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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 LESLIE Z. BENET, PH.D.
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`MYLAN - EXHIBIT 1002
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`TABLE OF CONTENTS
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`Qualifications.................................................................................................... 1
`I.
`Scope of Work .................................................................................................. 9
`II.
`III. Overview of the ’218 Patent ............................................................................. 9
`IV. File History of the ’218 Patent ........................................................................ 14
`V.
`Legal Standards .............................................................................................. 21
`VI. Level of Ordinary Skill in the Art and Relevant Time ..................................... 24
`VII. Claim Construction ......................................................................................... 25
`VIII. Summary of Opinions ..................................................................................... 32
`IX. The State of the Art ......................................................................................... 34
`X. Asserted References Disclose or Suggest Each of the Claimed
`Features of the ’218 Patent. ............................................................................. 51
`Kubitza Abstracts Render Claims 1-4 Obvious. .............................................. 58
`Abstracts in further view of Forsman Make Claims 1-4 Obvious. ................... 74
`XI. No Unexpected Results ................................................................................... 79
`XII. Concluding Statements ................................................................................... 97
`XIII. Appendix – List Of Exhibits ........................................................................... 99
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`GROUND 1: The Teachings of the ’610 Publication in view of the
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`GROUND 2: The Teachings of the ’610 Publication and the Kubitza
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`-i-
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`I, Leslie Z. Benet, declare as follows:
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`I.
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`QUALIFICATIONS
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`1.
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`I am currently a Professor of Bioengineering and Therapeutic
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`Sciences, Schools of Pharmacy and Medicine, at the University of California, San
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`Francisco (“UCSF”).
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`2.
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`I received my Bachelor of Arts in English in 1959 and my Bachelors
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`of Science in Pharmacy in 1960 from the University of Michigan. In 1962, I
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`received a Master’s Degree in Pharmaceutical Chemistry, also from the University
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`of Michigan. Three years later, in 1965, I was awarded a doctorate degree from
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`UCSF in Pharmaceutical Chemistry. Since obtaining that degree, I have received
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`nine honorary doctorate degrees, five from European universities and four from US
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`institutions, the last in June, 2016 from the University of Lisbon. I held a licentiate
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`in Pharmacy and am a credentialed Applied Pharmacologists with the American
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`Board of Clinical Pharmacology.
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`3.
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`In 1965, I joined the faculty of the School of Pharmacy at Washington
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`State University, in Pullman, Washington. In 1969, I joined the Departments of
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`Pharmacy and Pharmaceutical Chemistry within the School of Pharmacy at UCSF
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`as an Assistant Professor. From 1969 to 1976, I progressed first from Assistant
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`
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`Professor to Associate Professor, and then to Professor. I served as chairman of the
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`department at UCSF from 1978-1998.
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`4. My areas of specialization over the course of my career include
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`pharmacokinetics/pharmacodynamics, biopharmaceutics, drug delivery and dosage
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`forms, drug metabolism, drug transporters, bioequivalence, animal and human drug
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`pharmacology and other scientific aspects of drug regulatory issues.
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`5.
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`In addition to my teaching responsibilities, I have held leadership
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`positions in a number of organizations in my field of study, including:
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`a)
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`From 1985 to 1986, I served as President of the Academy of
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`Pharmaceutical Research and Science (formerly the Academy of
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`Pharmaceutical Sciences).
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`b)
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`In 1986, I founded and served as the first President of the
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`American Association of Pharmaceutical Scientists (AAPS). From
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`1986 to 1993, I variously held the positions of Treasurer, Member,
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`and Chair of the Board of Directors of AAPS.
`
`c)
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`From 1988 to 2004, I served as a Specialist Member, Chairman,
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`Past Chair and Member of the Executive Committee of the Board of
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`Pharmaceutical Sciences for the International Pharmaceutical
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`-2-
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`
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`Federation (FIP). From 2007 through 2012, I served as Chair of the
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`FIP Foundation for Education and Research.
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`d)
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`From 1992 to 1995 I served as a Member, President, and Chair
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`of the Board of Directors of the American Association of Colleges of
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`Pharmacy (AACP).
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`6.
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`I have been awarded numerous awards, prizes and honors for work I
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`have conducted in my field, including:
`
`a)
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`In 1982, I received the American Pharmacists Association
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`(APhA) Academy of Pharmaceutical Sciences Research Achievement
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`Award in Pharmaceutics and the University of Michigan, College of
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`Pharmacy Distinguished Alumnus Award.
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`b)
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`In 1987, I was elected to membership in the National Academy
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`of Medicine (NAM) of the U.S. National Academy of Sciences.
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`c)
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`In 1988, I received the Distinguished Service Award of the
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`American College of Clinical Pharmacology (ACCP), and in 1989 I
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`was chosen to receive the first AAPS Distinguished Pharmaceutical
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`Scientist Award.
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`d)
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`In 1990, I was the recipient of the Rho Chi Lecture Award, and
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`the UCSF School of Pharmacy Long Teaching Award.
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`-3-
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`
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`e)
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`In 1991, I received the AACP Volwiler Research Achievement
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`Award.
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`f)
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`In 1995, I received the Rawls-Palmer Progress in Medicine
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`Award of the American Society of Clinical Pharmacology and
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`Therapeutics (ASCPT) and delivered the American College of
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`Clinical Pharmacy “Therapeutic Frontiers Lecture.”
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`g)
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`In 1996, I received the AAPS Distinguished Service Award,
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`and in 2000 the APhA Takeru Higuchi Research Prize and the AAPS
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`Wurster Research Award in Pharmaceutics.
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`h)
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`In 2001, I was awarded the FIP Høst-Madsen Medal and the
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`UCSF Outstanding Faculty Mentorship Award.
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`i)
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`In 2003, I was listed as one of the most highly cited
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`pharmacologists worldwide, and continue to maintain that distinction
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`for the years 2001 through 2017, with my published peer reviewed
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`publications having been cited more than 26,000 times.
`
`j)
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`In 2004, I was awarded the Pharmaceutical Sciences World
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`Congress Research Achievement Award and the Controlled Release
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`Society’s Career Achievement in Oral Drug Delivery Award.
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`-4-
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`
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`k)
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`In 2007, I was selected as the Distinguished Clinical Research
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`Lecturer at UCSF and made an International Honorary Member of the
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`Japan Society for the Study of Xenobiotics.
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`l)
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`In 2008, I was selected for the Nagai Foundation Tokyo
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`Distinguished Lectureship.
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`m)
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`In 2010, I was selected to receive the ASCPT Oscar B. Hunter
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`Memorial Award in Therapeutics and in 2011, the ACCP
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`Distinguished Investigator Award.
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`n)
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`o)
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`In 2012, I was made an Honorary Member of FIP.
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`In 2012, the September issue of Pharmaceutical Research was
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`dedicated in my honor under the title “50 Years of Scientific
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`Excellence and Still Going Strong” and in 2013, the September issue
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`of the Journal of Pharmaceutical Sciences was dedicated in my honor
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`under the title “Perspectives on a Pharmacokinetics Legend.”
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`p)
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`In 2013 I received the APhA Ebert prize for what was viewed
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`as the most outstanding publication appearing in the Journal of
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`Pharmaceutical Sciences during the previous year, and the AAPS
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`Journal Outstanding Manuscript Award for the same recognition in
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`that journal.
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`q)
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`In 2015, I was awarded the North American Scientific
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`Achievement Award of the International Society for the Study of
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`Xenobiotics.
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`r)
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`In 2016, I received the Remington Honor Medal of the
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`American Pharmacists Association, the highest award in the
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`profession of pharmacy in the US and once again was chosen to
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`receive the UCSF Outstanding Mentorship award.
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`s)
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`In May 2017, a full day symposium in my honor entitled “The
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`Cutting Edge in Pharmaceutical Sciences – 50 Years of Progress
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`Celebrating Les Benet’s 80th Birthday” was held in conjunction with
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`the Pharmaceutical Sciences World Congress in Stockholm, Sweden.
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`7.
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`I have published more than 570 articles, 7 books, and been granted 12
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`patents in the areas of pharmacokinetics, biopharmaceutics, drug delivery and
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`pharmacodynamics. My published peer reviewed publications have been cited on
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`more than 26,000 occasions in the scientific literature. My most recent work
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`addresses the cooperative effects of metabolic enzymes of Cytochromes P-450 and
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`transport proteins as related to the oral bioavailability and hepatic elimination of
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`drugs. My most highly cited recent paper was my 2005 work describing a
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`Biopharmaceutics Drug Disposition Classification System in which I proposed
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`methodologies for predicting drug absorption and disposition, as well as drug-drug
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`interactions, for all therapeutic drug agents.
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`8.
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`Based on my expertise in the field of pharmacology,
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`pharmacokinetics, drug delivery and drug metabolism, I have been invited to serve
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`(and currently serve) on the editorial boards of several journals, including
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`Pharmacology (1978 to present), The AAPS Journal (1999 to present), Chemistry
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`and Pharmaceutical Bulletin (2000 to present), Expert Opinion on Drug
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`Metabolism and Toxicology (2004 to present) and Archives of Drug Information
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`(2007 to present). Selection to the editorial boards of these journals is based upon
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`recognition by the scientific community that the individual is an established leader
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`in the field of pharmacology, pharmacokinetics, drug delivery and drug
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`metabolism. As a member of these editorial boards, I have reviewed, evaluated,
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`and selected articles for publication based upon scientific merit in the general area
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`of pharmacology, pharmacokinetics, drug delivery and drug metabolism. In
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`addition to my roles on the above-mentioned editorial boards, I was a Founder and
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`Editor of the Journal of Pharmacokinetics and Biopharmaceutics (1973 to 1998)
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`and served as the Associate Editor for Pharmacology and Therapeutics (1995 to
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`2000).
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`-7-
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`9.
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`I served as Chair of the Pharmacology Study Section and the
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`Pharmacological Sciences Review Committee for the NIH, the FDA CBER Peer
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`Review Committee, the FDA Expert Panel on Individual Bioequivalence, the
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`Board of Pharmaceutical Sciences of the International Pharmaceutical Federation,
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`the Organizing Committee for the Millennial World Congress of Pharmaceutical
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`Sciences, and as a member of the FDA Generic Drugs Advisory Committee and
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`the FDA Science Board. In 2011, I completed a term as a member of the National
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`Research Council Biodefense Standing Committee for the Department of Defense
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`and in 2012 I completed a 9-year term as a member of the Institute of Medicine
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`(now the NAM), Forum on Drug Discovery, Development and Translation. I
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`presently serve as Chair of the Board of Directors of Medicines360 and on May 4,
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`2018 completed an 18 year term on the Board of Directors of Impax Laboratories.
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`10.
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`In addition to my activities related to drug development with the FDA,
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`NAM and NIH, I am a frequent consultant to the pharmaceutical industry as
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`indicated in my curriculum vitae. I believe that at one time or another I have
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`consulted in multiple areas of drug development for almost every major US and
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`European Pharma company and for the majority of Japanese companies.
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`Furthermore, I am the co-founder of four biopharmaceutical companies.
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`11. A copy of my curriculum vitae and publication list providing a more
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`comprehensive review of my work are being submitted simultaneously with this
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`declaration as Exhibit 1046. The curriculum vitae includes a list of occasions since
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`2006 where I have testified as an expert at trial or by deposition.
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`II.
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`SCOPE OF WORK
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`12.
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`I have been informed that a petition is being filed with the United
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`States Patent and Trademark Office for Inter Partes Review of U.S. Patent No.
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`9,539,218 (“the ’218 patent,” EX1001). I have been asked by the Petitioner to
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`analyze the ’218 patent and provide analysis and opinions as a technical expert. As
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`part of my analysis, I reviewed the ’218 patent and portions of its prosecution
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`history. EX1004. I have cited in this declaration various other documents that I
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`reviewed in preparing my opinions. I have listed those documents in the Appendix
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`in Section XIII.
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`13.
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`I am being compensated at the rate of $800 per hour for my work in
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`preparing this declaration. My compensation does not depend on the outcome of
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`this matter, and I have no financial interest in the outcome of this matter.
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`III. OVERVIEW OF THE ’218 PATENT
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`14. The ’218 patent issued on January 10, 2017. The ’218 patent is
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`entitled “Prevention and Treatment of Thromboembolic Disorders.” The first page
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`-9-
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`of the patent states that the ’218 patent resulted from the July 16, 2008 national
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`stage entry (U.S. Application No. 11/883,218, “the ’218 application”) of
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`PCT/EP2006/000431, filed on January 19, 2006. The ’218 patent claims priority to
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`European Application No. EP 05001893, filed on January 31, 2005. For the
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`purposes of this declaration, I have assumed that the ’218 patent is entitled to claim
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`the benefit of the January 31, 2005 foreign filing date of the European Application
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`No. EP 05001893.
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`15. The ’218 patent states:
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`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
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`disorder by administering a direct factor Xa inhibitor once daily in
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`oral dosage form to a patient in need thereof, wherein the factor Xa
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`inhibitor has a plasma concentration half life indicative of a bid or tid
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`administration interval, e.g. of 10 hours or less.
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`EX1001 (the ’218 patent), 1:4-10.
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`16. The ’218 patent states that in preferred embodiments the factor Xa
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`inhibitor is 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-
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`oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide. Id. at 3:18-32. For
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`convenience, I will refer to this compound using the name rivaroxaban.
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`17. All four claims of the ’218 patent recite methods of treating a
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`thromboembolic disorder. Claim 1 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-yl} methyl)-
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`2-thiophenecarboxamide no more than once daily for at least five
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`consecutive days in a rapid-release tablet to a patient in need thereof,
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`wherein the thromboembolic disorder is selected from the group
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`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.
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`18.
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` Claims 2-4 of the ’218 patent all depend from claim 1 and recite as
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`follows:
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`Claim 2:
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`The method of claim 1, wherein the thromboembolic disorder is
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`pulmonary embolisms.
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`Claim 3:
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`The method of claim 1, wherein the thromboembolic disorder is deep
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`vein thrombosis.
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`Claim 4:
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`The method of claim 1, wherein the thromboembolic disorder is
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`stroke.
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`EX1001 (the ’218 patent), 11:6-11.
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`19. The ’218 patent states: “The term ‘treatment’ includes the therapeutic
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`and/or prophylactic treatment of thromboembolic disorders.” EX1001 (the ’218
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`patent), 7:25-26. The ’218 patent defines the term “thromboembolic disorders” to
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`include pulmonary embolism, deep vein thrombosis, stroke, and “economy class
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`syndrome,” among others. Id. at 7:32-8:12.
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`20. Regarding anticoagulant dosing, the ’218 patent states: “In general,
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`oral application is the preferable route of administration of a drug, and a less
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`frequent dose regimen is desirable. In particular, once daily oral application is
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`preferred due to favourable convenience for the patient and for compliance
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`reasons.” EX1001 (the ’218 patent), 2:35-39.
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`21. Regarding dosage forms, the ’218 patent states:
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`Oral dosage forms are recognized by those skilled in the art to include
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`such forms as liquid formulations, granules, gelcaps, hard gelatin
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`capsules or sachets filled with granules, and tablets releasing the
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`active compound rapidly or in a modified manner. Tablets are
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`preferred, in particular tablets rapidly releasing the active compound.
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`In the context of the present invention, rapid-release tablets are in
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`particular those which, according to the USP release method using
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`apparatus 2 (paddle), have a Q value (30 minutes) of 75%. Very
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`particularly preferred are rapid-release tablets containing
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`[rivaroxaban] as active ingredient. Preparation of such tablets is for
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`example described in PCT/04/01289, whose disclosure is hereby
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`included by way of reference.
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` EX1001 (the ’218 patent), 8:14-30.
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`22. The ’218 patent states that the “invention further relates to the use of
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`an oral dosage form of a direct factor Xa inhibitor [(e.g., rivaroxaban)]…wherein
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`said inhibitor has a plasma concentration half life of 10 hours or less when orally
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`administered to a human patient.” EX1001 (the ’218 patent), 3:10-16. The ’218
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`patent cites an abstract from a poster presented by the Kubitza group at the 45th
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`Annual American Society of Hematology Conference, held in 2003, Abstract
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`#3004 by Kubitza et al., stating that for rivaroxaban, “a plasma concentration half
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`life of 4-6 hours has been demonstrated at steady state in humans in a multiple
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`dose escalation study.” EX1001 (the ’218 patent), 3:36-42; see also Abstract
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`#3004, Kubitza et al., Multiple Dose Escalation Study Investigating the
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`Pharmacodynamics, Safety, and Pharmacokinetics of BAY 59-7939, an Oral,
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`Direct Factor Xa Inhibitor, in Healthy Male Subjects, 102 BLOOD 811a (2003)
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`(“Abstract #3004” or “Kubitza 1”) in EX1006 (“Kubitza Abstracts”) at 0013.
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`Kubitza reports terminal half-lives of 4-6 and 3-4 hours for the oral tablet and oral
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`solution, respectively. EX1006 (Kubitza Abstracts) at 0013, 0015 (Abstracts
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`#3004, #3010). The patent cites my chapter in Goodman & Gilman for the
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`definition of half-life: “‘Half life’ is the time it takes for the plasma concentration
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`or the amount of drug in the body to be reduced by 50%.” EX1001 (the ’218
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`patent), 2:42-46; see also Goodman and Gilman’s The Pharmacological Basis of
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`Therapeutics (1985), 7th Edition, Macmillan Publishing Company (“Goodman and
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`Gilman,” EX1022) at 28; see also EX1046 (my CV) at 69 (publication #155).
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`IV. FILE HISTORY OF THE ’218 PATENT
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`23. During prosecution, the Examiner rejected the claims based on
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`commonly assigned U.S. Patent No. 7,157,456 (“the ’456 Patent,” EX1008), U.S.
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`Patent No. 7,592,339 (“the ’339 Patent,” EX1009), or U.S. Patent Publ. No.
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`2003/0153610 to Straub et al. (“the ’610 publication,” EX1005), in light of the
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`Kubitza 1 abstract discussed above in paragraph 22 and a second Kubitza abstract
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`(“Abstract #3010” or “Kubitza 2”) found in the same abstract book. EX1004
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`(Prosecution History) at 0255-70; see also EX1006 (Kubitza Abstracts) at 0013
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`(Abstract #3004), 0015 (Abstract #3010, Kubitza et al., Single Dose Escalation
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`Study Investigating the Pharmacodynamics, Safety, and Pharmacokinetics of BAY
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`59-7939, an Oral Direct Factor Xa Inhibitor in Healthy Male Subjects).
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`24. The Examiner asserted that, in view of the cited art, a person of
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`ordinary skill in the art would have been motivated to administer rivaroxaban for
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`the treatment of thromboembolic disorders using a once daily rapid-release oral
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`dosage form. EX1004 (Prosecution History) at 0259, 0261, 0267-69. The
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`Examiner also noted that a person of ordinary skill in the art would have had
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`additional motivation to administer a once daily dosage regimen to increase
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`convenience and compliance of patients. Id.
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`25.
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`In response, Applicants argued that neither Kubitza 1 nor Kubitza 2
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`teaches the claimed dosing frequency for a rapid-release oral dosage form of
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`rivaroxaban. EX1004 (Prosecution History) at 0235, 0237. Applicants also argued
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`that Kubitza 1 and 2 did not render the claims obvious because both abstracts
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`taught only the administration of rivaroxaban to “healthy subjects,” not “patients
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`suffering from, or at risk from, a thromboembolic disorder.” Id. at 0237. Moreover,
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`Applicants asserted that it was surprising that once-daily dosing provided efficacy
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`that was similar to that of twice-daily dosing regimens (id. at 0235) and that the
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`half-life of rivaroxaban would have “le[d] away from once daily dosing with a
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`rapid-release oral dosage form.” Id. at 0237.
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`26. Unpersuaded by these arguments, the Examiner maintained the
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`rejection, concluding that Kubitza 1 and 2 teach the treatment of thromboembolic
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`disorders as “the patient population is interpreted to include healthy subjects since
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`anyone could potentially be at risk for deep venous thrombosis.” EX1004
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`(Prosecution History) at 0212. The Examiner also stated that the once-daily dosage
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`regimen recited in the claims would have been an obvious dosage regimen to
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`administer, as “a once daily dosage at a higher dosage is sometimes preferred in
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`instances where patient compliance is an issue.” Id. The Examiner also rejected
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`Applicants’ suggestion that the short half-life of rivaroxaban would lead a person
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`of ordinary skill in the art away from a once daily dosing regimen of a rapid-
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`release oral dosage form of rivaroxaban, as Kubitza 1 and 2 “both teach once daily
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`dosing” of a rapid-release dosage form. EX1004 (Prosecution History) at 0211-12.
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`The Examiner concluded that Applicants had failed to demonstrate that the
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`asserted unexpected results were “in fact unexpected and unobvious” and “of both
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`statistical and practical significance,” while being clear and commensurate in scope
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`with the claimed subject matter. Id. at 0213.
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`27. Applicants appealed the Examiner’s final rejection to the Patent Trial
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`and Appeal Board (PTAB) on April 20, 2012. The independent claim at issue on
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`appeal was as follows:
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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-yl} methyl)-
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`2-thiophenecarboxamide no more than once daily for at least five
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`consecutive days in a rapid-release oral dose form to a patient in need
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`thereof.
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`
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`Id. at 0110.
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`28. The Board’s June 3, 2016 decision (Appeal 2014-004087) affirmed
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`the Examiner’s rejection of the claims reciting methods of treatment comprising
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`the administration of rapid-release oral dosage forms of rivaroxaban. EX1004
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`(Prosecution History) at 0113-17. However, the Board found the record incomplete
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`with respect to a rapid-release oral tablet. Id.
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`29. The Board affirmed the Examiner’s determination that “treatment,” as
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`described in the patent, includes both therapeutic as well as prophylactic treatment
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`and that oral dosage forms include both liquid formulations and tablets. EX1004
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`(Prosecution History) at 0111 (FF2-FF3); EX1001 (the ’218 patent), 9:1-2, 10:3-6.
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`The Board also noted that the specification defines rapid-release tablets as
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`including “those which, according to the USP release method using apparatus 2
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`(paddle), have a Q value (30 minutes) of 75%.” EX1004 (Prosecution History) at
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`0111 (FF4); EX1001 (the ’218 patent), 10:7-9.
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`30. The Board also found that the ’456 patent recites treatment of
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`thromboembolic disorders by administering an effective amount of a compound in
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`a genus comprising rivaroxaban. EX1004 (Prosecution History) at 0112 (FF6). The
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`Board found that Kubitza 1 discloses administration of rivaroxaban to healthy male
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`subjects as a 5 mg once-daily oral dose on five consecutive days (FF8), that
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`rivaroxaban was safe and well tolerated, and that rivaroxaban inhibited factor Xa
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`activity. Id. (FF8-9). The Board found that Kubitza 2 discloses administering
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`rivaroxaban to healthy male subjects as a tablet and as an oral solution and that
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`rivaroxaban showed a rapid onset of action. Id. at 0112-13 (FF10-11). In addition,
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`the Board found that Kubitza 2 discloses that administration of the oral solution
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`achieved maximal plasma concentration in about 0.5 hours and that administration
`
`of the tablet resulted in lower peak concentrations of approximately 50% at 2 hours
`
`after administration. Id. The Board also found that Kubitza 2 discloses that
`
`rivaroxaban offers predictable anticoagulation with an excellent safety profile. Id.
`
`at 0113 (FF12). In addition, the Board found that the ’610 publication discloses
`
`rivaroxaban as a particularly preferred compound to treat or prevent
`
`thromboembolic disorders and states that suitable formulations include tablets and
`
`solutions. Id. (FF13).
`
`31. The Board affirmed the Examiner’s conclusion that the claims were
`
`unpatentable in view of the cited art because the ’456 and ’339 patents and the
`
`’610 publication are each directed to methods of treating thromboembolic
`
`disorders via the administration of rivaroxaban to a patient in need of
`
`thromboembolic disorder treatment. Kubitza 1 discloses administering rivaroxaban
`
`once daily for at least five consecutive days and Kubitza 2 discloses administration
`
`-18-
`
`
`
`
`of rivaroxaban in a rapid-release oral dosage form (an oral solution). EX1004
`
`(Prosecution History) at 0113-14. The Board also found that there would have been
`
`a motivation to combine the teachings of Kubitza 1 and 2 with the teachings of the
`
`’456 patent, the ’339 patent, or the ’610 publication because they each disclose the
`
`administration of rivaroxaban for the treatment of thromboembolic disorders. Id. at
`
`0114-15.
`
`32. The Board rejected Applicants’ argument that Kubitza 1 and 2 are
`
`irrelevant to the invention because they report pharmacodynamic, safety, and
`
`pharmacokinetic studies of rivaroxaban in healthy subjects. EX1004 (Prosecution
`
`History) at 0114-15. The Board found that, as the ’456 patent, ’339 patent, and
`
`’610 publication each teach the treatment of thromboembolic disorders via the
`
`administration of rivaroxaban, a person of ordinary skill in the art would have been
`
`motivated to combine any of these references with the teachings of Kubitza 1 and
`
`2. Id. Moreover, the Board concluded that the health of Kubitza 1 and 2’s subjects
`
`was irrelevant to the invalidity analysis as the patent specification defines
`
`treatment to include prophylactic treatment. Id. at 0115-16.
`
`33. With respect to dependent claim 5, which narrowed the rapid-release
`
`oral dosage form recited in the independent claim to a rapid-release tablet, the
`
`Board found that the Examiner had conceded that the asserted references did not
`
`-19-
`
`
`
`
`expressly disclose a rapid-release tablet. EX1004 (Prosecution History) at 0116.
`
`The Board concluded that it could not determine based on the evidence of record
`
`whether the disclosure in Kubitza 2 that its rivaroxaban tablet achieved peak
`
`concentration within 2 hours of administrations satisfied the rapid-release
`
`limitation or had a Q value in 30 minutes of 75% using the USP release method
`
`using apparatus 2 (paddle). Id. at 0116-17.
`
`34. On remand, the record does not reflect a search for prior art regarding
`
`making rapid-release tablets, but the office issued a Notice of Allowance after
`
`entering an examiner’s amendment, limiting the “rapid-release oral dosage form”
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`to a “rapid-release tablet.” EX1004 (Prosecution History) at 0054-55. While
`
`reaffirming that the cited art “render obvious a method of treating the claimed
`
`thromboembolic disorders comprising administering riv[a]roxaban no more than
`
`only [once] daily for at least five consecutive days in a rapid-release oral dosage
`
`form,” the Examiner concluded that the newly amended claims were allowable
`
`because the prior cited art does “not teach or render obvious said methods wherein
`
`a rapid-release tablet is utilized.” EX1004 (Prosecution History) at 0055 (emphasis
`
`added).
`
`-20-
`
`
`
`
`V. LEGAL STANDARDS
`
`35.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. § 103(a), 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 January 31, 2005.
`
`36.
`
`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.
`
`37.
`
`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
`
`-21-
`
`
`
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable and expected results to one of ordinary skill in the art.
`
`38.
`
`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.
`
`39.
`
`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.
`
`40.
`
`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
`
`-22-
`
`
`
`
`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.
`
`41.
`
`I also understand that “secondary considerations” may be weighed
`
`against evidence of obviousness where appropriate. 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
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