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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________________
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
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`v.
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`BAYER INTELLECTUAL PROPERTY GMBH,
`Patent Owner.
`
`_____________________________
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`Patent No. 9,539,218
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`_____________________________
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`DECLARATION OF NEIL E. DOHERTY, III, M.D., FACC
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`MYLAN - EXHIBIT 1003
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`TABLE OF CONTENTS
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`I.Qualifications ....................................................................................................... 1
`II.Scope of Work .................................................................................................... 2
`III.The ’218 Patent .................................................................................................. 3
`IV.Legal Standards ................................................................................................. 4
`V.Level of Ordinary Skill in the art and Relevant Time .......................................... 7
`VI.Claim Construction ............................................................................................ 7
`VII.Scientific Background .................................................................................... 14
`VIII.Background Knowledge of the POSA ........................................................... 23
`to a POSA in view of the ’610 Publication and Kubitza Abstracts. ................. 30
`X.No Unexpected Results From Once-Daily Dosing ............................................ 44
`XI.Concluding Statements .................................................................................... 49
`XII.Appendix – List of Exhibits ............................................................................ 51
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`IX.The Methods of Claims 1-4 of the ’218 Patent would have been Obvious
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`-i-
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`I, Neil E. Doherty, III, M.D., FACC, declare as follows:
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`I.
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`QUALIFICATIONS
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`1. My name is Neil Doherty, III. I have over 25 years of experience as a
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`practicing cardiologist. I am currently the Medical Director of the Citrus Valley
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`Cardiology Medical Group, Inc. in Glendora, California. I am also a clinical
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`professor of Internal Medicine/Cardiology at Western University Health Services.
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`2.
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`I received a Bachelor of Arts in 1977 from the University of
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`Pennsylvania. In 1982, I received my M.D. from Harvard Medical School. After
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`medical school, I undertook postdoctoral training, including: Internal Medicine
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`Internship and Residency at Cedars-Sinai Medical Center (1982-1985), General
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`and Thoracic Surgery Residency at Duke University Medical Center (1985-1987),
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`Surgery Research and Clinical Fellowship at Massachusetts General Hospital
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`(1987-1988), Cardiology Fellowship at Harbor-UCLA (1988-1990) and a Cardiac
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`MRI and Nuclear Cardiology Imaging Fellowship at UCSF (1990-1991).
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`3.
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` I have been Board certified by the American Board of Internal
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`Medicine in Internal Medicine since 1985. I was certified by the American Board
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`of Internal Medicine in the subspecialty of Cardiovascular Disease in 1991 and
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`recertified in 2001 and 2011. I received my nuclear cardiology license in 1992 and
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`became certified in the subspecialty of nuclear cardiology in 2003.
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`4.
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`I have been a Fellow of the American College of Cardiology, the
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`American College of Chest Physicians and the American Society of Nuclear
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`Cardiology. I served as Director of Cardiology at Foothill Presbyterian Hospital
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`from 1997-2005, and on the Board of Directors of the American Heart Association,
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`East San Gabriel Valley, from 2000-2003.
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`5.
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`I have over 25 years of experiences as a practicing cardiologist and
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`have authored or co-authored many publications for peer-reviewed journal articles
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`and book chapters. A summary of my education, experience, publications, awards
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`and honors, patents, publications, and presentations is provided in my CV, a copy
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`of which is submitted separately. EX1052.
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`II.
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`SCOPE OF WORK
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`6.
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`I understand that Mylan Pharmaceuticals Inc. may file a petition for
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`Inter Partes Review of U.S. Patent No. 9,539,218 (“the ’218 patent,” EX1001)
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`with the United States Patent and Trademark Office. I have been asked by the
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`Petitioner to provide my opinions regarding the ’218 patent.
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`7.
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`I am being compensated at the rate of $500 per hour for my work
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`performed in conjunction with drafting this declaration. My compensation does not
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`depend on the outcome of this matter, and I have no financial interest in the
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`outcome of this matter.
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`III. THE ’218 PATENT
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`8.
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`The title of the ’218 patent is “Prevention and Treatment of
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`Thromboembolic Disorders.” EX1001 (the ’218 patent). The abstract of the ’218
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`patent states: “The present invention relates to the field of blood coagulation, more
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`specifically it relates to a method of treating a thromboembolic disorder by
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`administering once daily a direct factor Xa inhibitor in oral dosage form to a
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`patient in need thereof, wherein the factor Xa inhibitor has a plasma concentration
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`half life indicative of a bid [twice daily] or tid [thrice daily] administration interval,
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`e.g. of 10 hours or less.” EX1001 (the ’218 patent), [57].
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`9.
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`Claim 1 of the ’218 patent recites:
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`A method of treating a thromboembolic disorder comprising
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`administering a direct factor Xa inhibitor that is 5-Chloro-N-({(5S)-2-
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`oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-
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`yl}methyl)-2-thiophenecarboxamide no more than once daily for at
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`least five consecutive days in a rapid-release tablet to a patient in need
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`thereof, wherein the thromboembolic disorder is selected from the
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`group consisting of pulmonary embolisms, deep vein thromboses, and
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`stroke.
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`EX1001 (the ’218 patent), 10:63-11:5. For convenience, I refer to the compound
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`recited in claim 1 as “rivaroxaban” throughout this declaration.
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`-3-
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`10. Claims 2-4 depend from claim 1 and recite that the thromboembolic
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`disorder is pulmonary embolisms, deep vein thromboses, and stroke, respectively.
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`Id. at 11:6-11.
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`11.
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`I understand that the earliest claimed priority date of the ’218 patent is
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`January 31, 2005.
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`IV. LEGAL STANDARDS
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`12.
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`I have been informed that a claimed invention is not patentable under
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`35 U.S.C. § 103(a), for obviousness, if the differences between the invention and
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`the prior art are such that the subject matter as a whole would have been obvious at
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`the time the invention was made to “a person having ordinary skill in the art” to
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`which the subject matter of the invention pertains. I understand that “a person of
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`ordinary skill in the art” is a hypothetical person who is presumed to have known
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`the relevant art at the time of the invention. As discussed above, I understand that
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`prior art for the purpose of this declaration includes references that were published
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`at least before January 31, 2005.
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`13.
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`I have been instructed that a determination of obviousness requires
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`inquiries into (i) the scope and content of the art when the invention was made; (ii)
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`the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the invention was made; and, to the extent they exist,
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`any secondary considerations.
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`14.
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`I understand that a claim can be found to be obvious if all the claimed
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`elements were known in the prior art and one skilled in the art could have
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`combined the elements as claimed by known methods with no change in their
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`respective functions, and the combination would have yielded nothing more than
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`predictable and expected results to one of ordinary skill in the art.
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`15.
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`I understand that improper hindsight must not be used when
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`comparing the prior art to the invention for obviousness. Thus, a conclusion of
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`obviousness must be firmly based on the knowledge and skill of a person of
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`ordinary skill in the art at the time the invention was made.
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`16.
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`I have been informed that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the patented invention. I understand that obviousness
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`may be demonstrated by showing that it would have been obvious to combine the
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`teachings of more than one item of prior art. I understand that in order for a
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`combination of references or teachings to render the claimed invention obvious,
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`there must be some supporting rationale for combining the cited references or
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`teachings as proposed.
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`17.
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`I am informed that the following are examples of principles that may
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`indicate that it would have been obvious to combine multiple teachings, resulting
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`in the claimed combination, if the claimed combination involves: (i) the
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`combination of prior art elements according to known methods to yield predictable
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`results; (ii) the simple substitution of one known element for another to obtain
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`predictable results; (iii) the use of a known technique to improve similar methods
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`or products in the same way; (iv) the application of a known technique to a known
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`method or product ready for improvement to yield predictable results; (v) the
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`application of a technique or approach that would have been “obvious to try” (e.g.,
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`choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success); (vi) predictable variations of a known work in
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`one field of endeavor prompted for use in either the same field or a different field
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`based on design incentives or other market forces; or (vii) some teaching,
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`suggestion, or motivation in the prior art that would have led one of ordinary skill
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`to modify the prior art reference or to combine prior art reference teachings to
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`arrive at the claimed invention.
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`18.
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`I also understand that “secondary considerations” may be weighed
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`against evidence of obviousness where appropriate. I understand that such
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`secondary considerations, where in evidence, may include: (i) commercial success
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`of a product due to the merits of the claimed invention; (ii) a long-felt, but
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`unsatisfied need for the invention; (iii) failure of others to find the solution
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`provided by the claimed invention; (iv) deliberate copying of the invention by
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`others; (v) unexpected results achieved by the invention; (vi) praise of the
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`-6-
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`invention by others skilled in the art; (vii) lack of independent simultaneous
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`invention within a comparatively short space of time; and (viii) teaching away
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`from the invention in the prior art. Secondary considerations are relevant where
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`there is a nexus between the evidence and the claimed invention.
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`V.
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`LEVEL OF ORDINARY SKILL IN THE ART AND RELEVANT TIME
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`19.
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`I have been advised that “a person of ordinary skill in the relevant
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`field” is a hypothetical person who is presumed to have known the relevant art
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`existing at the time of the invention (“prior art”). I have been informed that a
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`person of ordinary skill in the art is also a person of ordinary creativity. Based
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`upon my more than 25 years of experience in treating thromboembolic disorders, I
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`am well-acquainted with the level of skill in the art of the ’218 patent. It is my
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`opinion that a person of ordinary skill in the art of the ’218 patent would include an
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`M.D. with experience in treating thromboembolic disorders, including stroke, deep
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`vein thrombosis, and pulmonary embolism.
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`VI. CLAIM CONSTRUCTION
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`20.
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`I have been advised that, in the present proceeding, the ’218 patent
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`claims are to be given their broadest reasonable interpretation consistent with the
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`specification of the ’218 patent as it would be understood by one of ordinary skill
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`in the art. I understand that it is improper to narrow the scope of the claim by
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`reading limitations from the specification into a claim that have no express basis in
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`the claim. I also understand that the meaning given to a claim term should be
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`consistent with the ordinary and customary meaning of the term to a person of
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`ordinary skill in the art unless the term has been given a special definition in the
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`specification. I also understand that the meaning given to a claim term should be
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`consistent with the use of the claim term in the specification and drawings. I have
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`followed these principles in my analysis throughout this declaration.
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`A. “treatment [for]…a patient in need thereof”
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`21. Each of the claims of the ’218 patent recite a method of treatment for
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`a patient in need thereof. The term “treatment” is defined in the specification of the
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`’218 patent as including each of therapeutic and prophylactic treatment of
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`thromboembolic disorders. EX1001 (the ’218 patent), 7:25-26. I have been asked
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`whether prophylactic treatment may include administration to apparently healthy
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`people who are in need of preventing thromboembolic disorders from developing.
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`It could. Indeed, the specification of the ’218 patent includes the Economy Class
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`Syndrome in its discussion of “thromboembolic disorders.” Id. at 7:32-8:12. In my
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`opinion, the claims of the ’218 patent do not require that the patient receiving the
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`method of treatment recited in the claims be diagnosed with an existing
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`thromboembolic disorder. Prophylactic treatment may include administration to
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`apparently healthy people during long flights who are in need of preventing
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`thromboembolic disorders from developing.
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`22.
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`In fact, prior to January 2005, the occurrence of thromboembolic
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`disorders, particularly deep vein thromboses were widely reported in apparently
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`healthy adults traveling on airplanes, I have included here a handful of prior art
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`publications reflecting the prophylactic need for anticoagulants in apparently
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`healthy individuals to prevent thromboembolic disorders.
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`23. Prior to 2005, as is still the case today, Economy Class Syndrome was
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`understood by those of skill in the art, as well as laypersons, to involve the onset of
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`a thromboembolic disorder such as a venous or pulmonary thromboembolism,
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`DVT, or stroke in an individual who is traveling or has recently traveled in an
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`airplane. See, e.g., Morales, T. Preventing Economy Class Syndrome, CBS News,
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`September 13, 2004 (“News Article,” EX1010). Morales, for example, is a CBS
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`News article warning about the dangers and risks of Economy Class Syndrome
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`following the release of updated guidelines from the American College of Chest
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`Physicians (ACCP). Id. at 1. As reported in the News Article, the ACCP “strongly
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`advise[s]” individuals planning to travel on an airplane for longer than six hours to
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`take “precautions” to prevent the “travel-related blood clots” associated with
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`Economy Class Syndrome. Id. The News Article notes that the ACCP identified
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`the following factors as putting individual travelers at increased risk: age, weight,
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`recent surgery, a family history of blood clots or an existing medical condition or
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`disease that would make the traveler prone to clotting, pregnancy, and the use of
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`contraceptive pills or hormone-replacement therapy. Id. at 2. I note that at least one
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`risk factor listed in the News Article would easily apply to well over half of all air-
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`travelers. In view of this heightened risk of experiencing a thromboembolic
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`disorder associated with air travel, the ACCP recommended that travelers with this
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`heightened risk for suffering from Economy Class Syndrome take “a blood-
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`thinning medication” prior to flying in order to reduce the probability of
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`developing a thromboembolic disorder such as DVT or stroke while traveling. Id.
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`at 1.
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`24.
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`Indeed, publications discussing the risk of thromboembolic disorders
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`resulting from air travel were common in this time frame. Isayev, for example,
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`teaches that “[c]ases of PE [pulmonary embolism] and DVT occurring during or
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`after long flights have been reported with increasing frequency. In 1986, a report
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`observed that over a 3-year period, PE was the second most common cause of
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`sudden death among long-distance air travelers. Two recent prospective studies
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`found that 4.5% and 10% of passengers developed DVT after prolonged flights.”
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`Isayev et al., “Economy class” stroke syndrome, 58 NEUROLOGY (2002) 960-61
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`(“Isayev,” EX1011) at 961 (also clarifying that the name Economy Class Stroke
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`Syndrome was used “to emphasize that cramped seating condition is an important
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`risk factor. However, DVT/PE also has been described in passengers flying in the
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`business or first class cabin.”).
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`25.
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`Isayev also discusses “three cases of ischemic stroke in young adults
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`that occurred during or after an airplane flight,” wherein no “cause of stroke other
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`than the presence of a patent foramen ovale [(PFO)]” was found. EX1011 at 960;
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`see also id. at 961 (noting the “high prevalence” of PFO, ranging between 17% and
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`35%, in the general population). The first two young adults discussed by Isayev,
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`described as healthy and athletic, respectively, suffered from ischemic strokes
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`following multiple hours of airplane travel (4 hours and 14 hours, respectively). Id.
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`The third adult, also described as healthy, “was a passenger on 2 flights of
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`approximately 90 minutes each separated by 6 hours of sitting in a transient
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`lounge.” Id. Despite the short plane durations and the physical activity associated
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`with disembarking and re-embarking the planes, she was also found to have
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`suffered from an ischemic stroke due to Economy Class Syndrome. Id.; see also
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`Foerch et al., “Economy Class Stroke Syndrome, Correspondence, 59 NEUROLOGY
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`(2002) 962-63 (“Foerch,” EX1012) at 963 (wherein the authors of the Isayev
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`article confirm that “Although longer duration flights have a higher risk of
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`pulmonary embolism and probably also of stroke, our cases suggest that stroke can
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`be related to shorter duration flights as well.”). Isayev teaches that “[a]ll patients
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`were healthy, nonsmoking, nonobese individuals with no vascular risk factors and
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`no significant medical history,” also reporting that the results of laboratory
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`workups “including protein C, protein S, factor V mutation, anti-thrombin III,
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`lupus anticoagulant, anti-cardiolipin antibody, homocysteine level, antinuclear
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`antibodies, and sedimentation rate were normal in all three patients. The Third
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`patient also had normal factors VIII, IX, and XI.” Id.
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`26.
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`Isayev concludes by stating: “’Economy class’ stroke syndrome may
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`be underdiagnosed and is an eminently preventable cause of stroke” and by noting
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`that passengers who are at high risk for developing DVT may require preventative
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`anticoagulant therapy before flying. EX1011 (Isayev) at 960-61.
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`27. Foerch, which I mentioned above in paragraph 25, confirms the
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`conclusions of Isayev in a letter to the editor of the journal that published the
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`Isayev article. EX1012 (Foerch) at 962. Foerch states that, “[t]o underscore the
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`importance of their report, we would like to add three very similar patients (aged
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`21, 63, and 64 years) with otherwise unexplained ischemic strokes that occurred
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`during long-distance air travel (> 9000 km in each case) who were admitted to our
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`department within the past year.” Id. Foerch similarly notes that “none [of the
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`patients] showed evidence of atherosclerosis or other cardiovascular risk factors.
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`Of course, due to the worldwide increase of air travel activities, more people will
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`have a stroke in flight by mere chance.” Id. at 962-63. In their response to Foerch’s
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`letter, the authors of the Isayev article note an “important similarity” between the
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`two reports—that the “three cases reported by Foerch et al. were collected from a
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`single center within a very short period of time. This suggests that the ‘economy
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`class’ stroke syndrome is probably not rare, particularly with current high volumes
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`of intercontinental flights.” EX1012 (Foerch) at 963.
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`B. “rapid release tablet”
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`28. The claims of the ’218 patent recite administration of a “rapid-release
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`tablet” of rivaroxaban. The term “rapid-release tablet” was well-accepted by
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`physicians with experience in treating thromboembolic disorders in January 2005
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`to mean conventional tablets which were not modified to release the active drug in
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`a delayed or extended manner. This accepted meaning is the same meaning of the
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`term “rapid-release tablet” referenced in the ’218 patent.
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`29. The ’218 patent describes tablets as falling into one of two categories,
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`“tablets releasing the active compound rapidly or in a modified manner.” EX1001
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`(the ’218 patent), 8:12-30. The former is a conventional tablet, also called a rapid-
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`release tablet or an immediate-release tablet. The latter is often called a modified-
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`release tablet. Common examples of modified-release tablets include extended,
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`sustained, prolonged, and delayed release tablets. In the field of blood coagulation
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`and treating thromboembolic disorders, the default understanding of a physician in
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`January 2005 was that administration of an anticoagulant by tablet referred to
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`administration by a rapid-release tablet.
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`30. The ’218 patent also gives an example of a rapid release tablet that
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`has a Q value (30 minutes) of 75%. No such language appears in the claims of the
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`’218 patent, which use the broader language of “rapid-release tablet.” In my
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`opinion, the claims of the ’218 patent in view of the patent’s written description do
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`not exclude rapid-release tablets having a Q value (30 minutes) lower than 75%.
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`VII. SCIENTIFIC BACKGROUND
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`A. Overview of Arterial and Venous Thrombotic Disorders
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`31. Coagulation of blood involves the formation of blood clots. When
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`those blood clots obstruct the flow of blood through blood vessels, it is known as
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`thrombosis. Thrombosis can occur in veins or arteries and in some cases, can lead
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`to death.
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`32. There are two types of thrombosis: arterial thrombosis and venous
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`thrombosis. Venous thrombi form in conditions of slow or absent blood flow and
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`result from either an excessive activation of the coagulation cascade
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`(hypercoagulability) or from some disease process or venous pooling (stasis) of the
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`blood. Venous thrombosis in humans usually occurs in leg veins and often occurs
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`from vascular trauma caused by damage to the vessel wall, especially after
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`orthopedic surgery.
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`33. Arterial thrombosis occurs in high flow systems. The thrombus blocks
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`arterial flow and the tissues normally supplied by the affected artery are damaged
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`or die because of lack of oxygen. Arterial thrombi cause (1) stroke when the
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`thrombus develops in a brain vessel and (2) myocardial infarction (MI) or unstable
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`angina—collectively known as acute coronary syndrome—when the thrombus
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`develops in a coronary artery.
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`34. When a venous thrombus breaks loose and travels in the blood, it is
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`called a venous thromboembolism. Venous thromboembolism (VTE) is an
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`avoidable condition of deep vein thrombosis (DVT) that may result in pulmonary
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`embolism (PE). VTE occurs when red bloods cells, fibrin, and, to a lesser extent,
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`platelets and leukocytes coagulate to form a thrombus within an intact
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`cardiovascular system. A patient undergoing kip or knee orthopedic surgery incurs
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`the greatest risk for VTE. PE occurs when a segment of a thrombus within the deep
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`venous system detaches itself from the blood vessel, travels to the lungs, and
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`lodges within the pulmonary arteries. Both of these conditions, if not properly
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`detected and treated, can have serious consequences, such as sudden death or
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`recurrent VTE and post-thrombotic syndrome characterized by persistent pain,
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`swelling, skin discoloration or necrosis and ulceration of the affected limb.
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`35. As a general rule, thrombi cause localized occlusive ischemia
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`(inadequate blood flow at an organ such as the heart), whereas venous thrombi
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`fragments give rise to pulmonary embolic complications (inadequate blood flow to
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`the lungs).
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`B.
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`Overview of Anticoagulants
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`36. Anticoagulants are agents for prevention and treatment of
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`thromboembolic disorders. Anticoagulants in clinical use modulate one or more
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`steps in the coagulation pathway and inhibit thrombin generation, thrombin
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`activity, or both.
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`37. The fundamental reason for prescribing anticoagulants is to treat the
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`presence of a blood clot or for prophylaxis (to prevent the formation of a clot) to
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`prevent stroke.
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`38. Examples of anticoagulants are heparins, warfarin, direct thrombin
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`inhibitors, and factor Xa inhibitors. As discussed below, anticoagulants are
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`administered orally, intravenously, or subcutaneously.
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`(a) Heparins
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`39. The first anticoagulant, heparin, was discovered in 1916. Aside from
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`its use during cardiopulmonary bypass, its beneficial effects were not realized until
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`the early 1970s when low dose heparin was shown to prevent deep vein thrombosis
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`(DVT) after major surgery. Heparin is used to treat various arterial and venous
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`thrombotic diseases. Heparin and low molecular weight heparins activate
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`antithrombin III causing inhibition of factor Xa and thrombin (IIa).
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`40. There are several heparin products used in the United States. Low
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`molecular weight heparins (“LMWHs”) offer a more predictable dose-response
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`curve than unfractionated heparin. LMWHs are administered at a fixed dose based
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`on total body weight and do not require tight regulation and monitoring, as is
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`warranted with warfarin and unfractionated heparin. There are several LMWH
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`options available to prescribers such as: Enoxaparin (Lovenox® and Clexane®);
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`Dalteparin (Fragmin®); Ardeparin (Normiflo®); Certoparin (Sandoparin®);
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`Parnaparin (Fluxum®); Tinzaparin (Innohep® and Logiparin®); Reviparin
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`(Clivarin®); and Nadroparin (Fraxiparin®). I have used Enoxaparin (Lovenox®) and
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`Dalteparin (Fragmin®) for several years.
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`41. Enoxaparin (Lovenox®) was approved in 1993 for prevention of DVT,
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`which may lead to PE following hip replacement surgery. It was approved in 1998
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`for additional indications including: prevention of DVT, which may lead to PE; in
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`patients undergoing hip replacement surgery, during and following hospitalization;
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`in patients undergoing knee replacement surgery; and in patients undergoing
`
`abdominal surgery who are at risk for thromboembolic complications. Patients at
`
`risk include patients who are over 40 years of age, obese, undergoing surgery
`
`under general anesthesia lasting longer than 30 minutes or who have additional risk
`
`factors such as malignancy or a history of DVT or PE; the inpatient treatment of
`
`acute DVT with and without PE, when administered in conjunction with warfarin
`
`sodium; the outpatient treatment of acute, DVT without PE when administered in
`
`conjunction with warfarin sodium; and prevention of ischemic complications of
`
`-17-
`
`
`
`
`unstable angina and non-Q-wave myocardial infarction, when concurrently
`
`administered with aspirin. See Lovenox Injection (Aventis) 11/27/2000
`
`Supplemental Approval [New Indication], S36 Approval Letter; Approvable
`
`Letter; Final Labeling – FOI Document #5243106A (2000) (“Lovenox Label,”
`
`EX1025) at 0030. Lovenox® is available for subcutaneous administration in doses
`
`of 30 mg and 40 mg. Id. at 0030-31.
`
`42. Fondaparinux sodium (Arixtra®) is a synthetic pentasaccharide with a
`
`structure related to low-molecular weight heparins. Fondaparinux is an indirect,
`
`specific factor Xa inhibitor that was approved in 2001. Bauer et al., Fondaparinux,
`
`a Synthetic Pentasaccharide: The First in a New Class of Antithrombotic Agents –
`
`The Selective Factor Xa Inhibitors, CARDIOVASC. DRUG REV. 20(1): 37-52 (2002)
`
`(“Bauer,” EX1055) at 40-41.
`
`(b) Warfarin
`
`43.
`
`In 1933, after finding cattle hemorrhaging to death after surgery,
`
`researchers discovered that cattle had been ingesting moldy sweet clover, thus
`
`leading to the discovery of the anticoagulant effect of hydroxycoumarins contained
`
`in sweet clover. This discovery led to the development of warfarin, an orally
`
`administered anticoagulant. Warfarin is a vitamin K antagonist that blocks
`
`production of factors II, VII, IX, and X along the coagulation cascade. It is used for
`
`prophylaxis and treatment of venous and arterial thrombotic diseases.
`
`-18-
`
`
`
`
`
`44. Warfarin sodium (Coumadin®) is indicated for: prophylaxis and
`
`treatment of venous thrombosis and its extension, pulmonary embolism;
`
`prophylaxis and treatment of thromboembolic complications associated with atrial
`
`fibrillation and/or cardiac valve replacement; reduction in the risk of death,
`
`recurrent myocardial infarction, and thromboembolic events such as stroke or
`
`systemic embolization after myocardial infarction. Coumadin® Label (1999)
`
`(“Coumadin® Label,” EX1056) at 0012. Coumadin is available for oral
`
`administration as scored tablets in doses of 1, 2, 2.5, 3, 4, 5, 6, 7.5, or 10 mg. Id. at
`
`0019.
`
`(c) Direct Thrombin Inhibitors
`
`45. Direct thrombin inhibitors bind to thrombin (IIa) and block its
`
`interaction with substrates. By 1998, at least two thrombin inhibitors were
`
`available—hirudin and lepirudin. Both drugs were indicated for treatment of
`
`patients with heparin-induced thrombocytopenia (HIT). HIT is a deficiency of
`
`platelets in the blood caused by administration of heparin.
`
`46. Hirudin is a naturally occurring substance that is extracted from
`
`natural sources. Synthetic hirudin derivatives, e.g., Lepirudin and Bivalirudin, were
`
`developed to replace hirudin. Lepirudin (Refludan®) is a recombinant derivative of
`
`hirudin. Lepirudin was approved in the U.S. in 1998 for patients with HIT and
`
`thromboembolic disease. Lepirudin is administered intravenously at a dose
`
`-19-
`
`
`
`
`adjusted to maintain the activated partial thromboplastin time (“aPTT”) at 1.5 to
`
`2.5 times the median of the laboratory’s normal range for aPTT. Refludan® Label
`
`(2004) (“Refludan® Label,” EX1057) at 0014-15.
`
`47. Bivalirudin (Angiomax®) was approved in 2000 for use in conjunction
`
`with aspirin in patients with unstable angina undergoing percutaneous transluminal
`
`coronary angioplasty (PTCA). Angiomax® Label (2000) (“Angiomax® Label,”
`
`EX1058) at 0005. Bivalirudin is intended for intravenous injection and infusion.
`
`Id. at 0010. I have prescribed Angiomax®, rather than heparin, for all stents and
`
`percutaneous coronary intervention (PCI), for more than ten years, most
`
`interventionists have also prescribed Angiomax® for the same indications.
`
`48. Argatroban (Acova®) was approved in 2000 for prophylaxis or
`
`treatment of thrombosis in patients with HIT. Acova® Label (2000) (“Acova®
`
`Label,” EX1059) at 0011. Argatroban is a synthetic direct thrombin inhibitor. Id. at
`
`0002. The intravenously administered dosage is adjusted to maintain an aPTT at a
`
`certain level above baseline. Id. at 0018.
`
`49. Dabigatran etexilate (Pradaxa®) was approved in October 2010 for
`
`reducing the risk of stroke and systemic embolus in patients with non-valvular
`
`atrial fibrillation (NVAF). Pradaxa® Label (2015) (“Pradaxa® Label,” EX1060) at
`
`0003-04. In April 2014, it was approved for the treatment of DVT and PE in
`
`patients who have been treated with a parenteral anticoagulant for 5–10 days, and
`
`-20-
`
`
`
`
`to reduce the risk of recurrence of DVT and PE in patients who have been
`
`previously treated. Id. In November 2015, it was approved for the prophylaxis of
`
`DVT and PE in patients who have undergone hip replacement surgery. Id.
`
`Pradaxa® is orally administered in doses of 150 mg or 75 mg, twice daily. Id.
`
`(d)
`
`Factor Xa Inhibitors
`
`50. Factor Xa inhibitors bind and inhibit factor Xa of the coagulation
`
`cascade and prevent thrombin formation. Currently, four are three factor Xa
`
`inhibitors that directly bind to the active site of factor Xa: rivaroxaban (Xarelto®),
`
`apixaban (Eliquis®), edoxaban (Savaysa®), and betrixaban (Bevyzza®). All three
`
`agents are orally administered.
`
`51. Rivaroxaban (Xarelto®) was approved in July 2011 for the
`
`prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in
`
`patients undergoing hip replacement surgery or knee replacement surgery. Xarelto®
`
`Label (2012) (“Xarelto® Label,” EX1061) at 0003-04. In November 2011, it was
`
`also approved for reducing the risk of stroke and systemic embolism (SE) in
`
`patients with non-valvular atrial fibrillation (NVAF), for the treatment of DVT,
`
`PE, and for the reduction in the risk of
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