UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY’S LABORATORIES S.A. and
`DR. REDDY’S LABORATORIES, INC.
`Petitioners,
`v.
`
`MONOSOL RX, LLC
`Patent Owner.
`
`Patent No. 8,603,514
`
`DECLARATION OF BOZENA MICHNIAK-KOHN, PH.D.
`
`Dr. Reddy's - EX1002
`
`Page 1
`
`

`

`Table of Contents
`
`Page
`
`Qualifications.......................................................................................................................2
`I.
`Scope of Work .....................................................................................................................3
`II.
`Overview of the ’514 Patent ................................................................................................4
`III.
`File History of the ’514 Patent.............................................................................................6
`IV.
`Legal Standards..................................................................................................................10
`V.
`Level of Ordinary Skill and Relevant Time.......................................................................13
`VI.
`Claim Construction............................................................................................................14
`VII.
`VIII. The State of the Art............................................................................................................14
`IX.
`Asserted References Disclose or Suggest Each of the Claimed
`Features of the ’514 Patent ................................................................................................19
`A.
`Brief Overview of the Asserted References.......................................................... 19
`B.
`Detailed Analysis of the Claims ........................................................................... 27
`Concluding Statements ......................................................................................................44
`Appendix - List Of Exhibits...............................................................................................45
`
`X.
`XI.
`
`Page 2
`
`

`

`I, Bozena Michniak-Kohn, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`My name is Bozena Michniak-Kohn. I am a tenured Professor of Pharmaceutics
`
`in the Ernest Mario School of Pharmacy at Rutgers-The State University of New Jersey. I have
`
`been employed by Rutgers-The State University of New Jersey, initially as a tenured Associate
`
`Professor, and finally a full Professor, since 2005. In February 2011, I founded the Center for
`
`Dermal Research (CDR) at Rutgers-The State University of New Jersey and have served as the
`
`Director of the CDR since that time. In addition, I served all this time as the Director of the
`
`Laboratory for Drug Delivery at the NJ Center for Biomaterials, at Rutgers-The State University
`
`of New Jersey. I received my Ph.D in Pharmacology from De Montfort University in 1980.
`
`2.
`
`In 2016 I was appointed to the Board of Directors of the International
`
`Pharmaceutical Excipients Council of the Americas Foundation. I have also been a member of
`
`the Editorial Board for the Journal of Drug Research and Development since 2014.
`
`3.
`
`I currently serve as the Academic Chair of the Transdermal section of the Non-
`
`Invasive Macromolecule Consortium Working Group of the Catalent Applied Drug Delivery
`
`Institute (since 2014) and am a member of the faculty of the National Institute for
`
`Pharmaceutical Technology and Education (since 2014).
`
`4.
`
`I am the recipient of several awards and honors including the award of Fellow
`
`status of the American Association of Pharmaceutical Scientists, in July 2008.
`
`5.
`
`My research interests and experience focus on the optimization of topical,
`
`transdermal and transmucosal drug delivery, including sublingual drug delivery as well as the
`
`design and development of oral edible and transdermal drug containing polymer films.
`
`6.
`
`I have authored numerous publications related to drug delivery and formulation
`
`including Drying of biocompatible polymer films loaded with poorly water soluble drugs nano-
`
`-2-
`
`Page 3
`
`

`

`particles via low temperature forced convection, Int. J. Pharm. (2013), 445, 93-103; Preparation
`
`and characterization of hydroxypropyl methyl cellulose films containing stable BCS Class II
`
`drug nanoparticles for pharmaceutical applications, J. Pharmaceutics (2012), 423, 4960508;
`
`Synthesis and immobilization of microscale drug particles in polymeric films, (2011), Colloids
`
`and Surfaces B.: Bionterfaces (2011), 86(1), 181-188; and Preparation and characterization of
`
`hydroxypropyl methyl cellulose films containing stable BCS Class II drug nanoparticles for
`
`pharmaceutical applications, J. Pharmaceutics (2012), 423, 4960508.
`
`7.
`
`A summary of my education, experience, publications, patents, award and honors
`
`is provided in my CV, a copy of which is separately submitted as EX1003.
`
`II.
`
`SCOPE OF WORK
`
`8.
`
`I understand Mylan Technologies, Inc. (“Mylan”) has filed a petition for inter
`
`partes review challenging claims of U.S. Patent No. 8,603,514 (“the ’514 patent”). I have
`
`reviewed and considered Mylan’s IPR petition and the accompanying Declaration of Graham
`
`Buckton, Ph.D.. Applying my independent judgment and expertise, and after having
`
`independently reviewed and analyzed all of the materials that Dr. Buckton considered, and after
`
`having done the additional work of fact checking and considering whether potential
`
`counterarguments may exist, I have come to the same conclusions as Dr. Buckton regarding the
`
`obviousness of the ’514 patent. I agree with the analysis in his declaration as set forth below.
`
`For the sake of efficiency, given that I agree with Dr. Buckton’s analysis, I have adopted much
`
`of the language and organization from his declaration rather than needlessly rewriting passages.
`
`The opinions in this declaration are mine.
`
`9.
`
`I am being compensated at the rate of $650.00/hour for my time in this matter and
`
`I have no financial interest in the outcome.
`
`-3-
`
`Page 4
`
`

`

`III.
`
`OVERVIEW OF THE ’514 PATENT
`
`10.
`
`The ’514 patent is entitled “Uniform Films For Rapid Dissolve [sic] Dosage Form
`
`Incorporating Taste-Masking Compositions.” The first page of the patent states that an
`
`application for the ’514 patent (U.S. Application No. 11/775,484, “the ’484 application”) was
`
`filed on July 10, 2007 and claims priority to several applications. The patent states that the ’484
`
`application is a continuation-in-part of U.S. Application No. 10/768,809 (“the ’809 application).
`
`The ’809 application is itself a continuation-in-part application of PCT/US02/32594,
`
`PCT/US02/32542, and PCT/US02/32575, which were all filed on October 11, 2002. The earliest
`
`claimed priority date of the ’484 application is October 12, 2001, the filing date of U.S.
`
`Provisional Application No. 60/328,868 (“the ’868 application”).
`
`11.
`
`I am informed that a federal judge has found that the ’514 patent is only entitled
`
`to the benefit of U.S. Provisional Application No. 60/414,276 (“the ’276 application”) filed on
`
`September 27, 2002. For the purposes of my declaration and the prior art presented in the
`
`grounds herein, however, I have assumed that the applicable date is the earliest priority date
`
`claimed in the ’514 patent, October 12, 2001. However, the outcome of my opinions does not
`
`depend on which of these dates is used.
`
`12.
`
`The claims of the ’514 patent are generally directed to drug delivery film
`
`compositions made of water-soluble or water-swellable polymers. Independent claim 62 of the
`
`’514 patent recites the following:
`
`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;
`
`-4-
`
`Page 5
`
`

`

`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 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.
`
`EX1001 at 73:48-74:9.
`
`13.
`
`Claims 63-65 and 69-73 each depend directly from claim 62. Claims 63 and 64
`
`respectively recite that the particle size of the active is 150 microns or less and 100 microns or
`
`less. EX1001 at 74:10-13. Claim 65 recites that the variation in drug content is less than 5% by
`
`weight between film dosage units. Id. at 74:14-16. Claim 69 recites that the taste masking agent
`
`is present at 0.1-30% by weight of the entire composition. Id. at 74:29-31. Claim 70 recites that
`
`the taste masking agent is present at 0.01-10% by weight of the entire composition. Id. at 74:32-
`
`34. Claim 71 recites that the active is chosen from one of several drugs classes, including
`
`narcotics, analgesics, erectile dysfunction therapies, and combinations thereof. Id. at 35-45.
`
`Claim 72 recites that the viscosity of the film forming matrix is an amount that prevents the
`
`active agent from settling out during mixing or coating. Id. at 46-49. Claim 73 recites that the
`
`active is an opiate or opiate derivative. Id. at 50-51.
`
`-5-
`
`Page 6
`
`

`

`14.
`
`Independent claim 1 of the ’514 patent is similar to independent claim 62, but
`
`requires that the taste masking agent be “coated or intimately associated with said particulate to
`
`provide taste-masking of the active” instead of requiring that the taste-masking agent be a flavor,
`
`sweetener, or flavor enhancer. EX1001 at 67:34-56. Claims 2, 3, 9, 15, and 75 depend directly
`
`from claim 1. Claims 2 and 3 respectively recite a combined particulate and taste-masking agent
`
`particle size of 150 microns and 100 microns. Id. at 67:57-62. Claim 9 recites that the variation
`
`in drug content is less than 5% by weight between film dosage units. Id. at 68: 30-32. Claim 15
`
`recites that the active of the drug delivery composition is chosen from one of several drug
`
`classes, including narcotics, analgesics, erectile dysfunction therapies, and combinations thereof.
`
`Id. at 68:50-59. Claim 75 recites that the active is an opiate or opiate derivative and that the taste
`
`masking agent is one of the following: flavors, sweeteners, flavor enhancers, and combinations
`
`thereof. Id. at 74:53-56.
`
`IV.
`
`FILE HISTORY OF THE ’514 PATENT
`
`15.
`
`As noted above, the ’514 patent issued from the ’484 application and claims the
`
`benefit of October 12, 2001 as its earliest effective filing date.
`
`16.
`
`Applicants removed claim limitations directed to a “controlled release agent” on
`
`July 7, 2010 in response to a Restriction Requirement. EX1004 at 949-950, 955-956. Despite
`
`the title of the ’514 patent, the specification and issued claims of the ’514 patent are compatible
`
`with films with either a rapid or a slow release rate. For example, the ’514 patent states:
`
`“The term “controlled release” is intended to mean the release of active at a pre-selected
`
`or desired rate...Desirable rates include fast or immediate release profiles as well as
`
`delayed, sustained or sequential release...The polymers that are chosen for the films of
`
`the present invention may also be chosen to allow for controlled disintegration of the
`
`active. This may be achieved by providing a substantially water insoluble film that
`
`-6-
`
`Page 7
`
`

`

`incorporates an active that will be released from the film over time. This may be
`
`accomplished by incorporating a variety of different soluble or insoluble polymers and
`
`may also include biodegradable polymers in combination.”
`
`EX1001 at 13:5-20
`
`17.
`
`The ’514 patent also identifies certain advantages of slow release films:
`
`“The convenience of administering a single dose of a medication which releases active
`
`ingredients in a controlled fashion over an extended period of time as opposed to the
`
`administration of a number of single doses at regular intervals has long been recognized
`
`in the pharmaceutical arts. The advantage to the patient and clinician in having
`
`consistent and uniform blood levels of medication over an extended period of time are
`
`likewise recognized. The advantages of a variety of sustained release dosage forms are
`
`well known. However, the preparation of a film that provides the controlled release of an
`
`active has advantages in addition to those well-known for controlled-release tablets. For
`
`example, thin films are difficult to inadvertently aspirate and provide an increased
`
`patient compliance because they need not be swallowed like a tablet. Moreover, certain
`
`embodiments of the inventive films are designed to adhere to the buccal cavity and
`
`tongue, where they controllably dissolve.”
`
`Id. at 13:30-46.
`
`18.
`
`The challenged claims have no limitation with respect to dissolution or drug
`
`release rates, either expressly or implicitly. Thus, the ’514 patent teaches and claims films that
`
`are compatible with both rapidly dissolving and slowly dissolving films.
`
`19.
`
`The Examiner issued an Office Action on September 9, 2010 rejecting all claims
`
`of the ’484 application as anticipated under 35 U.S.C. §102(e) by U.S. Patent No. 7,067,116
`
`(“Bess”). EX1004 at 963-973. The Examiner stated that Bess disclosed orally dissolvable films
`
`-7-
`
`Page 8
`
`

`

`with active agents and taste masking agents and thus anticipated the claims. Id. at 966-969. The
`
`Examiner also rejected all claims as obvious under §103, over WO2000/42992 (EX1006,
`
`“Chen”) in view of U.S. Patent No. 5,653,993 (“Ghanta”). The Examiner stated that Chen
`
`disclosed water-soluble films with an active agent and taste-masking agents, including
`
`encapsulation of the active agent in a material other than the hydrocolloid of the film-forming
`
`matrix to mask taste. Id. at 969-971. The Examiner relied on Ghanta’s disclosure of taste-
`
`masked microcapsules that do not aggregate, and stated that in combination, Chen in view of
`
`Ghanta taught all of the elements of the claimed invention. Id. at 969-971. The Examiner also
`
`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 Schiraldi in view of U.S. Publication No.
`
`2004/0156901 (“Thakur”). Id. at 971-973.
`
`20.
`
`Applicants responded on December 9, 2010 by amending the claims to require
`
`that “the uniformity is determined by the composition having a variation of drug content of less
`
`than 10% per film unit. Id. at 999. Applicants primarily argued that neither Bess nor Chen in
`
`view of Ghanta disclosed such uniformity, which Applicants said that they had achieved using
`
`certain drying methods. Id. at 1009-1010.
`
`21.
`
`The Examiner responded in a Final Office Action on February 2, 2011
`
`maintaining all rejections and stating that the Applicants’ arguments were not persuasive. Id. at
`
`1162-1172. The Examiner stated that the prior art references do in fact disclose obtaining
`
`uniform solutions for film casting. Id. at 1165, 1169.
`
`22.
`
`Applicants responded on April 4, 2011 by amending the claims to add the
`
`limitation that the film-forming matrix comprised two or more substantially water soluble or
`
`water swellable polymers (this limitation was later changed to “one or more” Id. at 1298) and a
`
`-8-
`
`Page 9
`
`

`

`viscosity sufficient to maintain non-self-aggregating uniformity of the active. Id. at 1180.
`
`Applicants argued that none of the references taught the claim element of a viscosity for
`
`maintaining uniformity of the active. Id. at 1191, 1194. Applicants further stated that
`
`“uniformity is determined by the composition having a variation of drug content of less than
`
`10% per film dosage unit, as claimed.” Id. at 1194. Applicants submitted a supplemental
`
`amendment on April 15, 2011, amending several dependent claims to specify that drug variance
`
`is less than 5%, 2%, or 0.5% “per film dosage unit” rather than “per film unit.” Id. at 1207.
`
`Applicants also submitted a request for continued examination (RCE) and a petition for
`
`extension of time on June 1, 2011. Id. at 1223-1227.
`
`23.
`
`The Examiner issued an Office Action on June 19, 2012 maintaining the
`
`rejections based on the same references and arguments used previously. Id. at 1241-1253.
`
`Applicants responded on December 19, 2012, amending the claims to introduce the limitation
`
`that the films are cast film compositions, that uniformity was directed to uniformity after casting
`
`and drying, and that uniformity was measured in substantially equally sized individual unit
`
`doses. Id. at 1264.
`
`24.
`
`The Examiner issued a Final Office Action on March 13, 2013 maintaining the
`
`rejections over Bess and Chen in view of Ghanta and 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 not hold patentable weight in a composition claims [sic].” Id. at
`
`1290. The Examiner further stated that, “the skilled artisan would have understood the
`
`importance of providing a homogenous film in order to ensure appropriate dosing of active
`
`agents to provide correct efficacy of the drug to the patient’’ Id. at 1293.
`
`-9-
`
`Page 10
`
`

`

`25.
`
`On May 10, 2013, Applicants submitted an amendment and response after Final
`
`Office Action. Id. at 1297. Applicants stated that they had presented the Examiner with the
`
`declaration of B. Arlie Bogue (“Bogue Declaration”) during a May 1, 2013 interview to show
`
`uniformity of the claimed films. Id. at 1316. Applicants further stated that Figure 5 of Chen had
`
`been discussed to demonstrate that Chen’s films varied by greater than 10% of the active. Id.
`
`Applicants stated that the Examiner agreed in this interview that the combination of the Chen
`
`and Bess references had been overcome. Id. I have reviewed the Bogue Declaration and note
`
`that although it describes assessing certain films for active uniformity, it makes no mention of
`
`the use of taste-masking agents or the particle size of the active. Declaration of B. Arlie Bogue,
`
`March 13, 2013; Reexamination Control No. 95/002,170 (EX1007) at 2-3.
`
`26.
`
`The Examiner issued a Notice of Allowance on June 14, 2013. Id. at 1329.
`
`Applicants filed an Amendment after Notice of Allowance along with a detailed interview
`
`summary on June 18, 2013. Id. at 1351. In the detailed interview summary, Applicants stated
`
`that neither Chen nor Bess teach film dosage units with less than 10% variation in the amount of
`
`active. Id. at 1368. The Examiner issued an applicant-initiated interview summary on May 1,
`
`2013 stating that the Applicants presented a declaration and arguments regarding the teachings of
`
`Bess and Chen. Id. at 1375. The Examiner stated that the pending claims were allowable in
`
`light of the arguments made by the applicant and after review of Figure 5 of Chen. The Examiner
`
`further stated that “neither Bess nor Chen inherently result in a film having a uniformity in which
`
`the individual unit does not vary by more than 10% of the active.” Id.
`
`V.
`
`LEGAL STANDARDS
`
`27.
`
`I have been informed that a claimed invention is not patentable under 35 U.S.C.
`
`§ 103, for obviousness, if the differences between the invention and the prior art are such that the
`
`subject matter as a whole would have been obvious at the time the invention was made to “a
`
`-10-
`
`Page 11
`
`

`

`person having ordinary skill in the art” to which the subject matter of the invention pertains. I
`
`understand that “a person of ordinary skill in the art” is a hypothetical person who is presumed to
`
`have known the relevant art at the time of the invention. As discussed above, I understand that
`
`prior art for the purpose of this declaration includes references that were published before
`
`October 12, 2001.
`
`28.
`
`I have been instructed that, a determination of obviousness requires inquiries into
`
`(i) the scope and content of the art when the invention was made; (ii) the differences between the
`
`art and the claims at issue; (iii) the level of ordinary skill in the pertinent art when the invention
`
`was made; and, to the extent they exist, any secondary considerations.
`
`29.
`
`I am informed that a claim can be found to be obvious if all the claimed elements
`
`were known in the prior art and one skilled in the art could have combined the elements as
`
`claimed by known methods with no change in their respective functions, and the combination
`
`would have yielded nothing more than predictable and expected results to one of ordinary skill in
`
`the art.
`
`30.
`
`I am informed that improper hindsight must not be used when comparing the prior
`
`art to the invention for obviousness. Thus, a conclusion of obviousness must be firmly based on
`
`the knowledge and skill of a person of ordinary skill in the art at the time the invention was
`
`made.
`
`31.
`
`I have been informed that obviousness may also be shown by demonstrating that
`
`it would have been obvious to modify what is taught in a single piece of prior art to create the
`
`patented invention. I understand that obviousness may be demonstrated by showing that it
`
`would have been obvious to combine the teachings of more than one item of prior art. I
`
`understand that in order for a combination of references or teachings to render the claimed
`
`-11-
`
`Page 12
`
`

`

`invention obvious, there must be some supporting rationale for combining the cited references or
`
`teachings as proposed.
`
`32.
`
`I am informed that the following are examples of principles that may indicate that
`
`it would have been obvious to combine multiple teachings, resulting in the claimed combination,
`
`if the claimed combination involves: (i) the combination of prior art elements according to
`
`known methods to yield predictable results; (ii) the simple substitution of one known element for
`
`another to obtain predictable results; (iii) the use of a known technique to improve similar
`
`methods or products in the same way; (iv) the application of a known technique to a known
`
`method or product ready for improvement to yield predictable results; (v) the application of a
`
`technique or approach that would have been “obvious to try” (e.g., choosing from a finite
`
`number of identified, predictable solutions, with a reasonable expectation of success); (vi)
`
`predictable variations of a known work in one field of endeavor prompted for use in either the
`
`same field or a different field based on design incentives or other market forces; or (vii) some
`
`teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to
`
`modify the prior art reference or to combine prior art reference teachings to arrive at the claimed
`
`invention.
`
`33.
`
`I have been instructed that “secondary considerations” may be weighed against
`
`evidence of obviousness where appropriate. I understand that such secondary considerations,
`
`where in evidence, may include: (i) commercial success of a product due to the merits of the
`
`claimed invention; (ii) a long-felt, but unsatisfied need for the invention; (iii) failure of others to
`
`find the solution provided by the claimed invention; (iv) deliberate copying of the invention by
`
`others; (v) unexpected results achieved by the invention; (vi) praise of the invention by others
`
`skilled in the art; (vii) lack of independent simultaneous invention within a comparatively short
`
`-12-
`
`Page 13
`
`

`

`space of time; and (viii) teaching away from the invention in the prior art. I am informed that
`
`secondary considerations are relevant where there is a nexus between the evidence and the
`
`claimed invention.
`
`VI.
`
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`34.
`
`I have been advised that “a person of ordinary skill in the relevant field” is a
`
`hypothetical person who is presumed to have known the relevant art at the time of the invention.
`
`I am informed that a person of ordinary skill in the art is also a person of ordinary creativity. I
`
`have assumed for the purposes of this declaration that the relevant timeframe for assessing the
`
`patentability of the claims of the ’514 patent for the purposes of this declaration is October 12,
`
`2001, the earliest effective filing date of the application that led to the ’514 patent. Unless
`
`otherwise specifically noted, all of my opinions expressed herein regarding a person of ordinary
`
`skill in the art apply to a person of ordinary skill in the art as of October 12, 2001. However, the
`
`outcome of my opinions would not be different if a later date, such as September 27, 2002, was
`
`used.
`
`35.
`
`I have been asked to assume for purposes of this IPR that a person of ordinary
`
`skill in the relevant field as of October 12, 2001 would have been as Dr. Buckton describes, i.e.,
`
`would typically have had a Ph.D. in pharmaceutics, or in a drug delivery relevant field of a
`
`related discipline such as physical or polymer chemistry, or could have had a bachelor’s degree
`
`in pharmaceutics or a related field, plus two to five years of relevant experience in developing
`
`drug formulations. Additionally, a person of ordinary skill in the art would have been familiar
`
`with and able to understand the information known in the art relating to film formulations for
`
`mucosal applications and delivery of pharmaceutical drugs, including the publications discussed
`
`in this declaration.
`
`-13-
`
`Page 14
`
`

`

`VII. CLAIM CONSTRUCTION
`
`36.
`
`I have been advised that, in the present proceeding, the ’514 patent claims are to
`
`be given their broadest reasonable interpretation in view of the specification. I have been asked
`
`to apply Dr. Buckton’s interpretation of the phrase “flowable water-soluble or water swellable
`
`film-forming matrix” that appears in claims 1 and 62, i.e., that the phrase refers to the flowability
`
`of the film-forming matrix prior to casting and drying the film.
`
`VIII. THE STATE OF THE ART
`
`37.
`
`Below I describe some of the relevant aspects of what was generally known in the
`
`art as of October 12, 2001.
`
`38.
`
`Film dosage formulations are well-known in the art and have been utilized for
`
`decades to deliver active pharmaceutical ingredients to mucosal surfaces. In the early 1970s, the
`
`contraceptive film (“C-film”) was developed to deliver spermicidal agents to the vaginal mucosa.
`
`Frankman et al., Clinical evaluation of C-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. This drug delivery system involved formulation of spermicidal
`
`agents, such as cetylpyridine bromide or nonoxynol-9, in water-soluble polyvinyl alcohol films.
`
`EX1008 (Frankman) at 292. C-films were provided as square dosage units (5 x 5 cm), which
`
`would rapidly dissolve after mucosal application to deliver efficacious levels of spermicide. Id.
`
`39.
`
`Films for vaginal delivery of agents were also used to test efficacy of active
`
`agents 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). Thus, the notion of utilizing polymer-
`
`based films for delivery of actives was well established in the field for nearly thirty years prior to
`
`the alleged priority date of the ’514 patent.
`
`-14-
`
`Page 15
`
`

`

`40.
`
`Films for oral delivery of active agents were also known years before the earliest
`
`claimed priority date of the ’514 patent. For example, films for oral delivery were developed for
`
`the treatment of periodontal diseases. U.S. Patent No. 4,569,837 to Suzuki et al. (“Suzuki”)
`
`(EX1011). Suzuki discloses compositions made from water-soluble film forming polymers with
`
`viscous solutions (e.g., 530,000 centipoise (which in various texts, quoted below is abbreviated
`
`to “cps,” “cp,” “CP,” and which I refer to as “cP”)), resulting in cast films measuring 260
`
`microns thick for the delivery of antibacterial agents, such as chlorhexidine, to the periodontal
`
`pocket using film. EX1011 (Suzuki) at 2:51-59 and Example 1.
`
`41.
`
`As another example, films for the oral delivery of local numbing agents were
`
`known. U.S. Patent No. 6,159,498 to Tapolsky et al. (“Tapolsky”) (EX1012) at 7:43-51;
`
`Yamamura et al., Oral mucosal adhesive film containing local anesthetics: in vitro and clinical
`
`evaluation. 43 J Biomed Mater Res. 313317, 313 (1998) (“Yamamura”) (EX1013). Tapolsky
`
`teaches formulations of precipitated benzocaine in water-soluble hydroxyethyl cellulose /
`
`polyacrylic acid / sodium carboxymethyl cellulose films. EX1012 (Tapolsky) at 11:15-20.
`
`Yamamura teaches formulation of dibucaine in polymer films made from hydroxypropyl
`
`cellulose-M. EX1013 (Yamamura) at 313.
`
`42.
`
`As discussed in further detail in the paragraphs that follow, key parameters for
`
`optimizing film properties for drug delivery were also known in the art.
`
`43.
`
`Regarding polymer selection, it was well-established in the art that water-soluble
`
`and/or water-swellable polymer can be used to vary film properties. Specifically, it was known
`
`that water-soluble polymers are capable of dissolving in response to hydration by body fluids.
`
`EX1012 (Tapolsky) at 4:53-67. Advantageously, the use of water-soluble polymers allowed for
`
`the development of one-time use products, rather than products that need to be removed by a
`
`-15-
`
`Page 16
`
`

`

`user after drug release. Id. Schiraldi teaches that the use of water-soluble or water-swellable
`
`polymers in film matrices is particularly useful for the purposes of bioadhesion to mucosal
`
`surfaces. U.S. Patent No. 4,713,243 to Schiraldi et al. (“Schiraldi”) (EX1014) at 3:19-21, 4:7-8.
`
`Loesche teaches modulating the speed of active drug release by employing non-water soluble
`
`polymers to slow the dissolution rate of the film. U.S. Patent No. 4,568,535 to Loesche et al.
`
`(“Loesche”) (EX1015) at 7:66-8:11.
`
`44.
`
`It was also well known that viscosity of the polymer matrix was a key parameter
`
`for film casting. For example, Zaffaroni teaches the preparation of drug loaded bandages made
`
`by casting a film from a solution containing polymer and drug. Zaffaroni states,
`
`“Thus, the drug can be added to the rate controlling material in liquid form and
`
`uniformly distributed therethrough by mixing, and subsequently converted to a
`
`microporous structure by the various methods known to the art. One such method calls
`
`for dissolving a natural or synthetic polymer in a suitable solvent in which it has
`
`sufficiently solubility to permit the preparation of a solution that is sufficiently viscous for
`
`conventional film casting.”
`
`U.S. Patent No. 3,797,494 to Zaffaroni et al. (“Zaffaroni”) (EX1016) at 7:22-30.
`
`45.
`
`As another example, Heller discloses several examples of producing cast polymer
`
`films for delivering active agents, including formulation of micronized hydrocortisone, cortisone
`
`acetate, and (3-estradiol. U.S. Patent No. 4,249,531 to Heller et al. (“Heller”) (EX1017) at 22:1-
`
`6, 24:55-59, 27:13-17. In all these examples, Heller discloses that the solution containing the
`
`polymer and active is a “viscous dispersion” or a “viscous solution,” which is subsequently cast
`
`into a film. Id.
`
`-16-
`
`Page 17
`
`

`

`46.
`
`As another example, Suzuki teaches formulation of antibacterial agents with
`
`water-soluble film forming polymers that have a viscosity of 5-30,000 CP, such as 2080 CP in
`
`one embodiment. EX1011 (Suzuki) at 2:51-59 and Example 1.
`
`47.
`
`The teachings of Zaffaroni, Heller, and Suzuki regarding the use of a viscous
`
`solution for drug-delivery film casting are consistent with general teachings regarding cast films
`
`in other applications. For example, Swei teaches a casting composition of polymer and
`
`particulate filler. U.S. Patent No. 5,506,049 to Swei et al (“Swei”) (EX1018) at 5:51-58. Swei
`
`expressly notes the importance of optimizing viscosity to prevent filler particles from settling
`
`and relates how to determine an appropriate viscosity for a specific particle size, in keeping with
`
`the well-known, and long established, use of Stoke’s Law to control th