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 IPR2015-01836
`Patent 7,932,268 B2
`
`
`
`PATENT OWNER’S MOTION TO AMEND UNDER 37 C.F.R. § 42.121
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`Case IPR2015-01836
`Patent Owner’s Motion to Amend
`TABLE OF CONTENTS
`
`Page
`
`C. 
`
`2. 
`3. 
`
`b)
` 
`c)
` 
`d)
` 
`
`INTRODUCTION ........................................................................................... 1 
`I. 
`THE PROPOSED AMENDMENTS NARROW THE ISSUED CLAIMS .... 2 
`II. 
`III.  THE AMENDED CLAIMS ARE SUPPORTED BY THE WRITTEN
`DESCRIPTIONS ............................................................................................. 5 
`IV.  THE AMENDED CLAIMS ARE PATENTABLE ...................................... 10 
`A. 
`Person of Ordinary Skill in the Art ..................................................... 10 
`B. 
`The Amended Claims are Entitled to an Effective Filing Date of
`March 5, 2004 ...................................................................................... 10 
`The Substitute Claims are Patentable Over All Prior Art of
`Record.................................................................................................. 10 
`1. 
`The amended claims are entitled to an invention date of
`no later than January 2004 ........................................................ 11 
`Pink Sheet and Stein post-date the invention date .................... 13 
`The amended claims are patentable over other prior art of
`record......................................................................................... 14 
`Summary of References .................................................. 14 
`a)
` 
`(i) 
`Lomitapide Prior Art ............................................ 14 
`(ii)  Titration Art .......................................................... 16 
`No reason to combine ..................................................... 17 
`No reasonable expectation of success ............................ 20 
`Objective indicia of nonobviousness confirm the
`patentability of the substitute claims .............................. 22 
`(i) 
`Unexpected Results. ............................................. 22 
`(ii)  Long-felt Need. .................................................... 22 
`(iii)  Failure of Others. .................................................. 23 
`(iv)  Praise .................................................................... 24 
`(v) 
`Licensing/Commercial Success ........................... 24 
`Even if the Pink Sheet and Stein are prior art, the
`substitute claims are patentable ................................................ 24 
`Patent Owner is Not Aware of Other Material Prior Art .................... 25 
`
`4. 
`
`D. 
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`CONCLUSION .............................................................................................. 25 
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`U.S. Patent 7,932,268 B2
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`I.
`
`INTRODUCTION
`
`
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`Case IPR2015-01836
`Patent Owner’s Motion to Amend
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`Inventor Dr. Daniel Rader designed and conducted the first clinical trial
`
`demonstrating that serious adverse side effects of lomitapide could be mitigated
`
`with forced titration, even at higher doses. He thus paved the way for clinical use
`
`of lomitapide as an adjunct therapy in patients suffering from HoFH, a severe
`
`genetic disease. Shortly after completing the clinical trial, Dr. Rader filed a
`
`provisional patent application describing his invention. Nevertheless, in its
`
`institution decision, the Board found that Petitioner had “reasonably shown” that
`
`Dr. Rader’s ’268 patent could not claim priority to that provisional application
`
`because the claimed “mg” dose ranges of the ’268 patent “are not obtained” from
`
`the “mg/kg” doses disclosed in the provisional and the claimed piperidine N-oxide
`
`derivative of the compound is not apparent from the provisional.
`
`Although Patent Owner maintains its position that the ’268 patent claims are
`
`entitled to the March 5, 2004 priority date, in the event that the Board accepts the
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`Petitioner’s obviousness arguments and deems the issued claims unpatentable,
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`Patent Owner now contingently moves to substitute the canceled claim(s) with
`
`corresponding proposed amended claims 9-14. The amended claims clearly
`
`resolve both alleged deficiencies raised by Petitioner—first, by claiming dose
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`ranges on a mg/kg basis; second, by eliminating the piperidine N-oxide derivative
`
`from the scope of the claim. See Appendix A.
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`The resulting substitute claims meet the requirements of 35 U.S.C. §
`
`
`
`316(d)(3) insofar as they narrow the claims by, inter alia, shrinking the range of
`
`doses that may be administered in the claimed three-step method. In addition, the
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`amended claims have express support in both the original disclosure of the ’268
`
`patent and the provisional application.
`
`
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`With priority thus established, two of the references relied upon to contend
`
`that the claimed method is obvious—Pink Sheet (Ex. 1013) and Stein (Ex. 1014)—
`
`do not qualify as prior art. Neither was published more than a year prior to the
`
`filing of Dr. Rader’s patent application, and both were published after Dr. Rader
`
`conceived of and reduced to practice his invention. The third reference relied upon
`
`by Petitioner—Chang (Ex. 1015)—does not describe any dose regimen for
`
`lomitapide (let alone the claimed forced titration method) and is thus not
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`anticipatory. Patent Owner is not aware of any art or teaching that a person of
`
`ordinary skill in the art (POSA) would combine with Chang (or any other material
`
`art) to render the proposed amended claims obvious. Accordingly, Patent Owner
`
`has met its burden of proving patentability of the proposed amended claims.
`
`II. THE PROPOSED AMENDMENTS NARROW THE ISSUED CLAIMS
`The substitute claims retain the step-wise increasing dose regimen developed
`
`by Dr. Rader, but narrow the scope of the claims by: 1) narrowing the dose range
`
`and claiming it with reference to mg/kg/day dose amounts; and 2) claiming one
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`specific salt of lomitapide. See 35 U.S.C. § 316(d)(3); see also Idle Free Systems,
`
`
`
`Inc. v. Bergstrom, Inc., IPR2012-00027, at 3-6 (PTAB June 11, 2013) (Paper 26).
`
`Substitute claim 9 corresponds to original claim 1 and is exemplary:
`
`9. (Proposed substitute for original claim 1) 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 inhibitors, wherein a first dose level is
`from about 2 to about 13 mg/day, and a second dose level is from about 5 to
`about 30 mg/day 50% of the immediately following dose level, and wherein
`a third dose level is from about 10 0.2 to about 50 0.59 mg/kg/day based on
`a weight between 62.5 and 74.9 kg; and wherein the MTP inhibitor is
`represented by:
`
`
`or a pharmaceutically acceptable salt thereof or the piperidine N-oxide
`thereof-N-(2,2,2-trifluoroethyl)-9-[4-[4-[[[4’-(trifluoromethyl)[1,1’-
`biphenyl]-2-yl] carbonyl] amino]-1-piperidinyl]butyl]-9H-fluorene-9-
`carboxamide, methanesulfonate, and wherein each dose level is administered
`to the subject for about 1 to about 4 weeks.
`
`The substitute claims narrow the permissible range of doses in each step by
`
`(i) requiring the first and second level dose to be 50% of the doses they precede,
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`and (ii) restricting the dose range to an amount that is a subset of that originally
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`claimed. Original claim 1 allows for any increasing three-step dosing regimen
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`within the recited milligram per day ranges:
`
`
`
`Dose 1
`
`Dose 2
`
`Dose 3
`
`Original Claim 1
`
`About 2 to about
`13 mg/day
`
`About 5 to about
`30 mg/day
`
`About 10 to about
`50 mg/day
`
`Substitute claim 9 limits the regimen in two interrelated ways. First, by specifying
`
`that the third dose must be 0.2-0.59 mg/kg/day based on a weight between 62.5 kg
`
`and 74.9 kg, the permissible third dose is narrowed from “about 10 to about 50
`
`mg/day” to about 12.5 mg to 44.19 mg/day. Second, by requiring that doses 1 and
`
`2 be limited to 50% of the following dose, those ranges are limited to about 3.13
`
`mg to 11.05 mg/day and about 6.25 mg to 22.1 mg/day, respectively:
`
`
`
`Dose 1
`
`Dose 2
`
`Dose 3
`
`Limiting
`Amendments
`
`50% of Dose
`2
`
`50% of Dose
`3
`
`Converted to
`mg/day1
`
`About 3.13 to
`about 11.05
`mg/day
`
`About 6.25 to
`about 22.1
`mg/day
`
`About 0.2 to about 0.59
`mg/kg/day based on a weight
`between 62.5 kg and 74.9 kg
`About 12.5 to about 44.19
`mg/day
`
`Accordingly, the full scope of the ranges permitted within each dose level is
`
`narrower than those recited in the original claim:
`
`
`
`
`1 Patent Owner provides the equivalent mg doses to demonstrate that the substitute
`claims, while recited in terms of mg/kg/day, are nonetheless within the scope of the
`original claims.
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`Dose 1
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`Dose 2
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`Case IPR2015-01836
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`Dose 3
`
`Original Claim
`1
`
`Substitute
`Claim 9
`(converted to
`mg/day)
`
`About 2 to
`about 13
`mg/day
`About 3.13 to
`about 11.05
`mg/day
`
`About 5 to
`about 30
`mg/day
`About 6.25 to
`about 22.1
`mg/day
`
`About 10 to about 50 mg/day
`
`About 12.5 to about 44.19
`mg/day
`
`The substitute claim also limits the recited compound. Instead of any
`
`“pharmaceutically acceptable salt” or any “piperidine N oxide thereof,” the
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`substitute claim narrows the compound to a specific salt form of lomitapide
`
`(methanesulfonate). The recitations of substitute claim 9 narrow the claim set as a
`
`whole, as well as dependent claims 10-14 individually. See Appendix A.
`
`As the sole independent substitute claim 9 only adds features to the
`
`corresponding original claim, and does not remove any, the proposed amendments
`
`do not enlarge the scope of the patent. See REG Synthetic Fuels LLC v. Neste Oil
`
`OYJ, IPR2014-00192 (Final Decision June 5, 2015) (granting motion to amend
`
`where Patent Owner replaced broad ranges with narrowing ranges).
`
`III. THE AMENDED CLAIMS ARE SUPPORTED BY THE WRITTEN
`DESCRIPTIONS
`
`Each of the proposed substitute claims is supported in the original disclosure
`
`of the patent (U.S. Pat. App. No. 10/591,923 (the ’923 application) (Ex. 1008),
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`which issued as the ’268 patent, and U.S. Pat. App. No. 60/550,915 (the ’915
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`application) (Ex. 1006) to which the ‘923 application claims priority). 37 C.F.R.
`
`
`
`§§ 42.121(b)(1)-(2). These applications expressly disclose each and every
`
`limitation of the proposed substitute claims. Accordingly, a POSA would have
`
`understood that Dr. Rader was in possession of the substitute claims as of the filing
`
`date. Anascape, Ltd. v. Nintendo of Am. Inc., 601 F.3d 1333, 1335 (Fed. Cir.
`
`2010).
`
`Support for exemplary proposed substitute claim 9 in the ’915 and ’923
`
`Applications is provided below.
`
`Substitute Claim 9Element
`
`Support in ’915 App’n
`
`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 inhibitors,
`
`wherein a first dose level is
`from about 2 to about 13
`mg/day, and a second dose
`level is from about 5 to about
`30 mg/day 50% of the
`immediately following dose
`level, and
`
`
`
`[0020]: “The present invention relates
`to methods of treating a subject
`suffering from a disorder associated
`with hyperlipidemia. The methods
`comprise administering to the subject
`an effective amount of an MTP
`inhibitor to ameliorate hyperlipidemia
`in the subject. The administration
`comprises at least three step-wise,
`increasing dosages of the MTP
`inhibitor.”
`
`See also [0033] (hypercholesterolemia);
`¶ [00100] (Abstract); Claim 2.
`[0046] “In some embodiments, each
`dose level is no more than 50% of the
`immediately following dose level.”
`[0093] (Example 5) showing a 50%
`escalation between doses 1-4: “For
`BMS-201038-treated patients, study
`drug will be initiated at 6.25 mg/d for 1
`6
`
`Support
`in ’923
`App’n
`[0024];
`[0027];
`[0042]
`
`[0053];
`[0074];
`[00112]
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`Support in ’915 App’n
`Support
`in ’923
`App’n
`
`week and then will be titrated up to
`12.5 mg/day for 2 weeks followed by
`25 mg/day for 4 weeks and then to 50
`mg/day for 4 weeks.”
`
`See also Claim 18: “wherein each said
`dose level is no more than 50% of the
`immediately following dose level.”
`[0047] “In some embodiments, the
`third dose level is from about 0.2 to
`about 0.59 mg/kg/day.”
`
`[0093] (Example 5): “For BMS-
`201038-treated patients, study drug will
`be initiated at 6.25 mg/d for 1 week and
`then will be titrated up to 12.5 mg/day
`for 2 weeks followed by 25 mg/day for
`4 weeks and then to 50 mg/day for 4
`weeks. BMS-201038 treated subjects
`whose weight is between 62.5 and
`74.9 kg will titrate up to 62.5 mg/day
`for an additional 4 weeks.”
`[0097] (Example 6): “70 kg man”
`[0043] “In some embodiments, the
`inhibitor is BMS-201038. As used
`herein, the phrase ‘BMS-201038’
`refers to a compound known as N-
`(2,2,2-Trifluorethyl)-9-[ 4-[ 4-[[[ 4'-
`(trifluoromethyl)[l,1’biphenyl]-2-
`Yl]carbonyl]amino]-1-
`piperidinyl]butyl]9H-fluorene-9-
`carboxamide, methanesulfonate.”
`
`[0054];
`[00112];
`[00116]
`
`[0034]
`
`
`U.S. Patent 7,932,268 B2
`
`Substitute Claim 9Element
`
`wherein a third dose level is
`from about 10 0.2 to about
`50 mg/day 0.59 mg/kg/day
`based on a weight between
`62.5 and 74.9 kg; and
`
`wherein the MTP inhibitor is
`represented by:
`
`
`or a pharmaceutically
`acceptable salt thereof or the
`piperidine N-oxide thereof
`N-(2,2,2-trifluoroethyl)-9-[4-
`[4-[[[4’-
`(trifluoromethyl)[1,1’-
`biphenyl]-2-yl] carbonyl]
`
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`Support in ’915 App’n
`Support
`in ’923
`App’n
`
`U.S. Patent 7,932,268 B2
`
`Substitute Claim 9Element
`
`amino]-1-piperidinyl]butyl]-
`9H-fluorene-9-carboxamide,
`methanesulfonate, and
`wherein each dose level is
`administered to the subject
`for about 1 to about 4 weeks.
`
`[0097] (Example 6): “Six patients with
`hoFH were enrolled and completed the
`study per protocol. Subjects received
`once daily dosing of 4 doses of BMS-
`201038 (0.03, 0.1, 0.3 and 1.0 mg/kg)
`for 4 weeks at each dose.”
`
`See also [0048]; [0093].
`Support for proposed substitute claim 12 can be found in at least ¶ 0033 of
`
`[0063];
`[0056];
`[00112];
`[00115];
`[00116]
`
`the ’915 Application and ¶ ¶0018 and 0030 of the ’923Application. Support for
`
`proposed substitute claim 13 can be found in at least ¶0040 and claims 51-54 of the
`
`’915 Application and ¶0043 of the ’923 Application. Support for proposed
`
`substitute claim 14 can be found in at least ¶¶0040 and 36, and claims 5-7, 51-52,
`
`and 54 of the ’915 Application and ¶ 0043 of the ’923Application. Support for
`
`proposed substitute claim 15 can be found in at least ¶0056 of the ’915 Application
`
`and ¶0072 of the ’923 Application. Support for proposed substitute claim 16 can
`
`be found in at least ¶¶0045, 0047, 0049, 0051, and 0057 of the ’915 Application
`
`and ¶ ¶0052, 0054, 0056, 0058, and 0060-0062 of the ’923 Application.
`
`“[T]he hallmark of written description is disclosure.” Ariad Pharms., Inc. v.
`
`Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). Here, a POSA
`
`would understand the ’915 Application and the subsequent disclosures to describe
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`a step-wise increasing dosing method with lomitapide for use in the treatment of
`
`
`
`hypercholesterolemia and dyslipidemia that allows the patient to tolerate a
`
`therapeutic dose of lomitapide. Ex. 2023 (Sacks Dec.) at ¶¶26, 47, 154, 168-173
`
`see also Ex. 1006 at ¶0023 (“Accordingly, the present invention provides a . .
`
`method comprising the step of administering to the subject an effective amount of
`
`the inhibitor to ameliorate hyperlipidemia in the subject according to a treatment
`
`regimen that reduces and/or eliminates side effects associated with the use of the
`
`inhibitors.”). A POSA would understand that the application discloses a variety of
`
`ways in which to implement the invention. Ex. 2023 (Sacks Dec.) at ¶¶164-173.
`
`For example, the application describes the step-wise increasing dose levels in the
`
`following ways: dose levels separated by a log or ½ log unit, or 50% or 33% of
`
`the immediately following dose. Id.; see also Ex. 1006 at ¶0046. A POSA would
`
`understand that any of the dose ranges or methods of increasing the dose ranges
`
`identified in the written descriptions could be used, so long as the method entails at
`
`least three step-wise, increasing dose levels of the compound. Id. A POSA would
`
`also understand that the mg/kg/day dosage level can be applied based on the
`
`weight of between 62.5 kg and 74.9 kg because subject weights within that range
`
`are expressly disclosed. Ex. 2023 (Sacks Dec.) at ¶168; see also Ex. 1006 at
`
`¶0093. As each limitation in the substitute claims is expressly recited in the
`
`original disclosure itself as well as the priority applications, a POSA would have
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`understood the disclosures to demonstrate possession of the inventions. Therefore,
`
`
`
`the proposed amendments are supported.
`
`IV. THE AMENDED CLAIMS ARE PATENTABLE
`The substitute claims are patentable over all known prior art. Idle Free at 7.
`
`A.
`
`Person of Ordinary Skill in the Art
`
`A POSA in the field of the ’268 patent would have 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 on a team with a number of other individuals involved in drug
`
`discovery and development with advanced degrees in medicinal chemistry,
`
`pharmacology, or drug delivery sciences and having several years of experience in
`
`the development of drugs for the U.S. market. Ex. 2023 (Sacks Dec.) at ¶40.
`
`B.
`
`The Amended Claims are Entitled to an Effective Filing Date of
`March 5, 2004
`
`The substitute claims are supported by the written description of the ’915
`
`Application. See Section III. As a result, the substitute claims are entitled to the
`
`March 5, 2004 filing date of the ’915 Application.
`
`C. The Substitute Claims are Patentable Over All Prior Art of
`Record
`
`The substitute claims are patentable over all “prior art of record,” i.e., any art
`
`submitted during prosecution or in this proceeding. MasterImage 3D, Inc. v.
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`RealD Inc., IPR2015-00040, Paper 42, July 15, 2015.
`
`
`
`1. The amended claims are entitled to an invention date of no later
`than January 2004
`
`Dr. Rader conceived of the inventions recited in the substitute claims by
`
`December 2002 and reduced the inventions to practice by no later than January 18,
`
`2004. Ex. 2026 (Rader Dec.) at ¶¶36, 43, 47-52, 54, 58. Accordingly, the
`
`substitute claims are entitled to an invention date of no later than January 18, 2004.
`
`In mid-late 2002, Dr. Rader had the idea that an upward forced-titration
`
`dosing regimen with lomitapide could enable a patient to tolerate the known side
`
`effects associated with the compound—including hepatic fat accumulation and
`
`increases in transaminase levels, as well as gastrointestinal (GI) side effects. Id.
`
`Specifically, Dr. Rader believed that by starting with a low lomitapide dose and
`
`ramping up to a target therapeutic dose, the intestinal cells would adapt to MTP
`
`inhibition by increasing their ability to metabolize fat before being overloaded with
`
`lipid deposits. Id. Under Dr. Rader’s “acclimation” theory, such a force-titrated
`
`patient would thereby better tolerate therapeutic doses of lomitapide. Ex. 2026
`
`(Rader Dec.) at ¶¶34-41, 62; Ex. 2077 (December 2002 Final Clinical Trial
`
`Protocol Submitted to IRB) at 4 (“The primary objective is to evaluate the safety
`
`and tolerability of four doses of BMS-201038 given as an initial dose and then
`
`force-titrated for an additional three doses over a 16 week period”); Id. at 14
`
`(“[W]e hypothesize that the steatorrhea and liver lipid accumulation may be
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`reduced by the initiation of a very low dose of the drug with a gradual up
`
`
`
`titration.”). Accordingly, Dr. Rader conceived of his invention no later than
`
`December 2002. See Dawson v. Dawson, 710 F.3d 1347, 1352 (Fed. Cir. 2013).
`
`Dr. Rader proceeded to design and draft a clinical trial protocol that would
`
`test his hypothesis: starting patients at a dose of 0.03 mg/kg/day and upwardly
`
`titrating the compound in ½-log units—approximately tripling the dose at each
`
`dose level (0.03 mg/kg/day to 0.1 mg/kg/day to 0.3 mg/kg/day to 1.0 mg/kg/day).
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`Ex. 2026 (Rader Dec.) at ¶¶37-40; Ex. 2077 at 8. Dr. Rader selected a ½-log dose
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`escalation because it allowed patients to receive a dosage regime ranging from
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`known sub-therapeutic to known-therapeutic ranges in just four dose levels. Ex.
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`2026 (Rader Dec.) at ¶¶38-40. Dr. Rader believed that if the tested dose-tripling
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`method worked, that other methods, including a dose-doubling regimen would also
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`work. Ex. 2026 (Rader Dec.) at ¶48. Dr. Rader developed his “proof of concept”
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`protocol in December 2002 and the Institutional Review Board at the University of
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`Pennsylvania approved it in March 2003. Ex. 2026 (Rader Dec.) at ¶¶34-38, 42.
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`Patients began receiving lomitapide in accordance with the study protocol as of
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`June 2003. Ex. 2026 (Rader Dec.) at ¶43. Shortly thereafter, Dr. Rader began
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`receiving and analyzing data from the study. Ex. 2026 (Rader Dec.) at ¶¶43-47.
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`By the time the final patient had completed dosing on January 18, 2004, Dr. Rader
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`knew that his hypothesis had been proven. Ex. 2026 (Rader Dec.) at ¶¶36, 47-50.
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`For example, in October 2003, with one-third of the clinical trial patients
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`having completed the dose escalation phase of the protocol, Dr. Rader reported that
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`“[t]olerability has been surprisingly good” with his dosing method. Ex. 2081 at 1.
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`Dr. Rader concluded that the data “answered [his] major question,” i.e., whether he
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`could identify a dosing scheme for “the MTP inhibitor in these patients that will be
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`acceptably tolerated and result in a substantial reduction in cholesterol levels”. Id.
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`at 1. The study thus proved Dr. Rader’s initial theory to be true and to work for its
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`intended purpose: upward-forced titration increased patient tolerance to lomitapide
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`and allowed patients to take higher (and greater therapeutic) doses. Ex. 2026
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`(Rader Dec.) at ¶¶47-50, 62-64; Ex. 2005 at 9(“we are very encouraged by the
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`tolerability of the drug”). The last patient completed the study on January 18,
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`2004.
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`As Dr. Rader reduced his invention to practice no later than when the last
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`patient was dosed on January 18, 2004, he is entitled to an invention date no later
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`than that date, i.e., the date that all the patients completed his “proof of concept”
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`study confirming his idea.
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`2. Pink Sheet and Stein post-date the invention date
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`As the substitute claims are entitled to an invention date of no later than
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`January 2004, Pink Sheet (Ex. 1013) (published Feb. 16, 2004) and Stein (Ex.
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`1014) (allegedly published Feb. 5, 2004) are not prior art and the two instituted
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`grounds in this inter partes review are overcome.
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`
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`3. The amended claims are patentable over other prior art of record
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`Patent Owner is not aware of any prior art that would make the substitute
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`claims unpatentable. The most arguably relevant art can be grouped into two
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`categories: (1) Lomitapide Prior Art and (2) Dose Titration Prior Art. No single
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`reference contains each and every limitation of the substitute claims. As explained
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`below, the substitute claims are patentable over this prior art.
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`a)
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`Summary of References
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`(i)
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`Lomitapide Prior Art
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`Chang (Ex. 1015), Biller (Ex. 2303), and Gregg Patent (Ex. 2092) are
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`representative of the Lomitapide Prior Art. Chang—described along with Pink
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`Sheet and Stein as the “best” prior art by petitioner’s expert Dr. Zusman (Ex. 2022
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`(Zusman Tr.) at 139:19-23)—is a review article describing several MTP inhibitors,
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`including lomitapide (BMS-201038). Chang discloses that development of
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`lomitapide had been discontinued by the company that discovered the compound—
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`Bristol-Myers Squibb—after Phase II trials showed “AST and ALT elevations, of a
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`magnitude sufficient to halt development.” Ex. 1015 (Chang) at 567; see also Ex.
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`2011 (Pink Sheet 2000) (reference #43 in Chang).
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`Chang does not disclose any dose of lomitapide for use in humans in the
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`treatment of hypercholesterolemia. Nor does it disclose any method of dosing
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`lomitapide (or any other MTP inhibitor) in an increasing stepwise manner to
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`address adverse effects caused by the compound, let alone the specific method
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`
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`required by the substitute claims that requires each subsequent dose level to double
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`in strength (“50% of each preceding dose”). Instead, Chang suggests using a
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`regimen of dosing away from meals as an approach to address these known serious
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`adverse effects. Ex. 1015 (Chang) at 567. Because there is no suggestion of an
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`escalating dose for any reason, the substitute claims are patentable over Chang.
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`U.S. Patent No. 5,739,135 to Biller et al. (“Biller”) (Ex. 2303) and U.S.
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`Patent No. 5,883,109 to Gregg et al. (“Gregg Patent”) (Ex. 2092) were cited during
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`prosecution by the examiner and overcome by the applicant. Biller and Gregg
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`Patent teach MTP inhibitors and combinations with MTP inhibitors, including
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`lomitapide, that are useful for lowering serum lipid levels. Ex. 2303 (Biller) at
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`Abstract; Ex. 2092 (Gregg Patent) at Abstract. The patents teach dose forms for
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`using the MTP inhibitor and/or MTP inhibitor combination. See e.g., Ex. 2303
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`(Biller) at 60:40-42.in an amount from about “5 to about 500 mg per day in single
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`or divided doses of one to four times daily.” Gregg Patent further states that it
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`“may be advisable to start a patient on a low dose combination and work up
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`gradually to a high dose combination.” Ex. 2092 (Gregg Patent) at 23:52-54.
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`Neither Biller nor Gregg Patent discloses a stepwise increasing dosing
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`method with lomitapide. Nor does Biller or Gregg Patent disclose that MTP
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`inhibitors would cause significant adverse effects. Biller and Gregg Patent further
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`do not disclose that a stepwise, increasing dosing method could be used to reduce
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`
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`the adverse side effects; let alone the specific dose-doubling method disclosed in
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`the substitute claims. The amelioration of a drug-induced, dose-dependent side
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`effect like accumulation of hepatic fat in the liver, by giving more of the drug that
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`causes the side effect is surprising and unexpected. Ex. 2023 (Sacks Dec.) at
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`¶¶121, 148, 154; Ex. 2024 (Baillie Dec.) at ¶¶139-142; Ex. 2022 (Zusman Tr.) at
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`66:25-67:3. For at least these reasons, the substitute claims are patentable over the
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`Lomitapide Prior Art.
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`(ii)
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`Titration Art
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`The NIASPAN Label and Dedrick are representative of the Titration Art.
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`NIASPAN Label mentions titrating dose upward to reduce the incidence of
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`flushing of the skin. Ex. 1021 (PDR) at 1821 (“Tolerance to this flushing
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`develops rapidly over the course of several weeks.”). The label warns that the
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`dosage “should not be increased by more than 500 mg in any 4-week period.” Id.
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`U.S. Patent No. 6,582,698 to Dedrick et al. (Ex. 2302) was submitted to the
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`examiner during prosecution of the ‘268 patent family. It discloses methods of
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`using LFA-1 antibodies in the treatment of LFA-1 mediated diseases, like
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`psoriasis. Dedrick discloses that occurrence of adverse effects “such as fever,
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`[etc.,]” “is surprisingly reduced relative to administration using conventional
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`dosing schedules such as daily administration of equal doses,” when the antibody
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`is given as a “first conditioning dose . . . followed by a second higher dose.” Ex.
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`
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`2302 at 9:54-10:4.
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`None of the Titration Art relates to MTP inhibitors, let alone lomitapide
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`specifically. None of the Titration Art teaches that the specific dose titration
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`methods disclosed are applicable to other drugs. Further, none of the Titration Art
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`teaches the specific dose-doubling method required by the substitute claims. For at
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`least these reasons, there is no suggestion of any method of dosing lomitapide in an
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`increasing stepwise manner.
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`b)
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`No reason to combine
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`A POSA would not have been motivated to combine the Lomitapide Prior
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`Art with the Titration Art. Any such combination would rest on hindsight.
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`First, by 2004 no skilled artisan would have been motivated to further
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`develop lomitapide. MTP inhibitors had been disclosed to have serious side effects
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`such that at least one major pharmaceutical company ceased its development
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`project with lomitapide several years earlier. Ex. 1015 (Chang) at 567; Ex. 2011
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`(Pink Sheet 2000) at 1; Ex. 2083 (Gregg Dec.) at ¶¶15-18. Moreover, other MTP
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`inhibitors had been disclosed as potentially superior back-up agents to lomitapide.
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`Ex. 2020 (Robl 2001) at 854. No clinical data for lomitapide existed in the prior
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`art. Ex. 2023 (Sacks Dec.) at ¶¶90-91. The only information that a POSA would
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`have had regarding the use of lomitapide in humans was that it caused “AST and
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`ALT elevations, of a magnitude sufficient to halt development.” Ex. 1015 (Chang)
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`
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`at 567. Given that the BMS team that discovered the compound and developed it
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`for a decade, decided to abruptly halt the program after observing significant drug-
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`induced, dose-dependent side effects, Ex. 2083 (Gregg Dec.) at ¶¶17-18, a POSA
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`would not have been motivated to try further development with lomitapide. Ex.
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`2023 (Sacks Dec.) at ¶¶26, 88-91, 152. Indeed, Petitioner’s expert, Dr. Zusman,
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`testified that a compound that showed elevated AST an