UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BAYER INTELLECTUAL PROPERTY GmbH,
`Patent Owner.
`
`_____________________________
`
`Patent No. 7,157,456
`
`_____________________________
`
`
`
`DECLARATION OF SALVATORE D. LEPORE, PH.D.
`
`
`
`MYLAN - EXHIBIT 1002
`
`

`
`
`
`
`
`TABLE OF CONTENTS
`TABLE OF CONTENTS
`
`I.
`I.
`
`QUALIFICATIONS ..................................................................................... 1
`QUALIFICATIONS ................................................................................... .. 1
`
`II.
`II.
`
`SCOPE OF WORK ...................................................................................... 4
`SCOPE OF WORK .................................................................................... .. 4
`
`III. OVERVIEW OF THE ’456 PATENT .............................................................. 4
`III.
`OVERVIEW OF THE ’45 6 PATENT ............................................................ .. 4
`
`IV. FILE HISTORY OF THE ’456 PATENT ........................................................... 7
`IV.
`FILE HISTORY OF THE ’45 6 PATENT ......................................................... .. 7
`
`V.
`V.
`
`LEGAL STANDARDS ................................................................................. 7
`LEGAL STANDARDS ............................................................................... .. 7
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME .................................. 10
`VI.
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ................................ .. 10
`
`VII. CLAIM CONSTRUCTION .......................................................................... 12
`VII. CLAIM CONSTRUCTION ........................................................................ .. 12
`
`VIII. THE STATE OF THE ART.......................................................................... 12
`VIII. THE STATE OF THE ART ........................................................................ .. 12
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`IX.
`ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’456 PATENT. ............................................................ 24
`FEATURES OF THE ’45 6 PATENT. .......................................................... .. 24
`
`X.
`X.
`
`CONCLUDING STATEMENTS .................................................................... 84
`CONCLUDING STATEMENTS .................................................................. .. 84
`
`XI. APPENDIX – LIST OF EXHIBITS ............................................................... 86
`XI.
`APPENDIX — LIST OF EXHIBITS ............................................................. .. 86
`
`
`
`-i-
`
`

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`
`
`I, Salvatore D. Lepore, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am currently a tenured full professor of Chemistry and Biochemistry at
`
`Florida Atlantic University (FAU) where I lead a team of researchers on projects
`
`related to the chemistry of drug discovery. I have over 20 years of experience in this
`
`area. I have been a member of the faculty at Florida Atlantic University since 2000.
`
`2.
`
` I received a B.S. in chemical engineering from the University of South
`
`Florida in 1992 and a Ph.D. in organic chemistry from Purdue University in 1997.
`
`After completing my Ph.D., I was awarded a Postdoctoral Fellowship position at Eli
`
`Lilly and Company’s World Headquarters (1997-2000). Under the direction of Dr.
`
`Michael R. Wiley, my research focus was on the synthesis of small-molecule and
`
`peptide-based direct thrombin inhibitors. One of my most notable contribution to
`
`Lilly’s drug discovery program was the development of new solid-phase methods to
`
`prepare libraries of thrombin inhibitors containing a 2-hydroxybenzamidine moiety,
`
`leading to a significant improvement in oral bioavailability. My efforts while at Lilly
`
`resulted in four peer-reviewed publications, as well as three patent applications,
`
`including PCT Application No. WO 2006057845, entitled “Preparation of
`
`(hetero)aromatic ether amides as inhibitors of Factor Xa and/or thrombin,” which
`
`resulted in several issued patents.
`
`
`-1-
`
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`
`

`
`
`
`3.
`
`In August of 2000, I joined the faculty at Florida Atlantic University as
`
`an Assistant Professor in the Department of Chemistry and Biochemistry. I was
`
`promoted with tenure in 2006 to Associate Professor and in 2011 to Professor. My
`
`professional responsibilities include the scientific oversight of a team of doctoral
`
`students, technicians, and postdoctoral fellows. I teach doctoral level courses in the
`
`area of Medicinal Chemistry and Organic Synthesis with an emphasis on medicinally
`
`relevant organic small molecules. My research emphases over the course of my career
`
`at FAU fall into two main categories: the development of new reactions to expedite
`
`the incorporation of radiofluorine into small molecules for applications in positron
`
`emission tomography (PET); and, the development of synthesis methods involving
`
`allenes.
`
`4.
`
`I have been funded by the National Institutes of Health (NIH) as a
`
`Principal Investigator for several multi-year projects to develop Organic Chemistry
`
`reactions and apply them to the synthesis of therapeutically valuable compounds. One
`
`of these funded projects was to utilize the unique reactivity of allenes for the partial
`
`total synthesis of vitisinol D, a natural product that has been briefly studied by others
`
`as an antiplatelet agent. I serve as a Scientific Advisory Board Member for CHS
`
`Pharma and also as a subcontractor in their drug discovery effort. I have also served as
`
`
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`-2-
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`

`
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`a consultant to several biotech companies including Unison Pharmaceuticals and
`
`Xcovery.
`
`5.
`
`I am an Associate Editor for the journal Perspectives in Medicinal
`
`Chemistry since 2006. This is an international, peer-reviewed journal that provides
`
`drug design experts with updates on recent advances in the field. In addition to serving
`
`as a long-time and consistent reviewer of manuscripts for many of the pinnacle
`
`journals in my field (including the Journal of American Chemical Society and
`
`Organic Letters), I am also a high frequency reviewer for the European Journal of
`
`Medicinal Chemistry earning a “top-tenth percentile reviewer” status. I am the author
`
`of nearly 30 peer-reviewed publications as an independent investigator for which I am
`
`the corresponding author in nearly all cases. In addition to numerous conference
`
`presentations, I have been invited to present my work throughout the US and
`
`internationally. I am the listed inventor or co-inventor on six patents or patent
`
`applications.
`
`6.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately. EX1004.
`
`
`
`-3-
`
`

`
`
`II.
`
`SCOPE OF WORK
`
`7.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review of U.S. Patent No. 7,157,456 (“the
`
`’456 patent,” EX1001). I have been retained by the Petitioner as a technical expert to
`
`provide analysis and opinions regarding the ’456 patent. I have reviewed the ’456
`
`patent and relevant sections of its prosecution history in the United States Patent and
`
`Trademark Office. EX1006. I have also reviewed and considered various other
`
`documents in arriving at my opinions, and cite them in this declaration. For
`
`convenience, documents cited in this declaration are listed in the Appendix in Section
`
`XI.
`
`8.
`
`I am being compensated at the rate of $175/hour for my work. I have no
`
`financial interest in the outcome of this matter.
`
`III. OVERVIEW OF THE ’456 PATENT
`
`9.
`
`The ’456 patent issued January 2, 2007. The ’456 patent is entitled
`
`“Substituted Oxazolidinones and their use in the field of Blood Coagulation.” The first
`
`page of the patent states that the ’456 patent resulted from the June 24, 2002 national
`
`stage entry (U.S. Application No. 10/181,051, “the ’051 application”) of
`
`PCT/EP00/12492, filed on December 11, 2000. The ’456 patent claims priority to
`
`German Application No. 199 62 924, filed on December 24, 1999. For the purposes of
`
`
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`-4-
`
`

`
`
`this declaration, I have assumed that the ’456 patent is entitled to claim the benefit of
`
`the December 24, 1999 foreign filing date of the ’924 application.
`
`10. The ’456 patent is directed to oxazolidinone-based compounds for use in
`
`the field of blood coagulation disorders. Independent claim 1 of the ’456 patent
`
`discloses a genus of chemical compounds comprising an oxazolidinone core with a
`
`variety of optional substituents. Dependent claims 2-5, 10, and independent claims 6
`
`and 16 further limit the substituent groups of the compound of claim 1. For example,
`
`independent claim 16 recites the following:
`
`16. A compound having the following formula:
`
`O
`
`N
`
`O
`
`O
`
`N
`
`O
`
`NH
`
`S
`
`O
`
`Cl
`
`
`
`Dependent claim 14 specifies that the compound of claim 6 is purified and isolated.
`
`11. Dependent claims 8 and 17-19 are directed towards pharmaceutical
`
`combinations comprising a compound within the scope of claims 1, 6, 14, and 16,
`
`respectively and one or more pharmacologically acceptable auxiliaries or excipients.
`
`Independent claim 27 recites:
`
`27. A composition comprising a compound having formula (a):
`
`
`
`-5-
`
`

`
`
`
`O
`
`N
`
`O
`
`O
`
`N
`
`O
`
`NH
`
`S
`
`Cl
`
`O
`
` (a)
`
`or a pharmaceutically acceptable salt or hydrate thereof, wherein the
`
`composition is substantially free of the enantiomer of the
`
`compound of formula (a) and substantially free of the salts and
`
`hydrates of the enantiomer of the compound of formula (a).
`
`Dependent claim 28 recites the pharmaceutical composition of claim 27 additionally
`
`comprises one or more pharmacologically acceptable auxiliaries or excipients.
`
`12. Dependent claims 7, 11, 12, and 20-22 recite various chemical processes
`
`for synthesizing the compounds of claims 1 and 6. Finally, dependent claims 13, 24,
`
`26, and 30 recite methods of treating thromboembolic disorders such as myocardial
`
`infarct, pulmonary embolism, or deep vein thrombosis via the administration of a
`
`compound of claim 1 or one of the claimed pharmaceutical compositions comprising
`
`the compounds of claims 1, 6, or 14.
`
`13. The compound of claim 16 is also known as (S)-5-chloro-N-((2-oxo-3-(4-
`
`(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide. For
`
`convenience, this compound will be referred to as “rivaroxaban.”
`
`
`
`-6-
`
`

`
`
`IV. File History of the ’456 Patent
`
`14. As noted above, the ’456 patent issued on January 2, 2007. On October 3,
`
`2003 the Examiner issued a restriction requirement, and the Applicants elected a
`
`subset of oxazolidinones comprising a phenylmorpholinone substituent. EX1006 at
`
`3468-75; id. at 3463-64. Rejections were issued for failing to comply with the written
`
`description and enablement requirements under 35 U.S.C. § 112 (id. at 3416-20; id. at
`
`0720-28; id. at 0678-90; id. at 0619-29), however, the Examiner did not issue a
`
`rejection over the prior art. In the Notice of Allowance, which was mailed April 27,
`
`2006, the examiner noted the “closest prior art of record” to be PCT application No.
`
`WO 97/09328 to Hutchinson et al., which describes a genus of oxazolidinones with
`
`antimicrobial activity. Id. at 0598-91.
`
`V. LEGAL STANDARDS
`
`15.
`
`I have been informed that a claimed invention is not patentable under 35
`
`U.S.C. § 103, for obviousness, if the differences between the invention and the prior
`
`art are such that the subject matter as a whole would have been obvious at the time the
`
`invention was made to “a person having ordinary skill in the art” to which the subject
`
`matter of the invention pertains. I understand that “a person of ordinary skill in the
`
`art” is a hypothetical person who is presumed to have known the relevant art at the
`
`time of the invention. As discussed above, I understand that prior art for the purpose
`
`
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`-7-
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`of this declaration includes references that were published at least before December
`
`24, 1999.
`
`16.
`
`I have been instructed that, a determination of obviousness requires
`
`inquiries into (i) the scope and content of the art when the invention was made; (ii) the
`
`differences between the art and the claims at issue; (iii) the level of ordinary skill in
`
`the pertinent art when the invention was made; and, to the extent they exist, any
`
`secondary considerations.
`
`17.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one skilled in the art could have combined
`
`the elements as claimed by known methods with no change in their respective
`
`functions, and the combination would have yielded nothing more than predictable and
`
`expected results to one of ordinary skill in the art.
`
`18.
`
`I understand that improper hindsight must not be used when comparing
`
`the prior art to the invention for obviousness. Thus, a conclusion of obviousness must
`
`be firmly based on the knowledge and skill of a person of ordinary skill in the art at
`
`the time the invention was made.
`
`19.
`
`I have been informed that obviousness may also be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior art to create the patented invention. I understand that obviousness may
`
`
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`-8-
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`

`
`
`be demonstrated by showing that it would have been obvious to combine the teachings
`
`of more than one item of prior art. I understand that in order for a combination of
`
`references or teachings to render the claimed invention obvious, there must be some
`
`supporting rationale for combining the cited references or teachings as proposed.
`
`20.
`
`I am informed that the following are examples of principles that may
`
`indicate that it would have been obvious to combine multiple teachings, resulting in
`
`the claimed combination, if the claimed combination involves: (i) the combination of
`
`prior art elements according to known methods to yield predictable results; (ii) the
`
`simple substitution of one known element for another to obtain predictable results;
`
`(iii) the use of a known technique to improve similar methods or products in the same
`
`way; (iv) the application of a known technique to a known method or product ready
`
`for improvement to yield predictable results; (v) the application of a technique or
`
`approach that would have been “obvious to try” (e.g., choosing from a finite number
`
`of identified, predictable solutions, with a reasonable expectation of success); (vi)
`
`predictable variations of a known work in one field of endeavor prompted for use in
`
`either the same field or a different field based on design incentives or other market
`
`forces; or (vii) some teaching, suggestion, or motivation in the prior art that would
`
`have led one of ordinary skill to modify the prior art reference or to combine prior art
`
`reference teachings to arrive at the claimed invention.
`
`
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`-9-
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`
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`21.
`
`I also understand that “secondary considerations” may be weighed
`
`against evidence of obviousness where appropriate.
`
`22.
`
`I understand that such secondary considerations, where in evidence, may
`
`include: (i) commercial success of a product due to the merits of the claimed
`
`invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of others
`
`to find the solution provided by the claimed invention; (iv) deliberate copying of the
`
`invention by others; (v) unexpected results achieved by the invention; (vi) praise of
`
`the invention by others skilled in the art; (vii) lack of independent simultaneous
`
`invention within a comparatively short space of time; and (viii) teaching away from
`
`the invention in the prior art. Secondary considerations are relevant where there is a
`
`nexus between the evidence and the claimed invention.
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`23.
`
`I have been advised that “a person of ordinary skill in the relevant field”
`
`is a hypothetical person who is presumed to have known the relevant art at the time of
`
`the invention. A person of ordinary skill in the art is also a person of ordinary
`
`creativity. As discussed above, I have assumed that the relevant timeframe for
`
`assessing the validity of claims of the ’456 patent for the purposes of this declaration
`
`is December 24, 1999. Unless otherwise specifically noted, all of my opinions
`
`
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`-10-
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`
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`expressed herein regarding a person of ordinary skill in the art apply to a person of
`
`ordinary skill in the art as of December 24, 1999.
`
`24. By virtue of my education, experience, and training, I am familiar with
`
`the level of skill in the art of the ’456 patent prior to December 24, 1999. In my
`
`opinion, a person of ordinary skill in the relevant field as of December 24, 1999 would
`
`typically include an individual with an advanced degree (e.g., a Ph.D.) in organic
`
`chemistry, medicinal chemistry or a related field, or could have less education but
`
`considerable professional experience in one or more of these fields. In particular, one
`
`of ordinary skill in the art at the time of the alleged invention of the ’456 patent would
`
`likely include an individual or a team of individuals having some combination of the
`
`following skills and experience, in addition to the educational level discussed above:
`
`(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; and (v) the ability to understand work presented or published by others in
`
`the field, including the publications discussed in this declaration.
`
`
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`-11-
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`
`
`VII. CLAIM CONSTRUCTION
`
`25.
`
`I have been advised that, in the present proceeding, the ’456 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`specification. I also understand that, absent some reason to the contrary, claim terms
`
`are typically given their ordinary and accustomed meaning as would be understood by
`
`one of ordinary skill in the art. I have followed these principles in my analysis
`
`throughout this declaration.
`
`VIII. THE STATE OF THE ART
`
`26. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of December 24, 1999.
`
`27.
`
`Prior to 1999, thromboembolic disorders were known to arise from
`
`malfunctions occurring in the blood coagulation process. Kamata, K., et al., Structural
`
`basis for chemical inhibition of human blood coagulation factor Xa, 95 PROC. NATL.
`
`ACAD. SCI. USA (1998) 6630-35 (“Kamata,” EX1014). Kamata teaches how blood
`
`clots can form as a result of the coagulation cascade: “Blood clots are formed by a
`
`zymogen activation cascade of serine proteases, and the last protease of the cascade,
`
`thrombin, converts fibrinogen to fibrin, which cross-links to form blood clots.”
`
`EX1014 at 6630. Kamata describes factor Xa as existing at the intersection of the
`
`extrinsic and intrinsic blood coagulation pathways: “Factor X is secreted into the
`
`
`
`-12-
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`
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`blood as the zymogen form of the serine protease and is converted to an active form,
`
`factor Xa, by the factor VIIa/tissue factor complex (in the extrinsic pathway) or by the
`
`factor IXa/factor VIIIa complex (in the intrinsic pathway).” Id.
`
`28. Kamata describes that the inhibition of thrombin has led to the
`
`development of anticoagulants, “[b]ut factor Xa, which is also essential for both the
`
`intrinsic and extrinsic pathways of the coagulation process, is thought to be a better
`
`target of antithrombotic drugs because many thrombin inhibitors have been shown to
`
`increase the risk of abnormal bleeding.” Id.
`
`29. Kamata describes the primary binding pockets of factor Xa, teaching the
`
`presence of an S1 pocket and an “aryl binding site” which is also referred to in the art
`
`as the S4 pocket. EX1014 at 6632. Katakura teaches that hydrophobic saturated
`
`heterocycles can bind in the S4 pocket, and also teaches that aromatic groups can bind
`
`in the S1 pocket. See, e.g., Katakura, S., et al., Molecular model of an interaction
`
`between factor Xa and DX-9065a, a novel factor Xa inhibitor: contribution of the
`
`acetimidoylpyrrolidine moiety of the inhibitor to potency and selectivity for serine
`
`proteases, 30 EUR. J. MED. CHEM. (1995) 387-94 (“Katakura,” EX1015) (noting that
`
`the S1 binding pocket of factor Xa preferentially binds a planar aromatic moiety over
`
`a saturated heterocycle, which in turn binds in the S4 pocket).
`
`
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`-13-
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`
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`30. Linezolid, an oxazolidinone with two modular arms that was also known
`
`as U-100766 or PNU-100766, was well known in the art to have impressive
`
`pharmaceutic and pharmacokinetic properties, including 100% oral bioavailability.
`
`F
`
`O
`
`O
`
`N
`
`N
`
`O
`
`Linezolid
`
`NH
`
`O
`
`CH3
`
`
`
`Stalker, D., Linezolid Pharmacokinetics, OXAZOLIDINONES: A NEW CLASS OF
`
`ANTIBIOTICS SYMPOSIUM, 1998 (“Stalker,” EX1017).
`
`31. Linezolid belongs to a class of compounds known as oxazolidinones,
`
`which are comprised of a five-membered heterocyclic core and exhibit a range of
`
`biological activities. Many oxazolidinones are functionalized with two pendant
`
`groups that can be modified to optimize various therapeutic activities. Gante, J. et al.,
`
`New Peptidomimetics in the Chemistry of Fibrinogen Receptor Antagonists, 2 LETT.
`
`PEPT. SCI., (1995) 135-40 (“Gante,” EX1018).
`
`32.
`
`In the mid 1990’s, some oxazolidinones were identified as useful
`
`anticoagulants. U.S. Patent No. 5,532,255, to Raddatz et al., filed April 29, 1994
`
`(“Raddatz,” EX1019); see also, U.S. Patent No. 5,614,535, to Juraszyk et al., filed
`
`August 18, 1995 (“Juraszyk,” EX1020). Raddatz and Juraszyk teach that these
`
`
`
`-14-
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`

`
`
`oxazolidinones can be optimized for more than one therapeutic use; in addition to the
`
`anti-thrombotic activity noted above, “the compounds are also suitable as anti-
`
`microbial active substances which are able to prevent infections[.]” EX1019 at 2:25-
`
`34; see also EX1020 at 3:5-9.
`
`33.
`
`In addition to being impressive for its oral bioavailability, linezolid was
`
`also known to be well-tolerated by humans, whereas other oxazolidinone-based
`
`pharmaceuticals were known to pose toxicity problems. Brickner, S. J., Oxazolidinone
`
`Antibacterial Agents 2 CURR. PHARM. DES. 175-194 (1996) (“Brickner I,” EX1021).
`
`Brickner I notes that clinical trials of the oxazolidinone Dup-721 were apparently
`
`halted due to toxicity concerns. EX1021 at 178. Linezolid, also known as U-100766,
`
`however, was found to not have the toxicity observed with Dup-721. Id. Dup-721
`
`comprised an 4’-acetyl group off of the phenyl group. Id. Replacing this 4’-acetyl
`
`group with the nitrogen-containing morpholine ring in linezolid, as shown below,
`
`avoided the toxicity observed in Dup-721. Id.; see also Gleave, D. M., et al.,
`
`Synthesis and Antibacterial Activity of [6,5,5] and [6,6,5] Tricyclic Fused
`
`Oxazolidinones, 8 BIOORG. MED. CHEM. LETT. (1998) 1231-36 (“Gleave,” EX1022) at
`
`1231 (showing both linezolid and des-fluorolinezolid).
`
`
`
`-15-
`
`

`
`
`
`O
`
`CH3
`
`NH
`
`O
`
`CH3
`
`NH
`
`O
`
`CH3
`
`NH
`
`O
`
`N
`
`O
`
`O
`
`O
`
`N
`
`O
`
`N
`
`O
`
`O
`
`CH3
`
`N
`
`F
`
`O
`
`N
`
`O
`
`4'-acetyl
`DUP-721
`Brickner, EX1021
`
`
`
`4'-morpholine
`Linezo lid
`Riedl, EX1008
`
`4'-morpholine
`Des-fluorolinezolid
`Gleave, EX1022
`
`
`
`34. Linezolid was described in the art as a promising oxazolidinone
`
`compound known to be “rapidly and extensively absorbed after oral dosing” in
`
`humans. EX1017 at 0002. Linezolid was also able to be formulated as an intravenous
`
`formulation, allowing for easy administration to patients who were too ill to take oral
`
`medication. Id. As noted by those in the art, “the average absolute bioavailability is
`
`103%. Therefore, linezolid may be given orally without a dose adjustment in patients
`
`who are able to receive oral medication.” Id. Thus, doctors could easily switch
`
`between intravenous and oral formulations of linezolid without performing
`
`calculations to identify the change in dosage required to alter administration routes.
`
`35. The 100% oral bioavailability of linezolid allowed for the entirety of the
`
`drug to be delivered to the blood stream without undergoing first pass elimination. Id.
`
`at 0002-03. Additionally, linezolid was known to not be a substrate of nor induce
`
`cytochrome p450 enzymes and to have relatively few unwanted drug-drug
`
`
`
`-16-
`
`

`
`
`interactions. EX1017 at 0003-05. Linezolid was also known to remain 100% orally
`
`bioavailable in the presence of food and to have a very high volume of distribution. Id.
`
`at 0002, 0004.
`
`36. As linezolid progressed through Phase III clinical trials, various
`
`formulations of linezolid, as well as a synthesis process capable of achieving a multi-
`
`kilogram-scale, were developed prior to the year 2000. EX1021 at 183. Linezolid’s
`
`total synthesis is relatively short, with those in the art able to access linezolid from
`
`commercially-available starting materials in just a handful of synthetic steps. EX1021
`
`at 183. The synthetic accessibility of linezolid further allows for analogues to be easily
`
`accessed. Brickner, S. J., et al., Synthesis and Antibacterial Activity of U-100592 and
`
`U-100766, Two Oxazolidinone Antibacterial Agents for the Potential Treatment of
`
`Multidrug-Resistant Gram-Positive Bacterial Infections 39 J. MED. CHEM. 673-79
`
`(1996) (“Brickner II,” EX1023). Regarding the established synthesis of linezolid,
`
`Brickner II teaches that it “is applicable to the synthesis of widely divergent 3-(4-
`
`substituted-aryl)-2-oxazolidinones,” and “proceeds with high efficiency from
`
`commercially available reagents.” EX1023 at 674-75. Thus, Brickner II teaches that
`
`new structural subunits could be easily introduced into linezolid’s core framework.
`
`37. Brickner II also teaches that the fluorine of linezolid was a late-stage add-
`
`on to enhance in vitro and in vivo antibacterial potency:
`
`
`
`-17-
`
`

`
`
`
`Additional enhancements in in vitro and in vivo potency were attained by
`
`fluorine substitution at the phenyl 3-position, leading to U-100592. A
`
`bioisostere of piperazine, the morpholinyl analogue U-10076 [linezolid],
`
`contemporaneously emerged from our extensive structure-activity
`
`relationship (SAR) studies.
`
`EX1023 at 674.
`
`38. Additionally, Brickner I teaches the 3’-fluorine of phenylated
`
`oxazolidinones could be exchanged for a simple hydrogen. EX1021 at 187; see also,
`
`EX1022 at 1231. Additionally, utilization of the simpler, non-fluorinated phenyl
`
`moiety allows for significantly cheaper starting materials to be utilized, thereby
`
`significantly reducing the cost of synthesizing the drug. Notably, the 3’-fluorinated
`
`starting material cost seven times more than the non-fluorinated starting material.
`
`Sigma-Aldrich Product Catalogue 1995-96 (“Sigma-Aldrich Catalogue,” EX1024) at
`
`529 and 733 (indicating a 7-fold decrease in cost of 4-fluoro-nitrobenzene as
`
`compared to 3,4-difluoro-nitrobenzene). Moreover, the 3’-des-fluoro bioisostere of
`
`linezolid was known to be synthetically accessible. See e.g., EX1022 at 1235
`
`(Compounds 3a and 3b in Table I).
`
`39.
`
`Just as the 3’-fluorine of linezolid was a relic of the desire to optimize the
`
`antibacterial activity of oxazolidinones, the 5-acetamidomethyl side chain of linezolid
`
`
`
`-18-
`
`

`
`
`was also known to be important to maintaining antibacterial activity. EX1021 at 186.
`
`Regarding antimicrobial efficacy, Brickner I teaches:
`
`Analysis of the SAR concerning the 5-methyl substituent is suggestive
`
`that the oxazolidinone [antibacterial] binding site is very sensitive to the
`
`steric environment about the 5-position of the oxazolidinone, and not
`
`tolerant of drastic deviation from the ‘most active’ acetamidomethyl side
`
`chain. The superiority of this group was interpreted as an indication of a
`
`stronger intrinsic ‘binding attraction’ for the 5-acetamidomethyl
`
`oxazolidinones. In contrast, there is witnessed far greater tolerance for
`
`structural diversity in the ‘western half’ of the molecule, i.e., within the
`
`3-aryl group substituents.
`
`Id. Thus, it was known that the 5-acetamidomethyl side chain, like the 3’-fluorine,
`
`was strongly related to antimicrobial activity.
`
`40.
`
`It has also long been known that terminal 5-chlorothiophene moieties are
`
`useful for inhibiting blood platelet aggregation. U.S. Patent No. 4,075,340, to
`
`Maffrand et al., filed June 2, 1976 (“Maffrand,” EX1025), for example, describes
`
`compounds with “useful anti-inflammatory and antiarrhythmic activities and an
`
`inhibiting action on blood platelet aggregation.” EX1025 at [57]. Maffrand teaches
`
`compounds which possess this clinical activity and have terminal 5-chlorothiophene
`
`moieties. See EX1025 at Example 6 and claim 1. Compounds identified as being
`
`direct factor Xa inhibitors were also known in the art to possess terminal 5-
`
`
`
`-19-
`
`

`
`
`chlorothiophene moieties. See e.g., US Patent No. 5,958,918 to Ewing et al. (“the ’918
`
`patent,” EX1026) at 9:23-25; US Patent No 5,925,635 to Maduskuie, Jr. et al. (“the
`
`’635 patent,” EX1027) at 8:60-61, 62:31.
`
`41. Prior to December 1999, it was also known that metabolites of drug
`
`candidates “can guide structural modifications, thereby improving the activity and/or
`
`bioavailability.” Korfmacher et al., HPLC API/MS/MS: a powerful tool for integrating
`
`drug metabolism into the drug discovery process, 2 DRUG DISC. TODAY 532 (1997)
`
`(“Korfmacher,” EX1028). With regard to the importance of identifying and evaluating
`
`candidate drug metabolites, Korfmacher teaches:
`
`Metabolite identification in drug discovery provides early information
`
`that can lead to structural changes in the current lead compound,
`
`improving such pharmacokinetic parameters as oral bioavailability, half –
`
`life (t1/2), or Cmax. Often these parameters can be changed by improving
`
`the metabolic stability of the compound. In order to improve metabolic
`
`stability, it is very important to know how a compound is metabolized.
`
`The goal of drug discovery is to progress a lead compound into a final
`
`candidate drug that can be placed in the development stage . . . Early
`
`metabolite identification can provide information on how to improve the
`
`metabolic stability of the lead structure. In this way, future lead
`
`compounds might be a metabolite identified from the previous lead drug
`
`or an analog of the previous drug designed to block the major route of
`
`metabolism.
`
`
`
`-20-
`
`

`
`
`EX1028 at 534. Thus, as taught by Korfmacher, a person of ordinary skill in the art
`
`would have looked to synthesize and evaluate known metabolites when optimizing a
`
`therapeutic compound.
`
`42. The metabolic pathway of morpholine-containing pharmaceuticals was
`
`well-established in the art prior to December 1999. For example, Jauch teaches that
`
`the morpholine-containing agent moclobemide primarily metabolizes oxidatively in
`
`humans. Jauch, R. et al., Biotransformation of moclobemide in humans, Suppl. 360
`
`ACTA PSYCHIATR. SCAND.(1990) 87-90 (“Jauch,” EX1029).
`
`43.
`
` Jauch explains: “Consistent with other morpholine-containing
`
`compounds, metabolic pathways of moclobemide include mainly oxidative attack on
`
`the morpholine moiety,” leading to metabolites resulting from “morpholine C-
`
`oxidation.” EX1029 at 87. Jauch additionally states: “Quantitatively, the products of
`
`the oxidation of the morpholine ring are particularly prominent,” and notes
`
`“metabolites with a lactam structure . . . are formed.” Id. at 88. One such metabolite is
`
`the lactam shown below, which has undergone C-oxidation adjacent to the nitrogen of
`
`the morpholine ring to produce a lactam morpholinone derivative of moclobemide.
`
`
`
`-21-
`
`

`
`
`
`O
`
`N
`
`H2
`CR
`
`O
`
`morpholinone metabolite
`of moclobemide
`
`oxidative metabolism
`
`lactam formation
`
`H2
`C
`
`HN
`
`CO
`
`R=
`
`Cl
`
`
`
`H2
`CR
`
`N
`
`O
`
`morpholine subunit
`of moclobemide
`
`44. Metabolites containing the morpholinone subunit, or which are derived
`
`from a primary metabolite with a morpholinone subunit, make up over half of the
`
`metabolites described by Jauch. EX1029 at 88, Figure 1. Jauch teaches morpholinone
`
`formation as part of a “general pattern” of morpholine metabolism:
`
`From studies with a variety of compounds carrying a morpholine moiety,
`
`a general pattern of metabolic degradation reactions emerges. Carbo