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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN TECHNOLOGIES, INC.,
`Petitioner
`
`v.
`
`MONOSOL RX, LLC,
`Patent Owner
`
`____________________
`
`Case IPR2017-00200
`Patent 8,603,514
`____________________
`
`
`PATENT OWNER RESPONSE
`
`
`
`

`

`IPR2017-00200
`U.S. Patent No. 8,603,514
`
`Table of Contents
`
`
`INTRODUCTION .......................................................................................... 1
`I.
`II. OVERVIEW ................................................................................................... 5
`A.
`The Problem Addressed By The ’514 Patent ....................................... 5
`B.
`The Relative Experience Of The Experts ............................................. 7
`III. CLAIM CONSTRUCTION ........................................................................... 8
`A.
`Even The Broadest Reasonable Claim Interpretation Requires
`That Multiple Unit Doses Be Taken From A Single Cast Film
`Matrix ................................................................................................... 8
`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 ...................... 12
`Terms Construed By Board ................................................................ 15
`B.
`IV. 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 ..................................................... 18
`B. Deficiencies In Ilango And Chen ....................................................... 19
`1.
`Ilango........................................................................................ 19
`a)
`Ilango’s limited disclosure renders it unreliable ........... 19
`b)
`Ilango does not teach making a multi-dose film ........... 22
`c)
`Ilango’s statement about content variation is not
`tied to a “desired amount” of drug in each strip
`unit dose ......................................................................... 23
`
`2.
`
`2.
`
`
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`
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`-i-
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`d)
`
`e)
`
`f)
`
`IPR2017-00200
`U.S. Patent No. 8,603,514
`Ilango’s statement of “5% variation” can
`reasonably be interpreted as derived from drug
`content measured from one strip for each film
`formulation, not multiple “unit doses” .......................... 26
`Ilango’s dissolution and density data indicate the
`films lacked DCU .......................................................... 27
`Ilango provides no evidence that the drug
`remained in particle form, as opposed to being
`dissolved ........................................................................ 31
`Ilango fails to disclose viscosity of the film-
`forming matrix sufficient to aid in maintaining
`uniformity ...................................................................... 33
`Chen ......................................................................................... 36
`2.
`C. Motivation To Combine Ilango With Chen’s Taste-Masking
`Agent And Reasonable Expectation of Success................................. 36
`D. Objective Indicia Show That The Challenged ’514 Patent
`Claims Were Not Obvious ................................................................. 38
`1.
`There Was A Long-Felt Need For A Cast Film Meeting
`The Claimed 10% DCU Limitation And Others
`Previously Failed In Their Attempts To Create Such
`Films ......................................................................................... 39
`The Inventors Of The ’514 Patent Garnered Praise From
`Others For Their Solution To The DCU Problem ................... 43
`The Objective Evidence Of Non-Obviousness Has A
`Strong Nexus To The Claimed Invention ................................ 44
`CONCLUSION ............................................................................................. 46
`
`
`g)
`
`2.
`
`3.
`
`V.
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`-ii-
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`
`EXHIBIT LIST
`
`Description
`Trial Transcript, Reckitt Benckiser Pharms
`Inc. v. Watson Laboratories, Inc. et al., CA
`No. 14-1574-RGA (Nov. 3-4, 2015) (“Trial
`Tr.”)
`Reckitt Benckiser Pharmaceuticals Inc. v.
`Watson Laboratories, Inc. et al., Civil Case
`No. 1:13-1674, slip opinion (D. Del. June 3,
`2016) (Richard G. Andrews, J.) (Reckitt v.
`Watson)
`J. O. Morales and J. T. McConville,
`Manufacture and Characterization of
`Mucoadhesive Buccal Films, European
`Journal of Pharmaceutics and v
`Biopharmaceutics 77, pp. 187-99 (2011)
`A. F. Borges et al., Oral Films: Current Status
`and Future Perspectives II – Intellectual
`Property, Technologies and Market Needs,
`Journal of Controlled Release 206, pp. 108–21
`V.A. Perumal et al., Investigating a New
`Approach to Film Casting for Enhanced Drug
`Content Uniformity in Polymeric Films, Drug
`Dev. & Indust. Pharm. 34, pp. 1036-47 (2008)
`H. Kathpalia and A. Gupte, An Introduction to
`Fast Dissolving Oral Thin Film Drug Delivery
`Systems: A Review, Drug Delivery &
`Formulation 10, pp. 667-84 (2013)
`Declaration of Dr. Robert Langer
`Deposition Transcript of Dr. Graham Buckton
`V. A. Perumal, “Multipolymeric Monolayered Mucoadhesive
`Films for Drug Therapy,” Master’s Thesis (2007)
`Morales et al., “The Influence of Recrystallized Caffeine on
`Water-Swellable Polymethacrylate Mucoadhesive Bucca Films,”
`AAPS PharmSciTech, Vol. 14, No. 2, 475–484 (2013)
`U.S. Provisional App. Ser. No. 60/443,741
`Curriculum Vitae of Dr. Robert Langer
`
`-iii-
`
`
`
`
`Exhibit No.
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`2008
`2009
`
`2010
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`2011
`2012
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`

`

`IPR2017-00200
`U.S. Patent No. 8,603,514
`C.A. No. 1:14-cv-01451-RGA, Trial Tr.
`Lachman, L. et al., The Theory and Practice of Industrial
`Pharmacy (3d ed. 1986)
`S. Puttipipatkhachorn et al., “Drug physical state and drug-
`polymer interaction on drug release from chitosan matrix films”
`(2001)
`J. Siepmann and N. Peppas entitled “Modeling of drug release
`from delivery systems based on hydroxypropyl methylcellulose”
`(2001)
`Compos-Aldrete et al., “Influence of the viscosity grade and the
`particle size of HPMC on metronidazole release from matrix
`tablets”,
`European
`Journal
`of
`Pharmaceutics
`and
`Biopharmaceutics, 43:173–178 (1997)
`James E. De Muth, Basic Statistics and Pharmaceutical Statistical
`Applications (2d ed. 2006)
`Staniforth, J.N., “Particle size analysis,” Pharmaceutics – The
`Science of Dosage Form Design (Aulton ed.), Ch. 33 at p. 578
`(1988)
`P. Perugini et al., “Periodontal delivery of ipriflavone: new
`chitosan/PLGA film delivery system for a lipophilic drug,” Int’l J.
`of Pharmaceutics, 252:1–9 (2003)
`J. Yoo et al., “The physicodynamic properties of mucoadhesive
`polymeric films developed as female controlled drug delivery
`system,” Int’l J. of Pharmaceutics, 309:139–145 (2006)
`A. Dhanikula et al., “Development and Characterization of
`Biodegradable Chitosan Films for Local Delivery of Paclitaxel,”
`The AAPS Journal, 6(3):1–12 (2004)
`A. Ahmed et al., “Penciclovir solubility in Eudragit films: a
`comparison of X-ray, thermal, microscopic and release rate
`techniques,” J. Pharm. & Biomedical Analysis, 34:945–956
`(2004)
`C. Amnuaikit et al., “Skin permeation of propranolol from
`polymeric film containing terpene enhancers for transdermal use,”
`Int’l J. of Pharmaceutics, 289:167–178 (2005)
`U.S. Patent No. 7,425,292 to Yang et al.
`Sigma-Aldrich Product
`Information Sheet
`(Anhydrous)
`Shakeel et al., “Thermodynamics-based mathematical model for
`
`re Caffeine
`
`-iv-
`
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`
`2013
`2014
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`2015
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`2016
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`2017
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`2018
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`2019
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`2020
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`2021
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`2022
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`2023
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`2024
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`2025
`2026
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`2027
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`solubility prediction of glibenclamide in ethanol–water mixtures,”
`Pharm. Dev. Technol., 2014; 19(6): 702–707
`USP 905 (2002)
`Donald J. Wheeler, Advanced Topics in Statistical Process
`Control (1st ed. 1995)
`James E. De Muth, Basic Statistics and Pharmaceutical Statistical
`Applications (1st ed. 1999)
`David S. Jones, Pharmaceutical Statistics (2002)
`
`2028
`2029
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`2030
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`2031
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`-v-
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`
`IPR2017-00200
`U.S. Patent No. 8,603,514
`Patent Owner MonoSol Rx, LLC (“PO”) respectfully submits this Patent
`
`
`
`Owner Response to the Petition seeking inter partes review of U.S. Patent No.
`
`8,603,514 (“the ’514 Patent”) and the Board’s Decision to Institute (Paper 8). This
`
`filing is timely. Paper 9 at 7. PO submits that the Petition fails to establish that any
`
`challenged claim in the ’514 Patent is unpatentable for at least the following
`
`reasons.
`
`I.
`
`INTRODUCTION
`
`The ’514 Patent is directed to pharmaceutical films and is listed in FDA’s
`
`Orange Book for Suboxone® Film, a treatment for opioid dependence and the first
`
`sublingual film ever approved by FDA. Prior to the ’514 Patent, it was widely
`
`acknowledged that it was difficult to manufacture pharmaceutical films in a
`
`manner that kept an active drug ingredient substantially uniformly distributed
`
`throughout the film matrix during casting and drying, i.e., drug content uniformity
`
`or “DCU.” The inventors of the ’514 Patent discovered an elegant solution to the
`
`DCU problem—controlling both the viscosity of the wet matrix of a cast film and
`
`various drying parameters, e.g., air flow, in order to prevent active particles from
`
`migrating and agglomerating until the film was sufficiently dried to lock them in
`
`substantially uniform distribution. While the Claims do not use the phrase, drug
`
`content uniformity is shorthand for the heart of the invention in the ’514 Patent,
`
`that “the uniformity subsequent to casting and drying of the matrix is measured by
`
`
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`- 1 -
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`

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`IPR2017-00200
`U.S. Patent No. 8,603,514
`substantially equally sized individual unit doses which do not vary by more than
`
`
`
`10% of said desired amount of said at least one active.” Ex. 1001, ’514 Patent at
`
`67:53–56 (Claim 1), 74:6–9 (Claim 62).
`
`Mylan Technologies, Inc. (“Petitioner”) alleges that Claims 1–3, 9, 15, 62–
`
`65, 69–73, and 75 of the ’514 Patent (“the challenged ’514 Patent Claims”) are
`
`obvious in view of a single prior art combination: Ilango, a sparse, 4-page article
`
`missing significant details necessary to understand its methods and results, in view
`
`of Chen, which is relied upon only for its teachings about taste-masking agents.
`
`Not only does the combination of Ilango and Chen fail to present a prima facie
`
`case of obviousness of the challenged ’514 Patent Claims, Petitioner’s hindsight-
`
`driven obviousness argument ignores post-patent references that confirm: (1) there
`
`was a long-felt need for pharmaceutical films with high drug content uniformity,
`
`(2) others had tried and failed to create such films, and (3) pharmaceutical
`
`researchers consistently credited the inventors of the ’514 Patent with finding the
`
`causes for the problems in maintaining drug content uniformity and praised those
`
`inventors for crafting the patented solution. Thus, it should come as no surprise
`
`that the ’514 Patent has survived multiple invalidity attacks.
`
`Indeed, this proceeding is one of eleven challenges to the ’514 Patent in the
`
`past four years. In district court litigation, the court rejected generic manufacturers
`
`Par and Watson’s obviousness argument against Claims 62, 64, 65, 69, and 73 of
`
`
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`- 2 -
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`the ’514 Patent in light of testimony from Dr. Robert Langer (who also submits a
`
`
`
`declaration here). Ex. 1023, C.A. 1:13-cv-01674, D.I. 446 at 40. And in similar
`
`previous IPRs brought by Teva and Dr. Reddy’s Laboratories (“DRL”), the Board
`
`denied institution, finding that Teva’s petition was time-barred (IPR2016-00281,
`
`Paper 21 at 13–14) and that DRL failed to establish a reasonable likelihood any
`
`challenged claim was unpatentable (IPR2016-01111, Paper 14 at 2).
`
`Where prior challengers have already put their best foot forward, Petitioner
`
`resorts to the Ilango reference, an obscure article that is so lacking in essential
`
`experimental information that a world-renowned scientist, Dr. Robert Langer, who
`
`has conducted actual research relating to pharmaceutical films, would be unable to
`
`repeat Ilango’s experiments. Petitioner and its expert interpreted every vague
`
`disclosure in Ilango to Petitioner’s benefit. Based on that record, the Board issued
`
`its decision to institute. PO now presents Dr. Langer’s declaration and the
`
`deposition transcript of Petitioner’s expert, who readily agreed that Ilango’s
`
`disclosures could just as easily be interpreted contrary to Petitioner’s assumptions.
`
`On that ground alone, Petitioner cannot carry its burden to prove invalidity by a
`
`preponderance of the evidence.
`
`Unlike actual researchers in this field, Petitioner (and its expert declarant,
`
`Dr. Buckton) improperly asks the Board to use knowledge derived from the ’514
`
`Patent to fill in the missing gaps in Ilango. The Ilango reference is fundamentally
`
`
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`- 3 -
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`different from the claimed invention. The challenged ’514 Patent Claims each
`
`
`
`require that a “cast film” include a “matrix” containing a uniformly distributed
`
`particulate active such that “the uniformity subsequent to casting and drying of the
`
`matrix is measured by substantially equally sized individual unit doses which do
`
`not vary by more than 10% of said desired amount of said at least one active”
`
`(DCU). In contrast, Ilango describes a process for dividing a casting solution into
`
`multiple matrices that are poured into multiples molds and dried to form multiple
`
`films, and there is no evidence that anything more than a single unit dose (strip) is
`
`taken from each of these films. As a result, in the fundamentally different Ilango
`
`process, the boundaries of the mold, rather than the viscosity of the matrix of a cast
`
`film, aids in maintaining the uniformity of the active particles and multiple unit
`
`doses are not taken from a single cast film’s matrix to compare for drug content
`
`uniformity.
`
`Even if the Board decides that a multiple mold-based process like that in
`
`Ilango falls within the broadest reasonable interpretation of the claims, Ilango does
`
`not teach or suggest:
`
`(1) what the desired amount of drug content for any unit dose is and whether
`
`the stated “5% variation” in drug content is measured against that desired amount;
`
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`(2) whether that “5% variation” figure describes the range of drug content
`
`
`
`measurements or a standard deviation from a mean (such that the actual range
`
`varies from the mean by ±15%);
`
`(3) whether the drug is a particulate; and
`
`(4) whether more than one unit dose was tested for drug content for any film
`
`formulation.
`
`Chen, which Petitioner relies upon only for its disclosure of taste-masking
`
`agents, does nothing to cure these deficiencies. Consequently, the teachings of
`
`Ilango and Chen relied upon by Petitioner does not render the invention of the
`
`challenged ’514 Patent Claims obvious to a person of ordinary skill1 in the art.
`
`
`1 In the Decision to Institute, the Board preliminarily adopted Petitioner’s
`
`definition of the POSA as a person that “would likely have a Ph.D. in
`
`pharmaceutics, or in a drug delivery related discipline such as physical or polymer
`
`chemistry” and “would have experience formulating drugs for administration and
`
`would have the ability to understand literature published by others in the field,
`
`including the references discussed in th[e] Petition.” Petition at 12–13; Decision to
`
`Institute at 9. The definition proposed by PO’s expert, Dr. Robert Langer, is
`
`substantially the same. Ex. 2007, Langer ¶¶ 21–22.
`
`
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`- 5 -
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`
`II. OVERVIEW
`A. The Problem Addressed By The ’514 Patent
`At the time of the invention of the ’514 Patent, i.e., 2001, the development
`
`of drug-containing pharmaceutical films was in its infancy; the first prescription
`
`pharmaceutical film received FDA approval in 2009. Ex. 2007, Langer ¶ 46.
`
`Maintaining a substantially uniform distribution of an active during the casting and
`
`drying process had long been a problem. Id. ¶ 47. Indeed, the inventors of the ’514
`
`Patent stated that conventional film manufacturing processes were incapable of
`
`producing uniform films because they allowed for “aggregation or conglomeration
`
`of particles, i.e., self-aggregation, making them inherently non-uniform.” Ex. 1001,
`
`’514 Patent at 2:18–21. The inventors identified several factors as contributing to
`
`self-aggregation, and thus non-uniformity, during the drying process, including
`
`long drying times, intermolecular forces, inadequate mixing techniques, and
`
`uncontrolled air currents, which can lead to rippling and other film defects that
`
`may lead to disuniformity. Id. at 2:60–4:6.
`
`The ’514 Patent, however, discloses and claims a novel and inventive
`
`solution to this important problem that was known to significantly limit the
`
`potential utility and at-scale commercialization of drug-containing pharmaceutical
`
`films. Ex. 2007, Langer ¶ 47. Specifically, the claimed invention relates to
`
`maintaining a substantially uniform distribution of an active ingredient throughout
`
`
`
`- 6 -
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`

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`IPR2017-00200
`U.S. Patent No. 8,603,514
`the cast film matrix during the casting and drying process, including, preventing
`
`
`
`drug migration from one portion of the cast film matrix to another while the cast
`
`film matrix is dried. Id. ¶ 49. Key features of the claimed invention are a film-
`
`forming matrix comprised of one or more polymers and a particulate active. Id.
`
`Although the matrix is initially flowable to allow casting, it possesses a viscosity
`
`that aids in maintaining a uniform distribution of the active in the matrix during
`
`drying so that equally sized individual doses cut from the dried, cast film matrix do
`
`not vary in drug content by more than 10% from the desired amount, i.e., the
`
`resulting cast film has drug content uniformity. Id. The ’514 Patentees were able to
`
`maintain this level of DCU through each stage of a casting and drying process by
`
`optimizing both the viscosity of the film-forming matrix and the drying process
`
`parameters in order to prevent drug particle migration and aggregation. Id. (citing
`
`Ex. 1001, ’514 Patent at 8:56–9:3 (“[T]he term non-self-aggregating uniform
`
`heterogeneity refers to the ability of the films of the present invention to provide a
`
`substantially reduced occurrence of, i.e., little or no, aggregation or conglomeration
`
`of components within the film as is normally experienced when films are formed
`
`by conventional drying methods . . . .”); id. at 30:44–46 (“The films are
`
`controllably dried to prevent aggregation and migration of components, as well as
`
`preventing heat build up within.”)).
`
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`- 7 -
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`
`The Relative Experience Of The Experts
`
`B.
`PO’s expert, Dr. Langer, is a world-renowned pharmaceutical expert who
`
`obtained his Sc.D. from MIT in chemical engineering. Ex. 2007, Langer ¶ 14. He
`
`has conducted research relating to pharmaceutical films, as well as other drug
`
`delivery systems and biomedical polymers since 1974. Id. ¶ 15. During his career,
`
`Dr. Langer has received more than 220 major awards, has authored over 1350
`
`articles, and has been listed as an inventor on over 1250 issued or pending patents
`
`worldwide. Id. ¶¶ 9, 11. Dr. Langer served on FDA’s SCIENCE Board (its highest
`
`advisory board) from 1995 to 2002, serving as its Chairman from 1999 through
`
`2002. Id. ¶ 10.
`
`Most importantly, Dr. Langer had first-hand experience trying to make
`
`pharmaceutical films prior to 2002, and in his own research experience, trying to
`
`create uniform films was like “trying to break glass reproducibly.” Id. ¶ 15. In
`
`contrast, Petitioner’s expert, Dr. Buckton has never worked with pharmaceutical
`
`films as a standalone, drug-containing dosage form (as opposed to, e.g., film
`
`coatings that contain no active ingredient), much less before the 2001 date of
`
`invention. Ex. 2008, Buckton Dep. 134:6–16, 135:14–24. As a result, Dr.
`
`Buckton’s analysis is purely hindsight-driven.
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`
`III. CLAIM CONSTRUCTION
`A. Even The Broadest Reasonable Claim Interpretation Requires
`That Multiple Unit Doses Be Taken From A Single Cast Film
`Matrix
`
`In instituting trial, the Board stated that PO “has not explained or shown that
`
`the challenged claims include a limitation requiring multiple dosage units to be cut
`
`from the same continuous film.” Decision to Institute at 16. As preliminarily
`
`construed by the Board: “as broadly written, the claims do not require the matrix to
`
`remain undivided during casting and drying. Nor do the claims prevent the division
`
`of the matrix into individual molds from aiding in substantially maintaining non-
`
`self-aggregating uniformity of the active in the matrix composition.” Id. at 19. In
`
`preliminarily finding that Ilango’s process meets the claimed DCU limitation, the
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`Board treated the entire “resulting mass” mixed together in Ilango as the matrix,
`
`rather than just the amount of that mixture that was poured to make a particular
`
`cast film. Id. at 16. Based on that error, the Board preliminarily found that Ilango
`
`teaches forming a matrix from which multiple unit doses are made. Id.
`
`But as explained by Dr. Langer, the Board’s preliminary findings contradict
`
`a POSA’s understanding of the plain language of the challenged ’514 Patent
`
`Claims, as well as the specification and file history of the ’514 Patent, all of which
`
`support interpreting the Claims to require that for each “cast film” the “matrix” can
`
`be subdivided into multiple “individual unit doses” that are tested for drug content
`
`
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`- 9 -
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`

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`IPR2017-00200
`U.S. Patent No. 8,603,514
`uniformity. Indeed, the “matrix” derives its antecedent basis from the “cast film”
`
`
`
`claim element.
`
`1.
`
`The Express Claim Language Requires Individual Unit
`Doses That Are Taken From A Single Cast Film Matrix
`
`By their plain language, Claims 1 and 62 require “a cast film comprising a
`
`flowable . . . matrix” with “a particulate active substantially uniformly stationed in
`
`the matrix.” Ex. 1001, ’514 Patent at Claims 1 and 62; Ex. 2007, Langer ¶ 56. The
`
`Claims further require that, after drying, the uniformity of the matrix in the cast
`
`film can be quantified by measuring the drug content of multiple unit doses taken
`
`from it: “the uniformity subsequent to casting and drying of the matrix is measured
`
`by substantially equally sized individual unit doses which do not vary by more than
`
`10% of said desired amount of said at least one active.” Ex. 1001, ’514 Patent at
`
`Claims 1 and 62; Ex. 2007, Langer ¶ 56. Thus, the plain language of Claim 62 of
`
`the ’514 Patent expressly requires that “a [film] matrix”—not multiple film
`
`matrices—be cast and dried, and requires that its uniformity be measured by taking
`
`multiple “substantially equally sized individual unit doses” from that dried matrix.
`
`Ex. 2007, Langer ¶ 57.
`
`The Board’s preliminary interpretation of the claims as broad enough to
`
`encompass “the division of the matrix into individual molds” (Decision to Institute
`
`at 19) is contrary to the plain language of the Claims, which require that each cast
`
`film consists of a cast and dried “matrix” that must be subdivided into multiple
`
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`IPR2017-00200
`U.S. Patent No. 8,603,514
`“substantially equally sized individual unit doses.” Ex. 1001, ’514 Patent at Claims
`
`
`
`1 and 62; Ex. 2007, Langer ¶ 58. When a solution is poured into multiple molds
`
`and then allowed to dry such that a single unit dose results from each individual
`
`mold, as in Ilango, each mold represents a different matrix. When the individual
`
`molds in Ilango are each used to produce a single unit dose, the resulting collection
`
`of individually molded unit doses does not reflect the uniformity of a single matrix
`
`of a cast film, as required by Claims 1 and 62. Accordingly, under even the
`
`broadest reasonable interpretation of their express language, the Claims cannot
`
`read on the mold process disclosed by Ilango.
`
`The claim language also addresses the Board’s suggestion that “Patent
`
`Owner has not shown that the claim limitation for measuring uniformity
`
`subsequent to casting and drying requires analyzing any particular number or
`
`percentage of the substantially equally sized individual unit doses prepared from
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`the film-forming matrix.” Decision to Institute at 21. Both the express claim
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`language and the understanding of a POSA address this issue. First, the claim
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`language expressly requires testing “unit doses,” and therefore at least two unit
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`doses must be tested. Ex., 2007, Langer ¶ 169. Second, as Dr. Langer explains, a
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`POSA would have understood the claim language in the context of regulatory
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`requirements for pharmaceutical products, which require testing the drug
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`uniformity of multiple dosage units. Id. Therefore, under the express claim
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`U.S. Patent No. 8,603,514
`language and the understanding of a POSA, testing a single unit dose would be
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`
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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” (Ex. 2008, Buckton Dep. 90:25–91:2, 91:4–5, 95:13–21; Ex. 2007,
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`Langer ¶ 168), 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 ’514 Patent Claims all clearly require that the
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`drug content of multiple “unit doses” from a cast film 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 noted (Decision to Institute at 3, 15), the ’514 Patent
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`repeatedly and consistently identifies the problem it addresses as maintaining DCU
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`throughout a single cast film cut into multiple unit doses. Ex. 2007, Langer ¶¶ 59–
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`63. As the ’514 Patent explains, in this multi-dose film context, casting and drying
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`of the film can give rise to forces that cause particles of an active ingredient to
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`migrate and render the resulting film unit doses nonuniform. Id. ¶ 61 (citing Ex.
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`1001, ’514 Patent at 2:19–21, 2:47–49, 2:62–3:1, 4:7–11, 8:56–64, 23:14–16,
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`23:21–24, 25:27–31, 31:8–13, 32:12–15). On the other hand, the specification
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`clearly identifies “[t]he combination of ingredients . . . divided among individual
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`wells or molds” to make individual dosage units (as in Ilango) as an “alternative
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`method of preparing films” where “aggregation of the components during drying is
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`prevented by the individual wells,” not by the viscosity of the matrix or control of
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`
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`the drying process. Id. ¶ 64 (citing Ex. 1001, ’514 Patent at 43:12–19). This
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`alternative method is not an “embodiment” covered by the claims, which
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`specifically require that the “matrix has a viscosity sufficient to aid in substantially
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`maintaining non-self-aggregating uniformity” and that the uniformity of the matrix
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`of a particular cast film be shown by testing the drug content of “individual unit
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`doses” taken from that matrix. Id. ¶ 161.
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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.
`Ex. 1001, ’514 Patent at 4:30–42 (emphasis added).2 Various properties of the
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`films of the invention are then explained in relation to the understanding that the
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`films are cut up into individual unit doses. For example, “[t]he flexibility of the
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`films allows for the sheets of the film to be rolled and transported for storage or
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`prior to being cut into individual dosage forms.” Id. at 26:18–35.
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`2 Unless otherwise stated, all emphasis in this document was added by PO.
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`The specification’s discussion of the drug content uniformity testing is
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`
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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; see also Ex.
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`2007, Langer ¶¶ 59–60. Several references post-dating the ’514 Patent invention
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`also confirm the POSA’s understanding that the invention is directed to obtaining
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`DCU among multiple unit doses taken from a single larger film. See Section
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`IV.D.2.
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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. Ex. 2007, Langer ¶ 65. In responding to an
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`Office Action, the applicant confirmed that the claimed invention was “directed to
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`. . . a film, such that individual units cut from the film will have the same
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`amount of drug in them . . . .” Ex. 1004, Amendment and Response dated
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`December 9, 2010 at 14; see also Ex. 1004, Amendment and Response dated April
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`
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`4, 2011 at 17 (same). In doing so, the applicant made clear that the ‘514 Patent
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`Claims are directed to drug content uniformity among multiple “individual units
`
`cut from” a single film matrix.
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`
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`For at least these reasons, the broadest reasonable interpretation of Claims 1
`
`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
`
`in the sampled unit doses does not vary by more than 10% from the desired amount
`
`of active.
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`Terms Construed By Board
`
`B.
`For purposes of this proceeding, PO accepts the Board’s constructions for
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`the terms “viscosity sufficient to aid in substantially maintaining non-self-
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`aggregating uniformity of the active in the matrix,” “particulate active substantially
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`uniformly stationed in the matrix,” and “film-forming matrix . . . capable of being
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`dried without loss of substantial uniformity in the stationing of the particulate
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`active.” Decision to Institute at 6–8.
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`PO also accepts the Board’s construction of the term “desired amount” as
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`“the intended amount of active for individual dosage units.” Id. at 8. As Dr. Langer
`
`explains, however, the relevant intended amount is that intended to be in the dried,
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`individual unit doses, not the bulk amount included in the entire wet matrix before
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`
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`drying. Ex. 2007, Langer ¶ 69.
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`IV. THE CHALLENGED CLAIMS OF THE ’514 PATENT ARE NOT
`OBVIOUS OVER THE COMBINATION OF ILANGO AND CHEN
`A.
`
`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
`
`Pharmaceutical Films Were A Relatively New Dosage Form
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`pharmaceutical films, which were not FDA-approved at the time. Id. ¶¶ 46, 73.
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`Petitioner points to a hodgepodge of prior art efforts to develop pharmaceutica