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 JACK HIRSH, M.D.
`
`
`
`MYLAN - EXHIBIT 1003
`
`
`_____________________________
`
`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 JACK HIRSH, M.D.
`
`
`
`MYLAN - EXHIBIT 1003
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I. QUALIFICATIONS .................................................................................................. 1
`
`II. SCOPE OF WORK.................................................................................................... 3
`
`III. OVERVIEW OF THE ’456 PATENT ............................................................................ 3
`
`IV. FILE HISTORY OF THE ’456 PATENT ....................................................................... 5
`
`V. LEGAL STANDARDS .............................................................................................. 6
`
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME ................................................. 9
`
`VII. CLAIM CONSTRUCTION ....................................................................................... 10
`
`VIII.THE STATE OF THE ART ...................................................................................... 11
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`
`FEATURES OF THE ’456 PATENT. ...................................................................... 14
`
`GROUND 1. The Teachings of Ewing, the ’111 Publication, Riedl and
`
`Chiba Make Claims 13, 24, 26, and 30 Obvious. ............................................ 20
`
`X. CONCLUDING STATEMENTS ................................................................................ 25
`
`XI. APPENDIX – LIST OF EXHIBITS ........................................................................... 26
`
`
`
`-i-
`
`
`
`
`
`I, Jack Hirsh, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1. My name is Jack Hirsh. I am currently a consultant to the Faculty of
`
`Health Sciences at McMaster University and the Hamilton Health Sciences
`
`Corporation regarding intellectual property and commercialization matters as well as a
`
`Professor Emeritus in the Department of Medicine at McMaster University in Ontario,
`
`Canada. I have over 50 years of experience in the field of medicine.
`
`2.
`
`I received a Bachelor of Medicine, Bachelor of Surgery degree from the
`
`Melbourne University in 1958 and an M.D. from Melbourne University in 1962. I
`
`began my medical career as an Assistant Hematologist at the Royal Melbourne
`
`Hospital in Victoria, and continued as a Research Fellow at the Department of Internal
`
`Medicine at Washington University in St. Louis, Missouri. I have also served as a
`
`Visiting Research Scientist in the Department of Medicine and Blood and Vascular
`
`Research Unit at the University of Toronto, Ontario, Canada.
`
`3.
`
`I have also served as an Assistant Professor, and as a Professor, in the
`
`Department of Pathology and Medicine at McMaster University in Ontario Canada,
`
`after which I became a Chairman of the Department Medicine at McMaster. From
`
`1988 to 2003 I served as Director of the Hamilton Civic Hospitals Research Center in
`
`Ontario, Canada. I served as Vice-President of Research at Vascular Therapeutics
`
`
`
`1
`
`
`
`
`Inc. from 1994-1999, at GlycoDesign, Inc. from 1999-2003, at Hamilton Health
`
`Sciences from 2000-2002, and at Inflazyme from 2003-2004.
`
`4. My research has been funded by many grants and scholarships from
`
`organizations such as the Canadian Heart and Stroke Foundation, the Ministry of
`
`Health, and the Ontario Research Development Challenge Fund. I have served on the
`
`editorial board of peer-reviewed journals such as Haemostasis, Blood, Thrombus
`
`Research, the American Journal of Hematology, Review of Haematological Practice,
`
`Thrombosis & Haemostasis, Arteriosclerosis and Thrombosis, and the American
`
`Journal of Medicine.
`
`5.
`
`I have authored or co-authored many hundreds of publications of peer-
`
`reviewed journal articles as well as hundreds book chapters. I have received numerous
`
`honors and awards, including the Canadian Cardiovascular Society Research
`
`Achievement Award, the Outstanding Service Award as well as the Distinguished
`
`Research Professorship Award from the Heart and Stroke Foundation of Ontario, the
`
`Gairdner Foundation International Award for Achievement in Medical Science, the
`
`Henry M. Stratton Medal from the American Society of Hematology, and the Queen
`
`Elizabeth II Diamond Jubilee Medal.
`
`
`
`-2-
`
`
`
`
`
`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. EX1005.
`
`II.
`
`SCOPE OF WORK
`
`7.
`
`I have been informed 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 asked to analyze the ’456 patent. As part of
`
`my analysis, I reviewed the ’456 patent and portions of its prosecution history.
`
`EX1006. I have cited in this declaration various other documents that I reviewed in
`
`preparing my opinions. I have listed those documents in the Appendix in Section XI.
`
`8.
`
`I am being compensated at the rate of $700 per hour for my work. My
`
`compensation does not depend on the outcome of this matter.
`
`III. OVERVIEW OF THE ’456 PATENT
`
`9.
`
`The ’456 patent is titled “Substituted Oxazolidinones and their use in the
`
`field of Blood Coagulation.” Claims 1-6, 10, 14, and 16 of the ’456 patent recite
`
`oxazolidinones. Claim 16 is the most specific of these claims and recites the
`
`following:
`
`16. A compound having the following formula:
`
`
`
`-3-
`
`
`
`
`
`O
`
`N
`
`O
`
`O
`
`N
`
`O
`
`NH
`
`S
`
`O
`
`Cl
`
`
`
`I understand claims 1-6, 10, and 14 to comprise the structure as defined in claim 16.
`
`10.
`
`I am informed that 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, I will refer to this compound as “rivaroxaban.”
`
`11. Claims 8 and 17-19 recite pharmaceutical compositions comprising an
`
`oxazolidinone of claims 1, 6, 14, and 16, respectively, and one or more
`
`pharmacologically acceptable auxiliaries or excipients. Independent claim 27 recites a
`
`pharmaceutical composition comprising rivaroxaban which is free of impurities
`
`associated with the compound’s enantiomer. Claim 28 depends from claim 27 and
`
`recites a pharmaceutical composition as in claims 8 and 17-19. Claims 13, 24, 26, and
`
`30 describe administering an oxazolidinone of claim 1 or one of the claimed
`
`pharmaceutical compositions comprising the oxazolidinones of claims 1, 6, or 14, for
`
`the treatment of thromboembolic disorders, including myocardial infarct, pulmonary
`
`embolism and deep vein thrombosis.
`
`
`
`-4-
`
`
`
`
`IV. FILE HISTORY OF THE ’456 PATENT
`
`12. The ’456 patent issued from U.S. Application No. 10/181,051, which
`
`was filed as a national stage entry of Application No. PCT/EP00/12492, filed
`
`December 11, 2002. A restriction requirement was mailed on October 3, 2003 along
`
`with a rejection of all claims due to a lack of unity of invention. EX1006 at 3468-75.
`
`The applicant chose to retain claims which recited of phenylmorpholinone-substituted
`
`oxazolidinones. Id. at 3463-64. The claims were again rejected on April 19, 2004 for
`
`failure to comply with the written description requirement under 35 U.S.C. § 112. Id.
`
`at 3416-20. To overcome the rejection, the claims were amended and new claims
`
`directed toward the compound rivaroxaban were added. Id. at 0751-758.
`
`13. Citing 35 U.S.C. § 112 for lack of enablement, the Examiner again
`
`rejected claims which contained language regarding prodrugs, as well as claims which
`
`improperly depended from other claims, on January 25, 2005. Id. at 0720-28. The
`
`prodrug limitations were removed by applicants and dependent claims were corrected
`
`to be properly formatted and to comply with 35 U.S.C. § 112. Id. at 0697-0715.
`
`Claims reciting the treatment/prevention of disorders other than myocardial infarction,
`
`atherosclerosis, pulmonary embolism or deep venous thrombosis were rejected in a
`
`Final Rejection, mailed July 25, 2005, for lack of enablement. Id. at 0678-90. The
`
`claims were then amended to only comprise “methods for the prevention or treatment
`
`
`
`-5-
`
`
`
`
`of disorders within the group that the Examiner found enabled,” (id. at 0657),
`
`however, a second final rejection, dated February 3, 2006, was mailed, citing a lack of
`
`enablement for the prevention of the thromboembolic disorders recited in the claims.
`
`Id. at 0619-29. Following the prevention limitations being removed from the claims
`
`(id. at 0615-16), a Notice of Allowance was then mailed April 27, 2006. Id. at 0598-
`
`91.
`
`V. LEGAL STANDARDS
`
`14.
`
`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
`
`of this declaration includes references that were published at least before December
`
`24, 1999.
`
`15.
`
`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
`
`
`
`-6-
`
`
`
`
`the pertinent art when the invention was made; and, to the extent they exist, any
`
`secondary considerations.
`
`16.
`
`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.
`
`17.
`
`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.
`
`18.
`
`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
`
`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.
`
`
`
`-7-
`
`
`
`
`
`19.
`
`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.
`
`20.
`
`I also understand that “secondary considerations” may be weighed
`
`against evidence of obviousness where appropriate.
`
`21.
`
`I understand that such secondary considerations, where in evidence, may
`
`include: (i) commercial success of a product due to the merits of the claimed
`
`
`
`-8-
`
`
`
`
`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
`
`22.
`
`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. I have been informed that a person of ordinary skill in the art is also a
`
`person of ordinary creativity. I have assumed for the purposes of this declaration that
`
`the relevant timeframe for assessing the validity of claims of the ’456 patent for the
`
`purposes of this declaration is December 24, 1999. However, my opinions regarding a
`
`person of ordinary skill in the art would not change if the data were assumed to occur
`
`on December 11, 2002 or July 27, 2006.
`
`23.
`
`I am familiar with the level of skill in the art of the ’456 patent prior to
`
`December 24, 1999 because of my education and because of my experience with
`
`blood coagulation disorders for the past 50 years. In my opinion, a person of ordinary
`
`
`
`-9-
`
`
`
`
`skill in the relevant field as of December 24, 1999 would typically have, or would be a
`
`member of a team with individuals having, an M.D. with experience in the field of
`
`blood coagulation disorders, a Ph.D. with experience as a medicinal chemist and
`
`information about the role of factor Xa inhibitors in the anticoagulation pathway, or
`
`less education but considerable professional experience in one or more of these fields.
`
`One of ordinary skill in the art would also be capable of understanding work published
`
`in the field, including the publications discussed in this declaration. In addition, as
`
`pharmaceutical development is an inherently collaborative process, the skilled artisan
`
`would have access to, or be part of a team including, other skilled individuals such as
`
`medicinal chemists, organic chemists, pharmacologists, toxicologists, formulators,
`
`and clinicians.
`
`VII. CLAIM CONSTRUCTION
`
`24.
`
`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.
`
`
`
`-10-
`
`
`
`
`VIII. THE STATE OF THE ART
`
`25. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of December 24, 1999.
`
`26. A thrombus (blood clot) is an insoluble blood deposit made up of fibrin
`
`and red blood cells with variable platelet and erythrocyte components. Carville, D. G.
`
`M., et al., Thrombus precursor protein (TpPTM): marker of thrombosis early in the
`
`pathogenesis of myocardial infarction, 42 CLIN. CHEM. (1996) 1537-41 (“Carville,”
`
`EX1035). Thromboembolic disorders relate to the undesired formation of thrombi in
`
`the body, and include conditions in which a blood clot or a collection of blood clots
`
`create a blockage of a vein (thrombosis) or artery (thrombosis or embolism) in the
`
`body. Id. at 1537. Carville teaches: “Thrombosis plays a key role in the pathogenesis
`
`of many disease states, including myocardial infarction (MI), stroke, unstable angina
`
`(UA), deep vein thrombosis (DVT), and pulmonary embolism.” Id.
`
`27. Carville teaches “the role of thrombosis in MI has been understood for
`
`some time,” and notes “coronary artery thrombosis is the leading cause of mortality in
`
`the US, with 1.5 million cases of MI each year resulting in >700,000 deaths. In
`
`addition, >1 million cases of UA present to the emergency room (ER) each year in the
`
`US, of which 10-15% progress to MI.” Id. at 1537-38.
`
`
`
`-11-
`
`
`
`
`
`28.
`
`In addition to myocardial infarction and unstable angina, Carville notes
`
`additional thrombus-based disorders which can be deadly, including “[p]ostoperative
`
`DVT[, which] is responsible for increased mortality in surgical patients, its clinical
`
`sequela of pulmonary embolism being the largest single cause of postoperative
`
`mortality.” Id. at 1541. Thus, Carville teaches many disorders which were known to
`
`be related to thrombus formation, noting “great strides have been made in developing
`
`interventional and prophylactic therapies for postoperative thrombosis.” Id.
`
`29. Prior to 1999, physicians commonly used anticoagulants such as heparin,
`
`low molecular weight heparin, and warfarin to prevent and/or treat thromboembolic
`
`disorders. For example, anticoagulants such as warfarin were widely used to treat and
`
`prevent complications of acute ischemic syndromes including acute myocardial
`
`infarction and unstable angina. Anand, S. S., et al., Long-Term Oral Anticoagulant
`
`Therapy in Patients with Unstable Angina or Suspected Non-Q-Wave Myocardial
`
`Infarction 98 CIRCULATION (1998) 1064-1070 (“Anand,” EX1036). Anand teaches
`
`that administration of effective doses of anticoagulants resulted in a clinically relevant
`
`risk reduction in disorders involving thromboembolic events, such as myocardial
`
`infarction, ischemic stroke, and unstable angina:
`
`Previous trials of patients after MI indicate that moderate-intensity
`
`warfarin is both efficacious and safe. These trials were conducted without
`
`
`
`-12-
`
`
`
`
`
`aspirin use but demonstrated a 35% to 40% RR reduction in major
`
`vascular events. Three randomized controlled trials have demonstrated
`
`the benefits of variable-intensity warfarin (INR range, 1.5 to 4.5) in the
`
`prevention of thromboembolic events and stroke in patients with atrial
`
`fibrillation. The recent SPAF-III trial in which high-risk patients with
`
`chronic atrial fibrillation were randomized to warfarin (INR, 2 to 3) or
`
`aspirin plus fixed low-dose warfarin (INR, 1.2 to 1.4) demonstrated that
`
`moderate-intensity warfarin alone was more effective than low-dose
`
`warfarin and aspirin and resulted in a 67% risk reduction in ischemic
`
`strokes.
`
`Furthermore, trials in patients with unstable angina in which moderate-
`
`intensity warfarin was combined with aspirin demonstrate promising
`
`results that are consistent with the results of phase 2 of the OASIS pilot
`
`study.
`
`Id. at 1068.
`
`30. Though anticoagulants such as heparin and warfarin were widely used for
`
`treatment of these conditions, each of these anticoagulants was associated with certain
`
`complications and drawbacks. E.g., Taylor, F. C., et al., Evaluation of patients’
`
`knowledge about anticoagulant treatment, 3 QUALITY IN HEALTH CARE 79-85, at 79
`
`(1994) (“Taylor,” EX1037). For example, it was reported that “life-threatening
`
`bleeding and re-thrombosis” could occur if patients treated with warfarin or heparin
`
`“are over anticoagulated or under anticoagulated.” Id. It was well-established at the
`
`
`
`-13-
`
`
`
`
`time that the efficacy of the standard oral anticoagulant (warfarin) “can be adversely
`
`affected by many factors, including the patients’ concurrent drug treatment, changes
`
`in diet or alcohol intake, and physical illness.” Id.
`
`31. As another example, Palareti identifies bleeding as “the most serious
`
`complication of the use of oral anticoagulation in the prevention and treatment of
`
`thromboembolic complications.” Palareti, G., et al., Bleeding complications of oral
`
`anticoagulant treatment: an inception-cohort, prospective collaborative study
`
`(ISCOAT) 348 LANCET 423-28 (1996) (“Palareti,” EX1038) at 423.
`
`32. Because of the widespread adoption of oral anticoagulant therapy for
`
`treatment of thromboembolic disorders and the recognition that currently-available
`
`oral anticoagulants had certain drawbacks, undesired interactions, and risks, there
`
`remained in December 1999 a desire to develop additional oral anticoagulants to treat
`
`thromboembolic disorders.
`
`IX. ASSERTED REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’456 PATENT.
`
`A. Brief Overview of the Asserted References
`
`33.
`
`I understand that the references described below may be applied in
`
`assessing the validity of the ’456 patent.
`
`
`
`-14-
`
`
`
`
`
`(i) Ewing
`
`34. 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) was
`
`published in July 1999. I understand that Ewing can be applied in assessing the
`
`validity of the ’456 patent claims.
`
`35. Ewing discloses anticoagulants as “a crucial component in both acute
`
`intervention procedures and chronic prevention strategies for treatment and
`
`management of” thromboembolic-based disorders, including “myocardial infarction,
`
`stroke, deep vein thrombosis and pulmonary embolism.” EX1007 at 771.
`
`36. Ewing teaches certain advantages of anticoagulants that target factor Xa
`
`in comparison to then-existing anticoagulant therapeutics of the day: unfractionated
`
`heparin (UFH), low molecular weight heparins (LMWHs), and warfarin. Id. at 771,
`
`773. For example, Ewing states: “Direct inhibition of factor Xa activity in the
`
`prothrombinase complex blocks the single physiological source of thrombin
`
`generation.” Id. at 774. Ewing also states that “[i]nhibiting the source of thrombin
`
`generation [i.e., factor Xa] rather than its catalytic activity” could “afford superior
`
`anticoagulant agents.” Id.
`
`37. Ewing also reflects a high level of interest and optimism that existed at
`
`the time for developing factor Xa inhibitors. For example, Ewing states that “direct
`
`
`
`-15-
`
`
`
`
`inhibition of factor Xa activity should provide a potent anticoagulant devoid of the
`
`potentially limiting side effects observed with thrombin inhibitors.” Id. at 771. Ewing
`
`states that “[d]irect inhibition of factor Xa activity should have minimal impact upon
`
`normal hemostatic response/regulation processes…. As a consequence, the risk of
`
`bleeding complications might be minimized.” Id. at 774. Ewing also states that “[t]he
`
`risk of provoking prothrombotic rebound episodes observed with heparin and
`
`thrombin inhibitors would be minimized as well.” Id. Ewing was not alone in
`
`expressing this optimism. This state of thinking at the time motivated significant
`
`interest in developing Xa inhibitors.
`
`38. Ewing teaches that a variety of potent factor Xa inhibitors had been
`
`developed, that factor Xa inhibitors with strong oral pharmacokinetic and
`
`pharmacodynamics properties were desired, and that such improved factor Xa
`
`inhibitors may be obtained by using less basic factor Xa binding moieties. Id. at 783-
`
`84.
`
`(ii) The ’111 Publication
`
`39. WO 00/39111 to Beight et al. published July 6, 2000 (“the ’111
`
`publication,” EX1009) based on the December 15, 1999 International Application
`
`Number PCT/US99/29832 and the December 23, 1998 U.S. Provisional Application
`
`No. 60/113,778 (“the ’778 application” EX1010). I understand that the ’111
`
`
`
`-16-
`
`
`
`
`publication can be applied in assessing the validity of the ’456 patent, and have only
`
`utilized subject material in the ’111 publication that is also found in the ’778
`
`application. I have coupled citations to the ’111 publication with the relevant passages
`
`of the ’778 application to illustrate that the information cited can be found in both
`
`documents.
`
`40. The ’111 publication describes specific examples of inhibitors of factor
`
`Xa that it describes as useful “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, 1:9-20; EX1010, 0005:5-16.
`
`41. The ’111 publication outlines the blood coagulation cascade, including
`
`the role of factor Xa as a catalytic promoter of thrombin activation, and thereby,
`
`conversion of soluble fibrinogen to insoluble fibrin. EX1009, 1:26-2:27; EX1010,
`
`0005:22-0006:27. The ’111 publication also describes a continuing desire to develop
`
`factor Xa inhibitors for anticoagulant therapies. EX1009, 2:28-34; EX1010, 0006:28-
`
`34.
`
`42. The ’111 publication teaches that factor Xa inhibitors may be used for
`
`either “treatment and/or prophylaxis” of numerous thromboembolic disorders
`
`“includ[ing] venous thrombosis and pulmonary embolism, arterial thrombosis, such as
`
`
`
`-17-
`
`
`
`
`in myocardial ischemia, myocardial infarction, unstable angina, thrombosis-based
`
`stroke and peripheral arterial thrombosis.” EX1009, 19:29-34; EX1010, 0023:29-34.
`
`43. The ’111 publication also teaches standard factor Xa inhibition assays
`
`which were “standard assays known to those in the art.” EX1009, 27:7; EX1010,
`
`0031:7.
`
`(iii) Riedl
`
`44. Riedl, B. et al., Recent Developments with Oxazolidinone Antibiotics, 9
`
`EXP. OPIN. THER. PATENTS 625-633 (1999) (“Riedl,” EX1008) published in May
`
`1999. I understand that Riedl can be applied in assessing the validity of the ’456
`
`patent claims.
`
`45. Riedl discloses linezolid as having an “advantageous pharmacokinetic
`
`profile” including a “favourable safety profile.” Id. at 626. Riedl notes that linezolid
`
`achieved high plasma concentrations and was “well-tolerated in humans at clinically
`
`relevant doses.” Id. The structure of linezolid is shown below.
`
`F
`
`O
`
`O
`
`N
`
`N
`
`O
`
`linezolid
`(U-100766)
`
`NH
`
`O
`
`CH3
`
`
`
`
`
`-18-
`
`
`
`
`
`46. Riedl notes that pharmaceutical formulations of linezolid were known
`
`and discloses that linezolid was being evaluated in Phase III clinical trials. EX1008 at
`
`626-27. Riedl notes that linezolid was administrable both orally and intravenously.
`
`EX1008 at 627.
`
`(iv) Chiba
`
`47. 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), published in
`
`1998. I understand that Chiba can be applied in assessing the validity of the ’456
`
`patent.
`
`48. Chiba describes pharmacokinetic and pharmaceutical properties of
`
`linezolid, including its 100% oral bioavailability. EX1011 at 39. Chiba also describes
`
`the relatively low serum protein binding (32%), of linezolid, which means that most of
`
`the linezolid administered to the patient is available to act on a blood-localized target.
`
`Id.
`
`B. Detailed Analysis of the Claims
`
`49.
`
`I have read and reviewed the declaration of Dr. Salvatore D. Lepore and
`
`understand that, in his opinion, the compound having the structure recited in claims 1-
`
`6, 10, 14, and 16, referred to herein for convenience as rivaroxaban , as well as the
`
`
`
`-19-
`
`
`
`
`pharmaceutical formulations recited in claims 8, 17-19, and 27-28 of the ’456 patent,
`
`would have been obvious to a person of ordinary skill in the art designing a factor Xa
`
`inhibitor prior to December 24, 1999 in view of Ewing, Riedl, the ’111 publication,
`
`and Chiba. As explained in detail below, it is my opinion that it would have been
`
`obvious to a person of ordinary skill in the art to administer an effective amount of the
`
`factor Xa inhibitor rivaroxaban for the purposes and to the patients described in claims
`
`13, 24, 26, and 30. For example, it would have been obvious to administer an
`
`effective amount of a factor Xa inhibitor to inhibit thrombus formation in a patient
`
`with a myocardial infarct, pulmonary embolism, or deep vein thrombosis, as recited in
`
`claims 13, 24, 26, and 30 of the ’456 patent.
`
`50. Claims13, 24, 26, and 30 are presented below followed by my analysis of
`
`the claims. The analysis below identifies exemplary disclosure of the cited references
`
`with respect to the corresponding claim elements, and is not meant to be exhaustive.
`
`GROUND 1. The Teachings of Ewing, the ’111 Publication, Riedl and Chiba
`Make Claims 13, 24, 26, and 30 Obvious.
`
`51. As discussed above, I understand that Ewing (EX1007), the ’111
`
`publication (EX1009), Riedl (EX1008), and Chiba (EX1011) can be considered in
`
`evaluating the validity of the claims of the ’456 patent. Based upon my review of the
`
`declaration of Dr. Salvatore D. Lepore, I understand his opinion to be that the
`
`
`
`-20-
`
`
`
`
`structure recited in claims 1-6, 10, 14, and 16, referred to herein for convenience as
`
`rivaroxaban , as well as the pharmaceutical formulations recited in claims 8, 17-19,
`
`and 27-28 of the ’456 patent, would have been obvious to a person of skill in the art
`
`seeking to design a factor Xa inhibitor prior to December 24, 1999. As discussed in
`
`detail below, the use of a factor Xa inhibitor for the treatment of each of the
`
`conditions recited in claims 13, 24, 26, and 30 would have been obvious prior to
`
`December 24, 1999.
`
`Claim 13:
`
`A method for the treatment of a thromboembolic disorder
`
`comprising administering to a patient in need thereof an
`
`effective amount of a compound of claim 1, wherein the
`
`thromboembolic disorder is myocardial infarct, pulmonary
`
`embolism or deep venous thrombosis.
`
`Claim 24:
`
`A method for the treatment of myocardial infarct, pulmonary
`
`embolism or deep venous thrombosis comprising
`
`administering an effective amount of the composition of claim
`
`17 to a patient in need thereof.
`
`Claim 26:
`
`A method for the treatment of myocardial infarct, pulmonary
`
`embolism or deep venous thrombosis comprising
`
`administering an effective amount of the composition of claim
`
`18 to a patient in need thereof.
`
`
`
`-21-
`
`
`
`
`
`Claim 30:
`
`A method for the treatment of myocardial infarct, pulmonary
`
`embolism or deep venous thrombosis comprising
`
`administering an effective amount of the composition of claim
`
`28 to a patient in need thereof.
`
`52. As noted above, I understand that Dr. Lepore’s opinion to be that a
`
`person of ordinary skill in the art would have found it obvious to design the compound
`
`of claim 1 as a factor Xa inhibitor in view of the disclosures of Ewing, the ’111
`
`publication, Riedl, and Chiba. I also understand it would have been obvious to
`
`formulate an oxazolidinone such as rivaroxaban in a pharmaceutical composition as
`
`described in claims 17, 18 and 28 of the ’456 patent.
`
`53. Ewing describes antithrombotic therapy as “a crucial component in both
`
`acute intervention procedures and chronic prevention strategies for treatment and
`
`management” of thromboembolic-based disorders, including “myocardial infarction,
`
`stroke, deep vein thrombosis and pulmonary embolism.” EX1007 at 771 (emphasis
`
`added).
`
`54. Ewing evidences the knowledge of a person of ordinary skill in the art
`
`that factor Xa inhibitors were understood to be useful as anticoagulants in the
`
`inhibition of thrombus formation. For example, Ewing teaches “direct inhibition of
`
`factor Xa activity should provide a potent anticoagulant devoid of the potentially
`
`
`
`-22-
`
`
`
`
`limiting side effects observed with thrombin inhibitors.” Id. Ewing also teaches that
`
`“[d]irect inhibition of factor Xa activity in the prothrombinase complex blocks the
`
`single physiological source of thrombin generation.” EX1007 at 774.
`
`55.
`
`In addition to blocking the source of thrombin generation, Ewing notes
`
`that direct factor Xa inhibition may have benefits over the inhibition of other targets in
`
`the blood coagulation cascade: “Direct in
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
