Trials@uspto.gov
`571.272.7822
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` Paper No. 7
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` Entered: March 7, 2016
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`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
`____________
`
`
`Before MICHAEL P. TIERNEY, LORA M. GREEN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`GREEN, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`571.272.7822
`
`
`
`
`
`
` Paper No. 7
`
` Entered: March 7, 2016
`
`
`
`
`
`
`
`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
`____________
`
`
`Before MICHAEL P. TIERNEY, LORA M. GREEN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`GREEN, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`
`
`
`IPR2015-01836
`Patent 7,932,268 B2
`
`
`INTRODUCTION
`
`Coalition for Affordable Drugs VIII, LLC (“Petitioner”) filed a
`Petition requesting an inter partes review of claims 1–8 of U.S. Patent
`No. 7,932,268 B2 (Ex. 1001, “the ’268 patent”). Paper 1 (“Pet.”). The
`Trustees of the University of Pennsylvania (“Patent Owner”) filed a
`Preliminary Response to the Petition. Paper 6 (“Prelim. Resp.”).
`We have jurisdiction under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” Upon considering the Petition and the
`Preliminary Response, we determine that Petitioner has shown a reasonable
`likelihood that it would prevail in showing the unpatentability of claims
`1–8. Accordingly, we institute an inter partes review of those claims.
`Related Proceedings
`A.
`Petitioner states that it “is concurrently filing a Petition for Inter
`Partes Review of U.S. Patent No. 8,618,135 [IPR2015-01835], which is a
`member of the same family as the ‘268 patent.” Pet. 3.
`The ’268 Patent (Ex. 1001)
`B.
`The ’268 patent issued on April 26, 2011, with Daniel J. Rader as the
`
`listed inventor. Ex. 1001. It claims priority to Provisional application No.
`60/550,915, filed on March 5, 2004. Id. The ’268 patent relates to “methods
`of treating disorders associated with hypercholesterolemia and/or
`hyperlipidemia.” Id. at 6:35–37.
`
`The ’268 patent teaches that “[a] large number of genetic and acquired
`diseases can result in hyperlipidemia.” Id. at 1:60–61. Primary
`hyperlipidemias include “common hypercholesterolemia, familial combined
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`hyperlipidemia, familial hypercholesterolemia, remnant hyperlipidemia,
`chylomicronemia syndrome and familial hypertriglyceridemia.” Id. at 1:65–
`2:2. For example, with homozygous familial hypercholesterolemia
`(“HoFH”), total plasma cholesterol levels are over 500 mg/dl, and left
`untreated, patients develop atherosclerosis by age 20, and often do not
`survive past age 30. Id. at 3:45–52. Such patients, however, are often
`unresponsive to conventional drug therapy. Id. at 3:55–57.
`According to the ’268 patent, “[a] number of treatments are currently
`available for lowering serum cholesterol and triglycerides,” noting, however,
`that “each has its own drawbacks and limitations in terms of efficacy, side-
`effects and qualifying patient population.” Id. at 2:3–6. For example, statins
`may have side effects that include liver and kidney dysfunction. Id. at 2:22–
`40.
`The ’268 patent teaches that abetalipoproteinemia is a rare genetic
`
`disease that is characterized by extremely low cholesterol and triglyceride
`levels, and is caused by mutations in microsomal triglyceride transport
`protein (“MTP”). Id. at 5:1–7. Thus, the ’268 patent teaches that the
`“finding that MTP is the genetic cause of [abetalipoproteinemia] . . . led to
`the concept that pharmacologic inhibition of MTP might be a successful
`strategy for reducing atherogenic lipoproteins levels in humans.” Id. at
`5:30–35. Bristol-Myers Squibb developed a series of compounds, including
`BMS-201038, which are potent inhibitors of MTP. Id. at 5:47–49.
`According to the ’268 patent, however:
`Clinical development of BMS-201038 as a drug for large
`scale use in the treatment of hypercholesterolemia has been
`discontinued, because of significant and serious hepatotoxicities.
`For example, gastrointestinal side effects, elevation of serum
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`transaminases and hepatic fat accumulation were observed,
`primarily at 25 mg/day or higher doses.
`Id. at 6:20–25.
`
`Thus, according to the ’268 patent, the “invention is based on the
`surprising discovery that one may treat an individual who has
`hyperlipidemia and/or hypercholesterolemia with an MTP inhibitor in a
`manner that results in the individual not experiencing side-effects normally
`associated with the inhibitor, or experiencing side-effects to a lesser degree.”
`Id. at 7:11–16.
`
`The ’268 patent specifically teaches:
`In some embodiments, the MTP inhibitor is administered
`at escalating doses. In some embodiments, the escalating doses
`comprise at least a first dose level and a second dose level. In
`some embodiments, the escalating doses comprise at least a first
`dose level, a second dose level, and a third dose level. In some
`embodiments, the escalating doses further comprise a fourth dose
`level. In some embodiments, the escalating doses comprise a
`first dose level, a second dose level, a third dose level, a fourth
`dose level and a fifth dose level. In some embodiments, six,
`seven, eight, nine and ten dose levels are contemplated.
`Id. at 11:60–12:3. The ’268 patent teaches further:
`In some embodiments, the first dose level is from about 2
`to about 13 mg/day. In some embodiments, the second dose level
`is from about 5 to about 30 mg/day. In some embodiments, the
`third dose level is from about 10 to about 50 mg/day. In some
`embodiments, the fourth dose level is from about 20 to about 60
`mg/day. In some embodiments, the fifth dose level is from about
`30 to about 75 mg/day.
`Id. at 12:45–51. In addition, other lipid modifying compounds may be used
`with the MTP inhibitor. Id. at 11:34–41.
`
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`
`Illustrative Claim
`C.
`Petitioner challenges claims 1–8 of the ’268 patent. Claim 1 is the
`only independent claim, is illustrative of the challenged claims, and is
`reproduced below:
`1. A method of treating a 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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`
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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 4
`weeks.
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`D. The Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1–8 of the ’268 patent
`on the following grounds (Pet. 4):
`References
`Pink Sheet1 and Chang2
`Stein3 and Chang
`
`Petitioner relies also on the Declaration of Randall M. Zusman, M.D.
`(Ex. 1002), as well as the Declaration of Michael Mayersohn, Ph.D.
`(Ex. 1003).
`
`Basis
`§ 103(a)
`§ 103(a)
`
`Claims Challenged
`1–8
`1–8
`
`
`
`ANALYSIS
`Claim Construction
`A.
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable constructions in light of
`the Specification of the patent in which they appear. See 37 C.F.R.
`§42.100(b); (“Congress implicitly approved the broadest reasonable
`interpretation standard in enacting the AIA,” and “the standard was properly
`adopted by PTO regulation.”), In re Cuozzo Speed Techs., LLC, 793 F.3d
`
`
`1 Bayer/PPD Implitapide Development Follows Zetia Model as Statin Add-
`On, 66 THE PINK SHEET 17 (February 16, 2004) (Ex. 1013) (“Pink Sheet”).
`2 George Chang, Roger B'Ruggeri & H James Harwood Jr., Microsomal
`Triglyceride Transfer Protein (MTP) Inhibitors: Discovery of Clinically
`Active Inhibitors Using High-Throughput Screening and Parallel Synthesis
`Paradigms, 5 CURRENT OP. DRUG DISCOVERY & DEV. 562–570 (2002)
`(Ex. 1015) (“Chang”).
`3 Evan Stein, CEO & President, MRL Int’l (Division of PPD), Presentation
`Given at PPD’s Analyst Day, Microsomal Triglygeride [sic] Transfer
`Protein (MTP) Inhibitor (Implitapide) Program (Feb. 5, 2004) (Ex. 1014)
`(“Stein”).
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`1268, 1278–79 (Fed. Cir. 2015), cert. granted, sub nom. Cuozzo Speed
`Techs. LLC v. Lee, 84 U.S.L.W. 3218 (U.S. Jan. 15, 2016) (No. 15-446).
`Under the broadest reasonable construction standard, claim terms are
`presumed to have their ordinary and customary meaning, as would be
`understood by one of ordinary skill in the art in the context of the entire
`disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007).
`We determine that, for purposes of this Decision, none of the terms in
`the challenged claims require express construction at this time. See, e.g.
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999) (noting that only claim terms which are in controversy need to be
`construed, and then only to the extent necessary to resolve the controversy).
`Real Party in Interest
`B.
`Patent Owner contends that the Petition should be denied on the basis
`that Petitioner failed to name all of the real parties in interest. Prelim. Resp.
`11–13. Specifically, Patent Owner asserts that Petitioner named nine real
`parties in interest in its Petition, but failed to name IP Navigation Group,
`LLC and nXn Partners, LLC, which are listed in other Petitions filed by
`Coalition for Affordable Drugs (“CFAD”), the Petitioner here. Id. at 12.
`Patent Owner, thus, argues:
`Patent Owner has no ability to determine, in CFAD’s
`intricate web of subsidiary organizations, whether these two
`firms are real parties in interest to the present matter. However,
`the fact that they appear as real parties in interest in numerous
`petitions brought by CFAD, but are absent here, strongly
`suggests that CFAD has failed to meet its burden to properly
`name the real parties in interest to this case.
`Id. at 13.
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`The fact that the Coalition for Affordable Drugs may have named IP
`
`Navigation Group, LLC and nXn Partners, LLC as real parties in interest in
`other Petitions, but failed to name them as real parties in interest, is not
`sufficient, by itself, to demonstrate that Petitioner failed to name all the real
`parties in interest. Patent Owner points us to no evidence that IP Navigation
`Group, LLC and nXn Partners, LLC are real parties in interest in the instant
`proceeding.
`Effective Filing Date of the ’268 Patent
`C.
`“Patent claims are awarded priority on a claim-by-claim basis based
`on the disclosure in the priority applications.” Lucent Technologies, Inc. v.
`Gateway, Inc., 543 F.3d 710, 718 (Fed. Cir. 2008). A patent application is
`only entitled to the filing date of an earlier filed application “only if the
`disclosure of the earlier application provides support for the claims of the
`later application, as required by 35 U.S.C. § 112.” In re Chu, 66 F.3d 292,
`297 (Fed. Cir. 1995); accord Mendenhall v. Cedarapids Inc., 5 F.3d 1557,
`1566 (Fed. Cir. 1993) (“A patentee cannot obtain the benefit of the filing
`date of an earlier application where the claims in issue could not have been
`made in the earlier application.”), cert. denied, 511 U.S. 1031 (1994). “[I]t
`is the specification itself that must demonstrate possession. And while the
`description requirement does not demand any particular form of disclosure,
`. . . or that the specification recite the claimed invention in haec verba, a
`description that merely renders the invention obvious does not satisfy the
`requirement.” Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co., 598 F.3d
`1336, 1352 (Fed. Cir. 2010).
`Petitioner contends that the ’268 patent is not entitled to the filing date
`of its provisional application, Provisional application No. 60/550,915 (“the
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`’915 provisional”). Pet. 8–12. Specifically, Petitioner asserts that “[t]he
`’915 Provisional does not support the claimed dose ranges or the piperidine
`N-oxide derivatives.” Id. at 8.
`
`Petitioner notes that the independent claims of the ’268 patent recite
`using an MTP inhibitor that is the illustrated compound (lomitapide), salts
`thereof, or “the piperidine N-oxide thereof.” Pet. 10. Petitioner contends,
`however, that “the ‘915 Provisional nowhere uses the phrase, or presents by
`structure, a ‘piperidine N-oxide.’” Id. at 11. According to Petitioner, the
`“only discussion of ‘piperidine’ compounds in the ‘915 Provisional beyond
`the proffered chemical structures is, ‘[i]n some embodiments the MTP
`inhibitors are piperidine, pyrrolidine or azetidine compounds.’” Id. (quoting
`Ex. 1006, 11).
`
`Patent Owner responds that the provisional application discloses a
`piperidine. Prelim. Resp. 19 (citing Ex. 1006 ¶ 27). Patent Owner contends:
`A person of ordinary skill in the art at the time of the invention
`would have been aware of piperidine N-oxide compound
`derivatives, and would have understood that the disclosure of the
`piperidine compounds in the provisional application includes
`piperidine N-oxides, a sub-class of piperidines.
`Id. at 20.
`
`Patent Owner’s arguments, however, do not explain why the ordinary
`artisan would realize, upon reading the provisional application, that the
`invention relates to a piperidine N-oxide of the illustrated compound,
`lomitapide.
`As to the claimed dose ranges, Petitioner notes that independent claim
`1 requires an escalating dose range of from “about 2 to about 13 mg/day,”
`“from about 5 to about 30 mg/day,” and “from about 10 to about 50
`mg/day.” Id. at 9. Petitioner argues that the ’915 provisional focused on
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`different dose-range combinations, and that the “particular numerical ranges
`claimed (e.g., about 2–13 mg/day for the first dose) cannot be teased out of
`the multiplicity of dose ranges listed in the ‘915 Provisional, either expressly
`or inherently.” Id. (citing Ex. 1002 ¶¶ 83–90).
`Patent Owner responds that the “claimed dosage ranges are supported
`in the provisional application.” Prelim. Resp. 15. Specifically, Patent
`Owner argues:
`For example, the first claimed dosage level “from about 2 to
`about 13 mg/day,” is supported by Paragraph 0047 of the
`provisional application, which discloses
`that “[i]n some
`embodiments, the first dose level is from about 0.02 to about 0.59
`mg/kg/day. In some embodiments, [the] second dose level is
`from about 0.06 to about 0.19 mg/kg/day.” Ex. 1006 at 14. The
`skilled artisan would see that exemplary embodiments reference
`a 70 kg person, and would use this weight to calculate a range
`between 1.4 mg/day to 13.3 mg/day, which supports “about 2 to
`about 13 mg/day.” Id. at 23.
`Id. at 15–16 (footnote omitted). Patent Owner notes that the ’915
`provisional “discloses that patients weights may vary around the 70 kg mark,
`and that dosing may be adjusted accordingly.” Id. at 15 n. 2 (citing
`Ex. 1006, 22). Patent Owner makes similar arguments for the second and
`third dose levels (id. at 16), and presents a graphic showing the calculations
`(id. at 17).
`
`Again, Patent Owner’s arguments do not explain why the ordinary
`artisan would realize, upon reading the ’915 Provisional, that the invention
`relates to the three dosage ranges required by the challenged claims. The
`ordinary artisan would have to choose a 70 kg man as the default. And even
`after the calculations are performed using that assumption, the claimed
`dosage ranges are not obtained. Thus, even if we were to accept the
`calculation set forth by Patent Owner, assuming a 70 kg man, a range of 1.4
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`Patent 7,932,268 B2
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`mg per day to 13.3 mg per day is calculated for the first dose level. Id. at 17.
`The ordinary artisan would then need to envision immediately a dose range
`of about 2 to about 13 mg/day. See Purdue Pharma L.P v. Faulding Pharm.
`Co., 230 F.3d 1320, 1323 (Fed. Cir. 2000) (noting that in order to satisfy the
`written description requirement, “one skilled in the art, reading the original
`disclosure, must immediately discern the limitation at issue in the claims”).
`
`When we look at the second two calculations for the second two dose
`levels, the claimed ranges are even more difficult to discern. Thus, again
`assuming a 70 kg man, a range of 4.2 mg per day to 41.3 mg per day is
`calculated for the second dose level, whereas the claims require a dose level
`from about 5 to about 30 mg/day. Prelim. Resp. 17. Finally, making the
`same assumption as to the patient being treated, a range of 14 mg per day to
`41.3 mg per day is calculated for the third dose level, whereas the claims
`require a dose level from about 10 to about 50 mg/day. Id. In the case of
`that third dose level, the claimed outside dose level of 50 mg/day is higher
`than the calculated amount of 41.3 mg/day.
`
`Accordingly, based on the record before us at this time, we conclude
`that Petitioner has reasonably shown that the ’268 patent is not entitled to
`benefit to the ’915 provisional, and thus, for purposes of this decision, is
`only entitled to an effective filing date of March 7, 2005, the filing date of
`application No. 10/591,923, filed as PCT/US2005/007435 on that date.
`D. Obviousness over Pink Sheet (Ex. 1013) and Chang (Ex. 1015)
`Petitioner asserts that claims 1–8 are rendered obvious by the
`combination of Pink Sheet and Chang. Pet. 33–47. Patent Owner disagrees.
`Prelim. Resp. 35–45, 54–55.
`
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`
`Overview of Pink Sheet (Ex. 1013)
`i.
`Pink Sheet is a one page article entitled “Bayer/PPD Implitapide
`
`Development Follows Zetia Model as Statin Add-On.” Ex. 1013.
`According to the article, “PPD is conducting Phase II proof-of-concept
`studies on the use of implitapide (BAY-13-9952) as an add-on to statin
`therapy.” Id. Specifically, Pink Sheet teaches:
`PPD is conducting three 39-week Phase II studies with dose
`titration occurring every five weeks based on safety and
`tolerability examined at four weeks. The starting dose will be 10
`mg daily, escalating by 5 mg/day every five weeks to a maximum
`40 mg/day.
`
`Id.
`
`Overview of Chang (Ex. 1015)
`ii.
`Chang teaches that atherosclerosis can cause coronary heart disease,
`
`one of the most common causes of cardiovascular morbidity and mortality.
`Ex. 1015, 562. Elevated levels of total and low density lipoprotein (“LDL”)
`cholesterol are primary risk factors for atherosclerosis. Id. According to
`Chang, statins are effective in lowering LDL cholesterol and somewhat
`effective in lowering triglycerides, but have minimal effect on high density
`lipoprotein (“HDL”) cholesterol. Id. Although reducing LDL cholesterol
`can reduce the risk of coronary heart disease, patients who have significantly
`reduced their LDL cholesterol levels may still experience clinical event. Id.
`Thus, inhibitors of MTP are of interest “as a mechanism for reducing not
`only plasma total and LDL cholesterol, but also plasma very low density
`lipoprotein (VLDL) cholesterol and triglycerides.” Id.
`
`Chang discusses studies of implitapide (BAY-13-9952) and
`lomitapide (BMS-201038) in WHHL rabbits, an animal model for
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`homozygous familial hypercholesterolemia, in which statins are minimally
`effective. Id. at 565. Chang teaches:
`Studies with BAY-13-9952 administered at 12 mg/kg/day for 4
`weeks led to plasma total cholesterol and triglyceride reductions
`of 70 and 45%, respectively, conditions under which the hepatic
`VLDL secretion rate was decreased by 80%. BMS-201038 also
`showed efficacy in the WHHL rabbit, demonstrating an ED50
`value for total plasma cholesterol and triglyceride lowering of
`1.9 mg/kg and a complete normalization of atherogenic apoB-
`containing lipoprotein particles at a dose of 10 mg/kg.
`Id. (references omitted).
`
`Chang notes further that the clinical efficacy of MTP inhibitors,
`including implitapide (BAY-13-9952) and lomitapide (BMS-201038), has
`been reported. Id. at 566. Chang discloses:
`CP-346086 showed evidence of activity consistent with its
`mechanism of action. When administered as a single oral dose
`to healthy human volunteers, CP-346086 reduced plasma
`triglycerides and VLDL cholesterol in a dose-dependent manner,
`with ED50 values of 10 and 3 mg, respectively, and maximal
`inhibition (100 mg) of 66 and 87% when measured 4 h after
`treatment. In a 2-week, multiple-dose, safety and toleration
`study in healthy volunteers, CP-346086 (30 mg) administered at
`bedtime, produced an average decrease in plasma total and LDL
`cholesterol of 47 and 68%, respectively, relative to either
`individual baseline values or placebo, with little change in HDL
`cholesterol. Plasma triglycerides were also decreased by up to
`75% immediately after dose administration, but the reduction
`was transient.
`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.
`Id. (references omitted).
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`
`Analysis
`iii.
`Claims 1, 2, 5–8
`a.
`Petitioner relies on Chang for “a method of treating a subject suffering
`from hyperlipidemia or hypercholesterolemia using MTP inhibitors . . .
`specifically including lomitapide.” Id. at 38–39 (citing Ex. 1015, 564–65;
`Ex. 1002 ¶¶ 124, 125, 133, 134).
`
`Petitioner then relies on Pink Sheet for teaching a method of treating a
`subject suffering from hyperlipidemia or hypercholesterolemia, wherein the
`MPT inhibitor implitapide is administered in at least three step-wise,
`increasing doses. Pet. 38 (citing Ex. 1013; Ex. 1002 ¶¶ 110, 123, 126, 127,
`129, 130). According to Petitioner, the doses taught by Pink Sheet meet the
`limitations of claim 1 of “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,” as well as being
`administered from about 1 to 4 weeks. Id.
`
`Petitioner acknowledges that Pink Sheet modifies the dosage at 5
`weeks. Id. at 39. According to Petitioner, however,
`a skilled artisan considering the teachings of Pink Sheet 2004
`would understand that the disclosed dosing schedule (5-week
`steps) is a conservative approach in a clinical trial designed to
`evaluate safety and tolerability. (See Zusman, ¶¶ 135–36;
`Mayersohn, ¶¶ 66, 71). They would also understand that
`acceptable results at the 4-week mark indicate that intervals
`shorter than 5 weeks (i.e. 4 weeks or less) would be acceptable.
`(See Zusman, ¶¶ 135–36; Mayersohn, ¶¶ 66, 71). . . . [D]ose-
`titration at 4 week intervals was established clinical practice for
`many cholesterol-lowering medications.
`Pet. 39–40. Petitioner acknowledges further that Pink Sheet does not teach
`the use of the MTP inhibitor represented by the formula of claim 1,
`lomitapide. Id. at 38.
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`Petitioner contends that the ordinary artisan would have combined
`
`Chang with Pink Sheet as Chang teaches that lomitapide is one of three
`discussed MTP inhibitors, another of which is implitapide, the MTP
`inhibitor used by Pink Sheet, that are furthest along in clinical trials, with
`each working in humans and being similarly effective. Id. at 40. Chang,
`Petitioner contends, also noted the issues with side-effects associated with
`MTP inhibitors, and thus could not compete with statins as monotherapy.
`Id. at 41. That problem was also addressed by Pink Sheet, which reports a
`solution to the problem. Id. That is, Petitioner asserts,
`follow the clinical model established with ZETIA®, and use
`MTP inhibitors to target (a) niche conditions like HoFH and (b)
`levels of clinical improvement acceptable for adjunct therapy (in
`the 18-24% range), by using a lower dose starting at 10 mg/day,
`evaluating the dose every 4 weeks, then escalating stepwise by 5
`mg/day every 4-5 weeks to a maximum 40 mg daily dose.
`Id. Because Chang teaches that lomitapide had progressed to clinical trials
`and was similarly effective to implitapide, Petitioner argues that the ordinary
`artisan would have had a reason to use lomitapide as taught by Chang as the
`MTP inhibitor in the method of Pink Sheet. Id. at 42.
`Petitioner argues further that the ordinary artisan would have had a
`reasonable expectation of success of achieving the invention of claim 1, as
`implitapide and lomitapide have similar mode of action, the existing data
`suggested that they should be dosed similarly, and escalating, step-wise
`dosing that is adjusted at approximately 4 week intervals to account for side
`effects was routine clinical practice for cholesterol lowering medications.
`Id. at 45–46 (citing Ex. 1002 ¶¶ 43–47, 59–67, 97, 98, 103–105; Ex. 1003
`¶¶ 18, 19, 47–54).
`
`15
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`
`We conclude that Petitioner has shown a reasonable likelihood that
`
`independent claim 1 is rendered obvious by Pink Sheet and Chang. We have
`carefully considered Patent Owner’s arguments to the contrary, but they do
`not convince us otherwise.
`
`Patent Owner responds that Petitioner asserts that Pink Sheet merely
`reports on the Stein presentation, making the challenge based on Pink Sheet
`redundant on the ground based on Stein. Prelim. Resp. 35. Therefore,
`Patent Owner argues that we should decline to institute trial on the challenge
`based on Pink Sheet. Id. at 36.
`
`We determine that Stein adds additional material that is not disclosed
`by Pink Sheet. Thus, we do not accept Patent Owner’s suggestion to decline
`to institute trial on the challenge based on Pink Sheet based on the assertion
`that it is redundant to the challenge based on Stein.
`
`Patent Owner contends further that Pink Sheet “does not disclose a
`method of step-wise administration of increasing doses of implitapide for the
`treatment of patients, nor does it suggest that such a regimen could alleviate
`the known adverse events associated with high dosages of MTP inhibitors.”
`Prelim. Resp. 37–38. According to Patent Owner, the method disclosed by
`Pink Sheet was designed to determine a single, low dose of implitapide, and,
`not an escalating dosing regimen. Id. at 38.
`
`The method of challenged claim 1 requires “administering to the
`subject an effective amount of an MTP inhibitor, wherein said
`administration comprises at least three step-wise, [and] increasing dose
`levels of the MTP inhibitor.” We agree with Petitioner that Pink Sheet
`discloses that method, albeit with a different MTP inhibitor than that
`required by independent claim 1. Patent Owner provides no persuasive
`
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`IPR2015-01836
`Patent 7,932,268 B2
`
`evidence on this record that the ordinary artisan would discount that teaching
`just because it was in the context of a Phase II trial.
`
`Patent Owner argues also that Petitioner has failed to set forth a
`sufficient reason why the ordinary artisan would have substituted lomitapide
`for implitapide as taught by Pink Sheet. Prelim. Resp. 39–40. According to
`Patent Owner, Petitioner’s reasoning is based solely on the fact that both
`compounds are MTP inhibitors, but offers “nothing to suggest that MTP
`inhibitors are interchangeable with one another with respect to efficacy at
`the same dosages or with respect to the anticipated benefit of a dose
`escalation regime.” Id. at 40. Moreover, Patent Owner argues, while
`Petitioner relies on Chang as identifying three MTP inhibitors that have
`made it to clinical trials, Petitioner does not explain why the ordinary artisan
`would have chosen lomitapide over the other disclosed MTP inhibitors. Id.
`at 41.
`We determine, however, that Petitioner has sufficiently demonstrated
`
`that Chang provides a reason to substitute lomitapide for implitapide as
`taught by Pink Sheet. The fact that Chang discloses MTP inhibitors other
`than lomitapide, does not, by itself, make the selection of lomitapide any less
`obvious. See, e.g. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804,
`807 (Fed. Cir. 1989) (noting that the prior art’s disclosure of a multitude of
`combinations does not render any particular formulation less obvious).
`
`In addition, Chang notes that the clinical efficacy of MTP inhibitors,
`including implitapide (BAY-13-9952) and BMS-201038 (lomitapide), has
`been reported. Ex. 1015, 566. Chang discusses the clinical efficacy of CP-
`346086, and then notes that similar efficacy was reported for implitapide and
`lomitapide. Id. Given that implitapide and lomitapide are from the same
`
`17
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`IPR2015-01836
`Patent 7,932,268 B2
`
`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.
`
`Patent Owner further contends that Chang in general teaches away
`from the use of MTP inhibitors. Prelim. Resp. 41. In particular, Patent
`Owner relies on Chang’s teaching that “[a]lthough MTP inhibitors have
`demonstrated impressive lipid lowering efficacy in clinical studies,
`potentially significant adverse effects surround this mechanism.” Id.
`(quoting Ex. 1015, 6). According to Patent Owner, the ordinary artisan
`would not have combined Pink Sheet with Chang given that “clinical
`development of lomitapide had been previously halted due to safety
`concerns.” Id. at 41–42. In fact, Patent Owner asserts, Bristol-Meyers
`Squibb, abandoned lomitapide and donated its rights to the drug. Id. (citing
`Ex. 2001, 30).
`
`Chang was published in 2002, and reflected the understanding of the
`use of MTP inhibitors as monotherapy at that time. Pink Sheet, which was
`published February 16, 2004, acknowledges that MTP inhibitors had been
`pursued by a number of companies, but that the toxicity seen was most
`likely related to the high doses used during trials. Ex. 1013. Thus, Pink
`Sheet, which reflects the state of the art at the time of invention, suggests
`using the MTP inhibitor as an add-on therapy to statins, in which safety and
`efficacy would be studied using escalating doses. Id. Thus, Pink Sheet was
`aware of the potential adverse effects associated with MTP inhibitors, but
`was still pursuing Phase II studies. Id.
`
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`
`That is supported by the evidence cited by Patent Owner. In the
`
`Technology Donation Agreement (“Agreement,” Ex. 2001) cited by Patent
`Owner, the Agreement notes:
`The parties acknowledge that BMS-201,038, in clinical
`trials run by BMS prior to 2003, was shown to have significant
`and serious hepatotoxicities at the dosages used and therefore,
`while apparently efficacious for the treatment of certain lipid
`metabolism disorders, could not be developed as a
`pharmaceutical product of general or wide utility. However,
`based on certain available clinical data, the parties believed that
`BMS-201,038 might be useful as a treatment for certain rare and
`life-threatening disorders or conditions, for which there was no
`effective medical treatment. While it was not commercially
`feasible for BMS to develop the compound for such use,
`University was willing to pursue such development, and BMS
`was willing to facilitate University's development, with a view to
`benefiting the public.
`Id. at 30.
`
`Thus, Bristol-Meyers Squibb donated its rights to the Trustees of the
`University of Pennsylvania, Patent Owner in this proceeding, based on
`clinical data obtained prior to 2003. The Agreement notes, however,
`similarly to Pink Sheet, that it may be efficacious in certain groups of
`patients. See, e.g. Ex. 1013 (noting that the Phase II study hopes to
`“demonstrate implitapide’s safety and efficacy in ho
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