UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
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`
`
`COALITION FOR AFFORDABLE DRUGS VIII, LLC
`Petitioner,
`
`v.
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner
`
`______________
`
`Case: IPR2015-01836
`Patent No. 7,932,268
`______________
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`DECLARATION OF DR. S. DAVID KIMBALL, PH.D.
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`PENN EX. 2025
`CFAD v. PENN
`IPR2015-01836
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`TABLE OF CONTENTS
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`I. Summary of Opinions .......................................................................................... 1
`II. Materials Considered ........................................................................................ 3
`III. Qualifications .................................................................................................... 3
`IV. The Patents-at-Issue .......................................................................................... 8
`A. The ’268 Patent ............................................................................................. 8
`1. Overview ....................................................................................................... 8
`2. Existing Claims ............................................................................................. 8
`3. Proposed Claim Amendment ...................................................................... 10
`B. The ’135 Patent ........................................................................................... 12
`1. Overview ..................................................................................................... 12
`2. Existing Claims ........................................................................................... 12
`3. Proposed Claim Amendment ...................................................................... 16
`V. Legal Principles .............................................................................................. 19
`A.
`Patent Validity ............................................................................................. 20
`B. The Person of Ordinary Skill in the Art ...................................................... 20
`C. Obviousness ................................................................................................. 22
`VI. Opinions .......................................................................................................... 23
`A. Tutorial ........................................................................................................ 23
`1. The chemical structure of a drug molecule determines its biological
`performance. ...................................................................................................... 24
`2. MTP inhibitors are clinically efficacious compounds with significant
`toxicological issues. ........................................................................................... 41
`B. Obviousness ................................................................................................. 43
`1. Dr. Mayersohn’s analysis does not account for chemical structure. ........... 45
`2. The prior art provides no credible motivation for a POSA to choose
`lomitapide over any other MTP inhibitor. ......................................................... 59
`3. A POSA would not have a reasonable expectation of success in applying
`the same dosing regimen to both implitapide and lomitapide. .......................... 66
`4. Proposed Claim Amendment ...................................................................... 69
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`VII. Conclusion ...................................................................................................... 70
`VIII. Prior Expert Testimony ............................................................................... 71
`IX. Compensation ................................................................................................. 71
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`1.
`
`I, S. David Kimball, have been retained to testify on behalf of Patent
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`Owner the Trustees of the University of Pennsylvania (“Penn”) in this proceeding
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`as an expert in medicinal chemistry.
`
`I.
`
`SUMMARY OF OPINIONS
`2.
`
`I am aware that Petitioner Coalition for Affordable Drugs VIII, LLC
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`(“CFAD”) has sought to challenge the validity of U.S. Patents Nos. 7,932,268
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`(“the ’268 patent”) and 8,618,135 (“the ’135 patent”) (collectively, the “patents-at-
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`issue”) in separate Inter Partes Review (“IPR”) proceedings before the Patent Trial
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`and Appeal Board (“PTAB”) of the United States Patent and Trademark Office. I
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`am also aware that PTAB has instituted IPR proceedings with respect to each of
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`the patents-at-issue.
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`3.
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`I am aware that although Penn is the sole assignee and owner of the
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`patents-at-issue, the patent is currently licensed to Aegerion Pharmaceuticals, Inc.
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`(“Aegerion”). I am also aware that, according to the terms of this license,
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`Aegerion currently markets the drug compound lomitapide in the United States
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`under the trade name JUXTAPID®.
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`4.
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`I have been retained to address the assertions in the Declaration of
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`Michael Mayersohn, Ph.D. (CFAD Ex. 1003, “Mayersohn Dec.”) and the
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`Declaration of Randall J. Zusman, M.D. (CFAD Ex. 1002, “Zusman Dec.”)
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`regarding the alleged invalidity of the patents-at-issue. In my Declaration, I will
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`provide my opinion regarding how the chemical structure of a drug compound can
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`impact its biological performance and clinical use. It is my opinion that the
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`patents-at-issue are not invalid for obviousness because (1) there are significant
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`chemical differences between lomitapide, implitapide, and other contemporary
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`MTP inhibitors; (2) there is no motivation in the prior art for a person of ordinary
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`skill in the art to specifically select lomitapide for development over other MTP
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`inhibitors; and (3) a person of ordinary skill in the art would not have a reasonable
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`expectation of success dosing lomitapide in the same manner as proposed for
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`implitapide in “Bayer/PPD Implitapide Development Follows Zetia Model”, The
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`Pink Sheet, Vol. 66, No. 7, p. 17 (2004) (CFAD Ex. 1013, “Pink Sheet 2004”)
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`and/or Evan Stein, “Microsomal Triglyceride Transfer Protein (MTP) Inhibitor
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`(implitapide) program”, Presentation Given at PPD’s Analyst Day (February 5,
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`2004) (CFAD Ex. 1014, “Stein”).
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`5.
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`Additionally, I have been asked to address the non-obviousness of
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`certain proposed claims that I understand Penn has submitted with its Motion to
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`Amend in this proceeding to claim priority to Provisional U.S. Patent Application
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`No. 60/550,915 (“the ’915 Provisional”). As explained in further detail below, and
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`for reasons similar to those set forth above, it is my opinion that the proposed
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`claims are patentable and not obvious based on the prior art.
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`II. MATERIALS CONSIDERED
`6.
`In forming my opinions and views expressed in this declaration, I
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`have relied upon my knowledge, education and training, as well as my many years
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`of experience in the field of medicinal chemistry, as reflected in my qualifications
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`and credentials set forth below and in my curriculum vitae, Penn Ex. 2029. I have
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`also considered the documents cited herein and have taken into consideration the
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`documents listed in Penn Ex. 2033.
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`III. QUALIFICATIONS
`7.
`I am currently Associate Vice President for Research
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`Commercialization in the Office of Research and Economic Development at
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`Rutgers University in Piscataway, New Jersey, USA. I additionally serve as
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`Associate Vice President for Translational Science at Rutgers University and
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`Research Professor in the Department of Medicinal Chemistry at the Ernest Mario
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`School of Pharmacy.
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`8.
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`I received a B.A. with highest honors in experimental psychology and
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`a Ph.D. in Organic Chemistry and Chemical Biology, both from the State
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`University of New York at Stony Brook in 1978 and 1982, respectively.
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`9.
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`From 1982-2001, I was employed in drug discovery research in
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`Medicinal Chemistry in the Departments of Oncology & Cardiovascular Chemistry
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`at the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, New
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`Jersey. During that time, I held positions of increasing responsibility from Group
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`Leader to Associate Director, culminating as one of two Research Fellows within
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`the worldwide Discovery Chemistry organization. I was the co-chair of both the
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`Cyclin Dependent Kinase working group, where we developed a novel kinase
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`inhibitor for solid tumors, and the Thrombin Active Site Inhibitor working group,
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`where we discovered reversible thrombin active site inhibitors for the treatment of
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`venous and arterial thrombosis. I also led the Cardiovascular Chemistry research
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`group in the design and discovery of novel Calcium Antagonists for hypertension,
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`anti-anginal and cardiotonic agents, and worked in the Antibiotics group to
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`develop orally active monocyclic beta lactams.
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`10. Lomitapide was developed at BMS during my time there. Although I
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`did not formally work on the MTP inhibitor program at BMS, I was well
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`acquainted with both the people and underlying science involved in that program.
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`11. From 2001-2007, I was the Vice President of Chemistry at Lexicon
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`Pharmaceuticals in Princeton, New Jersey, where I was responsible for chemistry
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`resources including medicinal chemistry, process chemistry, analytical chemistry,
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`combinatorial chemistry and lead optimization groups. At Lexicon, I built and led
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`a department of 70 scientists, recruiting from top universities and the
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`pharmaceutical industry, managing chemistry outsourcing and delivering multiple
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`compounds into clinical trials.
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`12. From 2007-2008, I was the Senior Vice President of Discovery and
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`Nonclinical Development at Pharmacopeia, Inc. also in Princeton, New Jersey.
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`During this time, I was responsible for all drug discovery resources, biology and
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`chemistry, screening, external research alliances, preclinical and chemical
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`development activities.
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`13. From 2008-2011, I was the Chief Scientific Officer at Hydra
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`Biosciences (“Hydra”) in Cambridge, Massachusetts. From 2011 until October
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`2012, I held the position of Consulting Chief Scientific Officer at Hydra. My
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`responsibilities involved tactical and strategic leadership of all drug discovery and
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`development activities regarding Hydra’s Transient Receptor Potential ion channel
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`targets for pain and inflammation, including guiding and mentoring external
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`research alliances.
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`14.
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`In 2011, I assumed a position as a Research Professor at Rutgers
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`University. My initial responsibilities included building a collaborative research
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`laboratory to promote interdisciplinary biomedical research (Translational
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`Synthesis Laboratory), teaching Medicinal Chemistry to the Pharm.D. students at
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`the Ernest Mario School of Pharmacy, organizing courses in the Professional
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`Science Master’s program, and interfacing with the Dean and Provost of Life
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`Sciences to assist in the organizational and administrative integration of Rutgers
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`University with the University of Medicine and Dentistry of New Jersey (UMDNJ)
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`Robert Wood Johnson Hospital (RWJ) and The Cancer Institute of New Jersey
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`(CINJ). In September, 2012, I was assigned to report to the Vice President for
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`Research as Senior Scientific Advisor to the Vice President for Research, with the
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`responsibility of coordinating the strategic activities of the Offices of Research
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`Alliances, Technology and Commercialization and Economic Development.
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`Effective September, 2013, I became Associate Vice President for Translational
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`Research in the Office of Research and Economic Development at Rutgers
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`University, reporting to the Senior Vice President of Research and Economic
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`Development. In November, 2014, I assumed the role of Associate Vice President
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`of Research Commercialization, where I am additionally responsible for leading
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`the interface with faculty for patenting, licensing, marketing and new company
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`formation at Rutgers University. My faculty affiliations include membership at the
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`Cancer Institute of New Jersey in New Brunswick, NJ.
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`15.
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`I have authored over 45 peer-reviewed articles, and am named as an
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`inventor on more than 30 United States patents and pending patent applications.
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`Nearly all of my patents and publications relate to drug discovery and
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`development.
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`16. Throughout my career, I have received a number of teaching and
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`research awards, including the State University of New York’s Department of
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`Chemistry Teaching Award for 1980-81 and the President’s Award for Excellence
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`in Teaching in 1982 during my tenure as a doctoral student. While at Bristol-
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`Myers Squibb, I received the BMS Excellence Award in Research Leadership in
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`1996 and twice received the BMS President’s Award, as a member of the Drug
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`Formulation Team in 1997 and for University Recruiting in 1998. I have also been
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`an invited lecturer at the California Institute of Technology in Pasadena,
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`California, Stanford University in Palo Alto, California, the University of
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`California at Berkeley, Davis and Los Angeles in California, the Massachusetts
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`Institute of Technology in Cambridge, Massachusetts, Duke University in Durham,
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`North Carolina, and the University of Innsbruck in Austria. I was elected Chair of
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`the Gordon Conference on Medicinal Chemistry, and served as a member of the
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`long-term planning committee of the medicinal chemistry section of the American
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`Chemical Society.
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`IV. THE PATENTS-AT-ISSUE
`A. The ’268 Patent
`1. Overview
`17. The ’268 patent, entitled “Methods for treating disorders or diseases
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`associated with hyperlipidemia and hypercholesterolemia while minimizing side
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`effects”, was issued to Daniel J. Rader on April 26, 2011. The ’268 patent was
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`filed on March 7, 2005, and claims priority to Provisional U.S. Patent Application
`
`No. 60/550,915 (“the ’915 Provisional”), which was filed on March 5, 2004.
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`18. The claims of the ’268 patent are generally directed to methods of
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`treating hyperlipidemia or hypercholesterolemia in humans via the administration
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`of the MTP inhibitor lomitapide. Recitations of the individual claims are provided
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`below.
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`Existing Claims
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`2.
` Claim 1 is directed to “A method of treating a subject suffering from
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`19.
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`hyperlipidemia or hypercholesterolemia, the method comprising administering to
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`the subject an effective amount of an MTP inhibitor, wherein said administration
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`comprises at least three step-wise, increasing dose levels of the MTP inhibitors
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`wherein a first dose level is from about 2 to about 13 mg/day, a second dose level
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`is from about 5 to about 30 mg/day, and a third dose level is from about 10 to
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`about 50 mg/day; and wherein the MTP inhibitor is represented by:
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`or a phaarmaceuticcally accepttable salt t
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`de thereof, dine N-oxidhereof or tthe piperid
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`and
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`whereinn each dosee level is administereed to the suubject for aabout 1 to 44 weeks.”
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`220. Claimm 2 is direccted to “Thhe method
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`severe hhypercholeesterolemiaa.”
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`221. Claimm 3 is direccted to “Thhe method
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`of claim 11 wherein tthe disordeer is
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`of claim 1
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`1 wherein oone or morre of
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`Total Cholesterol,, LDL, fastting triglyccerides (TGG), VLDL,, lipoproteiin (a) (Lp(
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`a)),
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`and-lipooprotein B are reduceed by at leaast 15%, coompared too control leevels.”
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`222. Claimm 4 is direccted to “Thhe method
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`of claim 11 wherein oone or morre of
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`Total Cholesterol,, LDL, fastting triglyccerides (TGG), VLDL,, lipoproteiin (a) (Lp(
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`a)),
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`and-lipooprotein B are reduceed by at leaast 25%, coompared too control leevels.”
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`223. Claimm 5 is direccted to “Thhe method
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`inhibitoor is administered oraally.”
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`224. Claimm 6 is direccted to “Thhe method
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`of claim 11 wherein tthe MTP
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`of claim 1
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`1 wherein ssaid increa
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`sing
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`dose levvels furtherr comprisee a fourth ddose level.””
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`225. Claimm 7 is direccted to “Thhe method
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`of claim 1
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`1 wherein ssaid increa
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`sing
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`PEENN EX. 22025
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`dose levvels furtherr comprisee a fourth aand a fifth ddose level..”
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`26. Claim 8 is directed to “The method of claim 1, wherein the increasing
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`dose levels comprise a fourth dose level from about 20 to about 60 mg/day and a
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`fifth dose level from about 30 to about 75 mg/day.”
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`Proposed Claim Amendment
`
`3.
`I am aware that Penn has proposed an amendment to the claims of the
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`27.
`
`’268 patent in the event the PTAB finds the original claims unpatentable. I
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`understand that in its Motion to Amend, Penn has proposed cancellation of all the
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`existing claims of the ’268 patent and adding six substitute claims, numbered 9-14
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`28. Substitute claim 9 reads as follows: “A method of treating a subject
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`suffering from hyperlipidemia or hypercholesterolemia, the method comprising
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`administering to the subject an effective amount of an MTP inhibitor, wherein said
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`administration comprises at least three stepwise, increasing dose levels of the MTP
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`inhibitors, wherein a first and a second dose level is 50% of the immediately
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`following dose level, and wherein a third dose level is from about 0.2 to about 0.59
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`mg/kg/day based on a weight between 62.5 and 74.9 kg, and wherein the MTP
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`inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4’-(trifluoromethyl)[1,1’-biphenyl]-
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`2-yl] carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide,
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`methanesulfonate, and wherein each dose level is administered to the subject for
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`about 1 to 4 weeks”.
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`29. Substitute claim 10 reads as follows: “The method of claim 9 wherein
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`the disorder is severe hypercholesterolemia”.
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`30. Substitute claim 11 reads as follows: “The method of claim 9 wherein
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`one or more of Total Cholesterol, LDL, fasting triglycerides (TG), VLDL,
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`lipoprotein (a) (Lp(a)), and-lipoprotein B are reduced by at least 15%, compared to
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`control levels”.
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`31. Substitute claim 12 reads as follows: “The method of claim 9 wherein
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`one or more of Total Cholesterol, LDL, fasting triglycerides (TG), VLDL,
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`lipoprotein (a) (Lp(a)), and-lipoprotein B are reduced by at least 25%, compared to
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`control levels”.
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`32. Substitute claim 13 reads as follows: “The method of claim 9 wherein
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`the MTP inhibitor is administered orally”.
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`33. Substitute claim 14 reads as follows: “The method of claim 9 wherein
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`said increasing dose levels further comprise a fourth dose level”.
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`34.
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`I am not offering any opinion as to either (1) the effective date of
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`invention for these substitute claims or (2) whether these substitute claims properly
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`claim priority to the ’915 provisional.
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`35. Any opinions I have offered below regarding the obviousness of the
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`original claims of the ’268 patent apply with equal force to the amended claims
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`proposed by Penn. Accordingly, my opinion that the subject matter claimed by the
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`’268 patent is non-obvious will not change regardless of whether or not the PTAB
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`grants Penn’s proposed amendment.
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`B.
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`The ’135 Patent
`1. Overview
`36. The ’135 patent, entitled “Methods for treating disorders or diseases
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`associated with hyperlipidemia and hypercholesterolemia while minimizing side
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`effects”, was issued to Daniel J. Rader on December 31, 2013. The ’135 patent
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`was filed on March 11, 2011, and claims priority to Provisional U.S. Patent
`
`Application No. 60/550,915 (“the ’915 Provisional”), which was filed on March 5,
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`2004, and U.S. Patent No. 7,932,268 (“the ’268 patent”), which was filed on
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`March 7, 2005. The ’135 patent is a continuation of the ’268 patent.
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`37. The claims of the ’135 patent are generally directed to methods of
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`treating hyperlipidemia or hypercholesterolemia in humans via the administration
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`of the MTP inhibitor lomitapide. Recitations of the individual claims of are
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`provided below.
`
`2.
`Existing Claims
`38. Claim 1 is directed to “A method of treating a subject suffering from
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`hyperlipidemia or hypercholesterolemia, the method comprising administering to
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`the subject an effective amount of an MTP inhibitor, wherein said administration
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`comprisses at least three step-wise, incrreasing dosse levels o
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`f the MTP
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` inhibitor
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`whereinn a first dosse level is from abouut 2 to abouut 13 mg/dday, a seconnd dose levvel
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`is from about 5 to
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`about 30 mmg/day, annd a third ddose level iis from aboout 10 to
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`about 500 mg/day; and whereein the MTTP inhibitorr is represeented by:
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`or a phaarmaceuticcally accepttable salt thereof or tthe piperiddine N-oxidde thereof,
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`and
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`whereinn each dosee level is administereed to the suubject for aabout 1 to aabout 5
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`weeks.””
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`39. Claimm 2 is direccted to “Thhe method
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`of claim 11 wherein tthe disordeer is
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`severe hhypercholeesterolemiaa.”
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`440. Claimm 3 is direccted to “Thhe method
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`of claim 1
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`1 wherein oone or morre of
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`a)),
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`compared
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`to
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`and apoolipoproteinns A-I, A-III, B, and EE are reducced by at leeast 15%,
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`control levels.”
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`441. Claimm 4 is direccted to “Thhe method
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`of claim 11 wherein oone or morre of
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`Total Cholesterol,, LDL, fastting triglyccerides (TGG), VLDL,, lipoproteiin (a) (Lp(
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`a)),
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`PEENN EX. 22025
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`CFAD v. PEENN
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`PPR2015-011836
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`CI
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`13
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`Total Cholesterol,, LDL, fastting triglyccerides (TGG), VLDL,, lipoproteiin (a) (Lp(
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`and apolipoproteins A-I, A-II, B, and E are reduced by at least 25%, compared to
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`control levels.”
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`42. Claim 5 is directed to “The method of claim 1 wherein the MTP
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`inhibitor is administered orally.”
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`43. Claim 6 is directed to “The method of claim 1 wherein said increasing
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`dose levels further comprise a fourth dose level.”
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`44. Claim 7 is directed to “The method of claim 1 wherein said increasing
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`dose levels further comprise a fourth and a fifth dose level.”
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`45. Claim 8 is directed to “The method of claim 7 wherein said fourth
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`dose level is from about 20 to about 60 mg/day, and said fifth dose level is from
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`about 30 to about 75 mg/day.”
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`46. Claim 9 is directed to “A method of treating a subject suffering from
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`hyperlipidemia or hypercholesterolemia, the method comprising administering to
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`the subject an effective amount of an MTP inhibitor, wherein said administration
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`comprises at least three step-wise, increasing dose levels of the MTP inhibitor
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`wherein a first dose level is from about 2 to about 13 mg/day, administered to the
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`subject for about 2 weeks; a second dose level is from about 5 to about 30 mg/day,
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`administered to the subject for about 2 weeks to about 4 weeks; and a third dose
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`level is from about 10 to about 50 mg/day, administered to the subject for about 2
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`14
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`PENN EX. 2025
`CFAD v. PENN
`IPR2015-01836
`
`

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`weeks to about 4 wweeks; andd wherein tthe MTP innhibitor is
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`representeed by:
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`”
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`or a phaarmaceuticcally accepttable salt thereof or tthe piperiddine N-oxidde thereof.
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`a subject ssuffering frfrom
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`rising admministering
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`to
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`447. Claimm 10 is direected to “AA method oof treating
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`hyperlippidemia orr hyperchollesterolemia, the metthod comp
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`the subjject an effeective amount of an MMTP inhib
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`itor, whereein said addministratioon
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`three step
`comprisses at least
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`-wise, incrreasing dosse levels o
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`whereinn a first dosse level is from abouut 2 to abouut 13 mg/dday, adminiistered to tthe
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`subject for about 11 to about 12 weeks; a second ddose level
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`is from abbout 5 to abbout
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`and a thirdd dose leveel is
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`30 mg/dday, adminnistered to tthe subjectt for aboutt 4 weeks;
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`from abbout 10 to aabout 50 mmg/day, admministered
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`to the subjbject for ab
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`out 4 weekks;
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`and wheerein the MMTP inhibiitor is repreesented byy:
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`or a phaarmaceuticcally accepttable salt thereof or tthe piperiddine N-oxidde thereof.
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`”
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`PEENN EX. 22025
`
`CFAD v. PEENN
`
`
`PPR2015-011836
`
`CI
`
`15
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`

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`Proposed Claim Amendment
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`3.
`I am aware that Penn has proposed an amendment to the claims of the
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`48.
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`’135 patent in the event CFAD finds the original claims unpatentable. I understand
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`that in its Motion to Amend, Penn has proposed cancellation of all the existing
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`claims of the ’135 patent and adding eight substitute claims, numbered 11-18.
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`49. Substitute claim 11 reads as follows: “A method of treating a subject
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`suffering from hyperlipidemia or hypercholesterolemia, the method comprising
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`administering to the subject an effective amount of an MTP inhibitor, wherein said
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`administration comprises at least three stepwise, increasing dose levels of the MTP
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`inhibitors, wherein a first and a second dose level is 50% of the immediately
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`following dose level, and wherein a third dose level is from about 0.2 to about 0.59
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`mg/kg/day based on a weight between 62.5 and 74.9 kg; and wherein the MTP
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`inhibitor is N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4’-(trifluoromethyl)[1,1’-biphenyl]-
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`2-yl] carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide,
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`methanesulfonate, and wherein each dose level is administered to the subject for
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`about 1 to 5 weeks”.
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`50. Substitute claim 12 reads as follows: “The method of claim 11
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`wherein the disorder is severe hypercholesterolemia”.
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`16
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`PENN EX. 2025
`CFAD v. PENN
`IPR2015-01836
`
`

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`51. Substitute claim 13 reads as follows: “The method of claim 11
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`wherein one or more of Total Cholesterol, LDL, fasting triglycerides (TG), VLDL,
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`lipoprotein (a) (Lp(a)), and apolipoproteins A-I, A-II, B, and E are reduced by at
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`least 15%, compared to control levels”.
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`52. Substitute claim 14 reads as follows: “The method of claim 11
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`wherein one or more of Total Cholesterol, LDL, fasting triglycerides (TG), VLDL,
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`lipoprotein (a) (Lp(a)), and apolipoproteins A-I, A-II, B, and E are reduced by at
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`least 25%, compared to control levels”.
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`53. Substitute claim 15 reads as follows: “The method of claim 11
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`wherein the MTP inhibitor is administered orally”.
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`54. Substitute claim 16 reads as follows: “The method of claim 11
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`wherein said increasing dose levels further comprise a fourth dose level”.
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`55. Substitute claim 17 reads as follows: “A method of treating a subject
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`suffering from hyperlipidemia or hypercholesterolemia, the method comprising
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`administering to the subject an effective amount of an MTP inhibitor, wherein said
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`administration comprises at least three step-wise, increasing dose levels of the
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`MTP inhibitor, wherein a first dose level and a second dose level is 50% of the
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`immediately following dose level, wherein the first dose level is administered to
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`the subject for about 2 weeks; the second dose level is administered to the subject
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`17
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`PENN EX. 2025
`CFAD v. PENN
`IPR2015-01836
`
`

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`for about 2 weeks to about 4 weeks; and a third dose level is from about 0.2 to
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`about 0.59 mg/kg/day based on a weight between 62.5 and 74.9 kg, administered to
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`the subject for about 2 weeks to about 4 weeks; and wherein the MTP inhibitor is
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`N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4’-(trifluoromethyl)[1,1’-biphenyl]-2-yl]
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`carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide,
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`methanesulfonate”.
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`56. Substitute claim 18 reads as follows: “A method of treating a subject
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`suffering from hyperlipidemia or hypercholesterolemia, the method comprising
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`administering to the subject an effective amount of an MTP inhibitor, wherein said
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`administration comprises at least three step-wise, increasing dose levels of the
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`MTP inhibitor, wherein a first dose level and a second dose level is 50% of the
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`immediately following dose level, wherein the first dose level is administered to
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`the subject for about 1 to about 12 weeks; the second dose level is administered to
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`the subject for about 4 weeks; and a third dose level is from about 0.2 to about 0.59
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`mg/kg/day based on a weight between 62.5 and 74.9 kg, administered to the
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`subject for about 4 weeks; and wherein the MTP inhibitor is N-(2,2,2-
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`trifluoroethyl)-9-[4-[4-[[[4’-(trifluoromethyl)[1,1’-biphenyl]-2-yl] carbonyl]
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`amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide, methanesulfonate”.
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`18
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`PENN EX. 2025
`CFAD v. PENN
`IPR2015-01836
`
`

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`57.
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`I am not offering any opinion as to either (1) the effective date of
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`invention for these substitute claims or (2) whether these substitute claims
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`properly claim priority to the ’915 provisional.
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`58. Any opinions I have offered below regarding the obviousness of the
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`original claims of the ’135 patent apply with equal force to the amended claims
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`proposed by Penn. Accordingly, my opinion that the subject matter claimed by the
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`’135 patent is non-obvious will not change regardless of whether or not the PTAB
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`grants Penn’s proposed amendment.
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`V. LEGAL PRINCIPLES
`59.
`I am not a lawyer and am not an expert in patent law. However,
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`counsel for Penn has provided me with a basic overview of the legal concepts
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`relevant to this case.
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`60.
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`I have reviewed the CFAD Petition Dated August 28, 2015 (Paper No.
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`1, “CFAD Pet.”) as well as the PTAB’s Institution Decision dated March 7, 2016
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`(Paper No. 7, “Institution Decision”), and I understand that the legal issue to be
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`decided is whether the claims of the patents-at-issue are invalid as obvious. CFAD
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`Pet. at 4-5, Institution Decision at 6.
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`19
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`PENN EX. 2025
`CFAD v. PENN
`IPR2015-01836
`
`
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`A.
`61.
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`Patent Validity
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`I understand that it is a basic principle of patent law that the validity
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`of each claim in a patent is determined individually. The determination of whether
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`a patent claim is valid requires that the language of the claim be compared to the
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`alleged prior art.
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`62.
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`I understand that in an IPR proceeding, each claim may be invalidated
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`only if the Petitioner proves by a preponderance of the evidence that the claim is
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`invalid.
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`B.
`63.
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`The Person of Ordinary Skill in the Art
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`I understand that patent validity is evaluated from the perspective of a
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`person of ordinary skill in the art (“POSA”) to which the patent pertains. I also
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`understand that Penn’s clinical expert, Dr. Frank M. Sacks, M.D., has proposed the
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`following definition for a person of ordinary skill in the art:
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`In March 2004 and 2005, the person of ordinary skill in the fields of
`the patent would have an M.D. and several years of experience in
`treating patients with lipid disorders, including hyperlipidemia and
`hypercholesterolemia. The person of ordinary skill in the art would
`also have had access to and worked [on a team] with a number of
`other individuals involved in drug discovery and development with
`advanced degrees in medicinal chemistry, pharmacology, or drug
`delivery sciences and having several years of experience in the
`development of drugs for the U.S. market.
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`20
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`PENN EX. 2025
`CFAD v. PENN
`IPR2015-01836
`
`

`
`64.
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`I agree with Dr. Sacks’ POSA definition. Although I do not hold an
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`M.D. degree, I believe my background, knowledge, and experience gives me
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`sufficient insight as to the perspective of a POSA. I have worked on cross-
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`disciplinary teams on drug discovery and the development of drugs for the U.S.
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`market.
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`65.
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`I have considered the alternative definition of a POSA that CFAD’s
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`experts, Drs. Mayersohn and Zusman, have offered in each of their declarations.
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`CFAD Ex. 1003 (Mayersohn Dec.) at ¶ 26; CFAD Ex. 1002 (“Zus