UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
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`COALITION FOR AFFORDABLE DRUGS VIII, LLC
`Petitioner,
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`v.
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`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner
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`______________
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`Case: IPR2015-01836
`Patent No. 7,932,268
`______________
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`DECLARATION OF RICHARD E. GREGG, M.D.
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`_______________
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`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 RICHARD E. GREGG, M.D.
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`I, Richard E. Gregg, M.D., am competent to testify regarding the matters set
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`forth herein, which are based on my personal knowledge and experience.
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`1.
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`I currently serve as the Chief Scientific Officer at Vitae
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`Pharmaceuticals, Inc. (“Vitae”). Prior to joining Vitae in 2008, I spent 19 years at
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`Bristol-Myers Squibb Company (“BMS”), serving in the following positions:
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`Executive Director in the Department of Metabolic Diseases (1988-1996); Vice
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`President of Metabolic Diseases and Drug Discovery (1996-1998); Vice President
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`of Metabolic and Cardiovascular Drug Discovery (1999-2001); and Vice President
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`of Clinical Discovery responsible for Early Clinical Development, Clinical
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`Pharmacology, Translational Medicine, and Biomarker Technologies (2001-2007).
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`Prior to joining BMS, I spent ten years at the National Health Heart, Lung, and
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`Blood Institute, National Institutes of Health (“NHLBI NIH”) in Bethesda,
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`Maryland, where I studied disorders of lipid and lipoprotein metabolism. I met Dr.
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`Daniel Rader during my time at NHLBI NIH.
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`2.
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`I hold a Bachelor of Science degree in biochemistry (1970) and a
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`Master of Science degree in biochemistry (1971) from Iowa State University, and a
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`Doctor of Medicine degree from Stanford University School of Medicine (1976). I
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`completed my internship and residency in Internal Medicine at Strong Memorial
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`CFAD v. PENN
`IPR2015-01836
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`Hospital in Rochester, New York, and completed my fellowship in Endocrinology
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`and Metabolism at the NHLBI NIH. My C.V. is included as Ex. 2055.
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`3. While at NHLBI NIH, I studied patients who suffer from
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`abetalipoproteinemia, a rare inherited disorder that results in extremely low
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`cholesterol levels. Patients with this disease are not able to make certain
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`lipoproteins, particles that carry fats and fat-like substances (such as cholesterol) in
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`the blood. As a consequence, these patients cannot properly absorb fat and fat-
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`soluble vitamins like vitamin E and vitamin A from food. This, in turn, damages
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`their nervous system and eyes.
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`4.
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`In the summer of 1990, I went to a conference on lipids &
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`lipoproteins, where I met Dr. John Wetterau. Dr. Wetterau was working at the
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`University of Cincinnati and had been studying the function of microsomal transfer
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`protein (MTP) for about 6-8 years at that time. I realized that MTP was an
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`interesting target to study and that it may be the cause of abetalipoproteinemia,
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`which I studied at NHLBI NIH. I recruited Dr. Wetterau to join BMS to explore
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`the function of MTP, and Dr. Wetterau started working at BMS in 1990 in the
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`Department of Metabolic Diseases.
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`PENN EX. 2083
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`IPR2015-01836
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`5.
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`Sometime in late 1990-early 1991, I suggested that BMS initiate an
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`exploratory program to study the function of MTP. Dr. Wetterau and I
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`hypothesized that MTP might be important for assembly and secretion of
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`lipoproteins, although we did not have a definite understanding about the function
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`of MTP. Dr. Wetterau and I further hypothesized that mutations in MTP may be
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`the cause of abetalipoproteinemia and may be important in regulating cholesterol
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`levels. As such, I recognized that understanding the MTP function might assist
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`with efforts to develop treatments for various conditions associated with increased
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`lipid and cholesterol levels, such as hyperlipidemia and hypercholesterolemia.
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`BMS management recognized the potential value of exploring MTP function, and
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`launched an early stage exploratory program in 1991.
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`6.
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`As the leader of the program, I was responsible for managing the
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`exploratory program, setting the program goals and directions, and helping to
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`coordinate the program activities. I was managing a group of about 15 scientists
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`who were working on the exploratory program. Dr. Wetterau reported to me.
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`7.
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`During the initial stages of the exploratory program, I worked with
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`Dr. Wetterau and Dr. Rader, who was at NHLBI NIH at the time, to determine the
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`genetic cause of abetalipoproteinemia. Dr. Rader supplied samples obtained from
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`patients with abetalipoproteinemia that allowed us to perform genetic studies and
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`determine the cause of abetalipoproteinemia. In one study, we investigated the
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`possibility that mutations in MTP may be the cause of abetalipoproteinemia.
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`During our study, we discovered that MTP played an important role in the
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`assembly of very low density lipoprotein (VLDL) in the liver and chylomicrons in
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`the intestine. We postulated that MTP mediated the transfer of triglycerides from
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`their site of synthesis in the endoplasmic reticulum membrane to nascent
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`lipoprotein molecules within the endoplasmic reticulum as they were synthesized.
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`We published our study results in the journal SCIENCE. See Ex. 2056.
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`8.
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`In or around 1992, Dr. Wetterau and I cloned MTP cDNA and were
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`able to correlate the activity of MTP with certain disease states, including
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`hypercholesterolemia and hyperlipidemia. We also discovered that the function of
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`MTP was defective in abetalipoproteinemic patients. These findings led us to
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`hypothesize that inhibition of MTP may lead to lowering cholesterol and lipid
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`levels.
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`9.
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`Sometime around 1992, Dr. Scott Biller and I initiated a drug
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`discovery program at BMS focused on discovering a class of compounds that
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`could inhibit MTP. At one time, this program was a high priority at BMS. BMS
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`wanted to be the first company to market a drug that inhibited MTP in heart
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`disease patients. BMS saw tremendous potential in the inhibition of MTP.
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`10. Lomitapide, which was first synthesized in the mid-1990’s,
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`demonstrated remarkable lipid lowering effects in vitro and in vivo. In in vitro
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`studies, lomitapide appeared to inhibit lipid transfer by directly binding to MTP.
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`Initial in vivo studies were conducted in mice, rats, rabbits, guinea pigs, and dogs
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`to determine lomitapide’s effectiveness in lowering lipid levels. Lomitapide
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`demonstrated remarkable lipid-lowering properties in the initial in vivo studies.
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`Additional in vivo studies consisted of a series of animal toxicology studies of
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`lomitapide in rats and dogs. The studies showed that dose-related accumulation of
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`lipids in the liver and small intestine correlated with decreases in serum
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`triglyceride and cholesterol levels.
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`11. The effect of lomitapide on plasma lipid levels was also tested in
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`hamsters and homozygous Wattanabe-heritable hyperlipidemic (WHHL) rabbits, a
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`known model of homozygous familial hypercholesterolemia. Ex. 1018. The
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`animal studies in hamsters showed a dose-dependent decrease in total plasma
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`cholesterol. Id. at 2. The animal studies in WHHL rabbits showed that the
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`cholesterol and triglyceride levels were essentially normalized with no alteration in
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`PENN EX. 2083
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`IPR2015-01836
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`plasma transaminase levels (no alteration in AST and ALT levels). Id. After
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`completing these animal studies, BMS conducted several clinical trials of
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`lomitapide in the late 1990’s.
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`12. One of the clinical trials (CV145-002) involved administration of 10,
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`25, 50, or 100 mg/day of lomitapide, or a placebo, to 36 hypercholesterolemic, but
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`otherwise healthy volunteers for 14 days. Ex. 2058. Exhibit 2058 is a true and
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`accurate copy of an excerpt from the BMS-201038 Investigator Brochure General
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`Addendum. I participated in designing this trial. Volunteers in the 100 mg group
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`discontinued the study early due to intolerable gastrointestinal side effects. Id. at
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`47. All the volunteers in the study, including the volunteers in the 10 mg/day
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`group had increased hepatic fat content. Id. Preliminary results from the data
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`indicated that for the groups receiving 10 mg, 25 mg, and 50 mg of lomitapide for
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`14 days, the mean hepatic fat content at baseline was in the range of 1.9%, and at
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`the end of the study the mean hepatic fat content was in the range of 8.8%. Id. at
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`48.
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`13.
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`In February – December 1999, BMS conducted a Phase II clinical
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`study in which 25 mg/day of lomitapide or a placebo was administered to 76
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`hypercholesterolemic, but otherwise healthy, subjects for 4 weeks. Ex. 2057. I
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`participated in designing this study. Given the animal study results and the results
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`of the 10-100 mg day clinical study, I believed that lomitapide had the potential to
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`increase hepatic fat accumulation. The primary focus of the study was thus to
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`evaluate the effects of lomitapide on hepatic fat accumulation and, particularly, to
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`assess the rate of clearing of fat from the liver after administration of lomitapide
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`was discontinued. Id. at 2. The secondary objective of the study was to determine
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`the lipid-lowering effects of lomitapide. Id. Dr. Rader was one of the investigators
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`for this trial.
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`14. Lomitapide demonstrated excellent lipid-lowering results in the 1999
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`25 mg/day human study. On the flip side, the adverse gastrointestinal effects were
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`stronger than expected, resulting in some patients discontinuing treatment. Indeed,
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`nine patients receiving lomitapide discontinued the study due to adverse events in
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`contrast to no discontinuations in the placebo group. Id. at 4. Subjects also
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`experienced significantly elevated hepatic fat and transaminase levels. The mean
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`absolute increase in hepatic fat content for the 25 mg lomitapide group was 20.6%
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`as compared to essentially no change for the placebo group. Id. at 6. Further, it
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`took upwards of 6 weeks (and up to 6 months for some of the subjects) for
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`transaminase levels to return back to normal levels. Id.
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`CFAD v. PENN
`IPR2015-01836
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`15. Following this study, I considered it unlikely that patients would be
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`able to tolerate doses as high as 1.0 mg/kg/day (which translates to 70 mg/day in a
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`70 kg man) given that the study subjects experienced serious gastrointestinal side
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`effects when taking lomitapide at 25 mg/day. I expected that patients would
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`develop uncontrollable diarrhea and/or fecal intolerance at such a high dose and
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`discontinue treatment.
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`16.
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`In addition, after seeing that the hepatic fat content increase after
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`administration of lomitapide for 4 weeks at 25 mg/day in hyperlipidemic patients
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`who are predisposed to have fat accumulation in the liver was about three times the
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`hepatic fat content increase after 2 weeks in normal subjects at 10, 25, and 50
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`mg/day (20.6% vs. 6.9%), I was concerned about the ultimate extent of hepatic fat
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`accumulation upon continued administration of lomitapide and the potential for
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`long term liver toxicity from hepatic lipotoxicity. Further, I was concerned that the
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`toxicity associated with high levels of hepatic fat accumulation could be difficult to
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`reverse, particularly with administration of lomitapide at higher doses, and
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`believed that hepatic fat accumulation had to be closely monitored.
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`17. Given the study results, it was my belief that the side effect profile of
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`lomitapide presented too many risks to continue development for the heart disease
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`patient population BMS was then targeting. BMS thus made the decision to
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`discontinue further development on lomitapide at BMS, and I supported that
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`decision. Ex. 2011.
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`18. When the decision to discontinue further lomitapide development was
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`made, I and my colleagues at BMS had spent about 10 years exploring the MTP
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`function and its correlation with plasma lipid levels. The decision to discontinue
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`the research was very disappointing. I understood the function of MTP and the
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`mechanism for inhibiting MTP very well. We had gathered extensive knowledge
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`and experience regarding MTP inhibitors and their mechanisms of action. Yet,
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`despite our extensive knowledge and experience with MTP inhibitors, we did not
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`develop a treatment regimen for lomitapide that would mitigate the risk of hepatic
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`fat accumulation and would allow for hepatic fat content to stabilize or decrease.
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`19. After lomitapide research was discontinued at BMS, Dr. Rader and I
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`discussed the potential to develop lompitapide for the treatment of individuals with
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`severe hyperlipedemia, such as homozygous familial hypercholesterolemia
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`(HoFH). I thus discussed with Dr. Rader and BMS management the possibility of
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`transferring the rights to lomitapide to the University of Pennsylvania for further
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`studies to be conducted by Dr. Rader. I had not previously heard of BMS donating
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`the rights to a drug to a university; this was a highly unusual proposition.
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`20. The hope was that lomitapide could improve the lives of many
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`individuals suffering from HoFH that did not have viable treatment alternatives.
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`Treatment of HoFH requires aggressive treatment, including apheresis. I therefore
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`urged BMS management to donate the rights to lomitapide to the University of
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`Pennsylvania so that Dr. Rader could study the drug further to see if it could be
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`used for treatment of HoFH.
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`21. There was no potential gain either to me personally or to BMS from
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`the donation of rights to lomitapide. We simply wanted to help patients that did
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`not have a viable alternative. There was no acceptable oral therapy for these
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`individuals, as they are generally unresponsive to conventional therapies, such as
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`statins, and lomitapide could provide a long-awaited oral treatment for HoFH,
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`provided that hepatic fat accumulation was addressed.
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`22. The discussions to donate the lomitapide rights to the University of
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`Pennsylvania started sometime in 2001, and the donation agreement was not
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`signed until about 18 months later in 2002. Ex. 2001. Despite the fact that there
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`was tremendous need for the treatment, and despite the fact that lomitapide would
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`only be clinically tested on a very small subset of the population (HoFH is a very
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`rare disease), BMS was still very concerned about potential liability due to liver
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`toxicity. Yet, I thought that further studies of lomitapide at the University of
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`Pennsylvania needed to be explored because the benefits to patients suffering from
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`HoFH could outweigh the risks.
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`23.
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`In signing this declaration, I recognize that the declaration will be
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`filed as evidence in a contested case before the Patent Trial and Appeal Board of
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`the United States Patent and Trademark Office. I also recognize that I may be
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`subject to cross examination in the case and that cross examination will take place
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`within the United States. If cross examination is required of me, I will appear for
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`cross examination within the United States during the time allotted for cross
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`examination.
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`24.
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`I reserve the right to supplement my declaration in the future to
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`respond to any arguments that Petitioners might raise and to take into account new
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`information as it becomes available to me.
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`25.
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`I received no compensation for the time spent preparing to draft and
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`drafting this declaration.
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`PENN EX. 2083
`CFAD v. PENN
`IPR2015-01836
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`26.
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`I declare that all statements made herein of my own knowledge are
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`true, and that all statements made on information and belief are believed to be true;
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`and further that these statements were made with the knowledge that willful false
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`statements and the like so made are punishable by fine or imprisonment, or both,
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`under Section 1001 of Title 18 of the United States Code.
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`Date:
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`7,
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`Richard .
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`regg
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`13
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`PENN EX. 2083
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`CFAD V. PENN
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`IPR20l5—0l836
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