Petition for Inter Partes Review of USP 8,603,514
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`
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`In re Inter Partes Review of:
`)
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`U.S. Patent No. 8,603,514
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`Issued: December 10, 2013
`)
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`Application No.: 11/775,484
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`Filing Date: July 10, 2007
`)
`
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`For: Uniform Films for Rapid Dissolve Dosage Form Incorporating Taste-
`Masking Compositions
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`FILED VIA E2E
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`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 8,603,514
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`Petition for Inter Partes Review of USP 8,603,514
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`TABLE OF CONTENTS
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`Page
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`I.
`
`INTRODUCTION ........................................................................................... 1
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`A.
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`B.
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`C.
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`D.
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`E.
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`Brief Overview of the ’514 Patent ........................................................ 3
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`Brief Overview of the Prosecution History ........................................... 5
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`Brief Overview of the Scope and Content of the Prior Art ................... 9
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`Brief Overview of the Level of Skill in the Art .................................. 13
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`Background Knowledge in the Art Prior to October 12, 2001 ........... 14
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`II.
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`GROUNDS FOR STANDING ...................................................................... 20
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................. 21
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`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED FOR
`EACH CLAIM CHALLENGED................................................................... 23
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`V.
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`CLAIM CONSTRUCTION .......................................................................... 24
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`A.
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`B.
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`C.
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`D.
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`E.
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`“Flowable”Film-Forming Matrix ........................................................ 24
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`“viscosity sufficient to aid in substantially maintaining non-
`selfaggregating uniformity” ................................................................ 26
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`“active substantially uniformly stationed in the matrix” .................... 27
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`“taste-masking of the active” .............................................................. 27
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`“capable of being dried without loss of substantial uniformity” ........ 28
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`VI. DETAILED EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY .................................................................................. 30
`
`A.
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`[Ground 1] Claims 1-3, 9, 15, 62-65, 69-73, and 75 are Obvious
`under 35 U.S.C. § 103 over the Ilango (EX1005) in view of
`Chen (Ex1006). ................................................................................... 30
`
`VII. SECONDARY INDICIA OF NON-OBVIOUSNESS .................................. 60
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`Petition for Inter Partes Review of USP 8,603,514
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`VIII. CONCLUSION .............................................................................................. 61
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`IX. CERTIFICATE OF COMPLIANCE ............................................................ 62
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`X.
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`PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103.......... 63
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`XI. APPENDIX – LIST OF EXHIBITS .............................................................. 63
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`Petition for Inter Partes Review of USP 8,603,514
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`TABLE OF AUTHORITIES
`
`CASES
`
`Ariosa Diagnostics v. Verinata Health, Inc.,
`805 F.3d 1359 (Fed. Cir. 2015) ............................................................................. 14
`
`Cuozzo Speed Techs., LLC v. Lee,
`579 U.S. ---, 136 S. Ct. 2131 (2016) ........................................................ 24, 25, 30
`
`Graham v. John Deere Co. of Kansas City, 383 U.S. 1 (1966) .......................... 9, 60
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) ............................................................................. 24
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 418 (2007) ................................................................................. 9, 14
`
`Randall Mfg. v. Rea,
`733 F.3d 1355 (Fed. Cir. 2013) ............................................................................. 14
`
`Richdel, Inc. v. Sunspool Corp.,
`714 F.2d 1573 (Fed. Cir. 1983) ............................................................................. 61
`
`Tokai Corp. v. Easton Enterprises, Inc.,
`632 F.3d 1358 (Fed. Cir. 2011) ............................................................................. 61
`
`37 C.F.R. § 42.100(b) .............................................................................................. 24
`
`RULES
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`Petition for Inter Partes Review of USP 8,603,514
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`I.
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`INTRODUCTION
`
`Par Pharmaceutical, Inc. (“Par”) and IntelGenx Corp. (“IntelGenx”)
`
`(collectively “Petitioners”) request review of U.S. Patent No. 8,603,514 to Yang et
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`al. (“the ’514 patent,” EX1001), which issued on December 10, 2013. PTO records
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`indicate that the ’514 patent is assigned to MonoSol Rx, LLC (“Patent Owner”).
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`This Petition demonstrates that there is a reasonable likelihood that claims 1-3, 9,
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`15, 62-65, 69-73, and 75 (“the challenged claims”) are unpatentable for failure to
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`distinguish over newly applied prior art. This petition is substantively identical to
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`that submitted in IPR2017-00200, the proceedings Petitioners seek to join with
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`their simultaneously submitted motion for joinder. This petition relies on the
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`testimony of Dr. Buckton (EX1002) submitted with IPR2017-00200. No new
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`arguments or art are raised or relied on in this petition as compared to the petition
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`in IPR2017-00200.
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`The challenged claims are directed to a drug delivery film comprising a
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`particulate active ingredient and a taste-masking agent. Each component of the
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`claimed composition was described in the prior art, including the oral drug delivery
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`film, the polymer used to form the film, the viscosity of the film-forming matrix,
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`the particle size of the active ingredient, the uniform distribution of the active
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`ingredient, and the type of taste-masking agents as well as the manner of taste-
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`masking used in the film. EX1001, 67:34-56 & 73:48-74:9. The challenged claims
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`Petition for Inter Partes Review of USP 8,603,514
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`represent nothing more than adding a well-known taste-masking agent to a drug
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`delivery film intended for oral delivery.
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`This Petition applies a prior art reference to the claims of the ’514 patent that
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`has not been previously addressed in prosecution or district court litigation. In
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`those other proceedings, the Patent Owner has primarily asserted patentability over
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`the prior art based on the claim element that “individual unit doses … do not vary
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`by more than 10% of said at least one active.” However, Ilango et al., In-Vitro
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`Studies on Buccal Strips of Glibenclamide Using Chitosan, 59 Indian J. Pharm.
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`Sci. 232-235 (1997) (“Ilango,” EX1005), which had not previously been
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`considered by the Patent Office before the petition submitted in IPR2017-00200,
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`expressly discloses uniform cast films with a variance of less than 5% in the
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`amount of the active ingredient in uniformly sized individual unit doses. EX1005
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`(Ilango) at 234.
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`Thus, Ilango’s films satisfy each of the elements recited in the challenged
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`claims but for a taste-masking agent, such as a flavor, sweetener, flavor enhancer,
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`or coating. Taste-masking strategies, however, were well-known in the art of oral
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`delivery of drugs, as described in Chen, WO2000/42992 (EX1006) discussed
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`below. This Petition shows that a person of ordinary skill in the art would have
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`been motivated to employ a taste-masking strategy as disclosed in Chen with a film
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`containing an active ingredient, as described in Ilango, and would have had a
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`Petition for Inter Partes Review of USP 8,603,514
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`reasonable expectation of success. Other aspects taught in Chen and Ilango
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`establish that the remaining claim limitations of independent and dependent claims
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`were well-known in the prior art. Thus, based on the evidence provided in this
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`Petition, the challenged claims of the ’514 patent should be found unpatentable and
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`cancelled.
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`A. Brief Overview of the ’514 Patent
`The challenged claims are directed to drug delivery film compositions.
`
`Independent claim 62 is representative of the challenged claims and is reproduced
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`below:
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`62. A drug delivery composition comprising:
`(i) a cast film comprising a flowable water-soluble or water swellable
`film-forming matrix comprising one or more substantially water
`soluble or water swellable polymers; and a desired amount of at least
`one active;
`wherein said matrix has a viscosity sufficient to aid in substantially
`maintaining non-self-aggregating uniformity of the active in the
`matrix;
`(ii) a particulate active substantially uniformly stationed in the matrix;
`and
`(iii) a taste-masking agent selected from the group consisting of
`flavors, sweeteners, flavor enhancers, and combinations thereof to
`provide taste-masking of the active;
`wherein the particulate active has a particle size of 200 microns or less
`and said flowable water-soluble or water swellable film-forming
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`Petition for Inter Partes Review of USP 8,603,514
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`matrix is capable of being dried without loss of substantial uniformity
`in the stationing of said particulate active therein; and
`wherein 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.
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`EX1001, 73:48-74:9; see also EX1002, ¶¶15-17. Independent claim 1 is similar to
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`claim 62 except that instead of requiring that the taste-masking agent be a flavor,
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`sweetener, or flavor enhancer, claim 1 and its dependent claims require “a taste-
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`masking agent coated or intimately associated with said particulate to provide
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`taste-masking of the active.” EX1001, 67:34-56; see also EX1002, ¶¶15-17.
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`Accordingly, claim 1 refers to a particle size of a “combined active and taste-
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`masking agent.”
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`Claims 63-65 and 69-73 depend from claim 62, and claims 2, 3, 9, 15, and
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`75 depend from claim 1. Claims 2 and 63 recite a particle size of 150 microns or
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`less, and claims 3 and 64 recite a particle size of 100 microns or less. EX1001,
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`67:57-62 & 74:10-13; see also EX1002, ¶¶15-17. Claims 9 and 65 recite a 5% by
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`weight threshold for drug content uniformity. EX1001, 68:30-32 & 74:14-16; see
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`also EX1002, ¶¶15-17. Claims 69-70 specify weight percentage ranges for the
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`taste-masking agent of claim 62. EX1001, 74:29-34; see also EX1002, ¶¶15-17.
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`Claim 72 states that the film forming matrix of claim 62 has a “viscosity in an
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`Petition for Inter Partes Review of USP 8,603,514
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`amount sufficient to substantially prevent an active from settling out during mixing
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`or coating.” EX1001, 74:46-49; see also EX1002, ¶¶15-17. Claim 75 specifies that
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`the active of claim 1 is an opiate or opiate derivative and that the taste-masking
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`agent is selected from the same group specified in claim 62. EX1001, 74:53-56;
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`see also EX1002, ¶¶15-17.
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`Although the challenged claims have no limitations with regard to the
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`dissolution rate of the film, the title of the ’514 patent is “Uniform Films For Rapid
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`Dissolve Dosage Form Incorporating Taste-Masking Compositions.” EX1001,
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`cover. As explained by Dr. Buckton, who has years of experience in drug
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`formulation, the specification and issued claims of the ’514 patent are compatible
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`with films with either a rapid or a slow release rate. EX1002, ¶¶18-21 (discussing
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`the description in the ’514 patent (EX1001) at 13:5-20, 30-46 of the desirability of
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`delayed active release and methods of achieving the same consistent with the films
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`recited in the challenged claims).
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`Brief Overview of the Prosecution History
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`B.
`The ’514 patent issued based on U.S. Application No. 11/775,484 (“the ’484
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`application”), which was filed on July 10, 2007. EX1001, cover. The patent states
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`that the ’484 application is a continuation-in-part of U.S. Application No.
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`10/768,809 (“the ’809 application”). Id. The ’809 application is a continuation-in-
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`Petition for Inter Partes Review of USP 8,603,514
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`part of PCT/US02/32594, PCT/US02/32542, and PCT/US02/32575, all filed on
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`October 11, 2002.
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`The ’514 patent claims the benefit of the October 12, 2001, filing date of
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`U.S. Provisional Application No. 60/328,868 (“the ’868 application”) and the
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`benefit of the September 27, 2002, the filing date of U.S. Provisional Application
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`No. 60/414,276 (“the ’276 application”), as well as other provisional applications
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`filed after the ’868 application. EX1002, ¶13.
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`On June 3, 2016, in Case No. 13-cv-01674 in the District of Delaware, a
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`case, the district court found that the claims of the ’514 patent asserted in that
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`litigation (claims 62, 64, 65, 69 and 73) are entitled to only a later priority date of
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`September 27, 2002. EX1023 at 6; see also EX1002, ¶14. That date is the filing
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`date of the ’276 application. EX1001, cover. For the purposes of this Petition, the
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`earliest claimed priority date of October 12, 2001, is discussed with respect to each
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`claim. However, arguments presented in this Petition are equally applicable
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`regardless of whether the September 27, 2002, priority date adopted by the district
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`court is used.
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`In an Office Action of September 9, 2010, the Office rejected all claims as
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`anticipated under 35 U.S.C. §102(e) by U.S. Patent No. 7,067,116 (“Bess”), stating
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`that Bess describes orally dissolvable films with active agents and taste-masking
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`agents. EX1004 at 0966-69; EX1002, ¶22. The Office also rejected all pending
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`Petition for Inter Partes Review of USP 8,603,514
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`claims under §103 over WO2000/42992 (EX1006, “Chen”) in view of U.S. Patent
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`No. 5,653,993 (“Ghanta”) and further rejected the claims as obvious under §103
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`over U.S. Patent No. 4,713,243 (“Schiraldi”) in view of U.S. Patent No. 3,237,596
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`(“Grass”) and over Schiraldi in view of U.S. Publication No. 2004/0156901
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`(“Thakur”). EX1004 at 0971-73.
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`In response to these prior art rejections, Applicants amended the claims to
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`add the 10% active uniformity limitation and argued that the prior art failed to
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`expressly disclose 10% active uniformity. Id. at 0999-1010; EX1002, ¶23. The
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`Office maintained the rejections, and subsequent communications between the
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`Examiner and Applicants focused on whether the prior art inherently disclosed
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`10% active uniformity. EX1004 at 1162-72, 1194; EX1002, ¶¶24-25. Applicants
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`subsequently amended dependent claims directed to active uniformity to recite that
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`uniformity was determined “per film dosage unit” rather than “per film unit.”
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`EX1004 at 1207; EX1002, ¶25.
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`Applicants also added limitations regarding the polymer being water-soluble
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`or water swellable and the viscosity of the matrix, and argued that these limitations
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`distinguished the prior art. EX1004 at 1180, 1191, 1194; EX1002, ¶25.
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`After the Office again maintained the rejections, (EX1004 at 1241-53),
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`Applicants limited the claims to cast films, and specified that the uniformity was
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`Petition for Inter Partes Review of USP 8,603,514
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`measured after casting and drying using substantially equally-sized individual unit
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`doses. EX1004 at 1264; EX1002, ¶26.
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`The Office maintained the rejections over Bess and Chen in view of Ghanta,
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`stating that, “Applicant appears to be arguing the claims as a process of making
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`and not the final composition. The method in which the composition is made does
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`not hold patentable weight in a composition claims [sic].” EX1004 at 1290;
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`EX1002, ¶27.
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`Applicants subsequently submitted an amendment and response describing
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`an Examiner Interview in which they presented the Examiner with the declaration
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`of B. Arlie Bogue (“Bogue Declaration”) to demonstrate active uniformity of
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`Applicants’ films. EX1004 at 1297, 1316. The Bogue Declaration does not address
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`the use of a taste-masking agent in the film or the particle size of the active.
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`EX1002, ¶28; EX1007 at 2-3. Applicants also argued that Figure 5 of Chen failed
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`to demonstrate that Chen’s films varied by no more than 10% of the desired
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`amount of active. EX1004 at 1297, 1316.
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`The Office issued a Notice of Allowance. Id. at 1329. After allowance, both
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`Applicants and the Examiner filed interview summaries. Id. at 1351, 1375. The
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`Examiner stated: “[N]either Bess nor Chen inherently result in a film having a
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`uniformity in which the individual unit does not vary by more than 10% of the
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`desired amount of the active.” Id. at 1375; EX1002, ¶¶29-30.
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`Petition for Inter Partes Review of USP 8,603,514
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`C. Brief Overview of the Scope and Content of the Prior Art
`In obviousness cases, Graham v. John Deere Co. of Kansas City, requires an
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`evaluation of any differences between the claimed subject matter and the asserted
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`prior art. 383 U.S. 1, 17-18 (1966). As noted in KSR Int’l Co. v. Teleflex Inc., the
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`obviousness inquiry may account for inferences that would be employed by a
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`person of ordinary skill in the art. 550 U.S. 398, 418 (2007).
`
`Ilango et al., In-Vitro Studies on Buccal Strips of
`1.
`Glibenclamide Using Chitosan, 59 Indian J. Pharm. Sci. 232-235
`(1997) (“Ilango”) (EX1005)
`
`Ilango discloses cast film strips for oral drug delivery. Ilango’s cast films
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`comprise a water-soluble polymer, namely polyvinylpyrrolidone (PVP), and the
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`particulate active ingredient glibenclamide, an anti-diabetic active agent. EX1005
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`at 232; see also EX1002, ¶¶59-60. Ilango discloses four different embodiments of
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`its films each comprising PVP, polypropylene glycol, either 1% or 2% of the
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`active, and either chitosan or Eudragit (both water-swellable polymers). EX1005 at
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`232; see also EX1002, ¶¶59-60. Table 1 of Ilango summarizes the disclosed cast
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`film compositions and is reproduced below.
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`Petition for Inter Partes Review of USP 8,603,514
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`Id. at 233.
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`Ilango teaches the formation of a “viscous solution” of polymer, the
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`dispersion of the glibenclamide particles uniformly in the viscous solution through
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`continuous mixing, and the casting of the film in glass molds. EX1005 at 232; see
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`also EX1002, ¶¶61-62. The cast films are dried by allowing solvent to evaporate at
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`room temperature for about 24 hours, and the films are cut into individual unit
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`doses that are oval in shape and uniformly sized at 4 cm in length, 3 cm in width,
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`and 40 microns in thickness. EX1005 at 232; see also EX1002, ¶62. All of the cast
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`film formulations of Ilango were assessed for drug content uniformity and
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`individual unit doses are reported to contain active agent within 5% variance of the
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`target dose. EX1005 at 234; see also EX1002, ¶63. Ilango teaches that the
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`incorporation of the chitosan or Eudragit in the matrix “lead[s] to controlled
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`release of drug” from the mucoadhesive strips. EX1005 at 234; see also EX1002,
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`¶59.
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`Petition for Inter Partes Review of USP 8,603,514
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`Ilango was published in the September-October 1997 issue of the Indian
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`Journal of Pharmaceutical Sciences and is prior art to the challenged claims of the
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`’514 patent under 35 U.S.C. § 102(b). EX1002, ¶¶57-58. Ilango was not cited nor
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`discussed during prosecution of the ’514 patent.
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`2. WO2000/42992 to Chen et al. (“Chen “) (EX1006)
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`WIPO PCT Publication No. WO 00/42992 to Chen et al. (“Chen”) (EX1006)
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`published in English on July 27, 2000. EX1002, ¶64. Chen teaches the use of taste-
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`masking agents in film formulations for delivery of active agents. EX1002, ¶¶70-
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`72. As disclosed by Chen, taste-masking agents can be included in film
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`compositions to taste-mask actives meant to be delivered through the oral mucosa.
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`EX1002, ¶¶70-72. These taste masking agents include flavoring and sweetening
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`agents such as “essential oils or water soluble extracts of menthol, wintergreen,
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`peppermint, sweet mint, spearmint, vanillin, cherry.” EX1006, 10:7-14; see also
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`EX1002, ¶70. Chen teaches that the taste-masking agents can be mixed into the
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`film by dispersion or dissolution prior to casting. EX1006, 15:7-12 & 15:21-23;
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`see also EX1002, ¶70. Chen provides examples of cast film compositions that
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`include aspartame and peppermint incorporated at 3.13% (w/w) and 3.91% (w/w)
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`solids, respectively. EX1006, Table 3; see also EX1002, ¶¶71-72. Chen also
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`discloses that active agents may be taste-masked by encapsulation in a material
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`Petition for Inter Partes Review of USP 8,603,514
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`separate from the water-soluble polymer of the film-forming matrix. EX1006,
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`9:14-16; see also EX1002, ¶70.
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`Chen discloses a wide range of water-soluble polymers for use in cast films,
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`including polyvinylpyrrolidone (“PVP”), hydroxypropyl cellulose (“HPC”),
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`hydroxypropyl methyl cellulose (“HPMC”), methyl cellulose, polyethylene oxides
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`(“PEO”), polyvinyl alcohols, among several others. EX1006, 14:22-15:3; see also
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`EX1002, ¶66. Chen discloses fast dissolving formulations and slow dissolving
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`formulations, the latter incorporating high molecular weight hydroxypropylmethyl
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`cellulose (HPMC). EX1006, 24:3-5; see also EX1002, ¶66.
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`Chen teaches the administration of a range of different active agents,
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`including analgesics, opiates (e.g., hydromorphone), and anti-diabetics. EX1006,
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`4:8-9 & 10:22-11:12; see also EX1002, ¶¶67-68. Active agents are disclosed to be
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`readily incorporated into films by dispersion as colloidal particles,
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`microencapsulated in the film or mixed throughout the film. EX1006, 7:19-21; see
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`also at EX1002, ¶68. Chen also teaches a preference in drug delivery forms
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`designed for oral dissolution to use particle sizes not greater than 25 microns to
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`avoid the “gritty and unpleasant taste in the mouth” when the tablet or film
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`dissolves. EX1006, 2:18-20; see also EX1002, ¶¶65 & 69.
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`Chen also expressly discloses film-forming matrix viscosities ranging from
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`500 – 15,000 centipoise (“cps,” “cp,” “CP,” or “cP”). EX1006, 15:24-29; see also
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`Petition for Inter Partes Review of USP 8,603,514
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`EX1002, ¶¶73-74. Chen further describes drying cast films “to avoid destabilizing
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`the agents contained within the formulation.” EX1006, 15:24-29; see also EX1002,
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`¶74. Chen further teaches that a desired dose amount can be obtained by varying
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`the size of the dose unit cut from the film. EX1002, ¶75. Chen is prior art to the
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`challenged claims of the ’514 patent under 35 U.S.C. § 102(b).
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`D. Brief Overview of the Level of Skill in the Art
`A person of ordinary skill in the relevant field as of October 12, 2001, or
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`September 27, 2002, would likely have a Ph.D. in pharmaceutics, or in a drug
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`delivery related discipline such as physical or polymer chemistry. EX1002, ¶¶38-
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`39. In addition, the skilled artisan likely would have experience formulating drugs
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`for administration and would have the ability to understand literature published by
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`others in the field, including the references discussed in this Petition. Alternatively
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`a person of ordinary skill may have a bachelor’s degree in pharmaceutics, or in a
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`related field, plus two to five years of relevant experience in developing drug
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`formulations. EX1002, ¶¶38-39.
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`As noted above, this Petition is supported by the declaration of Dr. Graham
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`Buckton. EX1002, ¶¶1, 11-12. Dr. Buckton’s CV is attached as EX1003. Dr.
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`Buckton has extensive experience in pharmaceutical formulation development.
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`EX1002, ¶¶1-10.
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`Petition for Inter Partes Review of USP 8,603,514
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`Dr. Buckton possesses the necessary scientific background and technical
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`expertise to provide detailed analysis of the references discussed herein in relation
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`to the challenged claims and to explain the level of ordinary skill in the art as of
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`October 12, 2001, and September 27, 2002.
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`Background Knowledge in the Art Prior to October 12, 2001
`
`E.
`The background publications below reflect the knowledge of a skilled
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`artisan in the field at the time of the invention, i.e., before the earliest claimed
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`priority date of October 12, 2001, and thereby assist in understanding why one
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`would have been motivated to combine or modify the references as asserted in this
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`Petition. Ariosa Diagnostics v. Verinata Health, Inc., 805 F.3d 1359, 1365 (Fed.
`
`Cir. 2015). As established in KSR, 550 U.S. at 406, the knowledge of a skilled
`
`artisan is part of the store of public knowledge that must be consulted when
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`considering whether a claimed invention would have been obvious. Randall Mfg. v.
`
`Rea, 733 F.3d 1355, 1362-63 (Fed. Cir. 2013).
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`Cast films for drug delivery to mucosal surfaces have been known in the
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`prior art for decades prior to the effective filing date of the ’514 patent. EX1002,
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`¶¶42-56. For example, films for delivery of contraceptives to the vaginal mucosa
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`were described as early as the 1970s. Frankman et al., Clinical Evaluation of C-
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`Film, a Vaginal Contraceptive, 3 J. Int. Med. Res. 292-96, 292 (1975)
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`(“Frankman”) (EX1008); U.S. Patent No. 5,595,980 to Brode et al. (“Brode”)
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`(EX1009) at 1:20-28 & 4:23-27; see also EX1002, ¶43. These films incorporated
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`several different compounds such as cetylpyridine bromide or nonoxynol-9 in
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`water-soluble polymer films and were manufactured as uniformly sized square
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`dosages (5 x 5 cm). EX1002, ¶43. Nonoxynol-9 loaded films have also been tested
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`for the prevention of sexually transmitted infections. Roddy et al., A Controlled
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`Trial of Nonoxynol 9 Film to Reduce Male-to-Female Transmission of Sexually
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`Transmitted Diseases, 339 N. Engl. J. Med. 504-10, 504 (1998) (“Roddy”)
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`(EX1010); see also EX1002, ¶44.
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`Thereafter, films were adapted for a variety of drug delivery applications,
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`including oral delivery of active ingredients. EX1002, ¶45. For example, U.S.
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`Patent No. 4,569,837 to Suzuki et al. (“Suzuki”) (EX1011) discloses water-soluble
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`cast film compositions containing antibacterial agents, such as chlorhexidine, for
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`the treatment of periodontal disease. EX1011 at 2:51-59 & Example 1; see also
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`EX1002, ¶45. Suzuki describes making cast films from viscous solutions (e.g.,
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`30,000 CP) that resulted in films having a thickness of 260 microns. EX1011
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`(Suzuki), 2:51-59 & Example 1; see also EX1002, ¶45. As another example, U.S.
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`Patent No. 6,159,498 to Tapolsky et al. (“Tapolsky”) (EX1012) Tapolsky teaches
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`the formulation of precipitated benzocaine (a numbing agent) in water-soluble cast
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`films. EX1012 at 7:43-51; see also EX1002, ¶46. As still another example,
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`Yamamura teaches incorporation of dibucaine (a numbing agent) in water-soluble
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`Petition for Inter Partes Review of USP 8,603,514
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`hydroxypropyl cellulose-M cast films. Yamamura et al., Oral Mucosal Adhesive
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`Film Containing Local Anesthetics: In Vitro and Clinical Evaluation, 43 J Biomed
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`Mater Res. 313-317, 313 (1998) (“Yamamura”) (EX1013); see also EX1002, ¶46.
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`The body of prior art with which a skilled artisan would have been
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`acquainted prior to October 12, 2001, established several key parameters and how
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`they could be optimized during formulation of actives in cast films. EX1002, ¶47.
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`For example, the prior art extensively discussed the use of water-soluble and
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`water-swellable polymers to impart specific properties to cast films. EX1002, ¶48.
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`In addition, the use of a viscous polymer solution to aid in uniform dispersion of an
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`active in the film-forming matrix, the identification of an appropriate particle size
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`for the active that would be compatible with the thickness and usage of the films
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`being created, as well as the use of taste-masking agents to provide films for oral
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`drug delivery that have an appealing taste were also known in the art prior to
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`October 12, 2001. EX1002, ¶¶49-55.
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`Water-soluble and water-swellable polymers were widely used in the art for
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`their favorable properties, which were compatible with films for oral drug delivery.
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`EX1002, ¶48. For example, Tapolsky teaches that water-soluble polymers, which
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`dissolve in body fluids and deliver drug, are advantageous to use in the
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`development of one-time use products. EX1012 (Tapolsky), 4:53-67; see also
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`EX1002, ¶48. Schiraldi states that water-soluble and water-swellable polymers are
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`Petition for Inter Partes Review of USP 8,603,514
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`also useful in oral mucosal films for their adhesive properties. U.S. Patent No.
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`4,713,243 (“Schiraldi”) (EX1014), 3:19-21 & 4:7-8; see also EX1002, ¶48.
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`Loesche additionally discloses that films can become controlled release films by
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`inclusion of non-water soluble polymers, which cause the cast film to dissolve
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`more slowly. U.S. Patent No. 4,568,535 (“Loesche”) (EX1015) at 7:66-8:11; see
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`also EX1002, ¶48.
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`Similarly, several publications prior to October 12, 2001, discuss the
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`importance of viscosity in cast film compositions to obtain uniform distribution of
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`the active. EX1002, ¶¶49-52. For example, Zaffaroni teaches that drug-loaded cast
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`films are made by uniformly distributing drug in a solution that is sufficiently
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`viscous for casting. U.S. Patent No. 3,797,494 (“Zaffaroni”) (EX1016) at 7:22-30;
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`see also EX1002, ¶49. Heller states that active agents such as micronized
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`hydrocortisone, cortisone acetate, and β-estradiol can all be dispersed in viscous
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`polymer solutions. U.S. Patent No. 4,249,531 (“Heller”) (EX1017) at 22:1-6,
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`24:55-59, & 27:13-17; see also EX1002, ¶50. Suzuki and Swei additionally teach
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`specific viscosities that are sufficient to aid in substantially maintaining uniformity
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`of the active. EX1011 (Suzuki), 2:51-59 & Example 1 (530,000 CP, 2080 CP in an
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`embodiment); U.S. Patent No. 5,506,049 to Swei et al. (“Swei”) (EX1018) at 6:30-
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`34 (10 cp-100,000 cp, more preferably 100 cp-10,000 cp); see also EX1002, ¶¶51-
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`52. Swei further specifically notes that viscosity was an important parameter in
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`preventing particles suspended therein from settling and that a sufficient viscosity
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`for a given particular size could be determined using Stoke’s Law. EX1018 (Swei),
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`6:1-19; see also EX1002, ¶52. Thus, it was well established in the art as of October
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`12, 2001, that viscosity was an important parameter for film formulations of
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`suspended active agents, both in the broad reaching disclosures by Zaffaroni and
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`Heller and in the specific viscosity ranges indicated by Suzuki and Swei, which fall
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`squarely within the preferred range of the ’514 patent. EX1002, ¶¶49-52. The
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`skilled artisan would have been equipped with this prior art that enables
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`determining how much viscosity sufficiently aids in achieving uniformity of
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`distribution of the active agent. EX1002, ¶52.
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`Incorporation of active agents as particulates was also well known in the
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`field. The size of particulate active agents was generally in the tens to hundreds of
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`microns and did not exceed the thickness of the film itself. EX1002, ¶¶53-54. For
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`example, Bess discloses particulate actives of 20-200 microns in size in films that
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`were 230 microns thick. U.S. Patent No. 7,067,116 (“Bess”) (EX1019) at 4:34-35
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`& 13:5-7; see also EX1002, ¶¶53-54. In another example, Schmidt teaches a
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`particle size of 1-20 microns for use in films that ranged from 50-250 microns in
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`total thickness. U.S. Patent No. 4,849,246 (“Schmidt”) (EX1020) at 4:67-5:2 &
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`3:47-48; see also EX1002, ¶¶53-54. Higashi teaches a particle size of 105-177
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`microns for use in films that were 300 microns in thickness. European Patent No.
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`Petition for Inter Partes Review of USP 8,603,514
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`0241178 (“Higashi”) (EX1021) at 7:28-35 & 7:44-46, Example 3; see also
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`EX1002, ¶¶53-54. Thus, publications in the field not only taught particle sizes less
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`than 200 microns, but also confirmed that particle sizes should be smaller than the
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`thickness of the films such that they are compatible with the films themselves.
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`EX1002, ¶54.
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`The background art in the field further established the use of taste-masking
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`agents in oral film doses. EX1002, ¶55. Schmidt and Bess further discuss the
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`inclusion of flavoring agents to provide taste-masking in film compositions.
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`EX1020 (Schmidt), 4:46-49; EX1019 (Bess), 2:10-14; see also EX1002, ¶55. Bess
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`teaches that flavors such as peppermint, vanilla, cinnamon, cherry, and others can
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`be used to enhance the taste of film compositions. EX1019 (Bess), 6:39-7:31; see
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`also EX1002, ¶55. Bess further teaches that the inclusion of sweeteners is not
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`necessary for film doses that are not intended for oral drug delivery, thus
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`acknowledging that including taste-masking ag