UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`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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`______________
`
`Case: IPR2015-01836
`Patent No. 7,932,268
`______________
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`SUPPLEMENTAL DECLARATION OF
`THOMAS A. BAILLIE, PH.D., D.SC.
`______________
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`EXHIBIT 2305
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`1 of 46
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`PENN EX. 2305
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`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`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
`______________
`
`SUPPLEMENTAL DECLARATION OF
`THOMAS A. BAILLIE, PH.D., D.SC.
`______________
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`EXHIBIT 2305
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`TABLE OF CONTENTS
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`I. SUMMARY OF OPINIONS ............................................................................... 1
`II. MATERIALS CONSIDERED ......................................................................... 3
`III. OPINIONS ........................................................................................................ 3
`A. The Substitute Claims are Not Obvious Over Stein and/or Pink Sheet 2004
`in view of Chang ..................................................................................................... 5
`B. The Substitute Claims are Not Obvious Over Wetterau in View of ICH-E4,
`Chang, Guidance For Industry 2002, Reigner, and the ’653 Patent ..................... 11
`1. Motivation to Combine ............................................................................... 12
`2. Lack of Reasonable Expectation of Success ............................................... 23
`3. Individual Claim Analysis ........................................................................... 26
`C.
`Secondary Consideration Support a Finding of Non-Obviousness ............ 33
`1. Nexus ........................................................................................................... 34
`2. Unexpected Results ..................................................................................... 34
`3. Failure of Others .......................................................................................... 38
`IV. CONCLUSION .............................................................................................. 42
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`1.
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`I, Thomas A. Baillie, have been retained to testify on behalf of Patent
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`Owner the Trustees of the University of Pennsylvania (“Penn”) in this proceeding
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`as an expert in medicinal chemistry and pharmacology.
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`I.
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`SUMMARY OF OPINIONS
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`2.
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`I am aware that Petitioner Coalition for Affordable Drugs VIII, LLC
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`(“CFAD”) is challenging the validity of U.S. Patents Nos. 7,932,268 (“the ’268
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`patent”) and 8,618,135 (“the ’135 patent”) (collectively, the “patents-at-issue”) in
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`separate Inter Partes Review (“IPR”) proceedings before the Patent Trial and
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`Appeal Board (“PTAB”) of the United States Patent and Trademark Office. I am
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`also aware that PTAB has instituted IPR proceedings with respect to both of the
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`patents-at-issue.
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`3.
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`I am aware that Penn has proposed a contingent amendment to the
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`claims of the ’268 patent, in the event the PTAB finds the original claims
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`unpatentable. Specifically, I understand that Penn has contingently proposed the
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`addition of five substitute claims, numbered 9-14. I will henceforth refer to these
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`proposed new claims of the patents-at-issue as the “substitute claims.”
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`4.
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`I am aware that Penn is the sole assignee and owner of the patents-at-
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`issue, and that rights to the patent have been licensed to Aegerion Pharmaceuticals,
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`Inc. (“Aegerion”). I am also aware that Aegerion currently markets the drug
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`compound lomitapide in the United States for the treatment of homozygous
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`familial hypercholesterolemia (“HoFH”) under the trade name JUXTAPID®.
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`5.
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`I previously offered written testimony in this proceeding in my
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`Declaration of Thomas A. Baillie, Ph.D., D.Sc. (Penn Ex. 2024, “Baillie Dec.”). In
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`that Declaration, I opined that the both the original and substitute claims of the
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`patents-at-issue were not unpatentable as obvious.
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`6.
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`I am aware that both CFAD and its expert, Dr. Randall J. Zusman,
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`M.D., have recently asserted that the substitute claims of the patents-at-issue are
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`invalid as obvious. Petitioner’s Opposition To Patent Owner’s Contingent Motion
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`To Amend (Paper No. 30, “CFAD Opposition”); Supplemental Declaration of
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`Randall J. Zusman, M.D. (CFAD Ex. 1045, “Zusman Suppl. Dec.”). I have
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`reviewed both the CFAD Opposition and Dr. Zusman’s Supplemental Declaration,
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`and my opinions regarding the non-obviousness of the substitute claims have not
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`changed. Accordingly, I submit this declaration to respond to CFAD’s and Dr.
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`Zusman’s assertions regarding the alleged invalidity of the substitute claims.
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`7.
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`I hereby incorporate by reference the entirety of my prior Declaration
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`in this proceeding. While I will periodically refer to my non-obviousness opinions
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`expressed therein, I will not, for the sake of brevity, repeat the sections of that
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`Declaration regarding my qualifications, the claims of the patents-at-issue, legal
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`concepts relevant to my opinions, my tutorial on the background scientific issues
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`relevant to my testimony, my prior testimony in other proceedings, and my
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`compensation. Penn Ex. 2024 (Baillie Dec.) at ¶¶ 7-95, 147-48.
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`II. MATERIALS CONSIDERED
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`8.
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`In forming my opinions and views expressed in this Declaration, I
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`have relied upon my knowledge, education and training, as well as my many years
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`of experience in the field of medicinal chemistry and pharmacology, as reflected in
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`my qualifications and credentials set forth in the my previous Declaration, Penn
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`Ex. 2024 (Baillie Dec.) at ¶¶ 7-13, and in my curriculum vitae, Penn Ex. 2028. I
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`have also considered the documents cited herein and the documents listed in both
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`Penn Ex. 2032 and Penn Ex. 2307.
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`III. OPINIONS
`Dr. Zusman1 has asserted that the subject matter of substitute claims
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`9.
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`of the ’268 patent would have been obvious to a person of ordinary skill in the art.
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`1 I will focus my opinions on responding to the invalidity arguments made by
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`CFAD’s expert Dr. Zusman in his Supplemental Declaration. However, because
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`the invalidity arguments made by Dr. Zusman in his Supplemental Declaration are
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`substantively the same as those made by CFAD in its Opposition, my opinions
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`apply equally well in response to CFAD’s Opposition.
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`Particularly, Dr. Zusman argues that the substitute claims are obvious over three
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`distinct prior art combinations: (1) Pink Sheet 20042 in view of Chang3, (2) Stein4
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`in view of Chang, and (3) Wetterau5 in view of ICH-E4,6 Chang, Guidance For
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`2 “Bayer/PPD Implitapide Development Follows Zetia Model,” THE PINK SHEET,
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`Vol. 66, No. 7, p. 17 (2004) (CFAD Ex. 1013, “Pink Sheet 2004”).
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`3 Chang, et al., “Microsomal triglyceride transfer protein (MTP) inhibitors:
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`Discovery of clinically active inhibitors using high-throughput screening and
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`parallel synthesis paradigms,” CURRENT OPINION IN DRUG DISCOVERY & DEV.,
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`Vol. 5, No. 4, pp. 562-570 (2002) (CFAD Ex. 1015, “Chang”).
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`4 Evan Stein, “Microsomal Triglyceride Transfer Protein (MTP) Inhibitor
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`(implitapide) program,” Presentation Given at PPD’s Analyst Day (February 5,
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`2004).
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`5 Wetterau, et. al, “An MTP Inhibitor That Normalizes Atherogenic Lipoprotein
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`Levels in WHHL Rabbits,” SCIENCE, Vol. 282, pp. 751-754 (1998) (CFAD Ex.
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`1018, “Wetterau”).
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`6 ICH-E4, Dose-Response Information to Support Drug Registration (1994)
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`(CFAD Ex. 1043, “ICH-E4”).
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`Industry 2002,7 Reigner,8 and the ’653 Patent.9 Additionally, Dr. Zusman argues
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`that any secondary considerations of non-obviousness asserted by Penn regarding
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`the substitute claims do not apply because there is no nexus between the claimed
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`subject matter and the claimed secondary considerations. I disagree with Dr.
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`Zusman on all fronts. As described above, I previously offered testimony in this
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`proceeding regarding the validity of the substitute claims of the ’268 patent. Penn
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`Ex. 2024 (Baillie Dec.) at ¶ 144. None of the arguments offered by Dr. Zusman
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`have changed my opinion. I address each of Dr. Zusman’s arguments below.
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`A.
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`The Substitute Claims are Not Obvious Over Stein and/or Pink
`Sheet 2004 in view of Chang
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`10. Dr. Zusman argues that the substitute claims of the ’268 patent would
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`have been obvious over a combination of Chang and either Pink Sheet 2004 or
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`7 Guidance for Industry 2002, Estimating the Safe Starting Dose in Clinical Trials
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`for Therapeutics in Adult Healthy Volunteers (2002) (CFAD Ex. 1042, “Guidance
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`for Industry 2002”).
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`8 Reigner & Smith Blesch, “Estimating the starting dose for entry into humans:
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`principles and practice,” EUR J CLIN PHARMACOL, Vol.57, pp. 835–45 (2002)
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`(CFAD Ex. 1044, “Reigner”).
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`9 U.S. Patent No. 6,066,653 (Penn Ex. 2095, “ the ’653 Patent”).
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`Stein. CFAD Ex. 1045 (Zusman Supp. Dec.) at ¶¶ 82-86. Dr. Zusman offers four
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`arguments in support of his opinion, all of which I disagree with.
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`11.
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`First, Dr. Zusman argues that the substitute claims are invalid as
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`obvious for “for reasons that are similar to those set forth in [his] initial declaration
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`for the issued claims.” CFAD Ex. 1045 (Zusman Supp. Dec.) at ¶ 82. I disagree.
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`In my prior testimony in this proceeding, I provided a comprehensive explanation
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`of why I disagreed with Dr. Mayersohn’s initial opinions regarding the alleged
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`obviousness of the original claims of the patents-at-issue. Penn Ex. 2024 (Baillie
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`Dec.) at ¶¶ 96-143. Additionally, I opined that because both the original and
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`substitute claims of the patents-at-issue are based on the same underlying concept
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`of using a step-wise, forced titration dosing regimen to promote biological
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`adaptation, the substitute claims would be non-obvious for the same reasons that
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`the original claims are non-obvious. Id. at ¶ 144. My opinions regarding the
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`validity of the substitute claims have not changed after reading Dr. Zusman’s
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`Supplemental Declaration. Accordingly, I disagree with Dr. Zusman now for
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`exactly the same reasons I disagreed with him before.
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`12.
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`Second, Dr. Zusman argues that a POSA would not have been
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`dissuaded from developing lomitapide based on BMS’ withdrawal of the drug from
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`clinical trials in 2000 because Stein teaches that MTP inhibitors could potentially
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`still have utility in treating rare diseases like HoFH. CFAD Ex. 1045 (Zusman
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`Supp. Dec.) at ¶ 83. I disagree. In 2000, BMS discontinued its development of
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`lomitapide after the drug displayed unacceptable liver toxicity in human patients.
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`Penn Ex. 2011 (Pink Sheet 2000). 10 BMS disclosed neither the severity of this
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`toxicity nor at what dose level it occurred. There was also no other information in
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`the prior art which discussed what doses of lomitapide were toxic and/or
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`efficacious in humans. Without this critical information, a POSA would have no
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`way of knowing (a) whether the toxicity observed by BMS in the clinic was
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`sufficiently mild to justify HoFH development work; or (b) whether the therapeutic
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`window (i.e., the difference between the minimum effective dose and the minimum
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`toxic dose) for lomitapide was wide enough for the drug to be dosed safely to
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`HoFH patients.
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`13. Moderate increases in toxicity can sometimes be acceptable when
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`treating rare and serious diseases like HoFH. However, as described above, there
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`was nothing in the art to suggest that the liver toxicity that BMS observed with
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`lomitapide in the clinic could be managed sufficiently to allow use in the HoFH
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`context. This is especially true of Stein, which is merely a proposal for future
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`10 “MTP inhibitor research discontinued”, THE PINK SHEET (2000) (Penn Ex. 2011,
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`“Pink Sheet 2000”).
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`research and contains no clinical data whatsoever to support its alleged teachings.
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`Thus, Dr. Zusman offers no persuasive reasons why a POSA would have been
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`motivated to develop lomitapide in spite of its clinical failure.
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`14. Additionally, as I described in my prior Declaration, a POSA would
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`also have had numerous reasons not to develop lomitapide in the first place. These
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`reasons include: (1) the known mechanism-based toxicities associated with MTP
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`inhibitors; (2) the significant risk associated with dosing new clinical patients with
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`a drug which had already been withdrawn for safety reasons; and (3) the
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`availability of several more attractive MTP inhibitors, namely implitapide,11 CP-
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`346086,12 and BMS-212122.13 Penn Ex. 2024 (Baillie Dec.) at ¶¶ 122-23. In
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`short, there would have been little reason for a POSA to embark on the
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`development of a compound which had already been withdrawn from the clinic for
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`11 CFAD Ex. 1014 (Stein) at 21-30; CFAD Ex. 1014 (Pink Sheet 2004).
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`12 CFAD Ex. 1015 (Chang) at 5-6; Chandler, et. al, “CP-346086: an MTP inhibitor
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`that lowers plasma cholesterol,” J. LIPID RES., Vol. 44, pp.1887-1901 (2003)
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`(CFAD Ex. 1016, “Chandler”).
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`13 “A Novel Series of Highly Potent Benzimidazole-Based Microsomal
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`Triglyceride Transfer Protein Inhibitors,” JOURNAL OF MEDICINAL CHEMISTRY,
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`Vol. 44, pp. 851-56 (2001) (Penn Ex. 2020, “Robl”).
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`safety reasons, and, in my opinion, the only rationale that would point directly to
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`lomitapide is impermissible hindsight.
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`15.
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`Third, Dr. Zusman argues that the two-fold sequential dose increases
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`required by the substitute claims are taught by Stein. CFAD Ex. 1045 (Zusman
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`Supp. Dec.) at ¶¶ 84-86. I disagree. While Dr. Zusman is correct that Stein
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`describes an eventual two-fold increase in dose over the course of an entire
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`titration protocol, it nowhere mentions the two-fold, sequential dose escalations
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`required by the substitute claims. What Stein suggests instead is a much more
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`gradual dose escalation from 10 mg/day to 45 mg/day in seven 5 mg increments.
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`CFAD Ex. 1014 (Stein) at 36-37. Notably, the magnitude of the largest step-to-
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`step increase in Stein’s proposed regimen is 50%, four times smaller than that
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`required by the claims. Dr. Zusman’s statement that Stein “indicates a range of at
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`least 2.6X to ‘establish safe and effective dosing’”, CFAD Ex. 1045 (Zusman
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`Supp. Dec.) at ¶ 85, is therefore both incorrect and highly misleading in the context
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`of the substitute claims.
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`16. Dr. Zusman’s characterization of Stein’s dosing regimen is also
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`inconsistent with his deposition testimony, in which he described Stein’s regimen
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`as “low and slow” and involving a “small titration”:
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`Q. What would be the point of sort of titrating by 5 milligrams
`every five weeks and then monitoring for hepatic fat?
`A. Well, I believe that they believed that the time course of the
`response to any given dose would be complete after four weeks,
`and it's at four weeks at which this determination was made, the
`blood sampling and the imaging. That would then give them
`one week for that information to be digested and analyzed and a
`decision to be made whether at the next visit the patient would
`undergo dose titration. And this strategy of low and slow in
`terms of low dose, safety monitoring, small titration, safety
`monitoring, is, to me, a very well established and obvious
`strategy. You have a drug that you know is effective but you’re
`concerned about its safety and tolerability. So the way to define
`the utility of that drug is to start at very low dose and look at
`patients’ responses. You’re looking for a biological endpoint
`and you’re defining tolerability and safety.
`Q. And if the patient in Dr. Stein’s study in this low and slow
`titration theory couldn’t tolerate 15 milligrams, you wouldn’t
`force titrate them up to 20, correct?
`A. I presume that was part of the protocol, that would make
`sense to me.
`Q. You would stop them at the 15 milligrams?
`A. And you may even back off.
`Deposition of Deposition Transcript of Randall M. Zusman, M.D. (May 19, 2016)
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`(Penn Ex. 2022, “Zusman Tr.”) at 155:6-156:11.
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`17.
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`Fourth, Dr. Zusman’s assertion that “the choice to titrate at 2X is
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`nothing more than routine”, CFAD Ex. 1045 (Zusman Supp. Dec.) at ¶ 86, is
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`incorrect, especially in the context of the substitute claims. Dr. Zusman again
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`misleadingly conflates the distinction between a 2-fold overall dose increase with a
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`2-fold per step dose increase and also ignores Stein’s own warning that MTP
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`inhibitors had a narrow therapeutic window due to their significant and
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`documented hepatic toxicity, CFAD Ex. 1014 (Stein) at 21. Thus, a POSA reading
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`Stein would conclude that, due to their known toxicity, MTP inhibitors should be
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`titrated gradually to ensure patient safety. This is exactly the approach Stein
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`himself proposes for use with implitapide. Id. at 37. Conversely, a POSA would
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`likely view the 2-fold per step approach recited by the substitute claims as too
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`steep and too aggressive in the context of MTP inhibitors and their safety
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`problems.
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`18.
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`For the reasons described above, it remains my opinion that the
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`substitute claims of the ’268 patent are not invalid as obvious over Chang in
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`combination with either Pink Sheet 2004 or Stein.
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`B.
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`The Substitute Claims are Not Obvious Over Wetterau in View of
`ICH-E4, Chang, Guidance For Industry 2002, Reigner, and the
`’653 Patent
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`19. Dr. Zusman argues that the substitute claims of the ’268 patent are
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`invalid over a new six-way combination of Wetterau, ICH-E4, Chang, Guidance
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`For Industry 2002, Reigner, and the ’653 Patent. CFAD Ex. 1045 (Zusman Supp.
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`Dec.) at ¶¶ 27-81. Specifically, Dr. Zusman argues that a POSA could utilize the
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`data from the lomitapide WHHL rabbit model disclosed in Wetterau to eventually
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`arrive at the claimed dosing regimens through the use of the other five references
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`in his obviousness combination. Id. at ¶¶ 34-58. I disagree with Dr. Zusman’s
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`argument because it fundamentally misrepresents the role played by preclinical
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`animal studies in designing the type of clinical dosing strategy contemplated by the
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`substitute claims. Additionally, Dr. Zusman’s argument fails to provide the POSA
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`with either a motivation to combine the cited references, or a reasonable
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`expectation of success in reaching the claimed dosing regimens. A discussion of
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`each of these concepts, as well as an analysis of each of the substitute claims, is
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`provided below.
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`1. Motivation to Combine
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`20. Dr. Zusman asserts that a POSA would have been motivated to
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`combine the six references in his obviousness combination. CFAD Ex. 1045
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`(Zusman Supp. Dec.) at ¶¶ 27-31. I disagree. These references do not only fail to
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`provide a motivation for the POSA to reach the claimed regimens, but they also
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`frequently teach away from the claimed regimens.
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`21.
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`First, Dr. Zusman argues that Wetterau’s WHHL rabbit model would
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`provide the starting point for a POSA to dose lomitapide to humans for the
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`treatment of HoFH. CFAD Ex. 1045 (Zusman Supp. Dec.) at ¶¶ 32-35. I disagree.
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`As described in Section III.A, above, the withdrawal of lomitapide from the clinic
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`in 2000 due to serious liver toxicity would have discouraged a POSA from
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`developing lomitapide in the first place, even in the specialized context of HoFH.
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`22. Wetterau reports the results of a single two-week rabbit study at one
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`fixed dose level. CFAF Ex. 1018 (Wetterau) at 3. Wetterau provides scant details
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`regarding the toxicity observed in this study, and because only a single dose is
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`reported, there is nothing from which a POSA could infer a relationship between
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`toxicity (or efficacy for that matter) and dose. Id. A POSA would thus have had
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`no reasonable basis from which to expect that the efficacious 10 mg/kg rabbit dose
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`disclosed by Wetterau could be successfully and safely transferred to humans, let
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`alone in a multiple-step escalating dose protocol like that required by the claims.
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`23.
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`Furthermore, preclinical animal models like Wetterau’s WHHL rabbit
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`are only valuable as qualitative, but not quantitative, predictors of human efficacy
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`due to the pharmacological and pharmacokinetic differences between species. A
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`POSA therefore would not have looked to Wetterau as a starting point for dosing
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`lomitapide in humans because the predictive power of animal models is limited,
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`especially when it comes to quantitative measurements. Both of CFAD’s experts,
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`Drs. Zusman and Mayersohn, agree:
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`Dr. Zusman:
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`Q. So the WHHL rabbit test that the Chang reference refers to is
`essentially an animal efficacy screen for HoFH; is that fair?
`A. It’s a model in which drugs that work through non-statin
`mechanisms can be tested, hopefully to then project what the response
`might be in humans.
`Q. Right. And the point of the WHHL rabbit test is typically to
`determine whether a particular compound has efficacy for treating,
`you know, HoFH, correct?
`A. Right. That is one of the ways in which this model animal is
`utilized.
`Q. You don’t contend that the efficacy on a dosage basis seen in the
`WHHL rabbit model would be identical to what you would expect a
`human patient,
`right?
`A. No, I don’t believe that would be the case.
`Q. Right. And WHHL rabbits don’t necessarily have the same rate of
`absorption, metabolism, distribution and excretion as human patients,
`correct?
`DR. GONSALVES: Objection.
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`14
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`A. That’s correct.
`Penn Ex. 2022 (Zusman Tr.) at 92:9-93:9.
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`Dr. Mayersohn:
`
`A. So you want me to predict what’s going to happen to humans based
`on rabbits?
`Q. Right.
`A. My prediction would be they would both be effective in reducing
`the lipids we’re concerned about but perhaps not to the same extent.
`Q. Is there something in the studies that makes you conclude that, in
`fact, you --let me start over. Is there something in these two rabbit
`studies that suggests to you that the two drugs, in fact, would not have
`the same extent of reduction in humans?
`A. No, they could. I think importantly when it comes to that point,
`when you’re testing in humans, you will optimize the dosing regimen
`to determine what is best for the human. So these data, while they’re
`very useful, do not represent the endpoint with regard to development
`of the drug in the human.
`Q. What do you mean they don’t represent the endpoint?
`A. Well, you have now some leading information that says, well, we
`can probably go ahead, barring any significant adverse events, in
`humans and expect -- because this is a proven model for the human
`condition and expect that this was going to work in the human. You
`can’t ask too much of a model than that.
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`Deposition Transcript of Michael Mayersohn, Ph. D. (May 16, 2016) (CFAD 2021,
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`“Mayersohn Tr.”) at 112:9-113:14.
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`24.
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`Second, Dr. Zusman argues that ICH-E4 would have motivated a
`
`POSA to implement a three-step forced titration dosing regimen with lomitapide.
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`CFAD Ex. 1045 (Zusman Supp. Dec.) at ¶¶ 36-44. I disagree. Although ICH-E4
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`discusses forced titration, it notes that this approach is only useful in certain
`
`circumstances and has “critical disadvantages,” specifically (1) its inability to
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`distinguish between the effects of increased dose and increased time, and (2) its
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`tendency to give “poor information on adverse effects.” CFAD Ex. 1043 (ICH-E4)
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`at 13-14. Given the propensity of MTP inhibitors to cause significant and dose-
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`dependent liver toxicity (CFAD Ex. 1015 (Chang) at 6), these disclosures would
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`have discouraged a POSA from using a forced titration with lomitapide. Finally,
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`as described above, Dr. Zusman testified at his deposition that a “low and slow”
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`non-forced titration was “a very well established and obvious strategy” to
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`determine the safe and effective dose for an MTP inhibitor with known toxicity
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`issues. Penn Ex. 2022 (Zusman Tr.) at 155:6-156:11.
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`25.
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`Furthermore, the statement in ICH-E4 that “most side effects of drugs
`
`occur early and may disappear with continued treatment,” CFAD Ex. 1043 (ICH-
`
`E4) at 8, would not have suggested to a POSA that using forced titration with
`
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`lomitapide would be “safer for the patients.” Ex. 1045 (Zusman Supp. Dec.) at ¶¶
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`41-42. The known liver toxicities associated with MTP inhibitors were determined
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`to be “dose-dependent,” CFAD Ex. 1015 (Chang) at 6, meaning that they got
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`worse as dose was increased. Accordingly, a POSA attempting to dose lomitapide
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`to human patients would have almost certainly concluded that a forced titration
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`was more dangerous for the patients because the potential for toxicity would
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`increase with every escalation step. This would likely steer a POSA away from
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`forced titration and towards one of the other options disclosed in ICH-E4, such as
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`the optional titration,14 CFAD Ex. 1043 (ICH-E4) at 12, which did not carry the
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`same toxicity risks.
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`26.
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`Finally, ICH-E4 states that if forced titration is to be used it should be
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`done in a “gradual” manner to ensure patient safety. Id. at 11. Because, as
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`described above, a POSA would almost certainly not view a 2-fold per-step
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`increase of lomitapide (a drug with known toxicity issues) as “gradual,” this
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`disclosure taught away from the claimed dosing regimens.
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`27.
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`Third, Dr. Zusman argues that Reigner would have motivated a POSA
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`to use a 2-fold increase at each of the claimed dosing levels. CFAD Ex. 1045
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`14 Note that this is exactly the method adopted by Stein in his proposed trial with
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`another MTP inhibitor, implitapide. CFAD Ex. 1014 (Stein) at 37.
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`(Zusman Supp. Dec.) at ¶¶ 45-46. This argument represents an incorrect and
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`selective reading of Reigner. As an initial matter, Reigner is explicitly directed to
`
`determining the first dose of a new compound that will be used in human clinical
`
`trials. CFAD Ex. 1044 (Reigner) at 1. These so-called “first in human”
`
`experiments invariably occur in healthy volunteers. The primary purpose of these
`
`types of trials is to simply gather safety and pharmacokinetic data with which to
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`design phase II and phase III trials, where the efficacy of a drug is eventually
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`investigated. When it was removed from the clinic by BMS in 2000, lomitapide
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`had already cleared phase I trials and was in the midst of a phase II efficacy study.
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`Penn Ex 2011 (Pink Sheet 2000). This means that a POSA developing lomitapide
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`in 2004 would not have considered Reigner because the “first in human” trial had
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`already occurred.
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`28. Additionally, while Reigner does address the concept of dose
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`escalation, it does so only in the context of a phase I first in human study, which,
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`as noted above, would not have applied to lomitapide in 2004. CFAD Ex. 1044
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`(Reigner) at 2, 9. Reigner also states that dose escalation “should be more or less
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`rapid depending on the steepness of the dose/concentration–response curve and the
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`severity and reversibility of toxicities observed in animals.” Id. at 9. Given the
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`serious toxicities observed for lomitapide as well as other MTP inhibitors, CFAD
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`Ex. 1015 (Chang) at 6, it is unlikely that a POSA would have selected an
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`aggressive 2-fold stepwise dosing increase when administering lomitapide to
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`humans. Dr. Zusman agreed with this concept at his deposition when he testified
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`that a “low and slow” protocol with a “small titration” would have been optimal
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`for use with an MTP inhibitor with known toxicity issues. Penn Ex. 2022 (Zusman
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`Tr.) at 155:6-156:11.
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`29.
`
`Finally, Reigner proposes at least three different dose escalation
`
`strategies: arithmetic (x, 2·x, 3·x, 4·x, etc.); geometric (x, R·x, R2·x, R3·x, etc.); and
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`Fibonacci (x, 2·x, 3.3·x, 5·x, etc.). CFAD Ex. 1044 (Reigner) at 9. Notably, the
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`geometric strategy (which includes a 2-fold sequential increase) can theoretically
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`be carried-out in an infinite number of ways because the “R” variable can be any
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`number greater than 1. This means that, per Reigner’s advice to reduce the
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`steepness of a titration due to toxicity, id., a POSA might decide to use a geometric
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`escalation protocol with a relatively low R value (e.g., 1.5)15 to ensure patient
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`safety. Dr. Zusman’s failure to provide a rationale for his selection of a 2-fold
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`geometric dose escalation instead of the numerous other potential strategies
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`discussed in Reigner is clear evidence of impermissible hindsight.
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`15 An R value of 1.5 would correspond to a sequential dose increase of 50% (x,
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`1.5·x, 2.3·x, 3.4·x, etc.).
`
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`30.
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`Fourth, Dr. Zusman argues that Guidance for Industry would have
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`allowed a POSA to derive the third dosing level in the claimed regimen (about 0.2–
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`0.59 mg/kg/day) from the 10 mg/kg dose used in Wetterau’s rabbit model. CFAD
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`Ex. 1045 (Zusman Supp. Dec.) at ¶¶ 47-50. Dr. Zusman’s conclusion here is both
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`factually incorrect and again indicative of impermissible hindsight.
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`31. Guidance for Industry 2002 states in its Introduction that its purpose is
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`to provide a process for determining a first-in-human dose. CFAD Ex. 1042 at 4.
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`For the same reasons discussed above with respect to Reigner, a POSA developing
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`lomitapide in 2004 would not have considered Guidance for Industry 2002,
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`because the “first in human” trial of lomitapide had already occurred.
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`Furthermore, Guidance for Industry 2002 clearly does not relate to the escalating
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`dosing regimen found in the substitute claims. Not only is the type of “study”
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`covered by the claims directed towards efficacy in patients who need treatment (a
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`phase II or phase III objective), but Guidance for Industry 2002 expressly limits its
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`scope to determining a first dose in humans and “does not address dose
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`escalation.” CFAD Ex. 1042 (Guidance for Industry 2002) at 4. Accordingly,
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`there was not motivation for a POSA to look to Guidance for Industry 2002.
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`32. Dr. Zusman’s use of Guidance for Industry 2002 is also indicative of
`
`impermissible hindsight. For example, Guidance for Industry 2002 expressly
`
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`directs the POSA to carefully consider all non-human preclinical dosing
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`information prior to choosing the “most appropriate species” from which to
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`calculate a first-in-human dose, id. at 6, 11-12, but D
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