UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`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: IPR2015-01835
`Patent No. 8,618,135
`______________
`
`
`
`PATENT OWNER RESPONSE
`
`
`
`
`_______________
`
`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: IPR2015-01835
`Patent No. 8,618,135
`______________
`
`
`
`PATENT OWNER RESPONSE
`
`
`
`
`
`TABLE OF CONTENTS
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`IPR2015-01835
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`Page
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`I.
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`II.
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`INTRODUCTION ........................................................................................... 1
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`THE BOARD’S INSTITUTION DECISION ................................................. 6
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`A.
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`B.
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`C.
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`Claim Construction ............................................................................... 7
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`Effective Filing Date ............................................................................. 8
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`Person of Ordinary Skill in the Art ....................................................... 9
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`D. Grounds of Institution ......................................................................... 10
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`1.
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`2.
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`3.
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`Stein ................................................................................ 10
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`Pink Sheet 2004 .............................................................. 11
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`Chang .............................................................................. 12
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`III. PATENT OWNER’S DECLARANTS ......................................................... 13
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`IV. TECHNICAL BACKGROUND AND STATE OF THE ART .................... 15
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`The Role of Pharmacokinetics and Pharmacodynamics in Drug
`A.
`Dosing. ........................................................................................................... 15
`
`The Impact of Chemical Structure and Therapeutic Classes on
`B.
`the Selection of Dose. .................................................................................... 17
`
`C.
`
`D.
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`E.
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`Treatment of Hypercholesterolemia and Hyperlipidemia ................... 18
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`Statins .................................................................................................. 19
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`Familial Hypercholesterolemia ........................................................... 20
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`F. MTP Inhibitors and the Development of Lomitapide ......................... 21
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`G. Dr. Rader’s Invention .......................................................................... 23
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`i
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`
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`V. GROUND 1: CLAIMS 1-10 ARE NOT OBVIOUS IN VIEW OF
`PINK SHEET 2004 AND CHANG .............................................................. 26
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`A.
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`There was no motivation to develop lomitapide in March 2005. ....... 26
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`The Protocol Proposed in Pink Sheet 2004 is Fundamentally
`B.
`Different from the Claimed Invention. .......................................................... 35
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`C. A POSA Would Not Have Had a Reasonable Expectation of
`Success in Using the Pink Sheet 2004 Protocol with Lomitapide. ............... 38
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`VI. GROUND 2: CLAIMS 1-10 ARE NOT OBVIOUS IN VIEW OF
`STEIN AND CHANG ................................................................................... 45
`
`A.
`
`Stein Is Not Prior Art. ......................................................................... 45
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`The Stein Presentation is not a “printed
`1.
`publication.” ........................................................................................ 45
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`2.
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`The Stein Slides Are Not a “Printed Publication” .......... 47
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`CFAD Failed to Show Any Motivation to Combine Chang with
`B.
`Stein. 49
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`C. A POSA Would Not Have Had a Reasonable Expectation of
`Success in Using the Stein Protocol with Lomitapide. ................................. 50
`
`VII. NOTHING IN THE RECORD POINTS TO THE OBVIOUSNESS
`OF DEPENDENT CLAIMS 3 AND 4 .......................................................... 52
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`A. Dependent Claims 3 And 4 Are Patentable......................................... 52
`
`B. Dependent Claim 8 Is Patentable. ....................................................... 54
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`VIII. OBJECTIVE INDICIA OF NONOBVIOUSNESS SUPPORT THE
`PATENTABILITY OF THE PATENT CLAIMS ........................................ 56
`
`A.
`
`B.
`
`The Results of Claimed Dosing Method Are Unexpected. ................. 56
`
`The Invention Satisfied A Long-Felt, But Unmet, Need .................... 59
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`C. Others Failed to Accomplish What The Claims Achieved. ................ 61
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`ii
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`D. Others in the Field Praised the Claimed Invention ............................. 62
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`JUXTAPID®, the Commercial Embodiment of the Claimed
`E.
`Invention, is a Commercial Success. ............................................................. 62
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`IX. THE IPR PROCESS IS UNCONSTITUTIONAL ........................................ 64
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`X.
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`CONCLUSION .............................................................................................. 65
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`
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`iii
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`TABLE OF AUTHORITIES
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`
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`CASES:
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015), cert. granted, sub nom. Cuozzo
`Speed Techs. LLC v. Lee, 136 S.Ct. 890 (2016) ................................................... 7
`
`Page
`
`In re Hall,
`781 F.2d 897 (Fed. Cir. 1986) ............................................................................ 46
`
`Intercollegiate Broad. Sys., Inc. v. Copyright Royalty Board et al.,
`684 F.3d 1332 (D.C. Cir. 2012) .......................................................................... 62
`
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) .................................................................... 10, 44
`
`Mass. Inst. of Tech. v. Harman Int’l Indus.,
`584 F. Supp. 2d 297 (D. Mass. 2008) ................................................................. 43
`
`MCM Portfolio LLC v. Hewlett-Packard Co.,
`812 F.3d 1284 (Fed. Cir. 2015) .......................................................................... 62
`
`PPC Broadband, Inc. v. Corning Optical Comm. RF LLC,
`815 F.3d 734 (Fed. Cir. 2016) ............................................................................ 61
`
`PTAB DECISIONS:
`Air Liquide Large Indus. U.S. LP v. Praxair Tech., Inc., IPR2015-
`01074, Paper 11 (P.T.A.B. Oct. 26, 2015) ......................................................... 44
`
`Coalition for Affordable Drugs V LLC v. Biogen MA Inc., IPR2015-
`01136, Paper 23 (P.T.A.B. Sept. 2, 2015) .......................................................... 39
`
`Coalition for Affordable Drugs (ADROCA) LLC v. Acorda
`Therapeutics, Inc., IPR2015-00817, Paper 12 (P.T.A.B. Aug. 24,
`2015) ................................................................................................................... 45
`
`L-3 Commc’n Holdings, Inc. v. Power Survey, LLC, IPR2014-00832,
`Paper 9 (P.T.A.B. Nov. 14, 2014) ...................................................................... 43
`
`iv
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`
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`
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`Sandoz, Inc. v. EKR Therapeutics, LLC, IPR2015-00005, Paper 20 at
`11 (P.T.A.B. Apr. 24, 2015) ............................................................................... 50
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`STATUTES:
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`35 U.S.C. § 311(b) ................................................................................................... 43
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`35 U.S.C. § 312(a)(3) ............................................................................................... 50
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`v
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`I.
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`INTRODUCTION
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`U.S. Patent No. 8,618,135 (“’135 patent”) claims a novel forced dose
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`titration regimen for safely and effectively administering the microsomal transfer
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`protein (“MTP”) inhibitor lomitapide. Although Bristol Myers Squibb (“BMS”)
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`had discovered the potential therapeutic benefits of lomitapide, it ceased
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`development of the compound in 2000 after clinical studies revealed serious
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`adverse events when lomitapide was administered at doses as low as 25 mg/day.
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`Ex. 1008, [0022]. Dr. Dan Rader persevered, though, discovering that with a
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`forced titration regimen, patients could tolerate doses of lomitapide as high as 80
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`mg/day without experiencing significant liver toxicity. As a result of this
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`discovery, lomitapide became the first and only MTP inhibitor approved by the
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`Food and Drug Administration (“FDA”) and is now used to treat patients with
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`Homozygous Familiar Hypercholesterolemia (“HoFH”), a severe life-threatening
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`condition with few treatment options.
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`Nonetheless, relying on hindsight, Petitioner Coalition for Affordable Drugs
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`VIII LLC (“Petitioner” or “CFAD”) contends that Dr. Rader’s inventions were
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`obvious in view of a review paper generally describing a variety of MTP inhibitors
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`1
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`including lomitapide1 in combination with two documents2 (neither of which
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`appears in a scientific journal) that not only acknowledge lomitapide’s failure but
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`merely suggest a possible clinical study protocol for a different MTP inhibitor,
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`implitapide. As set forth herein, this prior art would not have motivated a person
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`of ordinary skill in the art (“POSA”) to resurrect lomitapide for further
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`development or caused an expectation that the clinical study protocol suggested for
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`implitapide would result in a treatment method that permitted lomitapide to be
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`safely used and tolerated in humans.
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`First, although both lomitapide and implitapide belong to the same
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`therapeutic class of MTP inhibitors, Chang and other prior art described dozens of
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`MTP inhibitors. There was no reason for the POSA to select lomitapide amongst
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`all those options. Indeed, there were many reasons not to select lomitapide, as it
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`had been terminated as a project following phase I and II clinical trials due to liver
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`toxicity, and had demonstrated a level of liver toxicity in animal studies that
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`CFAD’s expert Dr. Zusman characterized as simply “too hot to handle”.
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`Deposition Transcript of Dr. Randall M. Zusman, M.D., May 19, 2016 (Ex. 2022,
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`1 Ex. 1015, “Chang.”
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`2 Ex. 1013, “Pink Sheet 2004;” Ex. 1014, “Stein.”
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`2
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`
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`“Zusman Tr.”) at 172:19-24, 174:12-175:5. Thus, a POSA would have had no
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`reason to believe that lomitapide could successfully be administered in a dosing
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`regimen at all and no reason to select it for further development.
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`Second, a POSA would not have had any reason or motivation to use
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`lomitapide in the clinical study protocol that Stein and Pink Sheet 2004 had
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`proposed for implitapide, a compound with a significantly different chemical
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`structure. CFAD’s reliance on a single statement in Chang regarding the supposed
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`“similar efficacy” of lomitapide and implitapide is unavailing. That statement is
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`unsupported by any human data, and the animal data upon which Dr. Mayersohn,
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`CFAD’s expert, relied actually shows that the efficacy of the two compounds is
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`starkly different. A POSA, therefore, would not have concluded that lomitapide
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`and implitapide could be dosed similarly based on Chang. Moreover, a POSA
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`would not have considered Stein or Pink Sheet 2004 as credible medical references
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`in developing a dose regimen, as they contain none of the necessary scientific
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`information. Indeed, they provide merely the barest outline of a planned dose
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`finding study with implitapide.
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`Further, the clinical protocol proposed in Stein and Pink Sheet 2004 is a
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`dose finding study to find the single safe and effective dose for implitapide.
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`Notably, the proposed study focused on administration of doses lower than had
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`3
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`
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`been found toxic in prior implitapide human trials. These documents would not
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`have motivated a POSA to use the claimed forced dose titration treatment
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`regimen, starting at a low dose and proceeding upward through at least three dose
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`levels, which results in tolerance and reduced liver toxicity of lomitapide at
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`therapeutic doses.
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`Third, a POSA would have had no reasonable expectation that the protocol
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`in Stein and Pink Sheet 2004 proposed for implitapide would translate to
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`lomitapide. Stein and Pink Sheet 2004 provide no data from that planned clinical
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`trial for implitapide. And the relevant information critical to selecting a dose for
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`lomitapide is missing in the prior art. The doses tested in and results from the
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`earlier clinical trials with lomitapide are unreported, and there was no human
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`pharmacokinetic (“PK”) and pharmacodynamic (“PD”) information available for
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`lomitapide. A POSA would have undeniably needed such human clinical and
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`PK/PD information to select an appropriate dosing regimen for lomitapide. As
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`CFAD’s own experts have conceded, even with Stein and Pink Sheet 2004 in hand,
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`a POSA would have had to design and then conduct a clinical trial before they
`
`could reasonably predict what the outcome would be based on a regimen with
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`lomitapide—“[o]ne would actually have to do the trial to acquire the information.”
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`Ex. 2022 (Zusman Tr.) at 178:16-179:3. And as to the dependent claims requiring
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`4
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`a specific percentage reduction of lipoproteins (e.g., claims 3 and 4), and fourth
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`(about 20-60 mg/day) and fifth (about 30-75 mg/day) doses (e.g., claim 8), CFAD
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`provides no separate analysis of those elements and does not addresses how a
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`POSA would have been able to reasonably predict such a reduction without
`
`performing a clinical trial.
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`Finally, secondary considerations bolster the finding of non-obviousness.
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`The claimed dosing regimen exhibits unexpected results, as it ameliorates the dose-
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`dependent side effects observed with lomitapide by increasing the dose. Pfizer,
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`Bayer, and BMS had all worked diligently on developing MTP inhibitors,
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`including lomitapide, for the U.S. market but failed to obtain approval for any such
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`therapy. Dr. Gregg, who spent more than 10 years at BMS developing MTP
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`inhibitors, “considered it unlikely” that patients would be able to tolerate the high
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`doses of lomitapide proposed by Dr. Rader (including 1.0 mg/kg/day).
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`JUXTAPID®, the commercial embodiment of the claimed invention, satisfied a
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`long-felt, unmet need for the development of a tolerable, safe, and efficacious
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`treatment for HoFH, a devastating hyperlipidemia disease for which prior
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`treatment options were largely limited to liver transplants or cholesterol apheresis
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`(cleansing) of plasma, and is a commercial success.
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`5
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`
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`In sum, the record fails to demonstrate that the claims are obvious, and the
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`Board should therefore reject CFAD’s challenges.
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`II. THE BOARD’S INSTITUTION DECISION
`The patent claims are generally directed to methods of treating a subject
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`suffering from hyperlipidemia or hypercholesterolemia by administering
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`lomitapide in at least three stepwise, increasing dose levels. The dependent claims
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`are directed to, inter alia, the inclusion of fourth and fifth dosing levels, the
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`treatment of severe hypercholesterolemia, or the reduction of total cholesterol or
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`specific lipoproteins by at least 15% or 25% as compared to placebo.
`
`Claim 1 is illustrative:
`
`A method of treating a subject suffering from hyperlipidemia or
`hypercholesterolemia, the method comprising administering to the subject an
`effective amount of an MTP inhibitor, wherein said administration
`comprises at least three, step-wise, increasing dose levels of the MTP
`inhibitor 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, and wherein the MTP inhibitor is
`represented by:
`
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`6
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`or a pharmaceutically acceptable salt thereof or the piperidine N-oxide
`thereof, and wherein each dose level is administered to the subject for about
`1 to about 5 weeks.
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`A. Claim Construction
`In its Institution Decision, citing to In re Cuozzo Speed Techs., LLC, 793
`
`F.3d 1268, 1278–79 (Fed. Cir. 2015), cert. granted, sub nom. Cuozzo Speed Techs.
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`LLC v. Lee, 136 S.Ct. 890 (2016), the Board noted that claims of unexpired
`
`patents, like those at issue here, are given their broadest reasonable interpretation
`
`in light of the specification. IPR2015-01835, Paper 7 (“Institution Decision”) at 6-
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`7. The claims should be construed according to the same standard applicable in
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`district court. While the Board has adopted the ‘broadest reasonable interpretation’
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`claim-construction standard by regulation, Patent Owner respectfully submits that
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`this standard is legally impermissible for the reasons now being considered by the
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`U.S. Supreme Court.
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`Patent Owner does not contest any of the specific constructions proposed by
`
`CFAD for the claim terms. Nonetheless, Patent Owner submits that a POSA
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`7
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`
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`would have understood that the “method of treating a subject suffering from
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`hyperlipidemia or hypercholesterolemia, the method comprising administering to
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`the subject an effective amount of an MTP inhibitor, wherein said administration
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`comprises at least three, step-wise, increasing dose levels of the MTP inhibitor”
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`means that the claimed method of treating a human patient requires a forced dose
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`titration regimen including, but not limited to, at least three, step-wise, increasing
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`dose levels of lomitapide. Declaration of Dr. Frank Sacks, M.D. (Ex. 2023,
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`“Sacks”) ¶44.
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`Effective Filing Date
`
`B.
`The Board concluded in its Institution Decision that the ’135 patent likely
`
`cannot claim priority to the March 5, 2004 Provisional Application No.
`
`60/550,915, and is thus only entitled to an effective filing date of March 7, 2005,
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`the filing date of Application No. 10/591,923. Paper 7 at 11. Although Patent
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`Owner maintains that the claims are fully supported by the provisional application,
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`for purposes of this proceeding only, Patent Owner does not contest an effective
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`8
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`filing date of March 7, 2005, as the claims are nonobvious under either priority
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`date.3
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`Person of Ordinary Skill in the Art
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`C.
`As the ’135 patent is directed to methods of treating hypercholesterolemia
`
`and hyperlipidemia, and the discovery of dosing regimens for lomitapide that
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`would provide for an efficacious, safe, and tolerable treatment for those conditions,
`
`Patent Owner respectfully submits that:
`
`[I]n the 2004/2005 timeframe, a POSA in the field of the ’135 and ’268
`patents would have had an M.D. and several years of experience in treating
`patients with lipid disorders, including hyperlipidemia and
`hypercholesterolemia. The POSA would also have had access to and
`worked with individuals involved in drug discovery and development with
`degrees in medicinal chemistry, pharmacology, or drug delivery sciences
`and several years of experience in the development of drugs for the U.S.
`market.
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`Ex. 2023 (Sacks) ¶40.
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`Petitioner’s proposed POSA includes additional qualifications that are
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`unnecessary and erroneous, e.g., that the POSA consults PINK SHEET and remains
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`3 Patent Owner has also filed a contingent Motion to Amend, which proposes
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`substitute claims that are entitled to the March 5, 2004 priority date.
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`9
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`abreast of activities of pharmaceutical companies. Declaration of Dr. Randall M.
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`Zusman, M.D. (Ex. 1002, “Zusman”) ¶28. But at deposition Dr. Zusman admitted
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`that most treating physicians do not attend investor presentations for drug
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`companies and do not typically read THE PINK SHEET. Ex. 2022 (Zusman Tr.) at
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`125:3-12, 142:22-25; see also Ex. 2023 (Sacks) ¶41. Accordingly, the Board
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`should reject Petitioner’s proposal and adopt Patent Owner’s proposal. As set forth
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`below, however, under either proposal, the claims of the ’135 patent are
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`nonobvious.
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`D. Grounds of Institution
`The Board instituted review of claims 1-10 as obvious under 35 U.S.C. §
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`103(a) over (1) Pink Sheet 2004 and Chang, and (2) Stein and Chang. Paper 7 at
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`34.
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`1.
`Stein (Ex. 1014) is a slide deck purportedly presented on February 5, 2004
`
`Stein
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`by Dr. Evan Stein during a meeting sponsored by Pharmaceutical Products
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`Development, Inc. (“PPD”). The slides reference a proposed Phase II study of the
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`MTP inhibitor implitapide.
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`First, for the many reasons detailed infra, CFAD has not met its burden of
`
`proving that Stein qualifies as a “printed publication” within the meaning of 35
`
`U.S.C. §§ 102(a) or 102(b) (see Section VI.A., infra). CFAD has not established
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`10
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`that the slides marked as Ex. 1014 were actually presented on February 5, 2004, or
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`that they were available for public download prior to Dr. Rader’s invention.
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`Accordingly there is no evidence that Stein was available to the interested public
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`and therefore qualifies as a “printed publication.” See In re Klopfenstein, 380 F.3d
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`1345, 1350 (Fed. Cir. 2004). Moreover, because treating physicians typically do
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`not search investor day presentations for information on dosing regimens, a POSA
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`would have been unaware of what was presented. Ex. 2022 (Zusman Tr.) at
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`142:22- 25; Ex. 2023 (Sacks) ¶124. For this additional reason, Stein does not
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`qualify as a printed publication. Id. at 1351.
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`Second, even assuming Stein is prior art, substantive deficiencies limit its
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`relevance: (1) Stein relates to implitapide, a distinct compound with a completely
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`different chemical structure—and likely different PK/PD properties and
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`toxicities—from lomitapide; (2) Stein does not teach the claimed forced titration
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`dosing treatment method; and (3) Stein does not report any results for the proposed
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`clinical study. A POSA would have been unable to draw conclusions from Stein
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`on the safety and efficacy of dosing other MTP inhibitors.
`
`2.
`Pink Sheet 2004 (Ex. 1013) is a page from a pharmaceutical industry
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`Pink Sheet 2004
`
`newsletter reporting a presentation regarding a planned implitapide study. Pink
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`11
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`
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`Sheet 2004 does not report any additional information about the study that is not
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`already disclosed in Stein and, in fact, reports less. Pink Sheet 2004, therefore,
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`suffers from at least the same substantive deficiencies as Stein.
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`3.
`Noting the shortcomings identified above with regards to Stein and Pink
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`Chang
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`Sheet 2004—including that they only relate to implitapide— Petitioner asserts
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`Chang (Ex. 1015) in an effort to bridge the gap. Petitioner’s obviousness argument
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`hinges on the assertion that a POSA would have expected lomitapide and
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`implitapide to have comparable efficacy and safety when similarly dosed. For
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`support, Petitioner relies almost exclusively on a single sentence in Chang:
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`Similar efficacy was reported for BAY-13-9952 [implitapide], which
`produced a dose-dependent decrease in total cholesterol (45%), LDL
`cholesterol (55%) and triglycerides (29%) after 4 weeks of treatment
`at an oral dose of 160 mg/day [42••]. BMS-201038 [lomitapide] also
`showed similar efficacy in phase I and phase II clinical trials [43].
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`Pet. at 33-35, 48-49 (citing Ex. 1015 (Chang) at 5) (emphasis added). Even when
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`taken at face value, this statement does not support the conclusion that lomitapide
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`and implitapide could be dosed identically. Chang does not contain human PK or
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`PD data from which dosing comparisons for the two compounds can be made.
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`Chang would hardly motivate a POSA to pursue development of lomitapide. It
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`12
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`provides no data from the administration of lomitapide in humans. Instead, it
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`reports BMS’ discontinuation of lomitapide development due to adverse events.
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`Ex. 1015 (Chang) at 5, 8, n.43; MTP inhibitor research discontinued, THE PINK
`
`SHEET (July 31, 2000) (Ex. 2011, “Pink Sheet 2000”). As will be discussed below,
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`the doses at which BMS saw these adverse events are not reported in the prior art.
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`III. PATENT OWNER’S DECLARANTS
`Dr. Frank Sacks, M.D. is Professor of Cardiovascular Disease Prevention at
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`the Harvard School of Public Health and a Professor of Medicine at Harvard
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`Medical School. He is a recognized leader in the field of lipid disorders and has
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`treated hundreds of patients with hypercholesterolemia and hyperlipidemia. Dr.
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`Sacks opines that the claimed lomitapide dosing regimen was not obvious,
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`garnered praise, and satisfied a long-felt, unmet need for patients.
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`Dr. Thomas A. Baillie, Ph.D., D.Sc. is a Professor of Medicinal Chemistry
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`and Dean Emeritus of the School of Pharmacy at the University of Washington.
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`He holds a Ph.D. in organic chemistry and served as the worldwide leader of the
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`Drug Metabolism and Pharmacokinetics function at Merck Research Laboratories
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`for nearly fifteen years. Dr. Baillie opines that the claimed invention is not
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`obvious in view of the structural differences between implitapide and lomitapide
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`and the impact of such differences on PK/PD and dosing. Dr. Baillie also opines
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`that the claimed invention demonstrates unexpected results and that others failed to
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`accomplish what the claims achieved.
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`Dr. S. David Kimball, Ph.D. is the Associate Vice President for Research
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`Commercialization in the Office of Research and Economic Development at
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`Rutgers University. He also served as Associate Vice President for Translational
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`Science at Rutgers University and Research Professor in the Department of
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`Medicinal Chemistry at the Ernest Mario School of Pharmacy. Dr. Kimball holds
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`a Ph.D. in organic chemistry and chemical biology, and previously worked as a
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`medicinal chemist at BMS for nineteen years. Dr. Kimball opines that the claimed
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`invention is not obvious in view of the structural differences between implitapide
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`and lomitapide and the impact of such differences on other parameters, principally
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`potential toxicity concerns.
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`Dr. Daniel J. Rader, M.D. is the inventor of the ’135 patent. He is the
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`Seymour Gray Professor of Molecular Medicine at the University of Pennsylvania
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`Perelman School of Medicine. He holds an M.D. from the Medical College of
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`Pennsylvania and has over forty years of experience treating patients, particularly
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`those with lipid disorders. Dr. Rader describes the events that led to the discovery
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`of the claimed invention, and also explains how the claimed invention has
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`unexpected results and satisfied a long-felt, unmet need.
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`14
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`Dr. Richard E. Gregg, M.D., who worked at BMS from 1988- 2007, helped
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`launch and then oversaw the company’s MTP inhibitor program, which included
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`lomitapide. Dr. Gregg summarizes BMS’ lomitapide animal and clinical studies
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`and the company’s eventual decision to cease development of lomitapide. Dr.
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`Gregg also describes BMS’ decision to donate lomitapide to Dr. Rader’s
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`institution, the University of Pennsylvania.
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`IV. TECHNICAL BACKGROUND AND STATE OF THE ART
`A. The Role of Pharmacokinetics and Pharmacodynamics in Drug
`Dosing.
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`Pharmacokinetics (“PK”) describes how the body affects a drug through the
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`mechanisms of absorption and distribution, the chemical changes made to the drug
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`via metabolism, and the effects and routes of excretion of the drug and/or its
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`metabolites. Declaration of Dr. Thomas A. Baillie, Ph.D., D.Sc. (Ex. 2024,
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`“Baillie”) ¶72; Declaration of Dr. S. David Kimball, Ph.D. (Ex. 2025, “Kimball”)
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`¶75. Pharmacodynamics (“PD”) describes the biochemical and physiological
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`effects of drugs on the body (such as efficacy and/or toxicity), the mechanisms of
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`drug action, and the relationship between drug concentration and effect. Ex. 2024
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`(Baillie) ¶77; Ex. 2025 (Kimball) ¶76.
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`PK and PD have a complex interrelationship that determines drug dosing
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`strategy: PD determines what plasma levels are needed to achieve efficacy without
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`15
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`causing toxicity (the “therapeutic window”), while PK determines how much and
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`how often the drug should be dosed to achieve those plasma levels. Ex. 2024
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`(Baillie) ¶80. Because dosing depends on both of these interrelated factors, dosing
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`can be different for each drug. Id.; Ex. 2025 (Kimball) ¶77. CFAD’s expert, Dr.
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`Mayersohn, also recognizes the importance of PK/PD data in designing a dosing
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`regimen:
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`“the most useful information for a person of ordinary skill in the art
`seeking to determine an appropriate human dose or dose range for a
`new drug based on the dosing of similar or related drugs would be
`data
`showing
`the pharmacokinetic and pharmacodynamic
`relationship for those similar compounds.”
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`Ex. 1003 (Mayersohn) ¶41 (emphasis added).
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`The chemical structure of a compound ultimately determines its biological
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`properties, i.e., its PK/PD profile. Accordingly, structural differences between
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`drugs often indicate differences in biological performance. Ex. 2024 (Baillie)
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`¶¶81-84; Ex. 2025 (Kimball) ¶¶73, 75-76. Designing a drug dosing regimen
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`therefore requires the POSA to have an in-depth knowledge of the compound’s
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`structure and its resulting PK/PD properties. Ex. 2024 (Baillie) ¶80; Ex. 2025
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`(Kimball) ¶77.
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`The Impact of Chemical Structure and Therapeutic Classes on
`the Selection of Dose.
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`B.
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`A “therapeutic class” is a group of drugs that are all designed to engage with
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`the same biological target, such as MTP. Ex. 2024 (Baillie) ¶82. In contrast, a
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`“structural class” is a group of compounds that share one or more structural
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`features. Id. ¶83. From a clinical perspective, POSAs understood that just because
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`two drugs come from the same therapeutic class does not mean they will have
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`similar enough PK/PD properties to be dosed the same way. Ex. 2024 (Baillie)
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`¶¶84, 89; Ex. 2025 (Kimball) ¶80; Ex. 2023 (Sacks) ¶¶70-74, 96-97. This is
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`especially true if these drugs belong to different structural classes, which would
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`generally be expected to yield distinct PK/PD profiles. Ex. 2024 (Baillie) ¶¶ 83-
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`84.
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`In addition, while compounds from the same therapeutic class may exhibit
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`some of the same “on-target” toxicities, i.e., toxicities caused by the same
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`mechanism that causes the intended therapeutic effect, they may not exhibit the
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`same “off-target” toxicities, i.e., toxicities caused by other activities of the
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`molecule that are structure-dependent. This is particularly true where compounds
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`in the same therapeutic class are in different structural classes, like lomitapide and
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`implitapide. Ex. 2024 (Baillie) ¶¶79, 83, 88; Ex. 2025 (Kimball) ¶¶83-84. Some
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`critically important off-target toxicities that could result from a compound’s
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`structure include hERG inhibition and phospholipidosis. Ex. 2025 (Kimball) ¶85.
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`hERG channel blockers, while rare, can result in potentially fatal arrhythmias. Id.
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`¶¶87-90. Phospholipidosis can affect a variety of important cell types, and drugs
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`that induce this condition can be denied regulatory approval. Id. ¶¶91-93. Both of
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`these toxicities are strongly associated with Cationic Amphiphillic Drugs
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`(“CADs”), a class of drug molecules which are both lipophilic and carry a positive
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`charge at physiological pH. Id. ¶¶85-86. Accordingly, A POSA would have been
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`mindful of and generally avoided compounds with the potential to cause such off-
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`target toxicities.
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`C. Treatment of Hypercholesterolemia and Hyperlipidemia
`Hypercholesterolemia, a condition characterized by very high levels of
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`cholesterol in the blood, is a well-known risk factor for atherosclerotic
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`cardiovascular disease (“ASCVD”), the major cause of mortality in the Western
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`world. Ex. 1008, [0003]. ASCVD causes a build-up of plaque in the arteries,
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`making it difficult for them to carry oxygen-rich blood to the heart, brain, and
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`other parts of the body. Ex. 2023 (Sacks) ¶51. It is well understood that lowering
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`total cholesterol (“TC”) and low-density lipoprotein cholesterol (“LDL-C”) is
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`associated with a significant reduction in clinical cardiovascular events. Ex. 1008,
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`18
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`[0003].
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`Hypercholesterolemia is a form of hyperlipidemia, a condition in which
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`elevated levels of lipids are
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