF OVERVIEW OF THE SCOPE AND CONTENT OF THE PRIOR
`ART ......................................................................................................... 6
`
`D.
`
`BRIEF OVERVIEW OF THE LEVEL OF SKILL IN THE ART .............................. 6
`
`II.GROUNDS FOR STANDING ....................................................................................... 17
`
`III.MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 .................................................... 18
`
`IV.STATEMENT OF THE PRECISE RELIEF REQUESTED .................................................. 19
`
`V.CLAIM CONSTRUCTION .......................................................................................... 19
`
`VI.BACKGROUND KNOWLEDGE IN THE ART PRIOR TO DECEMBER 24, 1999 ................ 19
`
`VII.DETAILED EXPLANATION OF GROUNDS FOR UNPATENTABILITY .......................... 20
`
`A.
`
`[Ground 1] Claim 1 is Obvious Under 35 U.S.C. § 103 Over
`Ewing, Riedl, the ’111 Publication and Chiba. ...................................... 27
`
`VIII.CONCLUSION ...................................................................................................... 43
`
`IX.CERTIFICATE OF COMPLIANCE............................................................................... 44
`
`X.PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ................................. 45
`
`XI.APPENDIX – LIST OF EXHIBITS .............................................................................. 46
`
`
`
`
`
`-i-
`
`
`
`
`I.
`
`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) requests inter partes review of
`
`U.S. Patent No. 7,585,860 to Straub et al. (“the ’860 patent,” EX1001), which
`
`issued on September 8, 2009. PTO records indicate the ’860 patent is currently
`
`assigned to Bayer Intellectual Property GmbH (“Patent Owner”). This petition
`
`demonstrates that there is a reasonable likelihood that claim 1 of the ’860 patent is
`
`unpatentable over the asserted prior art. Additional petitions are also being filed to
`
`address U.S. Patent Nos. 7,157,456 and 7,592,339, over both of which the ’860 is
`
`terminally disclaimed.
`
`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. Claim 1
`
`of the ʼ860 patent is directed to a compound or hydrate thereof that is described in
`
`the patent as being able to bind to and inhibit factor Xa. The crystal structure of
`
`factor Xa was known, and the art had established the presence of dual binding
`
`pockets for inhibitors, termed the S1 and S4 pockets, on factor Xa. 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
`
`
`
`1
`
`
`
`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
`
`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. Id. 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. 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
`
`O
`
`R
`
`N
`
`O
`
`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.
`
`
`
`-2-
`
`
`
`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
`
`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
`Compo und 49
`
`The '111 Publication; EX1009
`Example 1
`
`The '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
`
`
`
`-3-
`
`
`
`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 taught as suitable for factor Xa
`
`binding and 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 exact 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 a readily 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 omit 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 optimization in the art. An assessment of
`
`
`
`-4-
`
`
`
`a factor Xa inhibitor compound based on the structure of linezolid by the person of
`
`
`
`ordinary skill would have identified morpholine ring-opened metabolites, as noted
`
`in Chiba (EX1011). The 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 recited in claim 1 of the ʼ860 patent.
`
`Evidence in support of the forgoing analysis is presented and discussed in
`
`detail below.
`
`A. BRIEF OVERVIEW OF THE ’860 PATENT
`
`The ’860 patent is entitled “Substituted Oxazolidinones and their Use in the
`
`Field of Blood Coagulation,” and has only two claims. EX1001. The ’860 patent is
`
`directed to rivaroxaban (structure shown below), describing it as a factor Xa
`
`inhibitor. Independent claim 1 of the ’860 patent recites:
`
`1.
`
`A compound of the formula:
`
`O
`
`N
`
`O
`
`O
`
`N
`
`O
`
`NH
`
`S
`
`O
`
`Cl
`
`
`
`or a hydrate thereof.
`
`
`
`-5-
`
`
`
`B.
`
`BRIEF OVERVIEW OF THE PROSECUTION HISTORY
`
`
`
`U.S. Patent Application 12/027,553 (“the ’553 application”) was filed on
`
`February 7, 2008 and claims priority through a series of continuations to
`
`PCT/EP00/12492, filed on December 11, 2000, which claims priority to German
`
`Application No. 199 62 924, filed on December 24, 1999. The ’533 application
`
`issued on September 8, 2009 as the ’860 patent.
`
`The Examiner first rejected the claims for lack of enablement under 35
`
`U.S.C. § 112 with regard to a prodrug claim limitation, as well as for nonstatutory
`
`double patenting over U.S. Patent No. 7,157,456. EX1006 at 0053-58. No
`
`rejections based on prior art were made by the Office. Applicants subsequently
`
`removed the prodrug claim limitations and filed a terminal disclaimer over the
`
`’456 patent. Id. at 0048-49. A Notice of Allowance was mailed shortly thereafter.
`
`Id. at 0023-28.
`
`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).
`
`
`
`-6-
`
`
`
`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).
`
`Ewing was published in July 1999 and is prior art to the claims of the ’860
`
`patent under 35 U.S.C. § 102(b). Ewing teaches using anticoagulants for the
`
`treatment and prevention of thromboembolic disorders. EX1007 at 771; EX1002,
`
`¶48. 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. 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.”
`
`
`
`-7-
`
`
`
`Id. Additionally, Ewing states that “the risk of bleeding complications might be
`
`
`
`minimized” by using factor Xa inhibitors. Id; EX1002, ¶49. Ewing states “[t]he
`
`risk of provoking prothrombotic rebound episodes observed with heparin and
`
`thrombin inhibitors would be minimized as 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, ¶50.
`
`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, ¶¶51-52. 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
`
`
`
`-8-
`
`
`
`“with strong oral pharmacokinetic properties.” Id. at 773-74; EX1002, ¶53. Ewing
`
`
`
`was not of record during examination of the ’860 patent.
`
`2)
`
`Riedl, B. et al., Recent Developments with Oxazolidinone
`
`Antibiotics, 9 EXP. OPIN. THER. PATENTS 625-633 (1999) (“Riedl,”
`
`EX1008).
`
`Riedl was published in May 1999 and is prior art to the claims of the ’860
`
`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, ¶55. 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 . . .
`
`
`
`-9-
`
`
`
`and may be useful in the treatment of thrombosis and myocardial infarction.”
`
`
`
`EX1008 at 630, 633; EX1002, ¶56.
`
`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
`
`position.” Id. at 629; EX1002, ¶57. 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, ¶58. Riedl was not
`
`substantively discussed during examination of the ’860 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. The ’111 publication was not of record during examination of
`
`the ’860 patent.
`
`
`
`-10-
`
`
`
`
`
`
`
`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
`
`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)).
`
`
`
`-11-
`
`
`
`As explained by Dr. Lepore, the ’778 application provides written
`
`
`
`description support for at least one claim of the ’111 publication. EX1002, ¶¶66-67.
`
`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, ¶65.
`
`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 th e '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:
`
`
`
`-12-
`
`
`
`
`
`Q1
`L1
`
`A6
`
`A3
`
`R2
`
`A5
`A4
`
`Formula 1
`The '111 Publication; EX1009
`and the '778 Application; 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):
`
`
`
`wherein Ro is hydrogen and Rp is a 4-morpholino group. EX1009, 3:5-6:10;
`
`EX1010, 0007:5-0010:10; EX1002, ¶66. 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,
`
`¶66. Thus, the ’778 application provides written description support for at least
`
`one claim of the ’111 publication. EX1002, ¶67.
`
`
`
`-13-
`
`
`
`The ’111 publication teaches the role of factor Xa in the blood coagulation
`
`
`
`cascade, noting it as a target for anticoagulant therapy. EX1002, ¶61. 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, ¶60. The ’111 publication discloses 15 specific direct factor
`
`Xa inhibitors, each comprising one of three modules (e.g., 4’-morpholinophenyl,
`
`4’-pyridinylpiperidinyl, or 4’-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, ¶¶62-63.
`
`OCH3
`
`Cl
`
`S
`
`Terminal Moieties
`
`OCH3
`
`X
`
`X = F or H
`
`S
`
`Cl
`
`Cl
`
`N
`
`HN
`
`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
`
`
`
`-14-
`
`
`
`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, ¶64. The ’111 publication
`
`also describes assays commonly used to measure factor Xa activity. EX1009, 27:7;
`
`EX1010, 0031:7.
`
`Chiba, K., et al., Absorption, Distribution, Metabolism, and 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 ’860 patent under 35 U.S.C. § 102(b).
`
`Chiba discloses pharmacokinetic properties of linezolid, including 100% oral
`
`bioavailability. EX1011 at 39; EX1002, ¶70. 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 antibacterial
`
`potency.” Chiba teaches that these metabolites are formed via morpholine ring
`
`oxidation. EX1011; EX1002, ¶70. Chiba was not of record during examination of
`
`the ’860 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 ’860 patent would include an individual or a team of individuals
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`having some combination of the following skills and experience: (i) experience
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`with the synthesis of organic compounds; (ii) experience designing pharmaceutical
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`compounds; (iii) an understanding of general principles of drug design and
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`delivery, including pharmacology, pharmacokinetics, toxicology, and formulation;
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`(iv) an understanding of the role of anticoagulants, including factor Xa inhibitors,
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`in the treatment and prevention of thromboembolism disorders; and (v) the ability
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`to understand work presented or published by others in the field, including the
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`publications discussed in this petition. EX1002, ¶¶22-23.
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`Typically, a person of ordinary skill in the relevant field as of the earliest
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`alleged priority date, i.e., December 24, 1999, would have, or be a member of a
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`team with a member having, an advanced degree (e.g., a Ph.D.) in organic
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`chemistry, medicinal chemistry, or a related field. The skilled artisan may also
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`have, or be a member of a team having, a medical degree (e.g., an M.D.) with
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`experience treating thromboembolism disorders using anticoagulants.
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`Alternatively, a person of ordinary skill in the relevant field might have less
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`education but considerable professional experience in one or more of these fields.
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`EX1004.
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`Dr. Salvatore Lepore is a medicinal chemist who began his career in
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`pharmaceutical research and drug development nearly 20 years ago, and worked in
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`the development of factor Xa inhibitors in the late 1990s and early 2000s. EX1002,
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`¶¶1-2. Dr. Lepore is currently a Professor of Chemistry and Biochemistry at
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`Florida Atlantic University where he teaches courses on organic chemical reactions
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`and drug design, and leads research efforts focused on the development of new
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`synthetic organic reaction methodology and their application to the total synthesis
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`of compounds of therapeutic interest. EX1002, ¶3. Dr. Lepore earned his Ph.D. in
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`1997 from Purdue University, after which he conducted research as a postdoctoral
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`fellow at Eli Lilly and Company. EX1002, ¶2. Dr. Lepore has authored or co-
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`authored many peer-reviewed journal articles and book chapters and has been the
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`recipient of numerous awards. Id. at ¶¶4-5. A summary of his education,
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`experience, awards and honors, patents, publications, and presentations is provided
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`in his CV, submitted as EX1004. See also, EX1002, ¶¶ 1-6.
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`Dr. Lepore is a well-qualified expert in the field of drug design, and
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`possesses the expertise necessary to determine and explain the level of ordinary
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`skill in the art during the relevant time frame, i.e., prior to December 24, 1999.
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`EX1002, ¶¶1-6; see also EX1004.
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`II. GROUNDS FOR STANDING
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`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’860 patent is
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`available for inter partes review, and Petitioner is not barred or estopped from
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`requesting inter partes review of the ’860 patent on the grounds identified.
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
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`Real Party-in-Interest (37 C.F.R. § 42.8(b)(1)): The following real parties-in-
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`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
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`indirectly wholly owned subsidiary of Mylan N.V.; and Mylan N.V.
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`Related Matters (37 C.F.R. § 42.8(b)(2)):
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`IPR petitions for related 7,157,456 and 7,592,339 are being filed by the
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`present Petitioner as IPR2017-00041 and IPR2017-00043, respectively.
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`Petitioner and other entities are involved in litigation over the ’860 patent
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`and related patents in the action styled CA No. 1:15-cv-00902-SLR, filed by Bayer
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`Intellectual Property GmbH et al. in the District of Delaware. (EX1016). A
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`complaint asserting the ’860 patent against Petitioner was served no earlier than
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`October 9, 2015. Petitioner also identifies the following pending actions involving
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`the ’860 patent: Bayer GmbH v. Breckenridge Pharmaceutical, Inc., No. 1:16-cv-
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`00628, in the District of Delaware; Bayer GmbH v. InvaGen Pharmaceutical Inc.,
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`No. 1:16-cv-00064, in the District of Delaware; and Bayer GmbH v. Micro Labs
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`Ltd., No. 1:16-cv-00242, in the District of Delaware.
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`Lead and Back-Up Counsel (37 C.F.R. § 42.8(b) (3)):
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`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
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`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
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`Back-Up Counsel: Jad A. Mills (Reg. No. 63,344)
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`Service Information (37 C.F.R. § 42.8(b) (4)):
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`Petitioner hereby consents to electronic service.
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`
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`Email: sparmelee@wsgr.com; mrosato@wsgr.com; jmills@wsgr.com
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`Post: WILSON SONSINI GOODRICH & ROSATI
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`701 Fifth Avenue, Suite 5100, Seattle, WA 98104-7036
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`Tel.: 206-883-2542 Fax: 206-883-2699
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED
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`Petitioner requests review of claim 1 of the ’860 patent under 35 U.S.C. §
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`311 and AIA § 6 and that this claim be canceled as unpatentable:
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`Ground
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`Claim
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`Obvious under §103 over
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`1
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`1
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`V. CLAIM CONSTRUCTION
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`Ewing, Riedl, the ’111 publication,
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`and Chiba
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`In an inter partes review, a claim in an unexpired patent is given its broadest
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`reasonable construction in light of the specification. 37 C.F.R. § 42.100(b);
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`Cuozzo Speed Techs., LLC v. Lee, 15-446, slip op. at 2 (U.S. June 20, 2016).
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`Claims terms are also “generally given their ordinary and customary meaning,”
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`which is the meaning that the term would have to a person of ordinary skill in the
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`
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`art at the time of the invention in view of the specification. In re Translogic Tech.,
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`Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); EX1002, ¶24. Under either standard,
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`there is a reasonable likelihood that Petitioner will prevail with respect to the
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`challenged claims. No terms are believed to require special construction at this
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`time for the purposes of this inter partes review proceeding.
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`VI. BACKGROUND KNOWLEDGE IN THE ART PRIOR TO DECEMBER 24, 1999
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`The background publications below reflect knowledge skilled artisans would
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`bring to bear in reading the prior art at the time of the invention, i.e., the earliest
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`claimed German priority date of December 24, 1999, and thereby assist in
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`understanding why one would have been motivated to combine or modify the
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`references as asserted in this petition. Ariosa Diagnostics v. Verinata Health, Inc.,
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`No. 15-1215, slip op. 1, 11-12 (Fed. Cir. Nov. 16, 2015). As established in KSR,
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`550 U.S. at 406, the knowledge of a skilled artisan is part of the store of public
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`knowledge that must be consulted when considering whether a claimed invention
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`would have been obvious. Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir.
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`2013).
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`Prior to December 24, 1999, it was known that anticoagulants were useful in
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`the treatment of thromboembolic disorders, which arise from malfunctions in the
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`blood coagulation cascade. Kamata, K., et al., Structural basis for chemical
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`inhibition of human blood coagulation factor Xa, 95 PROC. NATL. ACAD. SCI. USA
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`(1998) 6630-35 (“Kamata,” EX1014); EX1002 at ¶26. While Kamata teaches that
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`multiple targets in the coagulation cascade contribute to the formation of blood
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`clots, Kamata notes that one particular component of the blood coagulation
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`cascade, “factor Xa, which is also essential for both the intrinsic and extrinsic
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`pathways of the coagulation process, is thought to be a better target of
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`antithrombotic drugs because many thrombin inhibitors have been shown to
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`increase the risk of abnormal bleeding.” EX1014 at 6630; EX1002, ¶27. Kamata
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`describes factor Xa binding sites, including an S1 pocket and an “aryl binding
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`site,” also known in the art as an S4 pocket. EX1014 at 6630; EX1002, ¶28. These
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`pockets were identified as capable of binding planar aromatic groups and saturated
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`heterocycles, respectively. Id. at 6632; see also, Katakura, S. et al., Molecular
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`model of an interaction between factor Xa and DX-9065a, a novel factor Xa
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`inhibitor: contribution of the acetimidoylpyrrolidine moiety of the inhibitor to
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`potency and selectivity for serine proteases, 30 EUR. J. MED. CHEM. (1995) 387-94
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`(“Katakura,” EX1015); EX1002, ¶¶27-28.
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`Prior to December 1999, linezolid was known to have impressive
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`pharmaceutical properties, including 100% oral bioavailability. Stalker, D.,
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`Linezolid Pharmacokinetics, OXAZOLIDINONES: A NEW CLASS OF ANTIBIOTICS
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`
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`SYMPOSIUM, 1998 (“Stalker,” EX1017); EX1002, ¶¶29-30. Linezolid belongs to a
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`class of compounds known as oxazolidinones, which were identified in the mid-
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`1990s as useful antimicrobials and antithrombotics. U.S. Patent No. 5,532,255, to
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`Raddatz et al., filed April 29, 1994 (“Raddatz,” EX1019); see also, U.S. Patent No.
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`5,614,535, to Juraszyk et al., filed August 18, 1995 (“Juraszyk,” EX1020);
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`EX1002, ¶31. Though linezolid entered clinical trials because of its antimicrobial
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`properties, it was recognized that modifications to the two pendant groups off the
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`oxazolidinone ring allowed for optimization of different therapeutic activities,
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`including anticoagulant properties. Gante, J. et al., New Peptidomimetics in the
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`Chemistry of Fibrinogen Receptor Antagonists, 2 LETT. PEPT. SCI., (1995) 135-40
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`(“Gante,” EX1018); EX1002, ¶¶29-30.
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`Linezolid was known to be highly accessible from commercially-available
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`starting materials through a straightforward synthetic process. Brickner, S. J.,
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`Oxazolidinone Antibacterial Agents 2 CURR. PHARM. DES. 175-194 (1996)
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`(“Brickner I,” EX1021) at 183; see also, Brickner, S. J., et al., Synthesis and
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`Antibacterial Activity of U-100592 and U-100766, Two Oxazolidinone
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`Antibacterial Agents for the Potential Treatment of Multidrug-Resistant Gram-
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`Positive Bacterial Infections 39 J. MED. CHEM. 673-79 (1996) (“Brickner II,”
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`EX1023); EX1002, ¶35. Brickner II describes linezolid’s synthesis as easily
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`adaptable to “widely divergent 3-(4-substituted-aryl)-2-oxazolidinones,” and
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`highlights that the synthesis “proceeds with high efficiency from commercially
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`available reagents.” EX1023 at 674-75.
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`Given linezolid’s favorable properties, it was advanced into clinical trials,
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`and was found to be well-tolerated by humans. EX1021. Linezolid was also
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`identified as being “rapidly and extensively absorbed after oral dosing” in humans,
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`as well as being administrable via intravenous routes. EX1017 at 0002; EX1002,
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`¶33. The 100% oral bioavailability of linezolid, coupled with its dual
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`administration routes allowed for linezolid to “be given orally without a dose
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`adjustment in patients who are able to receive oral medication.” Id. As explained
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`by Dr. Lepore, this allowed doctors to “easily switch between intravenous and oral
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`formulations of linezolid without performing calculations to identify the change in
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`dosage required to alter administration routes.” EX1002, ¶33. Linezolid was also
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`known to have limited drug-drug interaction concerns, and remained 100% orally
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`bioavailable in the presence of food. EX1017 at 0002, 0004; EX1002,
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