UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`MYLAN TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`MONOSOL RX, LLC,
`Patent Owner.
`____________
`
`Case IPR2017-00200
`Patent 8,603,514
`__________________
`
`DECLARATION OF ROBERT S. LANGER, Sc.D.
`
`Mylan v. MonoSol
`IPR2017-00200
`MonoSol Ex. 2007
`
`Page 1
`
`

`

`Table of Contents
`
`INTRODUCTION ..........................................................................................1
`I.
`SCOPE OF THIS DECLARATION ..............................................................2
`II.
`III. MATERIALS CONSIDERED.......................................................................3
`IV.
`SUMMARY OF QUALIFICATIONS...........................................................3
`V.
`COMPENSATION.........................................................................................8
`VI.
`LEGAL STANDARDS AND LEVEL OF SKILL ........................................8
`A.
`Petitioner’s Burden Of Proof................................................................8
`B.
`Person Of Ordinary Skill In The Art....................................................8
`C.
`Obviousness........................................................................................11
`D.
`Claim Construction.............................................................................12
`VII. SUMMARY OF OPINIONS........................................................................13
`VIII. REVIEW OF THE DISCLOSURES OF THE ’514 PATENT....................15
`A.
`The ’514 Patent ..................................................................................15
`1.
`The ’514 Patent Claims At Issue .............................................15
`2.
`The Problem Addressed By The ’514 Patent...........................19
`3.
`Drug Migration Was Generally Not A Problem When
`Unit Doses Were Made In Individual Molds That Prevent
`Migration To Other Dosing Units............................................22
`The ’514 Patent Distinguishes Approaches In Which Unit
`Doses Are Made In Individual Wells From The DCU
`Problem Addressed In The Patent ...........................................23
`A POSA Would Understand The Claims Of The ’514
`Patent, Under Their Broadest Reasonable Construction,
`As Directed To Individual Unit Doses That Are Taken
`From A Single Film Matrix .....................................................23
`a.
`The Panel’s Statement On Construction In The
`Decision To Institute .....................................................24
`The Express Language Of The Claims Concerns A
`Film Matrix Subdivided Into Individual Unit
`Doses..............................................................................25
`
`4.
`
`5.
`
`b.
`
`-i-
`
`Page 2
`
`

`

`IX.
`
`6.
`
`2.
`
`3.
`
`Understanding The Claims As Limited To A
`Multi-Dose Film Is The Only Interpretation
`Consistent With The Specification................................26
`The Specification Clearly Identifies The
`Preparation Of Unit Doses In Individual Molds As
`An “Alternative” To The Claimed Invention................30
`The File History Also Indicates The Claims Are
`Directed To The Multi-Dose Film Interpretation..........31
`The 10% Drug Content Uniformity Limitation:
`Substantially Equally Sized Individual Unit Doses Which
`Do Not Vary By More Than 10% Of The Desired
`Amount Of Active....................................................................31
`THE ’514 PATENT CLAIMS WERE NOT OBVIOUS OVER
`ILANGO AND CHEN .................................................................................33
`A.
`State Of The Art At The Date Of Invention.......................................35
`1.
`Pharmaceutical Films Were A Relatively New Dosage
`Form.........................................................................................35
`Little Was Known About The Causes Of Loss Of Drug
`Content Uniformity In Individual Dosing Units Taken
`From A Single Matrix, Much Less Solutions For That
`Problem ....................................................................................36
`Prior Art Films Dr. Buckton Discusses Do Not Mention
`DCU .........................................................................................44
`a.
`The Roddy, Frankman, Brode References ....................45
`b.
`The Suzuki Reference....................................................48
`c.
`The Tapolsky And Yamamura References....................49
`d.
`The Heller Reference.....................................................50
`e.
`The Schiraldi, Loesche And Zaffaroni References .......50
`f.
`The Bess, Schmidt And Higashi References.................51
`The Swei Reference .................................................................56
`4.
`Publications That Post-Date The Invention Of The ’514 Patent
`Acknowledge The Problems It Addressed And Confirm It Was
`A Novel Solution................................................................................59
`
`B.
`
`c.
`
`d.
`
`e.
`
`-ii-
`
`Page 3
`
`

`

`2.
`
`3.
`
`4.
`
`1.
`
`V.A. Perumal et al., “Investigating A New Approach to
`Film Casting For Enhanced Drug Content Uniformity In
`Polymeric Films,” Drug Dev. & Indust. Pharm.,
`34:1036–1047 (2008) (“Perumal 2008,” Ex. 2005).................61
`V. A. Perumal, “Multipolymeric Monolayered
`Mucoadhesive Films For Drug Therapy,” Master’s
`Thesis (2007) (“Perumal Thesis”; Ex. 2009)...........................70
`Morales et al., “Manufacture And Characterization Of
`Mucoadhesive Buccal Films,” European Journal Of
`Pharmaceutics And Biopharmaceutics, 77:187–199
`(2011) (“Morales 2011”; Ex. 2003).........................................77
`Morales et al., “The Influence Of Recrystallized Caffeine
`On Water-Swellable Polymethacrylate Mucoadhesive
`Bucca Films,” AAPS PharmSciTech, Vol. 14, No. 2,
`475–484 (2013) (“Morales 2013”; Ex. 2010)..........................80
`Deficiencies In The Ilango And Chen References Cited By
`Dr. Buckton ........................................................................................82
`1.
`Ilango et al., “In-Vitro Studies On Buccal Strips Of
`Glibenclamide Using Chitosan,” Indian J. Pharm. Sci.
`59:232–35 (1997) (“Ilango”; Ex. 1005)...................................83
`a. What Ilango Discloses Generally ..................................88
`b.
`Ilango Lacks Clear Descriptions Of Its Methods
`And Its Disclosure Is Insufficient To Allow
`Reproduction..................................................................89
`Ilango Provides No Evidence That The Drug
`Remained In Particle Form, As Opposed To
`Being Dissolved.............................................................92
`Ilango Provides No Teaching Of How To Utilize
`Viscosity To Solve DCU, And That Ilango Relies
`On Evaporation At Room Temperature And Does
`Not Add Heat In Drying Underscores That Ilango
`Is Not Addressing The DCU Problem Solved By
`The ’514 Patent..............................................................98
`
`C.
`
`c.
`
`d.
`
`-iii-
`
`Page 4
`
`

`

`e.
`
`f.
`
`Ilango’s Teachings Related To Making Unit Doses
`Individually In Molds Would Not Lead A Person
`Of Ordinary Skill To The Claimed Invention,
`Which Requires A Multi-Dose Film From Which
`Multiple Individual Unit Doses Are Taken...................99
`There Is No Evidence That Ilango’s Statement
`About Content Variation Related To A “Desired
`Amount” Of Drug In Each Strip Dosage Unit,
`Much Less That The Drug Content Of The Strips
`Varied By Less Than 10% Of That Amount...............102
`Chen Application WO2000/42992 (“Chen”; Ex. 1006)........109
`2.
`The ’514 Patent Claims Are Not Obvious Over Ilango And
`Chen..................................................................................................118
`1.
`There Was No Motivation For A Person of Ordinary
`Skill To Combine Ilango And Chen ......................................119
`A Person Of Ordinary Skill Would Not Have Reasonably
`Expected That The Combination Of Ilango And Chen
`Would Lead To The Invention Of The ’514 Patent
`Claims ....................................................................................122
`
`2.
`
`D.
`
`-iv-
`
`Page 5
`
`

`

`Exhibit No.
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`2008
`2009
`
`2010
`
`2011
`2012
`2013
`
`EXHIBIT LIST
`
`Description
`Trial Transcript, Reckitt Benckiser Pharms
`Inc. v. Watson Laboratories, Inc. et al., CA
`No. 14-1574-RGA (Nov. 3-4, 2015) (“Trial
`Tr.”)
`Reckitt Benckiser Pharmaceuticals Inc. v.
`Watson Laboratories, Inc. et al., Civil Case
`No. 1:13-1674, slip opinion (D. Del. June 3,
`2016) (Richard G. Andrews, J.) (Reckitt v.
`Watson)
`J. O. Morales and J. T. McConville,
`Manufacture and Characterization of
`Mucoadhesive Buccal Films, European
`Journal of Pharmaceutics and v
`Biopharmaceutics 77, pp. 187-99 (2011)
`A. F. Borges et al., Oral Films: Current Status
`and Future Perspectives II – Intellectual
`Property, Technologies and Market Needs,
`Journal of Controlled Release 206, pp. 108–21
`V.A. Perumal et al., Investigating a New
`Approach to Film Casting for Enhanced Drug
`Content Uniformity in Polymeric Films, Drug
`Dev. & Indust. Pharm. 34, pp. 1036-47 (2008)
`H. Kathpalia and A. Gupte, An Introduction to
`Fast Dissolving Oral Thin Film Drug Delivery
`Systems: A Review, Drug Delivery &
`Formulation 10, pp. 667-84 (2013)
`Declaration of Dr. Robert Langer
`Deposition Transcript of Dr. Graham Buckton
`V. A. Perumal, “Multipolymeric Monolayered Mucoadhesive
`Films for Drug Therapy,” Master’s Thesis (2007)
`Morales et al., “The Influence of Recrystallized Caffeine on
`Water-Swellable Polymethacrylate Mucoadhesive Bucca Films,”
`AAPS PharmSciTech, Vol. 14, No. 2, 475–484 (2013)
`U.S. Provisional App. Ser. No. 60/443,741
`Curriculum Vitae of Dr. Robert Langer
`C.A. No. 1:14-cv-1451-RGA, Trial Tr.
`
`-v-
`
`Page 6
`
`

`

`Lachman, L. et al., The Theory and Practice of
`Pharmacy (3d ed. 1986)
`S. Puttipipatkhachorn et al., “Drug physical state and drug-
`polymer interaction on drug release from chitosan matrix films”
`(2001)
`J. Siepmann and N. Peppas entitled “Modeling of drug release
`from delivery systems based on hydroxypropyl methylcellulose”
`(2001)
`Compos-Aldrete et al., “Influence of the viscosity grade and the
`particle size of HPMC on metronidazole release from matrix
`tablets”,
`European
`Journal
`of
`Pharmaceutics
`and
`Biopharmaceutics, 43:173–178 (1997)
`James E. De Muth, Basic Statistics and Pharmaceutical Statistical
`Applications (2d ed. 2006)
`Staniforth, J.N., “Particle size analysis,” Pharmaceutics – The
`Science of Dosage Form Design (Aulton ed.), Ch. 33 at p. 578
`(1988)
`P. Perugini et al., “Periodontal delivery of ipriflavone: new
`chitosan/PLGA film delivery system for a lipophilic drug,” Int’l J.
`of Pharmaceutics, 252:1–9 (2003)
`J. Yoo et al., “The physicodynamic properties of mucoadhesive
`polymeric films developed as female controlled drug delivery
`system,” Int’l J. of Pharmaceutics, 309:139–145 (2006)
`A. Dhanikula et al., “Development and Characterization of
`Biodegradable Chitosan Films for Local Delivery of Paclitaxel,”
`The AAPS Journal, 6(3):1–12 (2004)
`A. Ahmed et al., “Penciclovir solubility in Eudragit films: a
`comparison of X-ray,
`thermal, microscopic and release rate
`techniques,” J. Pharm. & Biomedical Analysis, 34:945–956
`(2004)
`C. Amnuaikit et al., “Skin permeation of propranolol from
`polymeric film containing terpene enhancers for transdermal use,”
`Int’l J. of Pharmaceutics, 289:167–178 (2005)
`U.S. Patent No. 7,425,292 to Yang et al.
`Sigma-Aldrich
`Product
`Information
`(Anhydrous)
`Shakeel et al., “Thermodynamics-based mathematical model for
`solubility prediction of glibenclamide in ethanol–water mixtures,”
`Pharm. Dev. Technol., 2014; 19(6): 702–707
`
`Sheet
`
`re Caffeine
`
`Industrial
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`2026
`
`2027
`
`-vi-
`
`Page 7
`
`

`

`2028
`2029
`
`2030
`
`2031
`
`USP 905 (2002)
`Donald J. Wheeler, Advanced Topics in Statistical Process
`Control (1st ed. 1995)
`James E. De Muth, Basic Statistics and Pharmaceutical Statistical
`Applications (1st ed. 1999)
`David S. Jones, Pharmaceutical Statistics (2002)
`
`-vii-
`
`Page 8
`
`

`

`I, Robert S. Langer, make the present Declaration in support of Patent
`
`Owner’s Response to the Petition for Inter Partes Review of U.S. Patent No.
`
`8,603,514 (“the ’514 Patent,” Ex. 1001). To that end, I hereby declare as follows:
`
`I.
`
`1.
`
`INTRODUCTION
`
`My name is Dr. Robert S. Langer. I am currently an Institute Professor (one
`
`of 13 Institute Professors, the highest rank awarded to a faculty member) at the
`
`Massachusetts Institute of Technology (MIT). My appointments include those in:
`
`the Department of Chemical and Biomedical Engineering at MIT; Whitaker
`
`College of Health Sciences, Technology, and Management; and the Harvard-MIT
`
`Division of Health Sciences and Technology.
`
`2.
`
`I have been retained by the firm Troutman Sanders LLP on behalf of Patent
`
`Owner MonoSol Rx, LLC (“MonoSol”) and real party-in-interest Indivior Inc. to
`
`provide my opinions regarding the patentability of certain claims of the ’514 Patent
`
`and related issues, including the opinions expressed by Dr. Graham Buckton, who I
`
`understand has been retained as an expert by Petitioner Mylan Technologies, Inc.
`
`(“Petitioner”).
`
`3.
`
`My opinions are based on my review of
`
`relevant documents and
`
`information, my experience in the fields of chemical engineering, pharmaceutical
`
`development, drug delivery, and polymer chemistry, particularly as applied to
`
`1
`
`Page 9
`
`

`

`pharmaceutical products, and my understanding of the relevant legal framework as
`
`explained to me by counsel.
`
`II.
`
`4.
`
`SCOPE OF THIS DECLARATION
`
`I am an expert
`
`in the fields of chemical engineering, pharmaceutical
`
`development, drug delivery, polymer chemistry and, in particular, the formulation
`
`and properties of polymeric films as those issues relate to the validity of certain
`
`claims of the ’514 Patent. I have been asked to consider and respond to certain
`
`arguments and opinions expressed in the Petition (Paper 2), the November 4, 2016
`
`Declaration of Graham Buckton, Ph.D. (Ex. 1002) (“Buckton Declaration”), and
`
`the Board’s Decision on Institution of Inter Partes Review (Paper 8) (“Decision to
`
`Institute”).
`
`5.
`
`I have previously opined on the validity of claims of the ’514 Patent in the
`
`United States District Court for the District of Delaware, Civil Action Nos. 14-
`
`01451-RGA, 14-01573-RGA, 14-01574-RGA, 15-01016-RGA, and 15-00477-
`
`RGA, in particular the latter two of which involved, in part, the same prior art
`
`references and invalidity arguments asserted by Petitioner and its expert in this
`
`proceeding.
`
`6.
`
`I understand that
`
`the Board instituted trial on a single ground of
`
`unpatentability—whether claims 1–3, 9, 15, 62–65, 69–73, and 75 of the ’514
`
`Patent (“’514 Patent Claims”) would have been obvious over the combination of
`
`2
`
`Page 10
`
`

`

`Ilango (Ex. 1005) and Chen (Ex. 1006). Accordingly, the opinions I provide below
`
`are addressed to that alleged ground of unpatentability.
`
`III. MATERIALS CONSIDERED
`
`7.
`
`In reaching my opinions in this case, I carefully reviewed the Petition (Paper
`
`2), Patent Owner’s Preliminary Response (Paper 7), Decision to Institute (Paper 8),
`
`and associated exhibits. I also carefully reviewed each document listed in the Table
`
`of Exhibits at the beginning of this Declaration (which is identical to the Table of
`
`Exhibits in the Patent Owner Response). I have also relied upon my personal
`
`knowledge, skill, training, experience, and knowledge in the field. All of the
`
`materials and information I relied on are of a type reasonably relied on by people
`
`in my field.
`
`IV.
`
`SUMMARY OF QUALIFICATIONS
`
`8.
`
`In addition to the brief summary provided below, my most recent curriculum
`
`vitae is submitted as Exhibit 2012 to this declaration, which summarizes my
`
`educational background, research and publications, honors and awards, and other
`
`credentials relevant to my qualifications as an expert in this case.
`
`9.
`
`I have authored or co-authored over 1350 articles and also have over 1250
`
`issued or pending patents worldwide, one of which was cited as the outstanding
`
`patent in Massachusetts in 1988 and one of 20 outstanding patents in the United
`
`States. My patents have been licensed or sublicensed to over 300 pharmaceutical,
`
`3
`
`Page 11
`
`

`

`chemical, biotechnology and medical device companies. A number of these
`
`companies were launched on the basis of these patent licenses. I was also recently
`
`named the Winner of the European Inventor Award 2016 for several patents
`
`related to a new therapeutic approach to fighting cancer by encapsulating anti-
`
`cancer drugs within biodegradable polymeric devices (EP1639029, EP1112348,
`
`EP2075015, and EP1024801).
`
`10.
`
`I served as a member of the United States Food and Drug Administration’s
`
`(FDA) SCIENCE Board, FDA’s highest advisory board, from 1995 through 2002
`
`and as its Chairman from 1999 through 2002.
`
`11. During my career, I have received over 220 major awards. I recently
`
`received the 2017 Memorial Sloan Kettering Medal for Outstanding Contributions
`
`to Biomedical Research. In 2016, I received the Benjamin Franklin Medal in Life
`
`Sciences from the Franklin Institute of Philadelphia, the Raymond and Beverly
`
`Sackler Award for Sustained National Leadership (Research!America), and the
`
`Irving Weinstein Foundation Distinguished Lecture Award (Americal Association
`
`for Cancer Research).
`
`In 2015,
`
`I
`
`received the Queen Elizabeth Prize for
`
`Engineering, the largest engineering prize in the world. In 2014, I received the
`
`Kyoto Prize for advanced Technology (Japan’s highest award for global
`
`achievement) and the Breakthrough Prize in Life Sciences which recognizes
`
`excellence in research aimed at curing intractable diseases and extending human
`
`4
`
`Page 12
`
`

`

`life (the largest science-based prize in the world). I received the 2013 Wolf Prize in
`
`Chemistry and the 2012 Priestley Medal, the highest award of the American
`
`Chemical Society. I am one of four living individuals to receive both the United
`
`States National Medal of Technology and Innovation (2011) and the United States
`
`National Medal of Science (2006), the two highest scientific honors bestowed in
`
`the United States. I received the 2002 Charles Stark Draper Prize, considered the
`
`equivalent of the Nobel Prize for engineers and the world’s most prestigious
`
`engineering prize, from the National Academy of Engineering. I am also the only
`
`engineer
`
`to receive the Gairdner Foundation International Award. Among
`
`numerous other awards that I have received are the Dickson Prize for Science
`
`(2002), Heinz Award for Technology, Economy and Employment (2003), the
`
`Harvey Prize (2003), the John Fritz Award (2003) (given previously to inventors
`
`such as Thomas Edison and Orville Wright), the General Motors Kettering Prize
`
`for Cancer Research (2004), the Dan David Prize in Materials Science (2005), the
`
`Albany Medical Center Prize in Medicine and Biomedical Research (2005) (the
`
`largest prize in the United States for medical research), the Max Planck Research
`
`Award (2008), the Prince of Asturias Award for Technical and Scientific Research
`
`(2008), the 2008 Millennium Prize, the Warren Alpert Foundation Prize (2011),
`
`and the Terumo International Prize (2012). I was inducted into the National
`
`Inventors Hall of Fame in 2006. In 1998, I received the Lemelson-MIT prize, the
`
`5
`
`Page 13
`
`

`

`world’s largest prize for invention, for being “one of history’s most prolific
`
`inventors in medicine.” I was elected in 1989 to the Institute of Medicine of the
`
`National Academy of Sciences and in 1992 to both the National Academy of
`
`Engineering and to the National Academy of Sciences. I am one of very few
`
`people ever elected to all three United States National Academies and the youngest
`
`in history (at age 43) to ever receive this distinction.
`
`12.
`
`I have been named by Forbes Magazine (1999) and Bio World (1990) as one
`
`of the 25 most important individuals in biotechnology in the world. I was named
`
`by Discover Magazine (2002) as one of the 20 most important people in this area. I
`
`was selected by Forbes Magazine (2002) as one of the 15 innovators worldwide
`
`who will reinvent our future. Time Magazine and CNN (2001) named me as one of
`
`the 100 most important people in America and one of the 18 top people in science
`
`or medicine in America. I was selected by Parade Magazine (2004) as one of 6
`
`“Heroes whose research may save your life.” I have served, at various times, on 15
`
`boards of directors and 30 Scientific Advisory Boards of such companies as
`
`Wyeth, Alkermes, Mitsubishi Pharmaceuticals, Warner-Lambert, and Momenta
`
`Pharmaceuticals.
`
`13.
`
`I have received honorary doctorates from the Gerstner Graduate School,
`
`Memorial Sloan Kettering Cancer Center, the ETH (Switzerland), the Technion
`
`(Israel), the Hebrew University of Jerusalem (Israel), the Universite Catholique de
`
`6
`
`Page 14
`
`

`

`Louvain (Belgium),
`
`the University of Liverpool (England), the University of
`
`Nottingham (England), the University of Western Ontario (Canada), Hanyang
`
`University (South Korea), the University of New South Wales (Australia), Albany
`
`Medical College, Pennsylvania State University, Uppsala University (Sweden),
`
`Yale University, Harvard University, Rensselaer Polytechnic Institute, Carnegie
`
`Mellon University, Northwestern University, the University of Maryland, Drexel
`
`University, Mount Sinai School of Medicine, Willamette University, Bates
`
`College, Boston University, Ben Gurion University, Tel Aviv University, the
`
`Karolinska Institute of Sweden,
`
`the Hong Kong University of Science and
`
`Technology, and the University of California at San Francisco.
`
`14.
`
`I received my Bachelor’s Degree from Cornell University in 1970 and my
`
`Sc.D. from the Massachusetts Institute of Technology (MIT) in 1974, both in
`
`Chemical Engineering.
`
`15. Based on my qualifications, education, and expertise, I consider myself
`
`competent to provide the opinions set out in this declaration. I have previously
`
`been accepted as an expert
`
`in pharmaceutical drug development,
`
`including
`
`pharmaceutical films, and have been permitted to provide my expert opinions as to
`
`the validity of the ’514 Patent claims in district court litigation against Par, Watson
`
`and Dr. Reddy’s Laboratories. (Ex. 2013, C.A. No. 1:14-cv-1451-RGA, Trial Tr. at
`
`1659:19–1664:3.) My research relating to pharmaceutical films, as well as other
`
`7
`
`Page 15
`
`

`

`drug delivery systems and biomedical polymers dates back to 1974. Through my
`
`own research, I was personally familiar with the difficulty of maintaining content
`
`uniformity in pharmaceutical films prior to 2001. Indeed, one of my colleagues
`
`compared trying to achieve drug content uniformity in such films to “trying to
`
`break glass reproducibly.”
`
`V.
`
`16.
`
`COMPENSATION
`
`I am being paid my standard consulting fee of $1500 per hour for my
`
`services and am being reimbursed for reasonable out-of-pocket expenses incurred
`
`as a result of my work on this matter. My compensation is not in any way
`
`dependent on the outcome of the proceeding.
`
`VI. LEGAL STANDARDS AND LEVEL OF SKILL
`
`17.
`
`I have been informed of the legal standards applicable to patent validity. I
`
`have relied upon these legal standards, as explained to me by counsel, in forming
`
`my opinions set forth in this declaration.
`
`A.
`
`Petitioner’s Burden Of Proof
`
`18.
`
`I am advised that
`
`in this proceeding the Petitioner has the burden of
`
`establishing unpatentability of any claim in the ’514 Patent by a preponderance of
`
`the evidence.
`
`B.
`
`Person Of Ordinary Skill In The Art
`
`19.
`
`I understand that the ’514 Patent must be read from the perspective of a
`
`person of ordinary skill in the relevant art at the time the invention was made. In
`8
`
`Page 16
`
`

`

`his Declaration, Dr. Buckton appears to apply a priority date of October 12, 2001
`
`for the ’514 Patent Claims. (Ex. 1002, Buckton Declaration ¶ 38.) For purposes of
`
`my analysis, I have been asked to assume that each reference cited by Dr. Buckton
`
`qualifies as “prior art” and, therefore, to accept the priority date as the relevant date
`
`of invention for purposes of my invalidity analysis.
`
`20.
`
`I understand that the person of ordinary skill in the art is a hypothetical
`
`person who is presumed to know the relevant art at the time of the invention.
`
`21.
`
`The ʼ514 Patent Claims are directed to film drug delivery compositions in
`
`which the active agent is uniformly distributed throughout the matrix and, after
`
`casting and drying, throughout the final dried film. The relevant field of invention
`
`is limited to pharmaceutical films that dissolve to release a drug (or “active”)
`
`ingredient that is evenly distributed throughout the film. (Ex. 1001, ’514 Patent at
`
`1:40–47 (describing the “Field of the Invention” as relating to “rapidly dissolving
`
`films and methods of their preparation” wherein the “films contain … active
`
`ingredients as … particles uniformly distributed throughout the film”).) Therefore,
`
`a person of ordinary skill to whom the ’514 Patent is directed would need to have a
`
`good understanding of at least: i) orally dissolving pharmaceutical dosage forms;
`
`and ii) measurements of uniformity of the active in the dosage composition.
`
`22.
`
`In my opinion, a person of ordinary skill in the art to whom the ’514 Patent
`
`is directed would have a good working understanding of these subjects and a Ph.D.
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`or its equivalent in pharmaceutics or pharmaceutical science or a related field, and
`
`at least two years of experience in developing and formulating dosage forms for
`
`drugs. Alternatively, this person could have had a good working understanding of
`
`these subjects and a Bachelor’s or Master’s Degree in an appropriate field and two
`
`to five years practical experience in developing and formulating dosage forms for
`
`drugs.
`
`23. My definition of the qualifications of the hypothetical person of ordinary
`
`skill appears to be consistent with Dr. Buckton’s definition of the person of
`
`ordinary skill within the context of the ’514 Patent:
`
`In my opinion, a person of ordinary skill in the relevant field as of
`October 12, 2001 would typically have 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 a bachelor’s degree in
`pharmaceutics, or in 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.
`
`(Ex. 1002, Buckton Declaration ¶ 39.)
`
`24.
`
`I also understand that the Board employed this description of the level of
`
`ordinary skill in the art in deiciding to institute this inter partes review. (Decision
`
`to Institute at 9.)
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`C.
`
`Obviousness
`
`25.
`
`I understand that a prior art reference taken by itself or combined with one
`
`or more other prior art references can render a patent claim obvious to one of
`
`ordinary skill in the art if the differences between the subject matter set forth in the
`
`patent claim and the prior art are such that the subject matter of the claim would
`
`have been obvious at the time the claimed invention was made. In analyzing
`
`obviousness, I understand that it is important to consider the scope of the claims,
`
`the level of skill in the relevant art, the scope and content of the prior art, and the
`
`differences between the prior art and the claims. I understand that secondary
`
`considerations of non-obviousness, such as the existence of a long-felt but
`
`unsolved need, unexpected results, commercial success of a product covered by the
`
`claims of the patent-in-issue, and praise by others, can provide objective indicia
`
`that claims were not obvious at the time of the invention.
`
`26.
`
`I also understand that, in assessing whether a claim is obvious, one must
`
`consider whether the claimed improvement was reasonably predictable such that
`
`the person of ordinary skill would have had a reasonable expectation of success in
`
`making or producing the subject matter of the patent claims in dispute.
`
`27.
`
`I further understand that a person of ordinary skill is a person of ordinary
`
`creativity, but that obviousness cannot be based on the hindsight combination of
`
`components selectively culled from the prior art.
`
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`28. When a particular claim is alleged to be obvious over a combination of
`
`multiple references, I understand that it is appropriate to consider whether a person
`
`skilled in the art would have been motivated to combine the references in the
`
`manner alleged to arrive at the claimed invention. I understand that no motivation
`
`for a particular combination exists when one or more of the references teach away
`
`from the claimed invention or teach away from using certain approaches in
`
`attempting to achieve or obtain the claimed invention. For example, a prior art
`
`reference teaches away from the patent’s particular combination if it leads in a
`
`different direction or discourages that combination, recommends steps that would
`
`not likely lead to the patent’s result, changes the basic principles of operation of a
`
`primary reference, or otherwise indicates that a seemingly inoperative device
`
`would be produced.
`
`D.
`
`Claim Construction
`
`29.
`
`I have been informed that
`
`in the context of this inter partes review
`
`proceeding, claim terms in the ’514 Patent are to be given their broadest reasonable
`
`interpretation in light of the specification of the patent. I have also been informed
`
`that under that standard, claim terms are to be given their ordinary and customary
`
`meaning, as would be understood by one of ordinary skill in the art at the time of
`
`the invention, unless the inventor defines a term in the specification.
`
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`VII. SUMMARY OF OPINIONS
`
`30.
`
`It is my opinion that the ’514 Patent Claims are not unpatentable, because
`
`the claimed invention would not have been obvious to a person of ordinary skill in
`
`the art in view of the Ilango and Chen prior art references cited in the Petition and
`
`the Buckton Declaration.
`
` When given their broadest reasonable interpretation, the claims of the
`’514 Patent are directed to a cast film from which multiple “equally sized
`individual unit doses” can be taken such that the active drug content of
`the unit doses does not vary by more than 10% of the “desired amount.”
`Consistent with this claim language,
`the specification repeatedly
`discusses the invention as solving the problem of cross-dose drug
`migration and aggregation during the drying process for such continuous,
`multi-dose films and expressly contrasts such films from those made in
`individual wells or molds, as in Ilango. Because the Ilango reference
`describes making unit doses in separate wells or molds, its statement of
`alleged drug content uniformity “within 5% variation” would not have
`taught a person of ordinary skill in the art at the time of the invention
`how to achieve a continuous, multi-dose film with unit doses that
`exhibited the claimed 10% drug content uniformity.
`
` Even if the ’514 Patent Claims could reasonably be read more broadly to
`encompass films made in wells or molds that each yield a single unit
`dose, the statement about drug content uniformity “within 5% variation”
`does not appear to be tied to the “desired amount” of drug in each film
`strip unit dose. Indeed, the other teachings and data in Ilango suggest that
`the drug content in the Ilango film strips was well below the desired
`amount of drug.
`
` Moreover, it is unclear that the glibenclamide films described in Ilango
`involve an active in particulate form. While the sparse description of the
`manufacturing
`process
`in
`Ilango
`discusses
`the
`“dispers[ing]”
`glibenclamide at an initial step in the mixing of the coating solution, each
`formulation contained a significant, but not precisely disclosed amount of
`ethanol,
`in which glibenclamide is soluble. The problem of drug
`migration and aggregation in continuous, multi-dose films arises from the
`
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`thermal and concentration gradients and other forces that act upon
`particles during drying. Therefore, maintaining the uniform distribution
`of an active ingredient is significantly more challenging when the active
`is in particulate form than when it is dissolved.
`
` Without the benefit of hindsight, a person of ordinary skill in the art
`would have had no motivation to apply the teachings of Chen to
`overcome these deficiencies in Ilango, or any reasonable expectation that
`such a combination would lead to films that met the 10% drug content
`uniformity limitation in the ’514 Patent claims. In particular, nothing
`would have suggested to a person of ordinary skill
`that
`the film
`formulations described in Ilango for use in a film-making process that
`relied on individual molds and room temperature evaporation of solvent
`over the course of a day