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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`PAR PHARMACEUTICAL, INC. and INTELGENX CORP.,
`Petitioner,
`
`v.
`
`MONOSOL RX, LLC,
`Patent Owner.
`
`____________________
`
`Case IPR2017-01557
`Patent 8,603,514
`____________________
`
`
`PATENT OWNER PRELIMINARY RESPONSE
`
`
`
`

`

`
`
`
`TABLE OF CONTENTS
`
`
`IPR2017-01557
`U.S. Patent No. 8,603,514
`
`Page
`
`
`I.
`INTRODUCTION .......................................................................................... 1
`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 .......... 8
`This Multi-Dose Film Interpretation Is The Only One
`That Is Consistent With The Intrinsic Evidence ...................... 10
`Terms Previously Construed By Board .............................................. 13
`B.
`THE CHALLENGED CLAIMS OF THE ’514 PATENT ARE NOT
`OBVIOUS OVER THE COMBINATION OF ILANGO AND CHEN ...... 14
`A.
`State Of The Art At The Date Of Invention ....................................... 14
`1.
`Pharmaceutical Films Were A Relatively New Dosage
`Form ......................................................................................... 14
`Little Was Known About The Causes Of Loss Of Drug
`Content Uniformity In Multi-Dose Films, Much Less
`Solutions For That Problem ..................................................... 16
`B. Deficiencies In Ilango And Chen ....................................................... 17
`1.
`Ilango does not teach making a multi-dose film ...................... 17
`2.
`Chen ......................................................................................... 20
`VI. THE BOARD SHOULD EXERCISE ITS DISCRETION UNDER 35
`U.S.C. §§ 314(a) AND 325(d) TO DENY THE PETITION ....................... 20
`VII. CONCLUSION ......................................................................................... 3030
`
`V.
`
`2.
`
`2.
`
`i
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`

`

`IPR2017-01557
`U.S. Patent No. 8,603,514
`
`EXHIBIT LIST
`
`Description
`Reckitt Benckiser v. DRL Trial Opinion
`Par Complaint
`Par Proof of Service
`Intelgenx Proof of Service
`
`
`
`Exhibit No.
`2001
`2002
`2003
`2004
`
`
`ii
`
`

`

`
`
`IPR2017-01557
`U.S. Patent No. 8,603,514
`Patent Owner MonoSol Rx, LLC (“PO”) respectfully submits this Patent
`
`
`
`Owner Preliminary Response to the Petition seeking inter partes review of U.S.
`
`Patent No. 8,603,514 (“the ’514 Patent”) filed by Par Pharmaceutical, Inc. and
`
`Intelgenx Corp. (collectively “Petitioner”) alleging that Claims 1–3, 9, 15, 62–65,
`
`69–73, and 75 of the ’514 Patent (“the Challenged Claims”) are unpatentable. The
`
`Petition is one of five IPR petitions filed against the ’514 patent, and one of eleven
`
`overall challenges to the patent over the past four years. Patent Owner’s
`
`Preliminary Response is timely under 35 U.S.C. § 313 and 37 C.F.R. § 42.107
`
`because it is filed within three months of the Notice of Filing Date. Paper 5 at 2.
`
`PO submits that the Petition (1) is time-barred under 35 U.S.C. § 315(b) and 37
`
`C.F.R. § 42.101(b), (2) fails to establish that any of the Challenged Claims is
`
`unpatentable, and (3) should be denied using the Board’s discretion under 35
`
`U.S.C. §§ 314(a) and 325(d).
`
`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
`
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`or “DCU.” The inventors of the ’514 Patent discovered an elegant solution to the
`
`
`
`DCU problem—controlling, among other things, 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 from one unit dose to the next and agglomerating before
`
`the film was sufficiently dried to lock them in a substantially uniform distribution.
`
`While the Claims do not use the phrase, drug content uniformity is shorthand for
`
`the heart of the invention: maintaining drug content uniformity throughout the
`
`manufacturing process 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.” Ex. 1001, ’514 Patent at 67:53–56 (Claim 1), 74:6–9 (Claim 62).
`
`The ‘514 Patent has been the subject of multiple validity attacks in both
`
`district court and at the PTAB—even withstanding attacks by this same Petitioner.
`
`For this reason alone, the Board should exercise its discretion under 35 U.S.C. §§
`
`314(a) and 325(d) to deny the petition. Indeed, this Petitioner previously
`
`challenged the validity of the ’514 Patent in district court, where the court’s
`
`opinion, which issued more than 15 months ago, found that Petitioner failed to
`
`demonstrate the claims 62, 64, 65, 69, and 73 of the ’514 Patent were unpatentable.
`
`Ex. 1023, C.A. 1:13-cv-01674, D.I. 446 at 42. In another previous district court
`
`litigation, the court rejected generic manufacturer Dr. Reddy’s Laboratories
`
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`obviousness arguments against Claims 62-65, 69, 71, and 73 of the ’514 Patent.
`
`
`
`Ex. 2001, C.A. 1:14-cv-01451, D.I. 312 at 42-43.
`
`Where prior challenges already put their best foot forward, Petitioner now
`
`resorts to the Ilango reference (Ex. 1005), which is fundamentally different from
`
`the claimed invention. The Challenged Claims of the ’514 Patent 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). Thus,
`
`the Challenged Claims expressly require that uniformity of an active in a cast
`
`matrix be shown by multiple unit doses from that same matrix—after it is dried—
`
`having an amount of active within 10% of the desired amount. In contrast, Ilango
`
`describes a process for dividing a solution into multiple matrices that are poured
`
`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
`
`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.
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`Chen (Ex. 1006), 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 do not render the invention
`
`of the challenged ’514 Patent Claims obvious to a person of ordinary skill in the
`
`art.
`
`II. OVERVIEW
`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. Maintaining a substantially
`
`uniform distribution of an active during the casting and drying process had long
`
`been a problem. 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
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`inventors identified several factors as contributing to self-aggregation, and thus
`
`non-uniformity, during
`
`the drying process,
`
`including
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`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.
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`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. Specifically, the claimed invention relates to maintaining a substantially
`
`uniform distribution of an active ingredient throughout 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. Key
`
`features of the claimed invention are a film-forming matrix comprised of one or
`
`more polymers and a particulate active. 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. 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 to prevent drug
`
`particle migration and aggregation. 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
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`experienced when films are formed by conventional drying methods . . . .”), 30:44–
`
`
`
`46 (“The films are controllably dried to prevent aggregation and migration of
`
`components, as well as preventing heat build up within.”)).
`
`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
`
`review may be instituted on a patent more than one year after Petitioner was served
`
`with a complaint alleging infringement of that patent. If Petitioner filed its Petition
`
`outside of that one-year-period, no inter partes review may be instituted. See, e.g.,
`
`Terremark N. Am. LLC v. Joao Control & Monitoring Sys., LLC, IPR2015-01482,
`
`Paper 10 at 5 (PTAB Dec. 28, 2015).
`
`Petitioner admitted that PO filed a complaint alleging infringement of the
`
`’514 Patent on April 4, 2014. Paper 4 at 2; see also Ex. 2002 (Complaint). Further,
`
`both Par and Intelgenx were served with that complaint on April 7, 2014. Ex. 2003
`
`(Par Proof of Service); Ex. 2004 (Intelgenx Proof of Service).
`
`The current Petition, however, was filed on June 9, 2017 (Paper 5 at 1),
`
`more than three years after Petitioner was served with the complaint. Accordingly,
`
`the Petition is time-barred. Seemingly acknowledging its petition is time-barred,
`
`Petitioner attempts to circumvent the time bar through the filing of a motion for
`
`joinder with IPR2017-00200: “Petitioners certify that, under 37 C.F.R. § 42.104(a),
`
`if the simultaneous motion for joinder is granted, the ’514 patent is available for
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`inter partes review.” Petition at 20. But that motion should be denied, and
`
`
`
`subsequently, the petition dismissed as time-barred.
`
`IV. CLAIM CONSTRUCTION
`A. Even The Broadest Reasonable Claim Interpretation Requires
`That Multiple Unit Doses Be Taken From A Single Cast Film
`Matrix
`
`In its decision instituting trial in a similar challenge brought by Mylan
`
`Technologies, Inc., 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.” IPR2017-00200, Paper 8 (“Mylan Institution
`
`Decision”) 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 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
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`multiple unit doses are made. Id.
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`But as explained in detail below, the Board’s preliminary findings in the
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`
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`Mylan Institution Decision contradict the plain language of the Challenged Claims
`
`of the ’514 Patent, 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,”
`
`uniformity of the active in the “matrix” must be shown by subdividing the dried
`
`matrix into multiple “individual unit doses” that are tested for drug content
`
`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. 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. Thus, the plain language of the Challenged Claims of the ’514 Patent expressly
`
`requires that “a [film] matrix”—not multiple film matrices—be cast and dried, and
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`requires that the uniformity of the active in that matrix be measured by taking
`
`
`
`multiple “substantially equally sized individual unit doses” from that dried matrix.
`
`The Board’s preliminary interpretation of the claims as broad enough to
`
`encompass “the division of the matrix into individual molds” (Mylan Institution
`
`Decision 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 “substantially equally sized individual unit doses.” Ex. 1001, ’514 Patent
`
`at Claims 1 and 62. When multiple, separate molds are used, as in Ilango, the “cast
`
`film” is the film that is dried within a single mold, and the “matrix” is only that
`
`portion of the active-containing liquid (the “resulting mass” in Ilango) that is cast
`
`within that single mold. Thus, when a liquid 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 contains 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 cast film matrix, as
`
`required by Claims 1 and 62. Accordingly, under even the broadest reasonable
`
`interpretation of their express language, the Challenged Claims cannot read on the
`
`mold process disclosed by Ilango.
`
`The claim language also addresses the Board’s suggestion in the Mylan
`
`Institution Decision that “Patent Owner has not shown that the claim limitation for
`
`- 9 -
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`measuring uniformity subsequent to casting and drying requires analyzing any
`
`
`
`particular number or percentage of the substantially equally sized individual unit
`
`doses prepared from the film-forming matrix.” Mylan Institution Decision at 21.
`
`Even if no specific number is required, a POSA would understand the express
`
`claim language makes clear that multiple (i.e., at least two) unit doses must be
`
`taken from a film matrix. First, the claim language expressly requires testing “unit
`
`doses,” not a single “unit dose,” and therefore at least two unit doses must be
`
`tested. Second, a POSA would have understood the claim language in the context
`
`of regulatory requirements for pharmaceutical products, which require testing the
`
`drug uniformity of multiple dosage units. Therefore, under the express claim
`
`language and the understanding of a POSA, testing a single unit dose would be
`
`insufficient to meet the claim limitation. Because the Ilango reference does not
`
`identify any particular number of unit doses (strips) of its films that were tested for
`
`“5% variation,” it is unnecessary for the Board to determine in this proceeding an
`
`exact number of unit doses that must be tested. What is important for this
`
`proceeding is that the Challenged Claims all clearly require that the drug content of
`
`multiple “unit doses” from a cast film matrix be tested.
`
`2.
`
`This Multi-Dose Film Interpretation Is The Only One That
`Is Consistent With The Intrinsic Evidence
`
`As the Board previously noted, the ’514 Patent repeatedly and consistently
`
`identifies the problem it addresses as maintaining DCU throughout a single cast
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`- 10 -
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`film cut into multiple unit doses. Mylan Institution Decision at 3, 15. As the ’514
`
`
`
`Patent explains, in this multi-dose film context, casting and drying of the film can
`
`give rise to forces that cause particles of an active ingredient to migrate and render
`
`the resulting film unit doses non-uniform. Ex. 1001, ’514 Patent at 2:19-21, 2:47-
`
`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
`
`the other hand, the specification clearly identifies “[t]he combination of ingredients
`
`. . . divided among individual wells or molds” to make individual dosage units (as
`
`in Ilango) as an “alternative method of preparing films” where “aggregation of the
`
`components during drying is prevented by the individual wells,” not by the
`
`viscosity of the matrix or control of the drying process. Ex. 1001, ’514 Patent at
`
`43:12-19. This alternative method is not an “embodiment” covered by the claims,
`
`which specifically require that the “matrix has a viscosity sufficient to aid in
`
`substantially maintaining non-self-aggregating uniformity” and that the uniformity
`
`of the matrix of a particular cast film be shown by testing the drug content of
`
`“individual unit doses” taken from that matrix. Ex. 1001, ’514 Patent at Claims 1
`
`and 62.
`
`From the outset, the Summary of the Invention defines the scope of the
`
`claimed invention:
`
`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
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`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).1 Various properties of the films
`
`of the invention are then explained in relation to the understanding that the films
`
`are cut up into individual unit doses. For example, “[t]he flexibility of the films
`
`allows for the sheets of the film to be rolled and transported for storage or prior to
`
`being cut into individual dosage forms.” Id. at 26:18-35.
`
`The specification’s discussion of the drug content uniformity testing is
`
`particularly instructive, because it consistently defines such testing in the context
`
`of “a manufacturing process [which] may include subjecting the film to drying
`
`processes [and] dividing the film into individual dosage units . . . . The cut film
`
`then may be sampled . . . [and] may be tested for uniformity in the content between
`
`samples.” Id. at 36:29-57. Indeed, the portion of the specification that explains the
`
`claimed testing of individual unit doses for drug content teaches the POSA to “cut
`
`the film into individual doses. The individual doses may then be dissolved and
`
`tested for the amount of active in films of particular size. This demonstrates that
`
`films of substantially similar size cut from different locations on the same film
`
`contain substantially the same amount of active.” Id. at 42:34-39.
`
`1 Unless otherwise stated, all emphasis in this document was added by PO.
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`The interpretation of the claims as limited to a multi-dose film is bolstered
`
`
`
`by the file history of the ’514 Patent. For example, in responding to an Office
`
`Action, the applicant confirmed that the claimed invention was “directed to . . . a
`
`film, such that individual units cut from the film will have the same amount of
`
`drug in them . . . .” Ex. 1004, Amendment and Response dated December 9, 2010
`
`at 14; see also Ex. 1004, Amendment and Response dated April 4, 2011 at 17
`
`(same). In doing so, the applicant made clear that the ‘514 Patent Claims are
`
`directed to drug content uniformity among multiple “individual units cut from” a
`
`single film matrix.
`
`
`
`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
`
`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.
`
`Terms Previously Construed By Board
`
`B.
`For purposes of this proceeding, PO accepts the Board’s previous
`
`constructions for the terms “viscosity sufficient to aid in substantially maintaining
`
`non-self-aggregating uniformity of the active in the matrix,” “particulate active
`
`substantially uniformly stationed in the matrix,” and “film-forming matrix . . .
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`IPR2017-01557
`U.S. Patent No. 8,603,514
`capable of being dried without loss of substantial uniformity in the stationing of the
`
`
`
`particulate active.” (Mylan Institution Decision at 3, 15) at 6-8.
`
`PO also accepts the Board’s previous construction of the term “desired
`
`amount” as “the intended amount of active for individual dosage units.” Id. at 8.
`
`But PO submits, however, the relevant intended amount when determining whether
`
`the 10% drug content uniformity limitation is met is the amount of drug intended
`
`to be in the dried, individual unit doses.
`
`V. 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
`
`pharmaceutical films, which were not FDA-approved at the time. Petitioner points
`
`to a hodgepodge of prior art efforts to develop pharmaceutical films2: spermicidal
`
`vaginal films from the 1970s (Petition at 14-15; Ex. 1002, Buckton ¶¶ 43-44, citing
`
`
`2 Petitioner also cites to some film art that has nothing to do with
`
`pharmaceuticals. See, e.g., Petition at 17-18 (citing Swei (Ex. 1018), a reference
`
`that discusses films for electronic circuits). This non-analogous art says nothing
`
`about drug content uniformity and would not even have been considered by a
`
`POSA seeking to make a pharmaceutical film.
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`U.S. Patent No. 8,603,514
`Roddy (Ex. 1010), Frankman (Ex. 1008), and Brode (Ex. 1009)); an early oral film
`
`
`
`treatment for periodontal disease (Petition at 15; Ex. 1002, Buckton ¶ 45, citing
`
`Suzuki (Ex. 1011)); films for the oral delivery of numbing agents (Petition at 16;
`
`Ex. 1002, Buckton ¶ 46, citing Tapolsky (Ex. 1012) and Yamamura (Ex. 1013));
`
`and films purportedly teaching taste-masking agents and certain particle sizes
`
`(Petition at 18-19; Ex. 1002, Buckton ¶¶ 53-55, citing Bess (Ex. 1019), Schmidt
`
`(Ex. 1020), and Higashi (Ex. 1021)). But there is no evidence that any of these
`
`films were even subject to, much less met, any drug content uniformity
`
`requirement. Indeed, neither Petitioner nor Dr. Buckton cites any of these
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`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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`
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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. Buckton 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 stationed
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`therein, because only a single unit dose is obtained from each film matrix, the
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`“uniformity [of the active] subsequent to casting and drying of the matrix” is not
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`shown “by substantially equally size unit doses [plural] which do not vary by more
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`than 10% of said desired amount of said at least one active,” as required by the
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`Challenged Claims.
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`Even if the each of the strips from the multiple glass moulds in Ilango
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`contains an amount of active within 5% of the desired amount as alleged by
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`Petitioner—but which PO disputes—the uniformity requirement of the Challenged
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`Claims cannot be satisfied by pointing to multiple unit doses each from a separate
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`matrix. In the Mylan Institution Decision, the Board stated that “as broadly written,
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`the claims do not require the matrix to remain undivided during casting and
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`drying.” Mylan Institution Decision at 19. PO respectfully disagrees. The claims
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`are directed to “a cast film comprising a flowable . . . film-forming matrix” in
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`which “uniformity [of the active in the matrix] subsequent to casting and drying
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`the matrix is measured by substantially equally-sized individual unit doses which
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`do not vary by more than 10% of said desired amount of said at least one active.”
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`Ex. 1001, ’514 Patent at Claims 1 and 62. But if the coating liquid