IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`COALITION FOR AFFORDABLE DRUGS VIII, LLC
`Petitioner
`v.
`TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner, based on Electronic Records of PTO
`U.S. Patent No. 7,932,268 B2 to Rader
`Filing Date: March 7, 2005
`Issue Date: April 26, 2011
`TITLE: METHODS FOR TREATING DISORDERS OR DISEASES ASSOCIATED
`WITH HYPERLIPIDEMIA AND HYPERCHOLESTEROLEMIA WHILE
`MINIMIZING SIDE EFFECTS
`________________________________
`
`Inter Partes Review Trial No. TBD
`________________________________
`
`Declaration of Michael Mayersohn, Ph.D. in Support of Coalition for
`Affordable Drugs’ Petition for
`Inter Partes Review of U.S. Patent No. 7,932,268 B2
`
`CFAD Ex. 1003 (1 of 57)
`
`

`
`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`TABLE OF CONTENTS
`
`
`
`INTRODUCTION. .......................................................................................... 1
`I.
`QUALIFICATIONS AND BACKGROUND. ................................................ 1
`II.
`SUMMARY OF THIS REPORT. ................................................................... 5
`III.
`IV. LIST OF MATERIALS CONSIDERED. ....................................................... 7
`A.
`Chang. .................................................................................................... 7
`B.
`The Pink Sheet. ...................................................................................... 8
`C.
`Stein 2004. ............................................................................................. 9
`V.
`PERSON OF ORDINARY SKILL IN THE ART. ....................................... 10
`VI. SCIENTIFIC AND TECHNICAL BACKGROUND. .................................. 11
`A.
`Pharmacokinetics................................................................................. 11
`B.
`B. Multiple Dosing and Steady State. ................................................ 12
`C.
`Using Drug Doses within a Drug Class to Propose Dosing. ............... 17
`VII. MTP INHIBITORS GENERALLY. ............................................................. 19
`VIII. IMPLITAPIDE AND ITS APPLICATION TO LOMITAPIDE. ................. 20
`A.
`Efficacy and Side Effects. ................................................................... 20
`B.
`Animal Models. ................................................................................... 22
`C.
`Human Studies. ................................................................................... 25
`D.
`Pink Sheet Teachings Pertinent to Lomitapide Dosing. ..................... 27
`E.
`Stein 2004 Teachings Pertinent to Lomitapide Dosing. ..................... 28
`F.
`Lomitapide Dosing Based on the Pink Sheet in view of Chang. ........ 29
`G.
`Lomitapide Dosing Based on Stein 2004 in view of Chang. .............. 30
`
`i
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`CFAD Ex. 1003 (2 of 57)
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`

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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`IX. THE ‘915 PROVISIONAL DOES NOT TEACH THE CLAIMED
`ESCALATING DOSE RANGES. ................................................................. 34
`X.
`CONCLUSION. ............................................................................................. 50
`
`
`
`ii
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`CFAD Ex. 1003 (3 of 57)
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`

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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`TABLE OF EXHIBITS
`
`Exhibit
`CFAD 1001
`
`Title
`Certified U.S. Patent No. 7,932,268.
`
`CFAD 1002
`
`Declaration of Randall M. Zusman, M.D.
`
`CFAD 1005
`
`Affidavit of Christopher Butler, Office Manager, Internet
`Archive, authenticating Internet Archive URLs (June 12,
`2015) (attaching as Ex. A:
`PPD News Releases(2004/02/13) (available at
`https://web.archive.org/web/20040213233245/http://www.ppdi
`.com/PPD_U6.htm?ID=126662);
`PPD News & IR Presentations(2003/12/12) (available at
`https://web.archive.org/web/20031212193444/http://ppdi.com/
`PPD_6_12.htm);
`PPD News & IR Presentations (2004/06/04) (available at
`https://web.archive.org/web/20040604203252/http://www.ppdi
`.com/PPD_6_12.htm)).
`
`CFAD 1006
`
`Certified U.S. Provisional Patent Application No. 60/550,915.
`
`CFAD 1007
`
`CFAD 1013
`
`CFAD 1014
`
`CFAD 1015
`
`U.S. Patent No. 7,932,268 (highlighting dosing information
`not present in U.S. Provisional Patent Application No.
`60/550,915).
`
`Bayer/PPD Implitapide Development Follows Zetia Model As
`Statin Add-On, 66 THE PINK SHEET 17 (Feb. 16, 2004).
`
`Evan Stein, CEO & President, MRL Int’l (Division of PPD),
`Presentation Given at PPD’s Analyst Day, Microsomal
`Triglygeride [sic] Transfer Protein (MTP) Inhibitor
`(implitapide) program (Feb. 5, 2004).
`
`George Chang et al., Microsomal triglyceride transfer protein
`(MTP) inhibitors: Discovery of clinically active inhibitors
`using high-throughput screening and parallel synthesis
`paradigms, 5 CURRENT OPINION IN DRUG DISCOVERY & DEV.
`562 (2002).
`
`iii
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`CFAD Ex. 1003 (4 of 57)
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`CFAD 1016
`
`CFAD 1018
`
`CFAD 1023
`
`Charles E. Chandler et al., CP-346086: an MTP inhibitor that
`lowers plasma cholesterol and triglycerides in experimental
`animals and in humans, 44 J. OF LIPID RES. 1887 (2003).
`
`John R. Wetterau et al., An MTP Inhibitor That Normalizes
`Atherogenic Lipoprotein Levels in WHHL Rabbits, 282 SCI.
`751 (1998).
`
`U.S. FOOD & DRUG ASS’N, ESTIMATING THE MAXIMUM SAFE
`STARTING DOSE IN INITIAL CLINICAL TRIALS FOR
`THERAPEUTICS IN ADULT HEALTHY VOLUNTEERS: GUIDANCE
`FOR INDUSTRY (2005).
`
`CFAD 1026
`
`Rowland & Tozer, Clinical Pharmacokinetics: Concepts and
`Applications, 58, 98 (1995)
`
`CFAD 1029 Michael Mayersohn. Ph.D. Curriculum Vitae
`
`CFAD 1032 M. Mayersohn, Principles and Applications of
`Pharmacokinetics, in MEDICAL TOXICOLOGY, 282 (2004)
`
`CFAD 1033
`
`Shiomi & Ito, “MTP inhibitor decreases plasma cholesterol
`levels in LDL receptor-deficient WHHL rabbits by lowering
`the VLDL secretion,” European Journal of Pharmacology,
`431:127-131 (2001)
`
`CFAD 1038 Margaret A. McDowell et al., Anthropometric Reference Data
`for Children and Adults: U.S. Population, 1999-2002, CDC
`ADVANCE DATA FROM VITAL & HEALTH STATS. NO. 361
`(2005)
`
`
`
`
`
`iv
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`CFAD Ex. 1003 (5 of 57)
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`Abbreviation
`‘268 patent
`
`TABLE OF ABBREVIATIONS
`Definition
`U.S. Patent No. 7,932,268
`
`MTP
`
`AST
`
`ALT
`
`LDL
`
`HDL
`
`VLDL
`
`apoB
`
`Microsomal triglyceride transfer protein
`
`Aspartate Aminotransferase
`
`Alanine Aminotransferase
`
`Low density lipoprotein
`
`High density lipoprotein
`
`Very low density lipoprotein
`
`apolipoprotein B
`
`‘915 Provisional
`
`U.S. Provisional Application No. 60/550,915
`
`LDL-C
`
`FH
`
`HoFH
`
`HeFH
`
`LDL cholesterol
`
`Familial hypercholesterolemia
`
`Homozygous familial hypercholesterolemia
`
`Heterozygous familial hypercholesterolemia
`
`NHANES
`
`National Health and Nutrition Examination Survey
`
`v
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`

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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`I.
`
`INTRODUCTION.
`
`1.
`
`I, Michael Mayersohn, Ph.D., am over the age of eighteen (18) years
`
`and otherwise competent to make this Declaration. I have personal knowledge of
`
`the facts set forth in this Declaration and am competent to testify to the same.
`
`2.
`
`I have been retained by counsel for the Coalition for Affordable Drugs
`
`VIII (“CFAD” or “Petitioner”) in connection with the above-captioned petition for
`
`inter partes review of U.S. Patent No. 7,932,268 B2 (CFAD Ex. 1001 (“‘268
`
`patent”)). Specifically, I have been advised that CFAD intends to request the
`
`United States Patent and Trademark Office cancel Claims 1-8 of the ‘268 patent as
`
`unpatentable for obviousness. I understand that this Declaration will be used to
`
`support unpatentability in any proceeding initiated in connection with this request.
`
`II. QUALIFICATIONS AND BACKGROUND.
`I am a Professor of Pharmaceutical Sciences in the College of
`3.
`
`Pharmacy at the University of Arizona. I have been in that position since 1983.
`
`Prior to that time, from 1976 to 1983, I was an Associate Professor of
`
`Pharmaceutical Sciences at the University of Arizona.
`
`4.
`
`From 1971 until 1976, I served as an Assistant and then Associate
`
`Professor of Pharmaceutical Sciences at the Faculty of Pharmacy, The University
`
`of Toronto, Toronto, Ontario, Canada.
`
`
`
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`5.
`
`I received my Bachelors of Science in Pharmacy from the College of
`
`Pharmaceutical Sciences Columbia University in 1966. In 1971, I received a Ph.D.
`
`in Pharmaceutics from the School of Pharmacy, State University of New York at
`
`Buffalo.
`
`6. My research interests include the general area of pharmaceutical
`
`sciences with a focus in pharmaceutics, biopharmaceutics, pharmacokinetics and
`
`pharmacodynamics. These specialty areas generally relate to an examination of
`
`the relationship between the physical and chemical characteristics of a drug and its
`
`dosage form and the fate and performance of that drug in the body. These areas
`
`also generally relate to the use and development of analytical procedures to
`
`quantitate drugs and metabolites in biological fluids and from these data the
`
`development of rigorous mathematical models to quantitate the kinetic processes
`
`of drug absorption, distribution, metabolism, excretion and response. My research
`
`also focuses on the design of rational drug dosing regimens based upon analytical,
`
`mathematical and clinical data.
`
`7.
`
`I have maintained an active research program, which has been funded
`
`by national, state, and private agencies. This program has involved numerous
`
`research projects and my supervision of the M.S. and Ph.D. dissertations of
`
`approximately 18 students and research of four postdoctoral research associates.
`
`
`
`2
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`8.
`
`I have conducted in situ and whole animal studies (in mice, rats, dogs
`
`and pigs) to characterize the pharmacokinetics and pharmacodynamics of drugs
`
`and their metabolites. I have also conducted clinical studies in human subjects to
`
`evaluate the pharmacokinetics of selected drugs and their metabolites. In addition,
`
`I have conducted theoretical/simulation or in silico experimentation to address a
`
`variety of problems.
`
`9.
`
`I have also conducted research studies in vitro to characterize the
`
`physical and chemical properties of drugs and drug dosage forms. I have further
`
`conducted in vitro studies to characterize the plasma protein binding of drugs and
`
`their metabolic properties in the presence of varying enzymatic preparations.
`
`10.
`
`I have published over 160 original research publications, 18 book
`
`chapters and symposia, and 15 professional/educational publications. I have given
`
`more than 65 invited presentations and contributed to over 160 submitted
`
`presentations. In recognition of my contributions to the fields of my research
`
`specialties, my peers have elected me as a Fellow of several organizations,
`
`including: the Academy of Pharmaceutical Sciences, American Pharmaceutical
`
`Association; American Association of Pharmaceutical Scientists; American
`
`College of Clinical Pharmacology. Fellow status is conferred on relatively few
`
`members of a scientific or professional organization.
`
`
`
`3
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`

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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`11.
`
`I am a member of several professional societies and organizations,
`
`including the American Association of Pharmaceutical Scientists, the American
`
`Society for Clinical Pharmacology and Therapeutics, and the American Society of
`
`Pharmacology and Experimental Therapeutics.
`
`12.
`
`I have served two five-year terms as a member of the United States
`
`Pharmacopeia Expert Committee. During my first five-year term the Committee
`
`was referred to as the Dissolution and Bioavailability Committee. During my
`
`second five-year term, during which I served as co-Chair, the Committee was
`
`referred to as the Biopharmaceutics Committee. This Committee sets the standards
`
`for dissolution testing and bioavailability used by the pharmaceutical industry and
`
`it is responsible for establishing those standards in official monographs.
`
`13.
`
`I served a four-year term as a member of the Advisory Committee on
`
`Pharmaceutical Sciences (formerly, the Generic Drug Advisory Committee) of the
`
`Food and Drug Administration.
`
` This Committee sets the standards for
`
`bioavailability and bioequivalence measurements that are required of the
`
`pharmaceutical industry.
`
`14.
`
`I am also the Course Director and Instructor of “Principles of
`
`Pharmacokinetics and Toxicokinetics for the Industrial Scientist,” which is
`
`sponsored by the University of Arizona and attended by pharmaceutical scientists.
`
`This course has been offered since 1994 and has enrolled over 600 scientists. I am
`
`
`
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`similarly a Course Director of on-site courses
`
`(“Selected Topics
`
`in
`
`Pharmacokinetics”) offered to the pharmaceutical industry and which have
`
`enrolled well over 1000 practicing pharmaceutical scientists.
`
`15. Attached to the accompanying Petition as CFAD Ex. 1029 is my
`
`curriculum vitae setting forth my educational experience, employment history,
`
`professional affiliations, and publications.1
`
`16.
`
`I have relied upon my education, background, and experience in
`
`forming the opinions set forth herein.
`
`III. SUMMARY OF THIS REPORT.
`I explain in this report that a person of ordinary skill in the art (as
`17.
`
`defined below) would have been aware before March 2004 that the two MTP
`
`inhibitors implitapide and lomitapide had both progressed to clinical trials in
`
`humans, and would have regarded them as very similar drugs in terms of chemical
`
`structure, biochemical mechanism(s) of action, and pharmacological response.
`
`Based on published data reporting on the trials in animals and humans, and the
`
`general knowledge of the person of ordinary skill in the art (including regarding
`
`MTP inhibitors), the ordinarily-skilled artisan before March 2004 would have
`
`
`
`1 I reserve the right to further explain my background and qualifications in
`deposition or at trial as needed.
`
`
`
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`reasonably expected implitapide and lomitapide to have similar beneficial and
`
`adverse effects at similar doses in humans.
`
`18. As of March 2004, implitapide and lomitapide had both been tested
`
`for efficacy in numerous animal models, including rodents. In particular, both
`
`implitapide and lomitapide had been tested in WHHL rabbits, considered to be an
`
`excellent animal model for humans with a condition referred to as HoFH, and both
`
`agents had produced similar results. (See CFAD Ex. 1015 (“Chang”) at 565;
`
`CFAD Ex. 1018 (“Wetterau”) at 753). In human studies, implitapide and
`
`lomitapide again showed “similar efficacy,” reducing LDL-C by over one-half at
`
`the higher doses tested. (Chang at 566). Both implitapide and lomitapide were
`
`associated with the same adverse side effects, including elevated plasma AST and
`
`ALT levels. (Id. at 567). Based on the publicly-available data by March 2004, a
`
`person of ordinary skill in the art would have concluded that implitapide and
`
`lomitapide were very similar drugs in terms of efficacy and adverse side effects.
`
`19. Because the two compounds demonstrated similar effects at similar
`
`doses in appropriate animal models as well as in humans, a person of ordinary skill
`
`in the art seeking to develop an initial dosing regimen for lomitapide would have
`
`begun by applying to lomitapide the same stepwise escalating dosing regimen for
`
`implitapide described in the February 16, 2004 Pink Sheet (CFAD Ex. 1013 (“Pink
`
`Sheet”)) and on page 38 of Stein 2004 (CFAD Ex. 1014 (“Stein 2004”)). The
`
`
`
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`ordinary skilled artisan would have had a reasonable expectation of success that
`
`such doses would lead to a clinical effect at least comparable to that of implitapide.
`
`20. A person of ordinary skill in the art would also, as a matter of course,
`
`have modified and optimized the escalating stepwise lomitapide dosing regimen
`
`through routine experimentation to balance such factors as safety, efficacy, and
`
`patient convenience. Such routine optimization, potentially including adjusting the
`
`number of weeks spent at each dose level, is standard practice for skilled artisans.
`
`IV. LIST OF MATERIALS CONSIDERED.
`In formulating my opinions, I have considered the documents cited
`21.
`
`and referenced in this declaration and the documents cited in the Table of Exhibits
`
`above. Among these references were Chang, the Pink Sheet, and Stein 2004.
`
`A. Chang.
`22. Chang, published in 2002 in the journal CURRENT OPINION IN DRUG
`
`DISCOVERY & DEVELOPMENT, and provides a review of MTP inhibitors. Chang
`
`explains the development of MTP inhibitors at Pfizer using high-throughput
`
`screening, and compares the molecular structures of several MTP inhibitors being
`
`developed by various drug companies. (Chang at 563-66). Chang provides a
`
`summary of the animal studies carried out on the compounds Pfizer CP-346086,
`
`BMS-201038 (lomitapide), and BAY-13-9952 (implitapide), including summaries
`
`of the efficacy of lomitapide and implitapide in WHHL rabbits. (Id. at 564-67).
`
`
`
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`Chang also summarizes the results of human clinical trials of lomitapide and
`
`implitapide. (Id. at 566-67).
`
`The Pink Sheet.
`
`B.
`23. The Pink Sheet published on February 16, 2004 discusses the
`
`pharmaceutical development company PPD, Inc.’s “Phase II proof-of-concept
`
`studies on the use of implitapide (BAY-13-9952) as an add-on to statin therapy.”
`
`(Pink Sheet; see also Stein 2004 at 1). The Pink Sheet reports as follows:
`
`PPD is conducting three 39-week Phase II studies with dose
`titration occurring every five weeks based on safety and
`tolerability examined at four weeks. The starting dose will be
`10 mg daily, escalating by 5 mg/day every five weeks to a
`maximum 40 mg/day.
`
`
`
`(Pink Sheet). The article includes several quotes from PPD’s CEO, Dr. Evan
`
`Stein, about the rationale for the studies and their dosing protocol, as well as the
`
`efficacy and side effects associated with implitapide and other MTP inhibitors.
`
`(See id.)
`
`24. The Pink Sheet is a well-known publication directed to the
`
`pharmaceutical industry. A person of ordinary skill in the art interested in MTP
`
`inhibitors, interested in developing a therapy for conditions such as HoFH, or
`
`curious about lipid-lowering therapies in development, would look to the Pink
`
`Sheet for information. Articles in the Pink Sheet are indexed and available on
`
`commonly-used databases such as Lexis-Nexis. Because the Pink Sheet provides
`
`
`
`8
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`

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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`timely reports on events in the pharmaceutical industry, including ongoing and
`
`proposed clinical studies, a person of ordinary skill in the art would have reviewed
`
`and considered the Pink Sheet for news and information on issues including the
`
`development and dosing of MTP inhibitors such as lomitapide.
`
`Stein 2004.
`
`C.
`25. Dr. Stein gave a presentation on PPD’s MTP inhibitor program on
`
`February 5, 2004 that was open to anyone who registered. (Stein 2004 at 1, 4; see
`
`CFAD Ex. 1005 at Ex. A (“PPD Press Release”)). In this presentation, Stein
`
`described PPD’s development program for the MTP inhibitor implitapide,
`
`including the results of Phase II human trials using various doses of implitapide.
`
`(Stein 2004 at 29-30, 32). He also described the stepwise escalating dose regimen
`
`he had developed for PPD’s implitapide trials. (Id. at 38). A person of ordinary
`
`skill in the art interested in the development of MTP inhibitors could apparently
`
`have attended the meeting or accessed the presentation itself via webcast or on the
`
`PPD website shortly thereafter. (PPD Press Release). A person of ordinary skill in
`
`the art would have looked to Stein 2004 for guidance on dosing ranges for MTP
`
`inhibitors such as lomitapide because Dr. Stein—an MD/PhD with experience in
`
`the research and development of lipid-lowering therapies and the CEO of a
`
`pharmaceutical development company—provided both a medical and a
`
`commercial justification for the clinical approach and dosage regimen described.
`
`
`
`9
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`

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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART.
`
`26.
`
`I have reviewed the definition of the person of ordinary skill in the art
`
`set forth in the Declaration of Dr. Randall Zusman. (See CFAD Ex. 1002
`
`(“Zusman Decl.”) ¶¶ 27-32). I agree with that definition and adopt it for the
`
`purposes of the opinions and analysis herein. I would particularly emphasize the
`
`“team” aspect of the definition of a person of ordinary skill in the art in drug
`
`development. In industry, individuals with the various skills and backgrounds
`
`listed form part of a “drug team” to develop a promising drug.
`
`27. As discussed below, given the guidance available in the literature
`
`before March 2004 (including Stein 2004 and/or the Pink Sheet), I do not consider
`
`it to require any particular sophistication for the person of ordinary skill in the art
`
`to take implitapide and lomitapide—which had already been tested with some
`
`success across a range of doses in humans, and which had a variety of in vitro and
`
`in vivo parameters already measured and established—and to review and apply that
`
`information to generate a similar and appropriate dosing regimen for humans.
`
`28.
`
`I provide the opinions and analysis in this Declaration from the
`
`perspective of a person of ordinary skill in the art (as defined in the Zusman
`
`Declaration and adopted herein) during the relevant time period.2
`
`
`
`
`2 This Declaration contains the opinions that a person of skill in the art would have
`known or understood as of March 5, 2004, which I understand to be the earliest
`
`
`
`10
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`VI. SCIENTIFIC AND TECHNICAL BACKGROUND.
`Pharmacokinetics.
`A.
`29. The word “pharmacokinetics” is derived from the Greek pharmakon,
`
`meaning “substance” or “drug,” and kineticos, meaning “movable” or “to move.”
`
`In combination, the word “pharmacokinetics,” and the scientific discipline that it
`
`represents, refer to a description of the rate processes associated with drug
`
`movement into (absorption or input), within (distribution or translocation), and in
`
`leaving (metabolism and excretion) the body. These processes are often referred to
`
`by the mnemonic ADME, which stands for Absorption, Distribution, Metabolism,
`
`and Excretion. In contrast to the field of pharmacology, in which one examines
`
`the “effect of the drug on the body,” pharmacokinetics is often expressed as
`
`examining the opposite, i.e., the “effect of the body on the drug.” The two areas of
`
`study, however, are inextricably connected.
`
`30. While pharmacology tends to be a qualitative science, a quantitative
`
`study of the time-course of a pharmacological or clinical effect over time is
`
`referred to as “pharmacodynamics.” The pharmacodynamic properties of a drug
`
`are often studied in combination with its pharmacokinetic properties in order to
`
`
`
`potential priority date for the ‘268 patent. I have been made aware that there is
`some dispute regarding the exact priority date of the claims of the ‘268 patent.
`Regardless of the ultimate decision on the priority date, the opinions of a person of
`skill in the art as I have described them in this Declaration would remain the same.
`
`
`
`11
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`develop so-called pharmacokinetic/pharmacodynamic models of the drug in
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`individuals and populations of patients.
`
` The
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`relationship between
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`pharmacokinetics and pharmacodynamics is set forth in the following diagram:
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`(CFAD Ex. 1032 (“Mayersohn 2004”) at 283).
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`31. As shown
`
`in
`
`the above diagram,
`
`
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`the pharmacokinetic and
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`pharmacodynamic events overlap. The driving force for the pharmacodynamic
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`events following drug dosing is generally the concentration of drug in the blood (or
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`plasma) or the rate at which those concentrations change.
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`B. Multiple Dosing and Steady State.
`32. Effective drug therapy, especially for chronic disease conditions or
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`physiological disorders, requires a multiple dosing regimen. Rarely can such a
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`condition be resolved or treated with a single dose of a drug. An effective dosing
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`regimen includes a maintenance dose that is given with a defined frequency, for
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`example, 100 mg taken twice a day (i.e., every 12 hours). Such a regimen would
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`also include a potential loading dose, route of administration and product selection
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`(with a defined bioavailability). The regimen may begin with a smaller dose,
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`
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`12
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`CFAD Ex. 1003 (18 of 57)
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`which is then periodically increased, or titrated upward. Such a regimen is
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`designed to achieve and ultimately maintain a desired therapeutic effect (with
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`minimal adverse events), which in turn requires dosing to achieve the desired
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`effects notwithstanding the fluctuations that naturally occur with each new dose.
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`This type of regimen—in which the dose is titrated until a maintenance dose is
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`achieved—is commonly used to dose cholesterol-lowering drugs, such as statins.
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`(See, e.g., Zusman Decl. ¶¶ 37-38, 44, 46-47, 65).
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`33.
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`In order to achieve and maintain the desired therapeutic effect, the
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`drug is administered in a multiple dosing regimen, as noted above. That regimen
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`will ultimately achieve a reasonable steady state, albeit with some fluctuation with
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`time and dose, the upper and lower bounds of which (Cmax and Cmin) are defined by
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`the known therapeutic plasma concentration range (or “therapeutic window”).
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`This process is illustrated in the following figure of plasma concentrations as a
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`function of time with multiple doses given every 6 hours.
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`
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`13
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`CFAD Ex. 1003 (19 of 57)
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`(CFAD Ex. 1026 (“Rowland & Tozer”) at 98) (additions made to original).
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`34. This figure illustrates the process of drug accumulation in the body
`
`
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`until a steady state is achieved. Accumulation occurs when subsequent doses are
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`given before all of the drug is lost from the previous dose. The extent of
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`accumulation is a function of the half-life of the drug and the dosing interval. The
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`time to achieve a steady state is a function only of the half-life of the drug (ca. 4-5-
`
`half-lives to achieve a steady state). Noted in the figure are values for Cmax and
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`Cmin, and two areas under the plasma concentration-time curves. The value for
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`dose until all drug has been eliminated from the body (i.e., to time infinity). The
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`𝐴𝐴𝐴0∞ represents the total area under the curve (or exposure) following the first
`value for 𝐴𝐴𝐴0𝜏 represents the area under the concentration-time curve during a
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`dosing interval (tau,τ) at steady state. These two areas are numerically equal and
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`
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`14
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`CFAD Ex. 1003 (20 of 57)
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`reflect how much of the dosed drug has been absorbed into the body and its
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`clearance from the body. Once a steady state is achieved, fluctuations during a
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`dosing interval at steady state (i.e., Cmax to Cmin) will be a function of the dosing
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`interval and half-life of the drug. The former is often chosen to minimize this
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`fluctuation.
`
`35. Studies in animals or early clinical studies in human subjects will
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`often use an experimental design intended to achieve different (usually ascending)
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`steady state drug plasma concentrations. This protocol involves administering a
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`starting dose (at a selected time interval) for a selected period of dosing (at least
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`until a steady state is achieved, but often longer), followed by increasing doses
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`administered for that same period of time. In this way the response to the drug
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`(both desired and adverse) can be related to the dose of drug and plasma
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`concentrations over a wide range of values and will include metrics for desired
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`effect and adverse events.
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`36. A protocol such as that described above can be illustrated in the
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`following figure, which indicates the incidence of the event being measured on the
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`vertical (Y-axis) and plasma concentrations on the horizontal (X-axis). This figure
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`also illustrates how one would detect and differentiate toxicity and adverse events
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`from the desired response and, from that information, suggest a therapeutic plasma
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`concentration range or therapeutic window.
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`
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`15
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`CFAD Ex. 1003 (21 of 57)
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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` (Rowland & Tozer at 57).
`
`
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`37. For a drug that is useful in therapy, the “ineffective” measure (line
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`starting at top left) decreases as dose or plasma concentration of the drug increases.
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`Accordingly, the “effectiveness” curve increases until, in theory, accounting for
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`100% incidence or resolution of the problem. While the drug exerts increasing
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`effectiveness as the dose and plasma concentrations rise, there is inevitably the
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`appearance of minor or serious toxicities, or adverse events, as noted by the labeled
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`lines in the figure (and which occur at higher doses or plasma concentrations). If
`
`one were to subtract the latter undesired events from the effectiveness curve, the
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`net result would be the “effectiveness-toxicity” curve or the “therapeutically
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`effectiveness” curve whose appearance is that of a parabola (red curve); it
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`increases, reaches a maximum and then declines as toxicity outweighs the desired
`
`
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`16
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`CFAD Ex. 1003 (22 of 57)
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`Declaration of Michael Mayersohn, Ph.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`response. If one were to draw two dashed vertical lines to delineate what would be
`
`considered the “therapeutic window”, they would be drawn to encompass
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`concentrations from about 4 to about 8 mg/L.
`
`38. As noted above, multiple dosing with ascending doses to increase
`
`drug plasma concentrations in order to achieve different steady states, would
`
`define the curves in the above illustration. Importantly, if one would like to further
`
`minimize the incidence of adverse events, the “therapeutic window” can be
`
`redefined to encompass lower concentrations (i.e., by moving the “window” closer
`
`to the origin to lower concentrations or doses). In the above illustration defining
`
`the therapeutic window to encompass the (lower) plasma concentrations of, for
`
`example, 3 to 6 mg/L, would reduce both effectiveness and adverse events, yet still
`
`represent a rational approach to therapy. This would be an especially attractive
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`approach to take in those instances where other adjunctive forms of therapy (e.g.,
`
`other drugs or procedures) can