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 7,932,268 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 No.: TBD
`
`Declaration of Randall M. Zusman, M.D. in Support of
`Coalition for Affordable Drugs’ Petition
`for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`
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`CFAD Ex. 1002 (1 of 135)
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`

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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`TABLE OF CONTENTS
`
`I.
`INTRODUCTION .................................................................................... 1
`II. MY EXPERIENCE AND QUALIFICATIONS ......................................... 1
`
`SUMMARY OF OPINIONS..................................................................... 4
`III.
`IV. LIST OF MATERIALS CONSIDERED.................................................... 8
`
`PERSON OF ORDINARY SKILL IN THE ART ...................................... 8
`V.
`VI. BACKGROUND.....................................................................................11
`A. Drug development—the cardiologist’s general perspective ..............11
`B.
`Cardiovascular disease—non-surgical treatment options and
`targets available by March 2004 .....................................................15
`1.
`Fibrates ................................................................................16
`2.
`Niacin ..................................................................................17
`3.
`Statins..................................................................................18
`4.
`Patient populations requiring more than just a statin drug .......19
`5. MTP Inhibitors.....................................................................21
`6. MTP Inhibitors: Animal and Human Studies .........................22
`7. MTP Inhibitors: specific dosing considerations......................24
`VII. THE 268 PATENT ..................................................................................30
`A.
`The 268 Patent File History ............................................................31
`B.
`The 915 Provisional Does Not Support the Claimed Escalating
`Dose Titration Regimen .................................................................34
`The Meaning of Certain 268 Patent Claim Terms ............................42
`
`C.
`
`VIII. COMPARISON BETWEEN THE 268 PATENT CLAIMS AND THE
`PRIOR ART............................................................................................44
`A. Disclosures, Knowledge and Information Available in the Art .........44
`1.
`Chang ..................................................................................45
`2.
`Stein 2004 ............................................................................47
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`3.
`The Pink Sheet .....................................................................50
`The Legal Parameters of Obviousness.............................................52
`B.
`C. Obviousness of the 268 Patent Claims: Pink Sheet in view of
`Chang............................................................................................55
`1.
`Subject matter claimed by the 268 Patent claim 1 would
`have been obvious to the person of ordinary skill ...................57
`(a)
`“A method of treating a subject suffering from
`hyperlipidemia or hypercholesterolemia, the
`method comprising . . .” .............................................. 58
`“Administering to the subject an effective amount
`of an MTP inhibitor . . .” ............................................. 59
`“Wherein said administration comprises at least
`three step-wise, increasing dose levels of the MTP
`inhibitors . . .”............................................................. 60
`“Wherein a first dose level is from about 2 to about
`13 mg/day, a second dose level is from about 5 to
`about 30 mg/day, and a third dose level is from
`about 10 to about 50 mg/day . . .” ................................ 60
`“Wherein the MTP inhibitor is represented by:
`
`(d)
`
`(b)
`
`(c)
`
`(e)
`
`(f)
`
` or a pharmaceutically
`acceptable salt thereof or the piperidine N-oxide
`thereof . . .” ................................................................ 61
`“Wherein each dose level is administered to the
`subject for about 1 to about 4 weeks.”.......................... 62
`The ordinarily skilled artisan would be motivated
`to combine the Pink Sheet with Chang ......................... 64
`The ordinarily skilled artisan would have a
`reasonable expectation of success ................................ 69
`268 Patent Claim 2 ...............................................................70
`268 Patent Claim 3 ...............................................................72
`
`(g)
`
`(h)
`
`2.
`3.
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`(b)
`
`(c)
`
`4.
`268 Patent Claim 4 ...............................................................74
`268 Patent Claim 5 ...............................................................75
`5.
`268 Patent Claim 6 ...............................................................76
`6.
`268 Patent Claim 7 ...............................................................77
`7.
`268 Patent Claim 8 ...............................................................78
`8.
`D. Obviousness of 268 Patent Claims: Stein 2004 in view of
`Chang............................................................................................79
`1.
`Subject matter claimed by the 268 Patent claim 1 would
`have been obvious to the person of ordinary skill ...................81
`(a)
`“A method of treating a subject suffering from
`hyperlipidemia or hypercholesterolemia, the
`method comprising . . .” .............................................. 82
`“Administering to the subject an effective amount
`of an MTP inhibitor . . .” ............................................. 83
`“Wherein said administration comprises at least
`three step-wise, increasing dose levels of the MTP
`inhibitors . . .”............................................................. 84
`“Wherein a first dose level is from about 2 to about
`13 mg/day, a second dose level is from about 5 to
`about 30 mg/day, and a third dose level is from
`about 10 to about 50 mg/day . . .” ................................ 85
`“Wherein the MTP inhibitor is represented by:
`
`(d)
`
`(e)
`
` or a pharmaceutically
`acceptable salt thereof or the piperidine N-oxide
`thereof . . .” ................................................................ 86
`“Wherein each dose level is administered to the
`subject for about 1 to about 4 weeks.”.......................... 86
`The ordinarily skilled artisan would be motivated
`to combine Stein 2004 with Chang .............................. 88
`The ordinarily skilled artisan would have a
`
`(f)
`
`(g)
`
`(h)
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`
`reasonable expectation of success ................................ 93
`268 Patent Claim 2 ...............................................................95
`2.
`268 Patent Claim 3 ...............................................................98
`3.
`268 Patent Claim 4 ............................................................. 100
`4.
`268 Patent Claim 5 ............................................................. 101
`5.
`268 Patent Claim 6 ............................................................. 102
`6.
`268 Patent Claim 7 ............................................................. 103
`7.
`268 Patent Claim 8 ............................................................. 103
`8.
`Claim Charts................................................................................ 104
`1.
`The Pink Sheet in view of Chang ........................................ 104
`2.
`Stein 2004 in view of Chang ............................................... 113
`
`E.
`
`IX. SECONDARY CONSIDERATIONS ..................................................... 122
`A. No Unexpected Results ................................................................ 123
`B.
`No Failure of Others .................................................................... 124
`C. No Skepticism in the Art .............................................................. 125
`CONCLUSION ..................................................................................... 126
`
`X.
`
`
`
`
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`TABLE OF EXHIBITS
`
`Exhibit Title
`1001
`U.S. Patent No. 7,932,268
`1003
`Declaration of Michael Mayersohn, Ph.D.
`1005
`Declaration of Christopher Butler, dated June 12, 2015,
`authenticating Internet Archive URLs attached as Ex. A:
`PPD News Releases(2/13/2004) (available at
`https://web.archive.org/web/20040213233245/http://www.pp
`di.com/PPD_U6.htm?ID=126662);
`PPD News & IR Presentations(12/12/2003) (available at
`https://web.archive.org/web/20031212193444/http://ppdi.co
`m/PPD_6_12.htm);
`PPD News & IR Presentations(6/4/2004) (available at
`https://web.archive.org/web/20040604203252/http://www.pp
`di.com/PPD_6_12.htm) (“PPD Screenshot”)
`U.S. Provisional Patent Application No. 60/550,915
`Highlighted 268 Patent identifying new dosing information not
`included in the 915 Provisional
`268 Patent File History, April 14, 2010 Amendment and
`Response
`268 Patent File History, Declaration of William Sasiela (“Sasiela
`Declaration”)
`268 Patent File History, September 13, 2010 Response
`Bayer/PPD Implitapide Development Follows ZETIA Model As
`Statin Add-On, 66 THE PINK SHEET 17 (Feb. 16, 2004) (“Pink
`Sheet”)
`Evan Stein, Microsomal Triglygeride [sic] Transfer Protein
`(MTP) Inhibitor (implitapide) program (Feb. 5, 2004) (“ Stein
`2004”)
`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 & DEVELOPMENT 562
`(2002) (“Chang”)
`
`1006
`1007
`
`1009
`
`1010
`
`1011
`1013
`
`1014
`
`1015
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`1016
`
`1017
`
`1021
`
`1022
`
`1027
`1028
`1031
`
`1038
`
`
`
`Chandler et al., CP-346086: an MTP inhibitor that lowers plasma
`cholesterol and triglycerides in experimental animals and in
`humans, 44 J. LIPID RESEARCH 1887 (2003) (“Chandler”)
`FDA approves ZETIA – first new class to treat cholesterol since
`statins introduced, (Oct. 28, 2002) (available at
`http://www.drugs.com/news/fda-approves-ZETIA-first-new-class-
`cholesterol-since-statins-introduced-3164.html) (“ZETIA
`Article”)
`TRICOR®, PRAVACHOL®, ADVICOR®, NIASPAN®,
`MEVACOR®, ZOCOR®, LIPITOR®, COLESTID®, LESCOL®,
`57 PHYSICIANS’ DESK REFERENCE 506, 1101, 1813, 2036, 2126,
`2547, 2729, 2865 (2003) (“PDR 2003”)
`ZETIA®, 58 PHYSICIANS’ DESK REFERENCE 2118, 3085 (2004)
`(“PDR 2004”)
`Curriculum Vitae
`Documents Considered
`Third Report of the National Cholesterol Education Program
`(NCEP) Expert Panel on Detection, Evaluation and Treatment of
`High Blood Cholesterol in Adults (Adult Treatment Panel III)
`Final Report, 106 CIRCULATION 3143 (2002) (“NCEP 2002”)
`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).
`(“CDC 2005 Anthropometric Reference Data”)
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`TABLE OF ABBREVIATIONS
`Definition
`Abbreviation
`U.S. Patent No. 7,932,268
`268 Patent
`U.S. Patent No. 8,618,135
`135 Patent
`915 Provisional U.S. Provisional Patent Application No. 60/550,915
`923 Application U.S. Patent Application No. 10/591,923
`(issued as the 268 Patent)
`118 Application U.S. Patent Application No. 13/046,118
`(issued as the 135 Patent)
`Microsomal triglyceride transfer protein
`Coronary Heart Disease
`Familial hypercholesterolemia
`Heterozygous familial hypercholesterolemia
`Homozygous familial hypercholesterolemia
`Low density lipoprotein
`Low density lipoprotein cholesterol
`High density lipoprotein
`Very low density lipoprotein
`Apolipoprotein B
`Total cholesterol
`Physician’s Desk Reference
`
`MTP
`CHD
`FH
`HeFH
`HoFH
`LDL
`LDL-C
`HDL
`VLDL
`apoB
`Total-C
`PDR
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`I.
`
`INTRODUCTION
`
`1.
`
`I, Randall M. Zusman, M.D., am over the age of eighteen (18) 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 (“CFAD” or “Petitioner”) in connection with the above-captioned inter
`
`partes review (“IPR”) Petition. Specifically, I have been advised that CFAD
`
`intends to request that the United States Patent and Trademark Office (“PTO”)
`
`cancel claims 1-8 of U.S. Patent No. 7,932,268 to Rader as unpatentable on
`
`obviousness grounds. I understand that this Declaration will be used to support
`
`unpatentability in any trial proceedings initiated in connection with these grounds.
`
`II. MY EXPERIENCE AND QUALIFICATIONS
`
`3.
`
`I graduated from the University of Michigan with a Bachelor of
`
`Science Degree in Chemistry with highest honors in 1969.
`
`4.
`
`I received my M.D. degree from the Yale University School of
`
`Medicine. I graduated in 1973, and also was a member of Alpha Omega Alpha (the
`
`national honorary medical society); and the recipient of the Louis Nahum Prize for
`
`outstanding research in cardiovascular physiology.
`
`5.
`
`I served my Internship and Junior Assistant Residency at the
`
`Massachusetts General Hospital (1973-1975) before becoming a Clinical Associate
`
`1
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`in the Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute,
`
`National Institutes of Health, Bethesda, MD (1975-1977).
`
`6.
`
`I returned to the Massachusetts General Hospital where I served as a
`
`Senior Assistant Resident in Medicine (1977), Chief Resident in Medicine (1978)
`
`and Clinical and Research Fellow in Medicine (1979-1980).
`
`7.
`
`I joined the faculty of the Medical Services, Massachusetts General
`
`Hospital and of the Harvard Medical School in July, 1980. I currently hold the
`
`titles of Associate Professor of Medicine, Harvard Medical School; Physician, and
`
`Director, Section of Hypertension and Vascular Medicine, Cardiology Division,
`
`Medical Services, Massachusetts General Hospital, Boston, MA and Consultant in
`
`Cardiology, Medical Department, Massachusetts
`
`Institute of Technology,
`
`Cambridge, MA.
`
`8.
`
`I have served as Editor-in-Chief and/or Associate Editor of many
`
`publications, in particular of the journals Clinical Research, the official publication
`
`of the American Federation for Clinical Research, and Hypertension, an official
`
`publication of the American Heart Association.
`
`9.
`
`I serve as a reviewer for many medical publications, including the
`
`New England Journal of Medicine, Circulation, Hypertension, the Journal of the
`
`American College of Cardiology, the Journal of Clinical Investigation, Circulation
`
`Research, the Journal of Biological Chemistry, as well as others.
`
`2
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`10.
`
`I am a non-interventional cardiologist. My practice involves the
`
`evaluation and management of patients with cardiovascular disease. I care for
`
`patients with a broad
`
`spectrum of cardiovascular diseases,
`
`including
`
`hypercholesterolemia, familial hypercholesterolemia, hyperlipidemia, coronary
`
`heart disease, angina pectoris, myocardial
`
`infarction, hypertension, atrial
`
`fibrillation, diabetes mellitus, and other cardiac as well as metabolic disorders.
`
`11.
`
`I have been board certified in internal medicine since 1976, and
`
`board certified in treating cardiovascular diseases since 1983.
`
`12. A major portion of my career has been devoted to clinical research.
`
`As noted in my curriculum vitae, I have conducted numerous clinical trials
`
`evaluating various therapies in the treatment of patients, including patients with,
`
`for example, hypercholesterolemia, angina pectoris, myocardial infarction, left
`
`ventricular dysfunction, hypertension, diabetes mellitus, and atrial fibrillation.
`
`13.
`
`In forming my opinions, I have relied on my knowledge, training,
`
`and experience in the relevant art. A copy of my current curriculum vitae, which
`
`describes my education and experience and a complete list of my publications, is
`
`provided as Exhibit 1027. I believe I am an expert in the subject matter described
`
`in the 268 Patent and have been since before 2004. As one who worked with and
`
`trained individuals who I consider to be persons of ordinary skill in the art in the
`
`relevant time periods, I also believe that I am qualified to offer opinions regarding
`
`3
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`what a person of ordinary skill in the art would have known or understood both as
`
`of March 5, 2004—which I understand to be the provisional application filing date
`
`to which Patent Owners have claimed priority for the 268 Patent—and as of
`
`March 7, 2005—the filing date of the non-provisional U.S. Patent Application that
`
`led to the issuance of the 268 Patent.1 I have considered the issues I discuss in this
`
`Declaration from the perspective of a person of ordinary skill in the art, as
`
`discussed further below.
`
`III. SUMMARY OF OPINIONS
`
`14.
`
`I have reviewed and considered the 268 Patent, its file history and
`
`related applications, including the 915 Provisional from which the 268 Patent
`
`claims priority.
`
`15.
`
`In my opinion, the 915 Provisional does not describe or support the
`
`specific set of escalating doses claimed in the 268 Patent, in particular the series of
`
`dose ranges found in the claimed escalating dose titration regimen. The dosages
`
`and dosing regimen disclosed in the 915 Provisional also do not indicate that the
`
`
`1 As discussed below, I understand that the Petitioners dispute the claimed priority
`date of the 268 Patent. Whether the priority date is determined to be March 5, 2004
`or March 7, 2005, in either time frame the person of ordinary skill in the art would
`have the same education, skill set, and years of training; would apply the same
`approaches to evaluating the art set forth in this Declaration and would possess the
`same expectations from the art.
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`Patentee was “in possession of” (had invented) the full scope and particular ranges
`
`of the 268 Patent’s claimed escalating dose titration regimen at the time Patentee
`
`filed the 915 Provisional application.
`
`16.
`
`I have reviewed and considered the 268 Patent in view of the general
`
`knowledge in the relevant field from the perspective of a person ordinarily skilled
`
`in the art relevant to the 268 Patent, as described above and below in Section V.
`
`17.
`
`In my opinion, methods encompassed by claims 1-8 of the 268 Patent
`
`would have been obvious to the person of ordinary skill in the art, as defined
`
`herein, in view of the prior art as it existed before: (a) March 5, 2004 (the 915
`
`Provisional filing date); or (b) March 7, 2005 (the filing date for the non-
`
`provisional application leading to the 268 Patent). This is because the claims
`
`encompass subject matter that, in turn, reflects nothing more than applying a
`
`known escalating dose titration regimen to achieve known and reasonably expected
`
`clinical results associated with a known MTP inhibitor drug. More specifically:
`
`18. During the relevant time period, a person of ordinary skill in the art
`
`would have been aware of the patient risks associated with high cholesterol. Such a
`
`person would have been well aware, either through research or clinical practice, of
`
`the many drugs and dosing regimens available to physicians to address the
`
`problems of the general patient population resulting from unacceptably high
`
`cholesterol levels in the blood. (See Section VI).
`
`5
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
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`19. During the relevant time period, a person of ordinary skill in the art
`
`also would have known about the high cholesterol patient sub-populations
`
`classified as having HeFH and HoFH. (See Section VI.B.4).
`
`20.
`
`The person of ordinary skill in the art would have known about the
`
`currently marketed drugs (e.g., statins, niacin, fibrates) designed to ameliorate
`
`excessive lipid levels in the blood, as well as drugs in development. The ordinarily
`
`skilled artisan would have been particularly interested in drugs under development
`
`from a different drug class with a different mechanism of action. The person of
`
`ordinary skill would also have known about the drug ezetimibe (ZETIA) as one
`
`prominent example of a drug from another class approved for use as adjunct
`
`therapy in combination with statins. (See Section VI.B).
`
`21. One drug class under development that the person of ordinary skill
`
`would have been aware of by March 2003 was the MTP inhibitor class. In my
`
`opinion, the person of ordinary skill in the art would have known of these drugs, of
`
`their unique mechanism of action, and of their reported high efficacy at reducing
`
`LDL and total cholesterol levels, in particular in HeFH and HoFH patients. MTP
`
`inhibitors were in fact particularly touted for their efficacy in FH patients. (See
`
`Section VI.B).
`
`22. Within the MTP inhibitor drug class, the art prior to March 2003 had
`
`identified a limited number of compounds which had been tested, and even fewer
`
`6
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`
`which had progressed to human clinical development—implitapide (BAY-13-
`
`9952), lomitapide (BMS-201038), and CP-346086. (See Sections VI.B.5-7,
`
`VIII.A). The art specifically confirmed that the drug compound BMS-201038
`
`(known today as lomitapide) possessed excellent in vitro and in vivo activity, was
`
`in human clinical trials, and was of particular interest. (See Section VIII.A).
`
`23. Given their recognized ability to lower serum cholesterol, a risk
`
`factor in coronary artery disease, MTP inhibitors originally were thought of as
`
`potential alternatives to the blockbuster statin drugs. Several major pharmaceutical
`
`groups were actively researching these compounds for this purpose. (See
`
`Sections VI.B.5-7, VIII.A).
`
`24. As of March 2004, the ordinarily skilled artisan would not have
`
`known of an FDA-approved dosing regimen for commercial sale of MTP
`
`inhibitors, since the drugs were still in clinical trials. However, the ordinarily
`
`skilled artisan would have possessed express teachings discussing how to dose
`
`MTP inhibitors for clinical use in a way that would also make their use
`
`commercially attractive (namely, as add-on therapy), as well as a proposed
`
`clinical dose-titration schedule
`
`for
`
`the MTP
`
`inhibitor
`
`implitapide. (See
`
`Sections VIII.A.2-3). Those
`
`implitapide
`
`teachings
`
`justified pursuing MTP
`
`inhibitor drugs as a class. They also provided a specific dosing regimen that the
`
`ordinarily skilled artisan could follow and apply to other MTP inhibitors of similar
`
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
`
`
`potency and clinical advancement, namely lomitapide (one of the most potent and
`
`clinically-advanced drugs in the class). (See, e.g., Sections VIII.C.1.(g)-(h),
`
`VIII.D.1.(g)-(h)).
`
`25.
`
`In my opinion, there is no meaningful difference—and certainly no
`
`non-obvious difference from the ordinarily skilled artisan’s perspective—between
`
`the known dosing regimen for implitamide as applied to lomitapide, and the
`
`clinical effects reasonably expected from that regimen, and, thus, the subject
`
`matter claimed by the 268 Patent.
`
`IV. LIST OF MATERIALS CONSIDERED
`
`26.
`
`In formulating my opinions, I have considered the 268 Patent and its
`
`prosecution history as well as each of the documents cited in this Declaration and
`
`cited in the IPR Petition. A list of documents that I have considered and reviewed
`
`in connection with forming my opinions is included as Exhibit 1028. In arriving at
`
`my opinions, I have relied upon my experience in the relevant art and have
`
`considered the point of view of a person of ordinary skill in the art as to the 268
`
`Patent, as defined below.
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`27.
`
`I understand that a person of ordinary skill in the art is a hypothetical
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`person who is presumed to be aware of all pertinent art, follows conventional
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`8
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`CFAD Ex. 1002 (16 of 135)
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`

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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`wisdom, pre-existing guidance or pathways known in the art, and is a person of
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`ordinary creativity.
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`28. With respect to the 268 Patent, the person of ordinary skill in the
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`early 2000s would likely have a graduate and/or post-graduate education in a
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`pertinent discipline such as medicine, medicinal chemistry, pharmacology, or drug
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`development and delivery. The person of ordinary skill in the art would remain
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`abreast of current developments in their field (including the activities of
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`pharmaceutical companies) by reviewing and analyzing relevant medical literature
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`as well as industry news publications, such as the Pink Sheet. The person of
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`ordinary skill in the art would also have an appreciation for the various factors that
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`relate to the treatment of cardiac-related disease.
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`29.
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`In the case of an individual with a medical degree, the person of
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`ordinary skill in the art would have, in addition to their degree, 3–5 years of
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`experience treating patients in the cardiovascular/cardiac field, including dose-
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`titration and dose-selection as balanced against side effects; as well as some
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`experience or working knowledge of clinical trial-related work (e.g., participating
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`in medical research through a fellowship).
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`30.
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`In the case of a pharmacologist or pharmacokineticist, such person
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`would have had, in addition to an advanced degree, several years of experience
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`developing or testing drug compounds; helping to design clinical trials; making
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`9
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`CFAD Ex. 1002 (17 of 135)
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`

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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`dose predictions; titrating doses; selecting doses for Phase III clinical trials;
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`balancing the patients’ needs for efficacy versus side effects; and assisting in the
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`selection of drugs to advance to clinical trials based on in vitro/in vivo activity.
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`31.
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`In the case of a medicinal chemist, such a person of ordinary skill in
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`this art would have had several years of experience synthesizing and testing drug
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`compounds and drug development, including designing or modifying drugs for
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`research and assisting in the selection of drugs to advance to clinical trials based on
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`in vitro/in vivo activity. The medicinal chemist of ordinary skill in the art would
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`also rely on those with medical and clinical trial knowledge and experience that is
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`standard within the art when it comes to dose selection.
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`32.
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`Further, the person of ordinary skill in the art would understand that
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`the process of drug product development requires a multi-disciplinary approach,
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`and would draw upon not only his or her own skills, but could also take advantage
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`of certain specialized skills of others, to solve any given problem.
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`33. As discussed below, I do not consider it to require great
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`sophistication to take a drug that has already been tested with some success in
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`humans—with a variety of in vitro and in vivo parameters already measured and
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`established—and to read and apply those prior results. There are standard
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`approaches known in the clinical field for getting approval for and carrying out
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`10
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`CFAD Ex. 1002 (18 of 135)
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`

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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`Phase I and Phase II work, and then continuing to Phase III clinical comparisons
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`prior to receipt of regulatory approval.
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`34.
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`The testimony that I provide in this Declaration is from the
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`perspective of a person of ordinary skill in the art (as defined above) during the
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`relevant time period.2 I believe I am well qualified to opine on the perspective of
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`an ordinarily skilled person—I have participated in numerous clinical trials,
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`authored numerous clinical trial reports, taught (and teach) individuals who have
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`(and will) become persons of skill in the art, and have worked with such ordinarily
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`skilled persons.
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`VI. BACKGROUND
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`A. Drug development—the cardiologist’s general perspective
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`35. As a clinical cardiologist, I treat patients with cardiac risk factors,
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`hypertension,
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`hypercholesterolemia,
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`familial
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`hypercholesterolemia,
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`hypertriglyceridemia, diabetes mellitus as well as other clinical cardiac disorders
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`(coronary artery disease, angina pectoris, congestive heart failure, atrial fibrillation,
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`2 This Declaration reports the opinions, motivations, and beliefs that a person of
`ordinary skill in the art would have held or understood before March 5, 2004,
`which I understand is the earliest possible priority date for the 268 Patent. As
`discussed below, however, I do not believe that the 915 Provisional provides
`adequate support for the 268 Patent’s claimed escalating dosing regimen.
`Regardless of the ultimate priority date determination, the opinions of an ordinarily
`skilled person as I have described them in this Declaration would remain the same.
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`11
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`CFAD Ex. 1002 (19 of 135)
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`Declaration of Randall M. Zusman, M.D.
`Petition for Inter Partes Review of U.S. Patent No. 7,932,268
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`etc.). In the treatment of these patients, my goal is to reduce their cardiac risk
`
`profile through the achievement of target values in the reduction of their blood
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`pressure, lipid values, and/or blood sugar levels. For each of these areas, there are
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`multiple drugs available that might help the patient to achieve his/her treatment
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`goal. For example, in the treatment of hypertension, I can choose among diuretics,
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`beta-adrenergic receptor blockers, alpha-adrenergic receptor blockers, angiotensin
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`converting enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors,
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`calcium channel blockers, as well as drugs of other mechanisms of action, to
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`reduce the hypertensive values of my patients. The art of blood pressure control is
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`to achieve a healthy blood pressure without causing undue side effects (fatigue,
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`depression, lightheadedness, sexual dysfunction, for example). In doing so, I
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`individualize the selection of medications based on the patient’s personal
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`characteristics as well as any co-morbidities that might be favorably or unfavorably
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`affected by my choice of antihypertensive therapy. Having many therapeutic
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`choices allows me to maximize the likelihood of a favorable clinical response;
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`each individual patient may ultimately take a variety of medications, at a variety of
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`dosages, and potentially at different times of the day, to achieve their blood
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`pressure goal.
`
`36.
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`Similarly, the treatment of h