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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`DR. REDDY’S LABORATORIES S.A. and
`DR. REDDY’S LABORATORIES, INC.,
`Petitioner
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`v.
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`MONOSOL RX, LLC,
`Patent Owner
`
`____________________
`
`Case IPR2017-01582
`Patent 8,603,514
`____________________
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`PATENT OWNER PRELIMINARY RESPONSE
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`TABLE OF CONTENTS
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`IPR2017-01582
`U.S. Patent No. 8,603,514
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`Page
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`V.
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`INTRODUCTION .......................................................................................... 1
`I.
`II. OVERVIEW ................................................................................................... 4
`III. THE PETITION IS TIME-BARRED UNDER 35 U.S.C. § 315(b) .............. 6
`IV. CLAIM CONSTRUCTION ........................................................................... 7
`A.
`Even The Broadest Reasonable Claim Interpretation Requires
`That Multiple Unit Doses Be Taken From A Single Cast Film
`Matrix ................................................................................................... 7
`1.
`The Express Claim Language Requires Individual Unit
`Doses That Are Taken From A Single Cast Film Matrix .......... 9
`This Multi-Dose Film Interpretation Is The Only One
`That Is Consistent With The Intrinsic Evidence ...................... 11
`Terms Previously Construed By Board .............................................. 14
`B.
`THE CHALLENGED CLAIMS OF THE ’514 PATENT ARE NOT
`OBVIOUS OVER THE COMBINATION OF ILANGO AND CHEN ...... 15
`A.
`State Of The Art At The Date Of Invention ....................................... 15
`1.
`Pharmaceutical Films Were A Relatively New Dosage
`Form ......................................................................................... 15
`Little Was Known About The Causes Of Loss Of Drug
`Content Uniformity In Multi-Dose Films, Much Less
`Solutions For That Problem ..................................................... 17
`B. Deficiencies In Ilango And Chen ....................................................... 18
`1.
`Ilango does not teach making a multi-dose film ...................... 18
`2.
`Chen ......................................................................................... 21
`VI. THE BOARD SHOULD EXERCISE ITS DISCRETION UNDER 35
`U.S.C. §§ 314(a) AND 325(d) TO DENY THE PETITION ....................... 21
`VII. CONCLUSION ............................................................................................. 29
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`2.
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`2.
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`IPR2017-01582
`U.S. Patent No. 8,603,514
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`EXHIBIT LIST
`
`Description
`Reckitt Benckiser v. Watson Trial Opinion
`Redline comparison of Teva Petition and Dr. Reddy’s Petition
`Redline comparison of Dr. Panyam’s and Dr. Celik’s declarations
`Reckitt Benckiser v. Dr. Reddy’s Laboratories Trial Opinion,
`C.A. 1:14-cv-01451, D.I. 312
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`Exhibit No.
`2001
`2002
`2003
`2004
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`Patent Owner MonoSol Rx, LLC (“PO”) respectfully submits this Patent
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`
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`Owner Preliminary Response to the Petition seeking inter partes review of U.S.
`
`Patent No. 8,603,514 (“the ’514 Patent”) filed by Dr. Reddy’s Laboratories S.A.
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`and Dr. Reddy’s Laboratories, Inc. (collectively “Petitioner”) alleging that Claims
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`1–3, 9, 15, 62–65, 69–73, and 75 of the ’514 Patent (“the Challenged Claims”) are
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`unpatentable. The Petition is one of five IPR petitions filed against the ’514 patent,
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`and one of eleven overall challenges to the patent over the past four years. Patent
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`Owner’s Preliminary Response is timely under 35 U.S.C. § 313 and 37 C.F.R. §
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`42.107 because it is filed within three months of the Notice of Filing Date. Paper 4
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`at 2. PO submits that the Petition (1) is time-barred under 35 U.S.C. § 315(b) and
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`37 C.F.R. § 42.101(b), (2) fails to establish that any of the Challenged Claims is
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`unpatentable, and (3) should be denied using the Board’s discretion under 35
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`U.S.C. §§ 314(a) and 325(d).
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`I.
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`INTRODUCTION
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`The ’514 Patent is directed to pharmaceutical films and is listed in FDA’s
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`Orange Book for Suboxone® Film, a treatment for opioid dependence and the first
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`sublingual film ever approved by FDA. Prior to the ’514 Patent, it was widely
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`acknowledged that it was difficult to manufacture pharmaceutical films in a
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`manner that kept an active drug ingredient substantially uniformly distributed
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`throughout the film matrix during casting and drying, i.e., drug content uniformity
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`or “DCU.” The inventors of the ’514 Patent discovered an elegant solution to the
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`
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`DCU problem—controlling, among other things the viscosity of the wet matrix of
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`a cast film and various drying parameters, e.g., air flow, in order to prevent active
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`particles from migrating from one unit dose to the next and agglomerating before
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`the film was sufficiently dried to lock them in a substantially uniform distribution.
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`While the Claims do not use the phrase, drug content uniformity is shorthand for
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`the heart of the invention maintaining drug content uniformity throughout the
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`manufacturing process such that “the uniformity subsequent to casting and drying
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`of the matrix is measured by substantially equally sized individual unit doses
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`which do not vary by more than 10% of said desired amount of said at least one
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`active.” Ex. 1001, ’514 Patent at 67:53–56 (Claim 1), 74:6–9 (Claim 62).
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`The ‘514 Patent has been the subject of multiple validity attacks in both
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`district court and at the PTAB—even withstanding attacks by this same Petitioner.
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`For this reason alone, the Board should exercise its discretion under 35 U.S.C. §§
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`314(a) and 325(d) to deny the petition. Indeed, Petitioner and the predecessor of
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`Petitioner’s ANDA for a generic version of Suboxone® Sublingual Film—Teva
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`Pharmaceuticals—have twice filed petitions for inter partes review of the ’514
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`Patent. The Board denied institution in both proceedings, finding that Teva’s
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`petition was time-barred (IPR2016-00281, Paper 21 at 13-14) and that Petitioner
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`failed to establish a reasonable likelihood any challenged claim was unpatentable
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`(IPR2016-01111, Paper 14 at 2). This Petitioner also previously challenged the
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`validity of the ’514 Patent in district court, where the court found that Petitioner
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`failed to demonstrate the claims 62-65, 69, 71, and 73 of the ’514 Patent were
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`unpatentable. Ex. 2004, C.A. 1:14-cv-01451, D.I. 312 at 42-43. In another previous
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`district court litigation, the court rejected generic manufacturers Par and Watson’s
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`obviousness argument against Claims 62, 64, 65, 69, and 73 of the ’514 Patent. Ex.
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`1023, C.A. 1:13-cv-01674, D.I. 446 at 40.
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`Where prior challenges already put their best foot forward, Petitioner now
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`resorts to the Ilango reference (Ex. 1005), which is fundamentally different from
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`the claimed invention. The Challenged Claims of the ’514 Patent each require that
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`a “cast film” include a “matrix” containing a uniformly distributed particulate
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`active such that “the uniformity subsequent to casting and drying of the matrix is
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`measured by substantially equally sized individual unit doses which do not vary by
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`more than 10% of said desired amount of said at least one active” (DCU). Thus,
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`the Challenged Claims expressly require that uniformity of an active in a cast
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`matrix be shown by multiple unit doses from that same matrix—after it is dried—
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`having an amount of active within 10% of the desired amount. In contrast, Ilango
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`describes a process for dividing a solution into multiple matrices that are poured
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`into multiples molds and dried to form multiple films, and there is no evidence that
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`anything more than a single unit dose (strip) is taken from each of these films. As a
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`result, in the fundamentally different Ilango process, the boundaries of the mold,
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`rather than the viscosity of the matrix of a cast film, aids in maintaining the
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`uniformity of the active particles and multiple unit doses are not taken from a
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`single cast film’s matrix to compare for drug content uniformity.
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`Chen (Ex. 1006), which Petitioner relies upon only for its disclosure of taste-
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`masking agents, does nothing to cure these deficiencies. Consequently, the
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`teachings of Ilango and Chen relied upon by Petitioner do not render the invention
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`of the challenged ’514 Patent Claims obvious to a person of ordinary skill in the
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`art.
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`II. OVERVIEW
`At the time of the invention of the ’514 Patent, i.e., 2001, the development
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`of drug-containing pharmaceutical films was in its infancy; the first prescription
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`pharmaceutical film received FDA approval in 2009. Maintaining a substantially
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`uniform distribution of an active during the casting and drying process had long
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`been a problem. Indeed, the inventors of the ’514 Patent stated that conventional
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`film manufacturing processes were incapable of producing uniform films because
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`they allowed for “aggregation or conglomeration of particles, i.e., self-aggregation,
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`making them inherently non-uniform.” Ex. 1001, ’514 Patent at 2:18–21. The
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`inventors identified several factors as contributing to self-aggregation, and thus
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`non-uniformity, during
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`the drying process,
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`including
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`long drying
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`times,
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`intermolecular forces, inadequate mixing techniques, and uncontrolled air currents,
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`
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`which can lead to rippling and other film defects that may lead to disuniformity. Id.
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`at 2:60–4:6.
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`The ’514 Patent, however, discloses and claims a novel and inventive
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`solution to this important problem that was known to significantly limit the
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`potential utility and at-scale commercialization of drug-containing pharmaceutical
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`films. Specifically, the claimed invention relates to maintaining a substantially
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`uniform distribution of an active ingredient throughout the cast film matrix during
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`the casting and drying process, including, preventing drug migration from one
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`portion of the cast film matrix to another while the cast film matrix is dried. Key
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`features of the claimed invention are a film-forming matrix comprised of one or
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`more polymers and a particulate active. Although the matrix is initially flowable to
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`allow casting, it possesses a viscosity that aids in maintaining a uniform
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`distribution of the active in the matrix during drying so that equally sized
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`individual doses cut from the dried, cast film matrix do not vary in drug content by
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`more than 10% from the desired amount, i.e., the resulting cast film has drug
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`content uniformity. The ’514 Patentees were able to maintain this level of DCU
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`through each stage of a casting and drying process by optimizing both the viscosity
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`of the film-forming matrix and the drying process parameters to prevent drug
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`particle migration and aggregation. Ex. 1001, ’514 Patent at 8:56–9:3 (“[T]he term
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`non-self-aggregating uniform heterogeneity refers to the ability of the films of the
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`present invention to provide a substantially reduced occurrence of, i.e., little or no,
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`aggregation or conglomeration of components within the film as is normally
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`experienced when films are formed by conventional drying methods . . . .”), 30:44–
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`46 (“The films are controllably dried to prevent aggregation and migration of
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`components, as well as preventing heat build up within.”)).
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`III. THE PETITION IS TIME-BARRED UNDER 35 U.S.C. § 315(b)
`35 U.S.C. § 315(b) and 37 C.F.R. § 42.101 make clear that no inter partes
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`review may be instituted on a patent more than one year after Petitioner was served
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`with a complaint alleging infringement of that patent. If Petitioner filed its Petition
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`outside of that one-year-period, no inter partes review may be instituted. See, e.g.,
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`Terremark N. Am. LLC v. Joao Control & Monitoring Sys., LLC, IPR2015-01482,
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`Paper 10 at 5 (PTAB Dec. 28, 2015).
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`Teva Pharmaceuticals USA, Inc. admitted that it “was served with a
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`complaint asserting the ’514 patent on December 3, 2014 in Reckitt Benckiser
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`Pharmaceuticals Inc., RB Pharmaceuticals Limited, et al. v. Teva Pharmaceuticals
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`USA, Inc., Civil Action 14-1451 (D. Del.).” IPR2016-00281, Paper 1 at 8.
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`Ownership of ANDA Nos. 205806 and 205299 was transferred from Teva to
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`Petitioner. Paper 3 at 2 (citing Reckitt Benckiser Pharmaceuticals Inc. et al. v. Dr.
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`Reddy’s Laboratories S.A. et al., C.A. No. 1:14-01451, DE. 203 (D. Del.)).
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`U.S. Patent No. 8,603,514
`Consequently, “[o]n September 22, 2016, the court ordered the Dr. Reddy’s
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`Laboratories S.A. and Dr. Reddy’s Laboratories, Inc. be substituted as defendants
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`in the action in the place of Teva.” Id. Accordingly, Petitioner stepped into the
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`shoes of Teva, including service of its complaint for infringement of the ’514
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`Patent on December 3, 2014.
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`The current Petition, however, was filed on June 12, 2017 (Paper 4 at 1),
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`well after the one-year-period expired. Accordingly, the Petition is time-barred.
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`Seemingly acknowledging its Petition is time-barred, Petitioner attempts to
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`circumvent the time bar through the filing of a motion for joinder with IPR2017-
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`00200: “Dr. Reddy’s Petition is timely under 37 C.F.R. § 42.122, which provides
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`that the time period set forth in 37 C.F.R. § 42.101(b) shall not apply when the
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`petition is accompanied by a request for joinder.” Paper 3 at 3. But for the reasons
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`stated in PO’s Opposition to the Motion for Joinder (Paper 7) that motion should
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`be denied, and subsequently, the petition dismissed as time-barred.
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`IV. CLAIM CONSTRUCTION
`A. Even The Broadest Reasonable Claim Interpretation Requires
`That Multiple Unit Doses Be Taken From A Single Cast Film
`Matrix
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`In its decision instituting trial in a similar challenge brought by Mylan
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`Technologies, Inc., the Board stated that PO “has not explained or shown that the
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`Challenged Claims include a limitation requiring multiple dosage units to be cut
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`from the same continuous film.” IPR2017-00200, Paper 8 (“Mylan Institution
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`Decision”) at 16. As preliminarily construed by the Board: “as broadly written, the
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`claims do not require the matrix to remain undivided during casting and drying.
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`Nor do the claims prevent the division of the matrix into individual molds from
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`aiding in substantially maintaining non-self-aggregating uniformity of the active in
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`the matrix composition.” Id. at 19. In preliminarily finding that Ilango’s process
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`meets the claimed DCU limitation, the Board treated the entire “resulting mass”
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`mixed together in Ilango as the matrix, rather than just the amount of that mixture
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`that was poured to make a particular cast film. Id. at 16. Based on that error, the
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`Board preliminarily found that Ilango teaches forming a matrix from which
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`multiple unit doses are made. Id.
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`But as explained in detail below, the Board’s preliminary findings in the
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`Mylan Institution Decision contradict the plain language of the Challenged Claims
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`of the ’514 Patent, as well as the specification and file history of the ’514 Patent,
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`all of which support interpreting the Claims to require that for each “cast film,”
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`uniformity of the active in the “matrix” must be shown by subdividing the dried
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`matrix into multiple “individual unit doses” that are tested for drug content
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`uniformity. Indeed, the “matrix” derives its antecedent basis from the “cast film”
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`claim element.
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`The Express Claim Language Requires Individual Unit
`Doses That Are Taken From A Single Cast Film Matrix
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`1.
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`By their plain language, Claims 1 and 62 require “a cast film comprising a
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`flowable . . . matrix” with “a particulate active substantially uniformly stationed in
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`the matrix.” Ex. 1001, ’514 Patent at Claims 1 and 62. The Claims further require
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`that, after drying, the uniformity of the matrix in the cast film can be quantified by
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`measuring the drug content of multiple unit doses taken from it: “the uniformity
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`subsequent to casting and drying of the matrix is measured by substantially
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`equally sized individual unit doses which do not vary by more than 10% of said
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`desired amount of said at least one active.” Ex. 1001, ’514 Patent at Claims 1 and
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`62. Thus, the plain language of the Challenged Claims of the ’514 Patent expressly
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`requires that “a [film] matrix”—not multiple film matrices—be cast and dried, and
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`requires that the uniformity of the active in that matrix be measured by taking
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`multiple “substantially equally sized individual unit doses” from that dried matrix.
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`The Board’s preliminary interpretation of the claims as broad enough to
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`encompass “the division of the matrix into individual molds” (Mylan Institution
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`Decision at 19) is contrary to the plain language of the Claims, which require that
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`each cast film consists of a cast and dried “matrix” that must be subdivided into
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`multiple “substantially equally sized individual unit doses.” Ex. 1001, ’514 Patent
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`at Claims 1 and 62. When multiple, separate molds are used, as in Ilango, the “cast
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`film” is the film that is dried within a single mold, and the “matrix” is only that
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`portion of the active-containing liquid (the “resulting mass” in Ilango) that is cast
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`
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`within that single mold. Thus, when a liquid is poured into multiple molds and then
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`allowed to dry such that a single unit dose results from each individual mold, as in
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`Ilango, each mold contains a different matrix. When the individual molds in Ilango
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`are each used to produce a single unit dose, the resulting collection of individually
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`molded unit doses does not reflect the uniformity of a single cast film matrix, as
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`required by Claims 1 and 62. Accordingly, under even the broadest reasonable
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`interpretation of their express language, the Challenged Claims cannot read on the
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`mold process disclosed by Ilango.
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`The claim language also addresses the Board’s suggestion in the Mylan
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`Institution Decision that “Patent Owner has not shown that the claim limitation for
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`measuring uniformity subsequent to casting and drying requires analyzing any
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`particular number or percentage of the substantially equally sized individual unit
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`doses prepared from the film-forming matrix.” Mylan Institution Decision at 21.
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`Even if no specific number is required, a POSA would understand the express
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`claim language makes clear that multiple (i.e., at least two) unit doses must be
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`taken from a film matrix. First, the claim language expressly requires testing “unit
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`doses,” not a single “unit dose,” and therefore at least two unit doses must be
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`tested. Second, a POSA would have understood the claim language in the context
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`of regulatory requirements for pharmaceutical products, which require testing the
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`drug uniformity of multiple dosage units. Therefore, under the express claim
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`language and the understanding of a POSA, testing a single unit dose would be
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`insufficient to meet the claim limitation. Because the Ilango reference does not
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`identify any particular number of unit doses (strips) of its films that were tested for
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`“5% variation,” it is unnecessary for the Board to determine in this proceeding an
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`exact number of unit doses that must be tested. What is important for this
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`proceeding is that the Challenged Claims all clearly require that the drug content of
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`multiple “unit doses” from a cast film matrix be tested.
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`2.
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`This Multi-Dose Film Interpretation Is The Only One That
`Is Consistent With The Intrinsic Evidence
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`As the Board previously noted, the ’514 Patent repeatedly and consistently
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`identifies the problem it addresses as maintaining DCU throughout a single cast
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`film cut into multiple unit doses. Mylan Institution Decision at 3, 15. As the ’514
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`Patent explains, in this multi-dose film context, casting and drying of the film can
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`give rise to forces that cause particles of an active ingredient to migrate and render
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`the resulting film unit doses non-uniform. Ex. 1001, ’514 Patent at 2:19-21, 2:47-
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`49, 2:62-3:1, 4:7-11, 8:56-64, 23:14-16, 23:21-24, 25:27-31, 31:8-13, 32:12-15. On
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`the other hand, the specification clearly identifies “[t]he combination of ingredients
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`. . . divided among individual wells or molds” to make individual dosage units (as
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`in Ilango) as an “alternative method of preparing films” where “aggregation of the
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`components during drying is prevented by the individual wells,” not by the
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`U.S. Patent No. 8,603,514
`viscosity of the matrix or control of the drying process. Ex. 1001, ’514 Patent at
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`43:12-19. This alternative method is not an “embodiment” covered by the claims,
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`which specifically require that the “matrix has a viscosity sufficient to aid in
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`substantially maintaining non-self-aggregating uniformity” and that the uniformity
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`of the matrix of a particular cast film be shown by testing the drug content of
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`“individual unit doses” taken from that matrix. Ex. 1001, ’514 Patent at Claims 1
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`and 62.
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`From the outset, the Summary of the Invention defines the scope of the
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`claimed invention:
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`The uniform films of this invention can be divided into equally
`sized dosage units having substantially equal amounts of each
`compositional component present. This advantage is particularly
`useful because it permits large area films to be initially formed, and
`subsequently cut into individual dosage units without concern for
`whether each unit is compositionally equal.
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`Ex. 1001, ’514 Patent at 4:30-42 (emphasis added).1 Various properties of the films
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`of the invention are then explained in relation to the understanding that the films
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`are cut up into individual unit doses. For example, “[t]he flexibility of the films
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`allows for the sheets of the film to be rolled and transported for storage or prior to
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`being cut into individual dosage forms.” Id. at 26:18-35.
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`1 Unless otherwise stated, all emphasis in this document was added by PO.
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`U.S. Patent No. 8,603,514
`The specification’s discussion of the drug content uniformity testing is
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`particularly instructive, because it consistently defines such testing in the context
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`of “a manufacturing process [which] may include subjecting the film to drying
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`processes [and] dividing the film into individual dosage units . . . . The cut film
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`then may be sampled . . . [and] may be tested for uniformity in the content between
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`samples.” Id. at 36:29-57. Indeed, the portion of the specification that explains the
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`claimed testing of individual unit doses for drug content teaches the POSA to “cut
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`the film into individual doses. The individual doses may then be dissolved and
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`tested for the amount of active in films of particular size. This demonstrates that
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`films of substantially similar size cut from different locations on the same film
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`contain substantially the same amount of active.” Id. at 42:34-39.
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`The interpretation of the claims as limited to a multi-dose film is bolstered
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`by the file history of the ’514 Patent. For example, in responding to an Office
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`Action, the applicant confirmed that the claimed invention was “directed to . . . a
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`film, such that individual units cut from the film will have the same amount of
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`drug in them . . . .” Ex. 1004, Amendment and Response dated December 9, 2010
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`at 14; see also Ex. 1004, Amendment and Response dated April 4, 2011 at 17
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`(same). In doing so, the applicant made clear that the ‘514 Patent Claims are
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`directed to drug content uniformity among multiple “individual units cut from” a
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`single film matrix.
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`U.S. Patent No. 8,603,514
`For at least these reasons, the broadest reasonable interpretation of Claims 1
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`and 62 requires that uniformity be shown by testing multiple individual unit doses
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`taken from the same dried film matrix of a cast film such that the amount of active
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`in the sampled unit doses does not vary by more than 10% from the desired amount
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`of active.
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`Terms Previously Construed By Board
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`B.
`For purposes of this proceeding, PO accepts the Board’s previous
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`constructions for the terms “viscosity sufficient to aid in substantially maintaining
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`non-self-aggregating uniformity of the active in the matrix,” “particulate active
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`substantially uniformly stationed in the matrix,” and “film-forming matrix . . .
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`capable of being dried without loss of substantial uniformity in the stationing of the
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`particulate active.” (Mylan Institution Decision at 3, 15) at 6-8.
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`PO also accepts the Board’s previous construction of the term “desired
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`amount” as “the intended amount of active for individual dosage units.” Id. at 8.
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`But PO submits, however, the relevant intended amount when determining whether
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`the 10% drug content uniformity limitation is met is the amount of drug intended
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`to be in the dried, individual unit doses.
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`IPR2017-01582
`U.S. Patent No. 8,603,514
`V. THE CHALLENGED CLAIMS OF THE ’514 PATENT ARE NOT
`OBVIOUS OVER THE COMBINATION OF ILANGO AND CHEN
`A.
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`State Of The Art At The Date Of Invention
`1.
`At the date of the invention of the ’514 Patent, little was known about oral
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`Pharmaceutical Films Were A Relatively New Dosage Form
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`pharmaceutical films, which were not FDA-approved at the time. Petitioner points
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`to a hodgepodge of prior art efforts to develop pharmaceutical films2: spermicidal
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`vaginal films from the 1970s (Petition at 15; Ex. 1002, Michniak-Kohn ¶¶ 38-39,
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`citing Roddy (Ex. 1010), Frankman (Ex. 1008), and Brode (Ex. 1009)); an early
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`oral film treatment for periodontal disease (Petition at 15-16; Ex. 1002, Michniak-
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`Kohn ¶ 40, citing Suzuki (Ex. 1011)); films for the oral delivery of numbing agents
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`(Petition at 16; Ex. 1002, Michniak-Kohn ¶ 41, citing Tapolsky (Ex. 1012) and
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`Yamamura (Ex. 1013)); and films purportedly teaching taste-masking agents and
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`certain particle sizes (Petition at 19; Ex. 1002, Michniak-Kohn ¶¶ 48-50, citing
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`Bess (Ex. 1019), Schmidt (Ex. 1020), and Higashi (Ex. 1021)). But there is no
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`2 Petitioner also cites to some film art that has nothing to do with
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`pharmaceuticals. See, e.g., Petition at 17-18 (citing Swei (Ex. 1018), a reference
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`that discusses films for electronic circuits). This non-analogous art says nothing
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`about drug content uniformity and would not even have been considered by a
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`POSA seeking to make a pharmaceutical film.
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`evidence that any of these films was even subject to, much less met, any drug
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`content uniformity requirement. Indeed, neither Petitioner nor Dr. Michniak-Kohn
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`cites any of these references in their obviousness analysis.
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`Many of these references dealt with dissolved, not particulate actives as
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`claimed, and therefore did not contemplate the forces that cause particle migration
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`and aggregation and prevent drug content uniformity in final, dried films. Ex.
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`1011, Suzuki (using a dissolved active); Ex. 1012, Tapolsky at 6:6-10 (teaching
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`that precipitation of polymer particles adversely affected uniformity). And one
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`reference led the POSA away from pharmaceutical films, openly suggesting that
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`films “may not be the optimal formulation.” Ex. 1010, Roddy at 508.
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`Unlike these references, the ’514 Patent focuses on the problem of
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`maintaining drug content uniformity through the casting and drying process so that
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`individual unit doses cut from the dried matrix will contain within 10% of the
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`intended amount of active. Although a few references in the prior art confirm the
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`understanding that pharmaceutical films could not be made with sufficient DCU
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`for regulatory approval, the underlying causes of this lack of DCU or the fact that
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`DCU could be lost during the casting and drying of homogeneously mixed coating
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`solutions, was not recognized in, much less solved by, any of the prior art cited by
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`Petitioner.
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`2.
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`Little Was Known About The Causes Of Loss Of Drug
`Content Uniformity In Multi-Dose Films, Much Less
`Solutions For That Problem
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`Prior to the ’514 Patent, those of ordinary skill incorrectly assumed that a
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`polymeric coating dispersion with a homogenously dispersed particulate active
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`would necessarily maintain that homogenous distribution throughout the casting
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`and drying process. The inventors of the ’514 Patent, however, discovered that
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`various forces acting on the particles could cause them to migrate and self-
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`aggregate and lead to non-uniformity of the active in the final, dried film. Ex.
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`1001, ’514 Patent at 2:21–26.
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`Prior art references like Schmidt make clear that POSAs were aware that
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`conventional processes for making pharmaceutical films would not yield films
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`with acceptable drug content uniformity for regulatory approval. Ex. 1020,
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`Schmidt at 1:56–2:2 (“[K]nown proposals do not make it possible to obtain the
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`requisite constant weight and uniform active ingredient distribution.”). But neither
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`Petitioner nor Dr. Michniak-Kohn cites any publication suggesting this uniformity
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`problem was solved in the prior art. Schmidt itself offers no data showing its films
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`were uniform, and it suggests that non-uniformity was inherent to monolayer films.
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`And despite noting the problem of lack of drug content uniformity, Schmidt
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`focuses on controlling variability in the thickness of the coating material applied
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`for drying, rather than the forces that cause the particle migration and aggregation
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`that lead to non-uniformity. Id. at 2:18-47.
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`B. Deficiencies In Ilango And Chen
`As set forth below, the teachings of Ilango and Chen, both alone and taken
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`in combination, fail to suggest to a POSA several of the limitations of the
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`Challenged Claims and therefore cannot render those claims obvious.
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`Ilango does not teach making a multi-dose film
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`1.
`Petitioner fails to establish that Ilango, alone or in combination with taste-
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`masking from Chen, teaches how to achieve drug content uniformity subsequent to
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`casting and drying of the matrix, where such uniformity is measured by
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`substantially equally sized individual unit doses which “do not vary by more than
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`10%” from the desired amount. Ilango fails to teach how to achieve such drug
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`content uniformity in a cast film, including the roles of viscosity or controlled
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`drying in maintaining drug content uniformity. To the extent a POSA could learn
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`anything from its sparse disclosures, Ilango only teaches films made using
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`individual wells, which the ’514 Patent distinguishes as an alternative that does not
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`address the drug content uniformity problems addressed and solved by the ’514
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`Patent and claimed in the Challenged Claims.
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`Under even their broadest reasonable interpretation, the Challenged Claims
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`require that the amount of active in multiple “individual unit doses” from a single
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`matrix be measured to establish the claimed level of uniformity is satisfied. See
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`Section IV.A.1. Ilango, however, discloses a process in which only a single unit
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`dose is obtained from a single matrix:
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`The resulting mass was then poured into glass moulds lined with
`Aluminium [sic] foil. The solvent was evaporated at room temperature
`for about 24 hours. The dried strip thus obtained was cut into required
`size consisting of required amount of the drug and stored in a
`dessicator. Strips having an oval form of 4 cm length and 3 cm width,
`40 micron thickness and density 1.2031±0.5 were used for the studies.
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`Ex. 1005, Ilango at 232. Specifically, in Ilango, a portion of the “resulting mass” is
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`poured into each of the glass moulds and allowed to dry to obtain a single strip
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`from each mould, i.e., “[t]he dried strip thus obtained.” That strip was then cut to
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`into the required size for a single unit dose, i.e., “an oval form of 4 cm length and 3
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`cm width.” Thus, in Ilango, while the “resulting mass” poured into each mould
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`could be considered a cast film comprising a matrix having an active stat