Coalition for Affordable Drugs VIII, LLC,
`Petitioner,
`v.
`The Trustees of the University of Pennsylvania,
`Patent Owner
`
`Case No. IPR2015-01835 (Patent 8,618,135 B2)
`Case No. IPR2015-01836 (Patent 7,932,268 B2)
`
`Inter Partes Review Hearing – December 1, 2016
`
`Patent Owner’s Demonstrative Exhibits
`
`1
`
`
`Petitioner,
`v.
`The Trustees of the University of Pennsylvania,
`Patent Owner
`
`Case No. IPR2015-01835 (Patent 8,618,135 B2)
`Case No. IPR2015-01836 (Patent 7,932,268 B2)
`
`Inter Partes Review Hearing – December 1, 2016
`
`Patent Owner’s Demonstrative Exhibits
`
`1
`
`
`
`Grounds Instituted by Board for the ’135 and ’268 Patents
`
`Patent
`
`Claims
`
`’135 Patent
`
`1‐10
`
`Grounds Instituted
`Obvious over Pink Sheet 2004 &
`Chang
`
`’135 Patent
`
`1‐10
`
`Obvious over Stein & Chang
`
`’268 Patent
`
`’268 Patent
`
`1‐8
`
`1‐8
`
`Obvious over Pink Sheet 2004 &
`Chang
`
`Obvious over Stein & Chang
`
`2
`
`Source: Institution Decision at 34 [33]
`
`
`
`Petitioner Has Not Shown That the Claims
`of the ’135 and ’268 Patents Are Obvious
`
` Petitioner fails to show a motivation to combine the Pink Sheet
`or Stein with Chang
`– The prior art suggested that lomitapide could not be dosed safely in humans
`– The Pink Sheet and Stein provide no motivation to use lomitapide
`– Chang provides no motivation to use a stepwise regimen for lomitapide, let
`alone in the claimed amounts
`– Chang’s unsupported statement about “similar efficacy” would not have
`motivated a POSA
`– General overlap in therapeutic class (i.e., MTP inhibitors) is not sufficient to
`combine specific teachings regarding lomitapide and implitapide
`
` A POSA would not have had a reasonable expectation of success
`– No showing that lomitapide and implitapide had “similar efficacy”
`– Chang’s rabbit data do not suggest similar dosing of lomitapide and implitapide
`– A POSA would have expected lomitapide and implitapide to have different
`PK/PD Properties
`
`Source: POR at 1‐6, 26‐38, 38‐44; MTA at 20‐22 [20‐21]; RMTA at 9‐10
`3
`
`
`
`Objective Indicia of Non‐Obviousness Confirm
`the Patentability of the Claims
`
` Unexpected Results: It was unexpected that increasing the dose of
`lomitapide would reduce side effects and thus allow patients to safely
`tolerate therapeutically effective doses
` Long‐felt Need: JUXTAPID® met the long‐felt need for effective
`treatment of HoFH
` Failure of Others: BMS abandoned lomitapide after a decade of
`research due to toxicity concerns; numerous other pharmaceutical
`companies (including Stein and PPD) also failed to develop an
`MTP inhibitor
` Praise: The successful use of Dr. Rader’s idea was published in
`the New England Journal of Medicine
` Licensing/Commercial Success: Aegerion Pharmaceuticals licensed the
`patents from Penn, and FDA‐approval of JUXTAPID® resulted in millions
`of dollars in sales, facilitating the growth of Aegerion
`
`Source: POR at 56‐64; MTA at 22‐24; RMTA at 10‐11
`
`4
`
`
`
`The Pink Sheet 2004 Provides No Motivation to Use
`Lomitapide
`
` The Pink Sheet 2004 is a one‐page article
` It describes the development strategy for
`implitapide and notes the protocol for
`Phase II proof‐of‐concept trials
` Pink Sheet 2004 does not disclose:
`– Lomitapide
`– Any results or data for the proposed protocol
`– That any subject would be administered more than
`the lowest dose
`
`Source: Ex. 1013, Pink Sheet 2004, p. 2; POPR at 40‐41 [38‐39]; POR at 10‐12, 26‐40, 49
`5
`
`
`
`Stein Provides No Motivation to Use Lomitapide
`
` Stein is a slide deck presented by
`Dr. Evan Stein for PPD, Inc.
` It describes a development plan for
`implitapide
` Stein does not disclose:
`– Lomitapide
`– Any results or data for the proposed protocol
`– That any subject would be administered more than
`the lowest dose
`
`Source: Ex. 1005, Butler Aff., p. 4; Ex. 1014, Stein, pp. 1, 37;
`POPR at 26‐30 [24‐28], 48‐49 [46‐47]; POR at 10‐12, 26‐38, 49; RMTA at 9
`6
`
`
`
`Chang Provides No Information Regarding
`the Human Dosing of Lomitapide
`
`Chang does not disclose:
` Any human data to support its “similar efficacy” statement
` Any dose of lomitapide used in humans
` PK/PD data for humans (or animals)
` The lomitapide therapeutic window in humans (or animals)
` That MTP inhibitors should be dosed similarly
` Rabbit data suggesting that lomitapide and implitapide can
`be dosed similarly
`
`7
`
`Source: POR at 12‐13, 31‐35
`
`
`
`The Board’s Decision on Motivation to Combine Was
`Based on an Incomplete Record
`
`“Given that implitapide and lomitapide are
`from the same class of therapeutics, that is
`MTP inhibitors, and that they are known to
`have similar clinical efficacy, based on the
`record before us, we determine that
`Petitioner has demonstrated a reasonable
`basis as to why the ordinary artisan would
`have used lomitapide as taught by Chang for
`implitapide in the method of Pink Sheet.”
`
`However:
` Sharing the same therapeutic class is not sufficient to show motivation
` Unsupported statement of “similar efficacy” would not have motivated
`a POSA to select lomitapide for a dose specific step‐wise regimen
`
`8
`
`Source: Institution Decision at 18
`
`
`
`Chang’s Statement About “Similar Efficacy”
`Is Unsupported and Would Not Have Motivated a POSA
`
` Chang does not disclose a scientific basis for its
`statement that lomitapide exhibited “similar efficacy”
`to other MTP inhibitors
`
` Only one reference is cited to support Chang’s
`proposition on “similar efficacy”
`(Footnote 43, Pink Sheet 2000)
`
` Pink Sheet 2000 provides no information regarding
`the efficacy of lomitapide or any other MTP inhibitor
`
` Pink Sheet 2000 provides no information regarding
`any doses of lomitapide used in humans
`
`Source: Ex. 1015, Chang, p. 5, 8; Ex. 2011, Pink Sheet 2000, p. 1; POPR at 46‐47 [44‐45]; POR at 12‐13, 31 [13]
`9
`
`
`
`Chang’s Animal Data Would Not Motivate a POSA to
`Develop Lomitapide for Human Use
`
` Chang’s source of lomitapide animal data is the 1998
`Wetterau paper (Ex. 1018), which was published before
`BMS withdrew lomitapide from the clinic
`
` The WHHL rabbit study cited by Chang was a single
`experiment in which five rabbits were administered one
`dose of lomitapide over two weeks
`
` Petitioner’s experts agree that the WHHL rabbit model
`cannot quantitatively predict human efficacy
`
` Chang states that lomitapide showed significant liver toxicity
`in humans that was not observed in several animal species
`
`Source: Ex. 1015, Chang, pp. 4‐6, Ex. 1018, Wetterau, pp. 2‐4; Ex. 2021, Mayersohn Tr., 112:9‐113:5;
`Ex. 2022, Zusman Tr., 92:9‐93:9; POR at 27, 32‐33, 36‐37; RMTA at 4, 7‐8
`10
`
`
`
`Drugs in the Same Therapeutic Class Are Not Necessarily
`Dosed Using the Same Regimen
`
` Drugs in the same therapeutic class work on the same
`biological target but have different chemical structures
`
` Differences in structure often cause differences in key
`PK/PD properties such as potency, off‐target toxicity,
`absorption, and metabolism
`
` A POSA would not expect compounds with different
`structures to have the same PK/PD properties
`
` If two compounds have dissimilar PK/PD properties,
`they will not be dosed using the same regimen
`
`11
`
`Source: POR at 17‐18, 41‐44
`
`
`
`A POSA Would Have No Motivation to Select Lomitapide
`For Use in the Stein and Pink Sheet 2004 Regimen
`
` A POSA would be discouraged from developing
`lomitapide after BMS withdrew the compound from
`the clinic due to liver toxicity
`
` A POSA would expect off‐target toxicities based on
`lomitapide’s chemical structure
`
` In view of these toxicities, a POSA would not have
`considered the use of lomitapide as a combination
`therapy with statins and/or targeted HoFH treatment
`
` There were more promising MTP inhibitors available
`in the literature
`
`12
`
`Source: POR at 12‐13, 26‐35
`
`
`
`A POSA Would Have Had No Reasonable Expectation of Success in
`Using the Stein/Pink Sheet 2004 Dosing Regimen with Lomitapide
`
` A POSA would have expected lomitapide and implitapide to
`have different PK/PD properties and thus to be dosed
`differently because they have different chemical structures
`
` No comparative human (or animal) PK/PD data existed for
`implitapide and lomitapide, so a POSA could not reasonably
`make any predictions regarding lomitapide dosing
`
` Stein and Pink Sheet 2004 describe a proposed dosing
`regimen—no evidence it would work even with implitapide
`
` No human dosing data available for lomitapide—a POSA
`could not know whether the doses proposed by Stein would
`be efficacious and/or toxic with lomitapide
`
`Source: POR 38‐44; MTA at 20‐22 [20‐21]; RMTA at 9‐10
`
`13
`
`
`
`Testimony Supporting Nonobviousness
`
`Patent Owner
`Declarant
`
`Frank Sacks, M.D.
`(Harvard Medical School)
`
`Thomas A. Baillie, Ph.D
`(University of Washington,
`ex Merck)
`
`S. David Kimball, Ph.D.
`(Rutgers, ex BMS)
`
`Daniel J. Rader, M.D.
`(University of Pennsylvania)
`
`Key Testimony
`
`The claimed lomitapide dosing regimen was not obvious,
`garnered praise, and satisfied a long‐felt, unmet need
`
`Nonobviousness in light of structural differences of
`implitapide and lomitapide and the effect on PK/PD
`properties and dosing; unexpected results; failure of others
`
`Nonobviousness in light of structural differences of
`implitapide and lomitapide and the effect on off‐target
`toxicity and PK/PD properties
`Sole inventor of both patents; describes the events that led
`to the discovery of the invention, conception and reduction
`to practice
`
`Richard E. Gregg, M.D.
`(ex. BMS)
`
`Describes the early clinical work on lomitapide at BMS and
`the discontinuation of the program
`
`14
`
`Source: POR at 13‐14
`
`
`
`Pink Sheet 2004 Is a One‐Page News Article on Planned
`Implitapide Study
`
`Source: Ex. 1013, Pink Sheet 2004, p. 2; POPR at 40‐41 [38‐39]; POR at 11‐12, 38‐40
`15
`
`
`
`The Stein Presentation Was Directed to
`Analysts and Investors
`
`“WILMINGTON, NC, January 15, 2004 ‐‐ PPD, Inc.
`(Nasdaq: PPDI) today confirmed that it will hold an
`analyst day for equity analysts and institutional investors
`on Thursday, February 5, 2004, at the Plaza Hotel in New
`York City from approximately 8:00a.m. to 12:00 p.m. EST.
`Chief Executive Officer Dr. Fred Eshelman and other PPD
`senior management will deliver presentations regarding
`PPD’s business strategies. Executives representing some
`of PPD’s strategic partners will also be presenting their
`business as it relates to PPD.
`To attend the presentations, register via the investors
`section of the PPD Web site, http://www.ppdl.com.
`Note that space is limited. The event will also be Webcast
`live, and all interested parties will be able to access the
`Webcast through the investors section of the PPD Web
`site. The Webcast will be archived shortly after the call
`for on‐demand replay.”
`
`Source: Ex. 1005, Butler Aff., p. 4; POPR at 28 [26]
`
`16
`
`
`
`The Stein Presentation Was Limited to Implitapide
`
`Source: Ex. 1014, Stein, p. 1; POPR at 26‐30 [24‐28]; POR at 10‐11
`17
`
`
`
`Stein Contains Limited Information Regarding the
`Proposed Dosing of Implitapide
`
`Source: Ex. 1014, Stein, p. 37; POPR at 48‐49 [46‐47]; POR at 35; RMTA at 9
`18
`
`
`
`Dr. Sacks: A POSA Would Not Use Stein or Pink Sheet
`2004 to Design a Human Dosing Regimen
`
`“I understand that the purpose of the Stein 2004
`presentation was to attract interest from investors.
`Accordingly in my opinion POSAs would have viewed
`the plans expressed in the slides with a healthy dose of
`skepticism. And in my opinion clinicians do not typically
`attend investor presentations for purposes of obtaining
`information on dosing regimens. See also Mayersohn Tr.
`at 192:5‐9. A POSA would instead look to peer‐reviewed
`medical literature.”
`
`“The Pink Sheet reports developments in the
`pharmaceutical industry to investors and employees
`of other pharmaceutical companies. The Pink Sheet
`does not purport to present comprehensive analyses
`or reviews of pharmaceuticals that are similar to
`research articles or reviews published in scientific and
`medical journals that are peer‐reviewed. A skilled
`physician would not use a newsletter like the Pink
`Sheet to devise a therapeutic regimen for patients.”
`
`Source: Ex. 2023, Sacks Decl., ¶ 124, ¶ 41; POR at 9‐12
`
`19
`
`
`
`Stein and Pink Sheet 2004 Describe a Protocol for
`Implitapide and No Data Demonstrating That It Will Work
`
`“It is important to note that although Stein and
`Pink Sheet 2004 both describe a clincal protocol
`for implitapide, this protocol is simply proposed,
`and there is no clinical data whatsoever to prove
`that it works. This is an important distinction for
`a POSA, who would have needed hard data to
`conclude that this dosing protocol had a
`reasonable chance of succeeding at all. Neither
`Stein nor Pink Sheet 2004 provide any concrete
`evidence that their proposed protocol worked
`with implitapide – let alone a structurally distinct
`molecule like lomitapide.”
`
`Source: Ex. 2024, Baillie Decl., ¶ 115; POR at 38‐44
`
`20
`
`
`
`A POSA Would Not Have Based a Lomitapide Dosing
`Regimen on Stein or Pink Sheet 2004
`
` The disclosures of Stein and Pink Sheet 2004
`are not directed to medical professionals
`
` Stein and Pink Sheet 2004 disclose a proposal
`to conduct a standard dose‐finding regimen
`for implitapide
`
` Stein and Pink Sheet 2004 provide no data
`to suggest that the proposed regimen would
`be successful
`
`21
`
`Source: POR at 10‐12, 26‐38, 49
`
`
`
`The Board’s Institution Decision Was Based on
`An Incomplete Record Regarding Similar Clinical Efficacy
`
`“Given that implitapide and lomitapide are
`from the same class of therapeutics, that is
`MTP inhibitors, and that they are known to
`have similar clinical efficacy, based on the
`record before us, we determine that
`Petitioner has demonstrated a reasonable
`basis as to why the ordinary artisan would
`have used lomitapide as taught by Chang for
`implitapide in the method of Pink Sheet.”
`
`22
`
`Source: Institution Decision at 18
`
`
`
`Chang’s “Similar Efficacy” Statement Is Unsupported
`
`“. . . CP‐346086 (30 mg) administered at bedtime,
`produced an average decrease in plasma total and LDL
`cholesterol of 47 and 68%, respectively, . . . Plasma
`triglycerides were also decreased by up to 75% . . .
`Similar efficacy was reported for BAY‐13‐9952,
`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.
`BMS‐201038 also showed similar efficacy in phase I
`and phase II clinical trials [43].”
`
`“43. Half‐year pharma operating highlights ‐ MTP
`inhibitor research discontinued. FOG Reports Pink
`Sheet (2000) 62:20.”
`
`Source: Ex. 1015, Chang, p. 5, 8; POPR at 46‐47 [44‐45]; POR at 12‐13 [13]
`23
`
`
`
`Pink Sheet 2000 (Ref. 43) Does Not Disclose Any Dosing
`Information for Lomitapide
`
`Source: Ex. 2011, Pink Sheet 2000, p. 1; POPR at 46‐47 [44‐45]; POR at 13, 31
`24
`
`
`
`Dr. Zusman Relied on Chang’s “Similar Efficacy” Statement
`In His Declaration
`
`“Human studies involving CP‐346086
`and Phase I and Phase II clinical trials
`with implitapide and lomitapide
`reduced plasma triglycerides and
`VLDL cholesterol in humans.
`(Id. at 566).”
`
`25
`
`Source: Ex. 1002, Zusman Decl., ¶ 98
`
`
`
`Dr. Zusman Did Not Consider Pink Sheet 2000 (Ref. 43)
`Before Submitting His Declaration to the Board
`
`Q. You have not seen the reference that Chang
`cites to in his paper reference 43, correct?
`
`A. No, I have not.
`
`Q. So you did not rely on reference 43 in forming
`or offering your opinions in this proceeding,
`correct?
`
`A. No, I did not, . . .
`
`Source: Ex. 2022, Zusman Tr., 98:16‐22; POR at 31
`
`26
`
`
`
`Petitioner’s Expert Dr. Zusman Conceded That Liver
`Toxicity Would Discourage a POSA from Developing a Drug
`
` Dr. Zusman testified that the FDA was “extraordinarily
`sensitized” to liver toxicity and was thus reluctant to
`approve hepatoxic compounds. (Tr. at 171:17‐172:6)
`
` Dr. Zusman conceded that if a drug caused a twofold
`increase in liver enzyme levels, it might be “too hot to
`handle”, and would have discouraged a POSA from
`developing it. (Tr. at 172:16‐24)
`
` Dr. Zusman admitted that a POSA’s concerns regarding
`liver toxicity would apply to MTP inhibitors generally.
`(Tr. at 174:11‐175:8)
`
`Ex. 2022, Zusman Tr., 171:17‐172:6, 172:16‐24, 174:11‐175:8; POR at 2, 27‐28; MTA at 18
`27
`
`
`
`Petitioner’s Experts Concede that the Prior Art Does
`Not Identify Any Dose of Lomitapide Used in Humans
`
`Dr. Mayersohn:
`Q. And as of 2004–2005, the prior art did not teach doses of lomitapide
`in humans that caused adverse events to a degree sufficient to cause
`Bristol‐Myers to discontinue the drug, correct?
`A. Well, it’s the same question you’ve been asking. No, there is no
`information in that abstract or that announcement.
`* * *
`Q. Yeah, I was asking if the specific dose that had been put into a human
`body was reported in the prior art.
`A. And the answer to the best of my knowledge was no.
`
`Dr. Zusman:
`Q.
`. . . . But as far as your declaration in this proceeding, you have not
`identified a reference nor do you state in your declaration what dose
`was used in the Phase 1 and Phase 2 clinical trials for lomitapide?
`I can’t recollect that reference right now, no, I cannot.
`Source: Ex. 2021 Mayersohn Tr., 170:18‐171:2 (objection omitted), 173:7‐11;
`Ex. 2022, Zusman Tr., 97:6‐12; POR at 28, 31, 34, 41
`
`A.
`
`28
`
`
`
`Dr. Zusman Conceded that the Prior Art Does Not
`Identify a Non‐Toxic Dose for Lomitapide in Humans
`
`Q. But Dr. Zusman, sitting here today, you don’t
`know what lower dose you could go to for
`lomitapide based on reading Chang.
`A. Based on only reading Chang, that’s correct.
`* * *
`Q. . . . And so reading Chang, a person of ordinary
`skill in the art doesn’t know what, quote,
`lower dose they would need to go to in order
`to reduce or eliminate these liver toxicities,
`correct, with lomitapide?
`A. Not precisely what dose one might employ.
`
`Source: Ex. 2022, Zusman Tr., 111:8‐13 (objection omitted), 111:22‐112:3; POR at 34
`29
`
`
`
`Chang Provides No Guidance on Dosing
`Lomitapide to Humans
`
`“. . . he points out in this review article that
`efficacious doses of the Pfizer compound
`were in the order of 30 milligrams per day;
`whereas efficacious doses of the Bayer
`compound, which is implitapide, were 160
`milligrams per day, so very, very different
`doses of these two drugs.
`So without understanding something
`about the doses that gave rise to a target
`efficacy, it’s very, very hard to ‐‐ impossible
`actually, to design any rational clinical trial
`with lomitapide where there is no
`information on the doses that were giving
`rise to a pharmacological effect.”
`
`Source: Ex. 1048 [1056], Baillie Tr., 46:19‐47:7; POR at 12‐13
`30
`
`
`
`Dr. Sacks: Chang’s Disclosures Regarding
`Lomitapide are Limited
`
`MTP Inhibitor
`
`CP‐346086
`
`Dose and
`Regimen
`single oral
`dose; dose
`unknown
`
`2‐week,
`multiple
`dose, 30 mg
`
`Population
`
`healthy
`volunteers
`
`healthy
`volunteers
`
`Effect on total
`cholesterol and LDL
`Reduced VLDL
`cholesterol in a dose‐
`dependent manner
`
`Triglycerides
`
`reduced plasma
`triglycerides
`
`average decrease in
`total cholesterol and
`LDL cholesterol of 47
`and 68%, respectively
`
`triglycerides
`decreased by up
`to 75%, but only
`transiently
`
`Implitapide
`(BAY‐13‐9952)
`
`4 weeks at
`160 mg/day
`
`Primary
`hyperlipidemia
`
`dose‐dependent
`decrease in total
`cholesterol and LDL
`cholesterol of 45 and
`55%, respectively
`
`triglycerides
`decreased (29%)
`
`Lomitapide
`(BMS‐201038)
`
`?
`
`?
`
`?
`
`Source: Ex. 2023, Sack Decl., ¶ 106; POR at 12‐13, 29‐33
`
`31
`
`
`
`The Board’s Institution Decision Was Based on an Incomplete
`Record Regarding Dosing of Drugs in the Same Therapeutic Class
`
`“Given that implitapide and lomitapide are
`from the same class of therapeutics, that is
`MTP inhibitors, and that they are known to
`have similar clinical efficacy, based on the
`record before us, we determine that
`Petitioner has demonstrated a reasonable
`basis as to why the ordinary artisan would
`have used lomitapide as taught by Chang for
`implitapide in the method of Pink Sheet.”
`
`32
`
`Source: Institution Decision at 18
`
`
`
`Therapeutic Class Does Not Determine Dosing Regimen
`
`“Despite belonging to the same therapeutic class,
`the individual statins differ in the degree of
`LDL‐cholesterol lowering achieved per mg dose.”
`* * *
`“. . . individual drugs in the same class (whether
`statins or MTP inhibitors) will have a unique profile,
`including that they differ in potency, time of day
`when they must be taken, their dosage range,
`their lipophilicity/hydrophobicity (which affects
`the side effect profile) and their compatibility with
`other drugs.”
`
`* * *
`“. . . a dose range for a member of a class of drugs
`and its toxicity profile cannot be used directly for
`another member of the same class; dose ranges and
`toxicity profiles can differ substantially and critically.”
`
`Source: Ex. 2023, Sacks Decl., ¶¶ 70, 73, 96‐97; POR at 17, 42
`33
`
`
`
`Members of the Same Therapeutic Class Do Not
`Necessarily Have the Same PK/PD Properties
`
`“From a clinical perspective, what this means is
`that just because two drugs come from the
`same therapeutic class does not mean that they
`will have similar enough PK/PD properties to be
`dosed in the same way. This is especially true of
`two drugs from different structural classes,
`which would generally be expected to have
`distinct PK/PD profiles.”
`
`Source: Ex. 2024, Baillie Decl., ¶ 84; POR at 17, 42
`
`34
`
`
`
`Dr. Baillie: Each Drug In a Therapeutic Class
`Has To Be Evaluated on Its Own Merits
`
`Q.
`
`I guess my point is today we’ve talked a lot about
`developing a dosing regimen, and I’m trying to understand
`what the role is of drugs in the same therapeutic class in
`determining that dosing regimen.
`
`A. Well, I would argue that there is very little influence of
`dosing regimens in other members of a therapeutic class.
`As I mentioned earlier, every compound has to be
`considered on its own merits. Every individual molecule
`will have its own PK properties. Every individual molecule
`will have its own pharmacodynamic properties. And since
`the PK/PD profile really is the primary determinant of
`clinical dose, you can’t assume that you can translate
`PK/PD relationships for one molecule in the same
`therapeutic class to another.
`
`Source: Ex. 1048 [1056], Baillie Tr., 47:10‐48:2; POR at 38‐44
`35
`
`
`
`Drugs in the Same Therapeutic Class Often Do Not
`Have the Same Potency – Statins
`
`Drug
`
`LDL Reduction
`10 mg 20 mg 40 mg
`
`
`
`
`
`
`
`Atorvastatin
`
`
`
`
`
`Fluvastatin
`
`Simvastatin
`
`Pravastatin
`
`Lovastatin
`
`38% 46% 51%
`
`n/d
`
`17% 23%
`
`28% 35% 41%
`
`19% 24% 34%
`
`n/d
`
`29% 31%
`
`Source: Ex. 2019, Jones, at 3‐4; Ex. 2023, Sacks Decl., at ¶¶ 70‐74; Ex. 2025, Kimball Decl., at ¶¶ 78‐80; POR at 17
`36
`
`
`
`Drugs in the Same Therapeutic Class Often Do Not
`Have Interchangeable Dosing Regimens – PDE5 Inhibitors
`Figure 4: PK/PD Properties of PDE5 Inhibitors
`Viagra®
`Levitra®
`Cialis®
`(Sildenafil)
`(Vardenafil)
`(Tadalafil)
`
`Stendra®
`(Avanafil)
`
`Drug
`
`
`
`Structure
`
`Biological
`half‐life (T1/2)
`Absorption
`Time (Tmax)
`Off‐Target
`PDE Inhibition
`
`Common
`Side Effects
`
`Dosing
`Frequency
`
`
`
`4 hrs
`
`4–5 hrs
`
`17.5 hrs
`
`5 hrs
`
`0.5–2.0 hrs
`
`0.5–2.0 hrs
`
`0.5–6.0 hrs
`
`0.50–0.75 hrs
`
`PDE1, PDE6
`Headache, flushing,
`nasal congestion,
`nasal pharyngitis,
`visual abnormalities
`
`PDE1, PDE6
`Headache, flushing,
`nasal congestion,
`nasal pharyngitis,
`visual abnormalities
`
`PDE11
`Headache, flushing,
`nasal congestion,
`nasal pharyngitis,
`back pain, myalgia
`
`n/a
`
`Headache, flushing,
`nasal congestion,
`nasal pharyngitis
`
`As needed
`
`As needed
`
`Daily OR as needed
`
`As needed
`
`Source: Ex. 2024, Baillie Decl., at ¶¶ 85‐90; POR at 42
`
`37
`
`
`
`Lomitapide and Implitapide Have Different
`Chemical Structures
`
`Lomitapide
`
`Implitapide
`
`Source: Ex. 2024 (Baillie Decl.) at ¶¶ 99‐100; Ex. 2025 (Kimball Decl.) at ¶¶ 101‐03; POR at 42‐44
`38
`
`
`
`Petitioner’s Expert Characterized Lomitapide and Implitapide
`As “Very Similar Drugs in Terms of Chemical Structure . . .”
`
`“I explain in this report that a person
`of ordinary skill in the art (as defined
`below) would have been aware
`before March 2004 that the two MTP
`inhibitors implitapide and lomitapide
`had both progressed to clinical trials
`in humans, and would have regarded
`them as very similar drugs in terms
`of chemical structure, biochemical
`mechanism(s) of action, and
`pharmacological response.”
`
`Source: Ex. 1003 (Mayersohn Decl.) at ¶ 17
`
`39
`
`
`
`Dr. Mayersohn Lacks Expertise to Evaluate
`Chemical Structures
`
`Q. So in forming your opinions, did you compare the
`chemical structure of lomitapide and implitapide?
`A. No. I’m not a medicinal chemist. I don’t have the
`ability to do that.
`
`* * *
`Q. What about these two structures is very similar?
`A. They’ve got a lot of rings, a bunch of nitrogens.
`They’re highly saturated. But beyond that,
`I can’t comment.
`
`Source: Ex. 2021, Mayersohn Tr., 74:15‐19, 78:10‐14; POR at 43
`40
`
`
`
`Dr. Mayersohn: PK/PD Data Is the Most Useful
`Information to a POSA in Designing a Dosing Regimen
`
`“As noted above, 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.”
`
`Source: Ex. 1003, Mayersohn Decl., ¶ 41; POR at 16, 41
`
`41
`
`
`
`Dr. Baillie: Designing a Dosing Regimen Requires
`Knowledge of a Drug’s PK and PD Properties
`
`“Designing an effective dosing regimen
`for a particular drug requires the POSA
`to have an in‐depth knowledge of the
`complex interrelationships between its
`PK and PD properties. . . . Whether two
`drugs can be expected to work using the
`same dosing regimen will therefore be
`highly dependent on whether they have
`comparable PK and PD properties.”
`
`Source: Ex. 2024, Baillie Decl., ¶ 80; POR at 15‐16
`
`42
`
`
`
`Dr. Zusman: The Prior Art Provides No
`PK/PD Data for Lomitapide
`
`Q. . . . . Dr. Zusman, the prior art that you’re
`aware of provides no PK or PD data for
`lomitapide, correct?
`
`A. Not that I’m personally aware of today.
`
`Source: Ex. 2022, Zusman Tr., 175:10‐13; POR at 41
`
`43
`
`
`
`Dr. Baillie: The Structural Differences Between Lomitapide
`and Implitapide Suggest Different PK/PD Properties
`
`“Lomitapide and implitapide are
`sufficiently different from a
`structural standpoint that any POSA
`would have expected them to have
`different PK/PD profiles. . . . given
`the lack of reliable and comparable
`PK/PD data for these drugs in the
`public domain, there is nothing
`which would have caused a POSA to
`doubt his initial expectation of
`dissimilar PK/PD characteristics.”
`
`Source: Ex. 2024, Baillie Decl., ¶¶ 113; POR at 44
`
`44
`
`
`
`Dr. Evan Stein: MTP Inhibitors Do Not Necessarily
`Have Interchangeable Dosing Regimens
`
`“All the examples of the opposed patent
`refer to one specific MTP inhibitor which is
`BMS‐201038, which is specified in dependent
`claim 6. Hence, the opposed patent does not
`teach the skilled person any other MTP
`inhibitor, and in which three‐stepwise dosages
`of such MTP inhibitor should be used for the
`treatment of a human being or an animal.
`Therefore, it is impossible for the skilled person
`to rework the present alleged invention over
`the broad scope of protection claimed. In
`particular, not all of the known MTP inhibitors
`may have an improved tolerability, safety or
`even effect if it is administered three‐stepwise
`with increasing dosage of the MTP inhibitor.”
`
`Source: Ex. 1020, Stein Opposition, pp. 5‐6; POPR at 45‐46 [43‐44]; POR at 43‐44
`45
`
`
`
`A POSA Would Not Substitute One Drug for Another
`In the Same Dosing Regimen Without Supporting Data
`
`Dr. Baillie:
`Q. Okay. So if you ‐‐ if a POSA had substituted lomitapide
`for implitapide in Stein’s protocol, would the
`aforementioned biological adaptation occur?
`A. Well, I mean, I think that’s – that’s very speculative
`because a POSA would never have thought about
`doing such a thing. I mean, why would you take
`a protocol for one molecule and think that a
`different molecule, that that same protocol would
`be appropriate? I think that it is scientifically
`inappropriate to do such a thing in the absence of
`the necessary data that we discussed this morning.
`
`Source: Ex. 1048 [1056], Baillie Tr., 100:21‐101:10; POR at 41‐42
`46
`
`
`
`A POSA Would Not Substitute One Drug for Another
`In the Same Dosing Regimen Without Supporting Data
`Dr. Kimball:
`Q. “In the case of two drugs with very different chemical
`structures, for example, lomitapide and implitapide,
`a POSA would not have been confident in dosing them
`using the same regimen because he would expect the
`two drugs to have very different pharmacokinetic
`properties.” Do you see that?
`A. I do.
`Q. You don’t cite to any article there. Is that just
`general knowledge?
`A. That’s general knowledge and the fact that I never
`heard of an example where you could cut and paste
`protocol from one drug onto another in clinical trials.
`It’s too much at risk.
`
`Source: Ex. 1056 [1052], Kimball Tr., 137:17‐138:8; POR at 41‐42
`47
`
`
`
`Dr. Kimball: Designing a Dosing Regimen Requires
`Knowledge of a Drug’s PK and PD Properties
`
`“Designing an optimal dosing regimen for a drug compound
`requires the POSA to consider the complex relationship
`between its PK and PD properties. . . . What this means is
`that the ability of two drugs to be effectively dosed using the
`same dosing regimen is closely tied to how similar their
`PK/PD properties are.”
`
`Ex. 2025, Kimball Decl., ¶ 77; POR at 15‐16
`
`48
`
`
`
`A Drug’s Chemical Structure Determines Its
`PK/PD Properties
`
`“As described above, the PK/PD properties of small molecule
`drugs like lomitapide result from the various chemical interactions
`that the drug undergoes within the human body . . . In the end,
`the strength of these chemical interactions (and therefore the
`strength of the resulting biological effects) depends on how
`compatible the drug’s chemical structure is with that of the
`molecular entities with which it interacts. What this means is that
`the chemical structure of a drug will ultimately determine its
`biological properties (i.e. PK/PD profile), and that structural
`differences between drugs will translate to differences in
`biological performance.
`
`Source: Ex. 2024 (Baillie Decl.) at ¶ 81; POR at 16, 42
`
`49
`
`
`
`Dr. Baillie: A POSA Would Not Expect Lomitapide
`And Implitapide to Be Interchangeable
`
`Q. Now, if a person of ordinary skill in the art was
`following Stein’s regimen with lomitapide,
`wouldn’t they start off with starting dose of
`10 milligrams daily of lomitapide?
`A. If they were to use the identical dosing protocol
`with lomitapide that Stein had proposed in this
`study for implitapide, that’s correct. Although,
`I don’t see what the rationale for picking
`the 10‐milligram starting dose would be for
`a different drug.
`
`Source: Ex. 1048 [1056], Baillie Tr., 96:9‐18; POR at 41‐42
`
`50
`
`
`
`The Prior Art Disclosed a Large Number of MTP Inhibitors
`
`Source: Ex. 2024 (Baillie Decl.) at ¶¶ 99‐100, Ex. 2025 (Kimball Decl.) at ¶¶ 101‐03; POR at 42‐44
`51
`
`
`
`Lomitapide’s Structure Suggests a Potential for
`Off‐Target Toxicity
`
` Lomitapide is a Cationic Amphiphilic Drug (“CAD”),
`it is both lipophilic and carries a positive charge
`at physiological pH
`
` CADs are associated with several membrane‐
`related toxicities such as phospholipidosis and
`hERG blockade
`
`Source: Ex. 2024 (Baillie Decl.) at ¶¶ 101‐02, 107; Ex. 2025 (Kimball Decl.) at ¶¶ 85‐93, 107‐11, POR at 17‐18
`52
`
`
`
`hERG Blockade Causes Potentially Fatal Arrythmias
`
`“. . . when hERG function is interrupted
`(e.g., via drug binding), a patient’s heart
`rate can become erratic and potentially
`fatal arrhythmias can occur.”
`
`Drugs Withdrawn from Market Due to hERG Toxicity:
`
`Source: Ex. 2025, Kimball Decl., ¶¶ 87‐89; POR at 18
`
`53
`
`
`
`Lomitapide Shows Striking Similarity to Known
`hERG Channel Blockers
`
`“The potential for hERG inhibition here is particularly
`concerning due both to the seriousness of the
`resulting side effect . . . and to the striking structural
`similarity between lomitapide and cisapride, a known
`hERG channel blocker:”
`
`Source: Ex. 2025, Kimball Decl., ¶ 117; POR at 29
`
`54
`
`
`
`Dr. Kimball: Lomitapide Was Developed Prior to the
`Widespread Understanding of hERG Toxicity
`
`Q. Okay. Do you know or have any idea whether BMS was
`vigilant to identify whether lomitapide was a CAD or had
`a chemical structure which substantially overlapped with
`known hERG inhibitors?
`
`A. I have no specific knowledge of that. It was prior to this
`understanding or would have likely been.
`* * *
`Q. Would it be surprising to you if BMS did not take those
`into consideration?
`A. At the time that this drug was put into clinical development,
`the issue of hERG was not understood.
`
`Source: Ex. 1056 [1052], Kimball Tr., 71:18‐25, 72:8‐14 (objection omitted); POR at 17‐18
`55
`
`
`
`Phospholipidosis Is a Membrane‐Related Toxicity
`Associated with CADs
`
`“Phospholipidosis is a type of cellular toxicity caused
`by the excess accumulation of phospholipids
`(which are normally found in the cell membrane)
`in a cell’s lysosomes. . . . Induction of
`phospholipidosis is classically associated with CAD
`molecu
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