`Filed: November 4, 2016
`
`Filed on behalf of: Mylan Technologies, Inc.
`By: Steven W. Parmelee (sparmelee@wsgr.com)
`
`Michael T. Rosato (mrosato@wsgr.com)
`
`Jad A. Mills (jmills@wsgr.com)
`
`Wilson Sonsini Goodrich & Rosati
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MYLAN TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`MONOSOL RX, LLC
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2017-00200
`Patent No. 8,603,514
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,603,514
`
`
`
`
`
`
`Table of Contents
`
`Page
`
`I.
`
`Introduction .................................................................................................. 1
`
`A.
`
`Brief Overview of the ’514 Patent....................................................... 3
`
`B.
`
`C.
`
`Brief Overview of the Prosecution History ......................................... 5
`
`Brief Overview of the Scope and Content of the Prior Art .................. 8
`
`D.
`
`Brief Overview of the Level of Skill in the Art ................................. 12
`
`E.
`
`Background Knowledge in the Art Prior to October 12, 2001 ........... 14
`
`II.
`
`Grounds for Standing .................................................................................. 21
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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
`
`V.
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`Claim Construction ..................................................................................... 24
`
`VI. Detailed Explanation Of Grounds For Unpatentability ................................ 30
`
`A.
`
`[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
`
`VIII. Conclusion .................................................................................................. 61
`
`IX. Certificate of Compliance ........................................................................... 62
`
`X.
`
`Payment of Fees under 37 C.F.R. §§ 42.15(a) and 42.103........................... 63
`
`XI. Appendix – List of Exhibits ........................................................................ 64
`
`
`
`-i-
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`
`
`
`
`I.
`
`INTRODUCTION
`
`Mylan Technologies, Inc. (“Petitioner”) requests review of U.S. Patent No.
`
`8,603,514 to Yang et al. (“the ’514 patent,” EX1001), which issued on December
`
`10, 2013. PTO records indicate that the ’514 patent is assigned to MonoSol Rx,
`
`LLC (“Patent Owner”). This Petition demonstrates that there is a reasonable
`
`likelihood that claims 1-3, 9, 15, 62-65, 69-73, and 75 (“the challenged claims”)
`
`are unpatentable for failure to distinguish over newly applied prior art.
`
`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
`
`film, the polymer used to form the film, the viscosity of the film-forming matrix,
`
`the particle size of the active ingredient, the uniform distribution of the active
`
`ingredient, and the type of taste-masking agents as well as the manner of taste-
`
`masking used in the film. EX1001, 67:34-56 & 73:48-74:9. The challenged claims
`
`represent nothing more than adding a well-known taste-masking agent to a drug
`
`delivery film intended for oral delivery.
`
`This Petition applies a prior art reference to the claims of the ’514 patent that
`
`has not been previously addressed in prosecution, district court litigation, or in a
`
`pending IPR involving a different petitioner (IPR2016-01111). In those other
`
`proceedings, the Patent Owner has primarily asserted patentability over the prior
`
`-1-
`
`
`
`
`
`art based on the claim element that “individual unit doses … do not vary by more
`
`than 10% of said at least one active.” However, Ilango et al., In-Vitro studies on
`
`Buccal strips of Glibenclamide using Chitosan, 59 Indian J. Pharm. Sci. 232-235
`
`(1997) (“Ilango,” EX1005), which has not previously been considered by the
`
`Patent Office, expressly discloses uniform cast films with a variance of less than
`
`5% in the amount of the active ingredient in uniformly sized individual unit doses.
`
`EX1005 (Ilango) at 234.
`
`Thus, Ilango’s films satisfy each of the elements recited in the challenged
`
`claims but for a taste-masking agent, such as a flavor, sweetener, flavor enhancer,
`
`or coating. Taste-masking strategies, however, were well-known in the art of oral
`
`delivery of drugs, as described in Chen, WO2000/42992 (EX1006) discussed
`
`below. This Petition shows that a person of ordinary skill in the art would have
`
`been motivated to employ a taste-masking strategy as disclosed in Chen with a film
`
`containing an active ingredient, as described in Ilango, and would have had a
`
`reasonable expectation of success. Other aspects taught in Chen and Ilango
`
`establish that the remaining claim limitations of independent and dependent claims
`
`were well-known in the prior art. Thus, based on the evidence provided in this
`
`Petition, the challenged claims of the ’514 patent should be found unpatentable and
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`canceled.
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`-2-
`
`
`
`
`
`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
`
`below:
`
`62. A drug delivery composition comprising:
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`(i) a cast film comprising a flowable water-soluble or water swellable
`
`film-forming matrix comprising one or more substantially water
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`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;
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`(ii) a particulate active substantially uniformly stationed in the matrix;
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`and
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`(iii) a taste-masking agent selected from the group consisting of
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`flavors, sweeteners, flavor enhancers, and combinations thereof to
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`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
`
`matrix is capable of being dried without loss of substantial uniformity
`
`in the stationing of said particulate active therein; and
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`wherein the uniformity subsequent to casting and drying of the
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`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.
`
`-3-
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`
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`
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`EX1001, 73:48-74:9; see also EX1002, ¶¶15-17. Independent claim 1 is similar to
`
`claim 62 except that instead of requiring that the taste-masking agent be a flavor,
`
`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.
`
`Accordingly, claim 1 refers to a particle size of a “combined active and taste-
`
`masking agent.”
`
`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
`
`less, and claims 3 and 64 recite a particle size of 100 microns or less. EX1001,
`
`67:57-62 & 74:10-13; see also EX1002, ¶¶15-17. Claims 9 and 65 recite a 5% by
`
`weight threshold for drug content uniformity. EX1001, 68:30-32 & 74:14-16; see
`
`also EX1002, ¶¶15-17. Claims 69-70 specify weight percentage ranges for the
`
`taste-masking agent of claim 62. EX1001, 74:29-34; see also EX1002, ¶¶15-17.
`
`Claim 72 states that the film forming matrix of claim 62 has a “viscosity in an
`
`amount sufficient to substantially prevent an active from settling out during mixing
`
`or coating.” EX1001, 74:46-49; see also EX1002, ¶¶15-17. Claim 75 specifies that
`
`the active of claim 1 is an opiate or opiate derivative and that the taste-masking
`
`agent is selected from the same group specified in claim 62. EX1001, 53-56; see
`
`also EX1002, ¶¶15-17.
`
`-4-
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`
`
`
`
`Although the challenged claims have no limitations with regard to the
`
`dissolution rate of the film, the title of the ’514 patent is “Uniform Films For Rapid
`
`Dissolve Dosage Form Incorporating Taste-Masking Compositions.” EX1001,
`
`cover. As explained by Dr. Buckton, who has years of experience in drug
`
`formulation, the specification and issued claims of the ’514 patent are compatible
`
`with films with either a rapid or a slow release rate. EX1002, ¶¶18-21 (discussing
`
`the description in the ’514 patent (EX1001) at 13:5-20, 30-46 of the desirability of
`
`delayed active release and methods of achieving the same consistent with the films
`
`recited in the challenged claims).
`
`B.
`
`Brief Overview of the Prosecution History
`
`The ’514 patent issued based on U.S. Application No. 11/775,484, the
`
`“the ’484 application”), which was filed on July 10, 2007. EX1001, cover. The
`
`patent states that the ’484 application is a continuation-in-part of U.S. Application
`
`No. 10/768,809 (“the ’809 application”). Id. The ’809 application is a continuation-
`
`in-part of PCT/US02/32594, PCT/US02/32542, and PCT/US02/32575, all filed on
`
`October 11, 2002.
`
`The ’514 patent claims the benefit of the October 12, 2001, filing date of
`
`U.S. Provisional Application No. 60/328,868 (“the ’868 application”) and the
`
`benefit of the September 27, 2002, the filing date of U.S. Provisional Application
`
`-5-
`
`
`
`
`
`No. 60/414,276 (“the ’276 application”), as well as other provisional applications
`
`filed after the ’868 application. EX1002, ¶13.
`
`On June 3, 2016, in Case No. 13-cv-01674 in the District of Delaware, a
`
`case involving Patent Owner but not Petitioner, the district court found that the
`
`claims of the ’514 patent asserted in that litigation (claims 62, 64, 65, 69 and 73)
`
`are entitled to only a later priority date of September 27, 2002. EX1023 at 6; see
`
`also EX1002, ¶14. That date is the filing date of the ’276 application. EX1001,
`
`cover. For the purposes of this Petition, the earliest claimed priority date of
`
`October 12, 2001, is discussed with respect to each claim. However, arguments
`
`presented in this Petition are equally applicable regardless of whether the
`
`September 27, 2002, priority date adopted by the district court is used.
`
`In an Office Action of September 9, 2010, the Office rejected all claims as
`
`anticipated under 35 U.S.C. §102(e) by U.S. Patent No. 7,067,116 (“Bess”), stating
`
`that that Bess describes orally dissolvable films with active agents and taste-
`
`masking agents. EX1004 at 0966-69; EX1002, ¶22. The Office also rejected all
`
`pending claims under §103 over WO2000/42992 (EX1006, “Chen”) in view of U.S.
`
`Patent No. 5,653,993 (“Ghanta”) and further rejected the claims as obvious under
`
`§103 over U.S. Patent No. 4,713,243 (“Schiraldi”) in view of U.S. Patent No.
`
`3,237,596 (“Grass”) and over Schiraldi in view of U.S. Publication No.
`
`2004/0156901 (“Thakur”). EX1004 at 0971-73.
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`-6-
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`
`
`
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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
`
`Examiner and Applicants focused on whether the prior art inherently disclosed
`
`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.
`
`Applicants also added limitations regarding the polymer being water soluble
`
`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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`measured after casting and drying using substantially equally-sized individual unit
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`doses. Id. at 1264; EX1002, ¶26.
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`The Office maintained the rejections over Bess and Chen in view of Ghanta,
`
`stating that, “Applicant appears to be arguing the claims as a process of making
`
`and not the final composition. The method in which the composition is made does
`
`-7-
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`
`
`
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`not hold patentable weight in a composition claims [sic].” Id. at 1290; EX1002,
`
`¶27.
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`Applicants subsequently submitted an amendment and response describing
`
`an Examiner Interview in which they presented the Examiner with the declaration
`
`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
`
`to demonstrate that Chen’s films varied by no more than 10% of the desired
`
`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
`
`active.” Id. at 1375; EX1002, ¶¶29-30.
`
`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
`
`evaluation of any differences between the claimed subject matter and the asserted
`
`prior art. 383 U.S. 1, 17-18 (1966). As noted in KSR Int’l Co. v. Teleflex Inc., the
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`-8-
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`
`
`
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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).
`
`i.
`Ilango et al., In-Vitro studies on Buccal strips of 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
`
`comprise a water-soluble polymer, namely polyvinylpyrrolidone (PVP), and the
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`particulate active ingredient glibenclamide, an anti-diabetic active agent. EX1005
`
`at 232; see also EX1002, ¶¶59-60. Ilango discloses four different embodiments of
`
`its films each comprising PVP, polypropylene glycol, either 1% or 2% of the active,
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`and either chitosan or Eudragit (both water-swellable polymers). EX1005 at 232;
`
`see also EX1002, ¶¶59-60. Table 1 of Ilango summarizes the disclosed cast film
`
`compositions and is reproduced below.
`
`Id. at 233.
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`-9-
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`
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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
`
`also EX1002, ¶¶61-62. The cast films are dried by allowing solvent to evaporate at
`
`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
`
`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 “leads to controlled release
`
`of drug from [the] mucoadhesive strips.” EX1005 at 234; see also EX1002, ¶59.
`
`Ilango was published in the September – October 1997 issue of the Indian
`
`Journal of Pharmaceutical Sciences and is prior art to the challenged claims of
`
`the ’514 patent under 35 U.S.C. § 102(b). EX1002, ¶¶57-58. Ilango was not cited
`
`nor discussed during prosecution of the ’514 patent.
`
`ii.
`
`WO2000/42992 to Chen et al. (“Chen”) (EX1006)
`
`WIPO PCT Publication No. WO 00/42992 to Chen et al. (“Chen”) (EX1006)
`
`published in English on July 27, 2000. EX1002, ¶64. Chen teaches the use of taste-
`
`masking agents in film formulations for delivery of active agents. Id. at ¶¶70-72.
`
`-10-
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`
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`As disclosed by Chen, taste-masking agents can be included in film compositions
`
`to taste-mask actives meant to be delivered through the oral mucosa. Id. These
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`taste masking agents include flavoring and sweetening agents such as “…essential
`
`oils or water soluble extracts of menthol, wintergreen, peppermint, sweet mint,
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`spearmint, vanillin, cherry….” EX1006, 10:7-14; see also EX1002, ¶70. Chen
`
`teaches that the taste-masking agents can be mixed into the film by dispersion or
`
`dissolution prior to casting. EX1006, 15:7-12 & 15:21-23; see also EX1002, ¶70.
`
`Chen provides examples of cast film compositions that include aspartame and
`
`peppermint incorporated at 3.13% (w/w) and 3.91 % (w/w) solids, respectively.
`
`EX1006, Table 3; see also EX1002, ¶¶71-72. Chen also discloses that active agents
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`may be taste-masked by encapsulation in a material separate from the water-
`
`soluble polymer of the film-forming matrix. EX1006, 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
`
`(“PEO”), polyvinyl alcohols, among several others. EX1006, 14:22-15:3; see also
`
`EX1002, ¶66. Chen discloses fast dissolving formulations and slow dissolving
`
`formulations, the latter incorporating high molecular weight hydroxypropylmethyl
`
`cellulose (HPMC). EX1006, 24:3-5; see also EX1002, ¶66.
`
`-11-
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`
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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
`
`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
`
`also at EX1002, ¶68. Chen also teaches a preference in drug delivery forms
`
`designed for oral dissolution to use particle sizes not greater than 25 microns to
`
`avoid the “gritty and unpleasant taste in the mouth” when the tablet or film
`
`dissolves. EX1006, 2:18-20; see also EX1002, ¶¶65 & 69.
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`Chen also expressly discloses film-forming matrix viscosities ranging from
`
`500 – 15,000 centipoise (“cps,” “cp,” “CP,” or “cP”). EX1006, 15:24-29; see also
`
`EX1002, ¶¶73-74. Chen further describes drying cast films “to avoid destabilizing
`
`the agents contained within the formulation.” EX1006, 15:24-29; see also EX1002,
`
`¶74. Chen further teaches that a desired dose amount can be obtained by varying
`
`the size of the dose unit cut from the film. EX1002, ¶75. Chen is prior art to the
`
`challenged claims of the ’514 patent under 35 U.S.C. § 102(b).
`
`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
`
`September 27, 2002, would likely have a Ph.D. in pharmaceutics, or in a drug
`
`delivery related discipline such as physical or polymer chemistry. EX1002, ¶¶38-
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`-12-
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`
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`
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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
`
`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
`
`related field, plus two to five years of relevant experience in developing drug
`
`formulations. Id.
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`As noted above, this Petition is supported by the declaration of Dr. Graham
`
`Buckton. EX1002 (“Buckton Declaration”), ¶¶1, 11-12. A summary of Dr.
`
`Buckton’s education and experience in the field is submitted as EX1003; see also
`
`EX1002, ¶10. Dr. Buckton is an Emeritus Professor of Pharmaceutics in the UCL
`
`School of Pharmacy at the University of London. Id. at ¶1. He received his Ph.D.
`
`in Pharmaceutics from Kings College London in 1985. Id. Dr. Buckton’s research
`
`has focused on interactions between different pharmaceutical materials as well as
`
`the formulation of drug dosage forms for delivery via the oral route. Id. at ¶¶5-6.
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`Dr. Buckton has also published on the subject of film forming materials and film
`
`coatings and served on various editorial boards. Id. at ¶¶7-8. Dr. Buckton has
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`served as a member of the British Pharmacopoeia Commission and has been a
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`member of working parties for the European and the United States Pharmacopoeias,
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`which set standards for pharmaceutical administration. Id. at ¶3. Dr. Buckton also
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`-13-
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`
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`has significant industry experience and has been recognized for his
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`accomplishments with several awards and honors. Id. at ¶¶2, 4, & 9.
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`Dr. Buckton possesses the necessary scientific background and technical
`
`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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`E.
`
`Background Knowledge in the Art Prior to October 12, 2001
`
`The background publications below reflect the knowledge of a skilled
`
`artisan in the field at the time of the invention, i.e., before the earliest claimed
`
`priority date of October 12, 2001, and thereby assist in understanding why one
`
`would have been motivated to combine or modify the references as asserted in this
`
`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.
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`Rea, 733 F.3d 1355, 1362-63 (Fed. Cir. 2013).
`
`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,
`
`¶¶42-56. For example, films for delivery of contraceptives to the vaginal mucosa
`
`were described as early as the 1970s. Frankman et al., Clinical evaluation of C-
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`-14-
`
`
`
`
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`Film, a vaginal contraceptive, 3 J. Int. Med. Res. 292-96, 292 (1975) (“Frankman”)
`
`(EX1008); U.S. Patent No. 5,595,980 to Brode et al. (“Brode”) (EX1009) at 1:20-
`
`28 & 4:23-27; see also EX1002, ¶43. These films incorporated several different
`
`compounds such as cetylpyridine bromide or nonoxynol-9 in water-soluble
`
`polymer films and were manufactured as uniformly sized square dosages (5 x 5
`
`cm). EX1002, ¶43. Nonoxynol-9 loaded films have also been tested for the
`
`prevention of sexually transmitted infections. Roddy et al., A controlled trial of
`
`nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted
`
`diseases, 339 N. Engl. J. Med. 504-10, 504 (1998) (“Roddy”) (EX1010); see also
`
`EX1002, ¶44.
`
`Thereafter, films were adapted for a variety of drug delivery applications,
`
`including oral delivery of active ingredients. EX1002, ¶45. For example, U.S.
`
`Patent No. 4,569,837 to Suzuki et al. (“Suzuki”) (EX1011) discloses water-soluble
`
`cast film compositions containing antibacterial agents, such as chlorhexidine, for
`
`the treatment of periodontal disease. EX1011 at 2:51-59 & Example 1; see also
`
`EX1002, ¶45. Suzuki describes making cast films from viscous solutions (e.g.,
`
`30,000 CP) that resulted in films having a thickness of 260 microns. EX1011
`
`(Suzuki), 2:51-59 & Example 1; see also EX1002, ¶45. As another example, U.S.
`
`Patent No. 6,159,498 to Tapolsky et al. (“Tapolsky”) (EX1012) Tapolsky teaches
`
`the formulation of precipitated benzocaine (a numbing agent) in water-soluble cast
`
`-15-
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`
`
`
`
`films. EX1012 at 7:43-51; see also EX1002, ¶46. As still another example,
`
`Yamamura teaches incorporation of dibucaine (a numbing agent) in water-soluble
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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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`As Dr. Buckton explains, the body of prior art with which a skilled artisan
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`would have been acquainted prior to October 12, 2001, established several key
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`parameters and how they could be optimized during formulation of actives in cast
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`films. EX1002, ¶47. For example, the prior art extensively discussed the use of
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`water-soluble and water-swellable polymers to impart specific properties to cast
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`films. Id. at ¶48. In addition, the use of a viscous polymer solution to aid in
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`uniform dispersion of an active in the film-forming matrix, the identification of an
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`appropriate particle size for the active that would be compatible with the thickness
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`and usage of the films being created, as well as the use of taste-masking agents to
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`provide films for oral drug delivery that have an appealing taste were also known
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`in the art prior to October 12, 2001. Id. at ¶¶49-55.
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`As explained by Dr. Buckton, water-soluble and water-swellable polymers
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`were widely used in the art for their favorable properties, which were compatible
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`with films for oral drug delivery. Id. at ¶48. For example, Tapolsky teaches that
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`water-soluble polymers, which dissolve in body fluids and deliver drug, are
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`advantageous to use in the development of one-time use products. EX1012
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`(Tapolsky), 4:53-67; see also EX1002, ¶48. Schiraldi states that water-soluble and
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`water-swellable polymers are also useful in oral mucosal films for their adhesive
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`properties. U.S. Patent No. 4,713,243 to Schiraldi et al. (“Schiraldi”) (EX1014),
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`3:19-21 & 4:7-8; see also EX1002, ¶48. Loesche additionally discloses that films
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`can become controlled release films by inclusion of non-water soluble polymers,
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`which cause the cast film to dissolve more slowly. U.S. Patent No. 4,568,535 to
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`Loesche et al. (“Loesche”) (EX1015) at 7:66-8:11; see 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 to Zaffaroni et al. (“Zaffaroni”)
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`(EX1016) at 7:22-30; see also EX1002, ¶49. Heller states that active agents such as
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`micronized hydrocortisone, cortisone acetate, and β-estradiol can all be dispersed
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`in viscous polymer solutions. U.S. Patent No. 4,249,531 to Heller et al. (“Heller”)
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`(EX1017) at 22:1-6, 24:55-59, & 27:13-17; see also EX1002, ¶50. Suzuki and
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`Swei additionally teach specific viscosities that are sufficient to aid in substantially
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`maintaining uniformity of the active. EX1011 (Suzuki), 2:51-59 & Example 1 (5-
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`30,000 CP, 2080 CP in an embodiment); U.S. Patent No. 5,506,049 to Swei et al
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`(“Swei”) (EX1018) at 6:30-34 (10 cp-100,000 cp, more preferably 100 cp-10,000
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`cp); see also EX1002, ¶¶51-52. Swei further specifically notes that viscosity was
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`an important parameter in preventing particles suspended therein from settling and
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`that a sufficient viscosity for a given particular size could be determined using
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`Stoke’s Law. EX1018 (Swei), 6:1-19; see also EX1002, ¶52. Thus, as described by
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`Dr. Buckton, it was well established in the art as of October 12, 2001, that
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`viscosity was an important parameter for film formulations of suspended active
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`agents, both in the broad reaching disclosures by Zaffaroni and Heller and in the
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`specific viscosity ranges indicated by Suzuki and Swei, which fall squarely within
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`the preferred range of the ’514 patent. EX1002, ¶¶49-52. The skilled artisan would
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`have been equipped with this prior art that enables determining how much
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`viscosity sufficiently aids in achieving uniformity of distribution of the active
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`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. Id. at ¶¶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 to Bess et al. (“Bess”)
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`(EX1019) at 4:34-35& 13:5-7; see also EX1002, ¶¶53-54. In another example,
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`Schmidt teaches a particle size of 1-20 microns for use in films that ranged from
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`50-250 microns in total thickness. U.S. Patent No. 4,849,246 to Schmidt et al.
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`(“Schmidt”) (EX1020) at 4:67-5:2 & 3:47-48; see also EX1002, ¶¶53-54. Higashi
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`teaches a particle size of 105-177 microns for use in films that were 300 microns in
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`thickness. European Patent No. 0241178 to Higashi et al. (“Higashi”) (EX1021) at
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`7:28-35 & 7:44-46, Example 3; see also EX1002, ¶¶53-54. Thus, publications in
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`the field not only taught particle sizes less than 200 microns, but also confirmed
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`that particle sizes should be smaller than the thickness of the films such that they
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`are compatible with the films themselves. 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 agents is motivated by simply by
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`virtue of developing doses intended for oral drug delivery. EX1019 (Bess), 6:56-58;
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`see also EX1002, ¶55. A person of ordinary skill in the art would recognize that
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`oral dosages meant to dissolve in the mouth would benefit from incorporation of
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`any one of the taste-maskers described in the art to improve palatability of the
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`active and the overall taste of the cast films. EX1002, ¶55.
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`The skilled artisan working in this field would also be aware of drug content
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`uniformity standards mandated by various regulatory authorities. Id. at ¶56. For
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`example, the European Pharmacopeia requires that unit doses of drugs vary by no
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`more than 5-10% of the target dose and the United States Pharmacopeia requires
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`that unit doses of drugs vary by no more than 15% of the target dose. EX1020
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`(Schmidt), 1:63-68; The United States Pharmacopeia: 20th Revision and the
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`National Formulary, Fifteenth Edition. Rockville, Md: United States
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`Pharmacopeial Convention, Inc. (1979) (“USP”) (EX1022); see also EX1002, ¶56.
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`The ’514 patent itself recognizes that it was publicly known that, “Currently, as
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`required by various world regulatory authorities, dosage forms may not vary more
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`than 10% in the amount of active present. When applied to dosage units based on
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`films, this virtually mandates that uniformity in the film be present.” EX1001,
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`2:42-46. Thus, a person of ordinary skill in the art would endeavor to meet the
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`requirements of regulatory agencies in order to obtain a commercially viable
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`product that complies with pharmaceutical regulations. EX1002, ¶56.
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`II. GROUNDS FOR STANDING
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`Petitioner certifies that, under 37 C.F.R. § 42.104(a), the ’514 patent is
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`available for inter partes review, and Petitioner is not barred or estopped from
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`requesting inter partes review of the ’514 patent on the grounds identified.
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`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
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`Real Party-in-Interest (37 C.F.R. § 42.8(b)(1)): The following real parties-in-
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`