`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`KASHIV PHARMA, LLC,
`Petitioner
`v.
`PURDUE PHARMA L.P.,
`THE P.F. LABORATORIES, INC., and
`PURDUE PHARMACEUTICALS L.P.,
`Patent Owners
`____________________
`Case IPR2018-00625
`Case IPR2018-00717
`U.S. Patent No. 9,492,392
`U.S. Patent No. 9,492,393
`___________________
`(Exhibit 2029)
`
`DECLARATION OF STEPHEN BYRN, Ph.D. IN SUPPORT OF
`PATENT OWNERS’ PRELIMINARY RESPONSE
`TO PETITION FOR INTER PARTES REVIEW
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`Declaration of Stephen Byrn, Ph.D.
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`TABLE OF CONTENTS
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`Case IPR2018-00625
`Case IPR2018-00717
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`I.
`
`Introduction ...................................................................................................... 1
`Background, Experience, and Qualifications ........................................ 2
`A.
`B. Materials Considered ............................................................................. 8
`Summary of Opinions ...................................................................................... 8
`II.
`III. Technical Background ..................................................................................... 9
`OxyContin® ........................................................................................... 9
`A.
`IV. The ’392 Patent ..............................................................................................10
`V.
`Legal Understandings ....................................................................................11
`Claim Construction ........................................................................................11
`VI. Person of Ordinary Skill in the Art ................................................................11
`VII. Claim Constructions ......................................................................................12
`“Compression Shaped” And “Compression” ......................................12
`A.
`“Curing” ..............................................................................................13
`B.
`“Selected From The Group Consisting of 4,000,000;
`C.
`7,000,000; And A Combination Thereof” ...........................................14
`Product-By-Process Limitations .........................................................15
`D.
`VIII. Unexpected Density results ...........................................................................17
`1.
`A POSA would have expected curing to increase the density .17
`2.
`Purdue’s data establishes an unexpected density decrease .......19
`IX. Conclusion .....................................................................................................27
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`Declaration of Stephen Byrn, Ph.D.
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`I, Stephen Byrn, hereby declare:
`
`
`
`
`I.
`
`INTRODUCTION
`
`Case IPR2018-00625
`Case IPR2018-00717
`
`1.
`
`2.
`
`I am a U.S. citizen and a resident of Indiana.
`
`I am the Charles B. Jordan Professor of Medicinal Chemistry in the
`
`Department of Industrial and Physical Pharmacy at Purdue University.
`
`3.
`
`I am also a consultant with an independent organization, Improved
`
`Pharma LLC, which is a pharmaceutical research and information company that
`
`my wife and I founded to provide pharmaceutical research and information,
`
`including analyzing drug substances and drug products, formulating drug products,
`
`and consulting on dosage forms and regulatory issues, as well as consulting for
`
`pharmaceutical litigation.
`
`4.
`
`Improved Pharma and I have been retained in this proceeding by
`
`Jones Day, counsel for patent owners Purdue Pharma L.P., The P.F. Laboratories,
`
`Inc., and Purdue Pharmaceuticals L.P. (collectively, “Purdue Pharma”), to consider
`
`Kashiv Pharma, LLC’s (“Kashiv”) Petition for Inter Partes Review of U.S. Patent
`
`No. 9,492,392 (IPR2018-00625) (“IPR625 Petition”) and U.S. Patent No.
`
`9,492,393 (IPR2018-00717) (“IPR717 Petition”), including the Declaration of Dr.
`
`Omidian (“Dr. Omidian’s Declaration”). I make this declaration in support of
`
`Purdue Pharma’s Preliminary Response to the IPR625 Petition IPR717 Petition
`
`and in response to Dr. Omidian’s Declaration.
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`
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`The 1000-series exhibit cites in this declaration are to the exhibits to
`
`5.
`
`the Petition. The 2000-series exhibits cites are to the exhibits to the Preliminary
`
`Response.
`
`6.
`
`Improved Pharma LLC is being compensated at the usual rate of $650
`
`per hour for my time of which I receive $650 per hour. My compensation does not
`
`depend in any way on the substance of my testimony or on the outcome of this or
`
`any other proceeding.
`
`A.
`7.
`
`Background, Experience, and Qualifications
`
`I received a Ph.D. in Chemistry from the University of Illinois in 1970
`
`and was a post-doctoral fellow at UCLA from 1970 to 1972. In 1972, I became a
`
`Professor of Pharmacy at Purdue University. I was Head of the Department of
`
`Medicinal Chemistry and Pharmacognosy at Purdue University in the School of
`
`Pharmacy and Pharmaceutical Sciences from 1988 to 1994. I was the Director of
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`the Center for AIDS Research at Purdue University from 1988 until 1998, and
`
`since 1994, I have been the Head of the Department of Industrial and Physical
`
`Pharmacy. I became the Charles B. Jordan Professor of Medicinal Chemistry in
`
`1992.
`
`8.
`
`I am an author of over 180 peer-reviewed publications in technical
`
`journals on topics relating to solid-state chemistry, formulation, X-ray
`
`crystallography, stability, medicinal chemistry, chemistry, among other things. I
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`am also co-author of the leading book in the field of solid-state chemistry of
`
`pharmaceuticals, “Solid Chemistry of Drugs.” I have organized and taught
`
`numerous courses in solid-state chemistry, manufacturing, analysis and related
`
`areas. I have also taught at the federal Food and Drug Administration, and I have
`
`also given over 270 invited lectures and symposium talks and presentations on
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`solid-state chemistry, polymorphs, and similar topics, as well as abuse deterrence.
`
`9. My current research focuses on formulation and solid-state chemistry,
`
`specifically related to abuse-deterrent products; amorphous formulations of
`
`anticancer drugs; formulation of antiviral drugs; and formulation of drugs for rare
`
`diseases, including tuberculosis, leprosy, worms, and other diseases prominent in
`
`Africa. I am also doing extensive work at Argonne National Laboratories, where I
`
`utilize synchrotron x-rays to analyze amorphous and liquid-crystal drugs. In the
`
`past, I have done extensive work on the solid-state chemistry of drugs and related
`
`areas as outlined in my publications and teaching activities in my curriculum vitae
`
`(Exhibit 1.)
`
`10. Under my supervision, over 50 students and post-doctoral associates
`
`have published numerous papers and theses on many different compounds and
`
`formulations. I currently have two Ph.D. students, one senior scientist, one
`
`master’s student, and two Pharm. D. and undergraduate students working in my
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`laboratory on a range of projects including, abuse-deterrent formulations,
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`chromatographic analysis, and amorphous formulations.
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`11.
`
`I have taught many courses throughout my career including medicinal
`
`analysis, advanced medicinal analysis, computers in pharmacy, solid-state
`
`chemistry, pharmaceutics, formulation, the molecular basis of manufacturing,
`
`sterile products, drug development, good regulatory practices, and devices.
`
`Currently, I am lecturing on innovation in the pharmaceutical industry with an
`
`emphasis on innovative solid forms, innovative formulations, and design of
`
`innovative medicines. I am also lecturing on a range of regulatory and
`
`manufacturing issues.
`
`12.
`
`I have founded or co-founded several academic and industrial
`
`programs/companies including Purdue University’s Center for AIDS Research;
`
`CAMP (Consortium for the Advancement of Manufacturing in Pharmacy); Purdue
`
`University’s MS program in regulatory sciences; Purdue University’s Africa
`
`program, entitled “Essential Medicines in Africa”; and SSCI, Inc., a research and
`
`information company in West Lafayette, IN. SSCI, Inc., which is now owned by
`
`Albany Molecular Research Institute, Inc., provides innovative problem solving
`
`and analytical research to a broad range of pharmaceutical companies. I am also a
`
`technical founder of the firm Andara, Inc., which is now owned by Neurometix,
`
`and a co-founder of the firm Improved Pharma.
`
`13.
`
`I am the past Chair of the Pharmaceutical Sciences Advisory
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`Committee at the FDA. The role of that Committee was and still is to advise the
`
`FDA on polymorphism issues, biopharmaceutical issues, as well as general
`
`chemical manufacturing control issues, including formulation, dissolution, and
`
`hydrates. I am the former Chair of the Drug Substances Technical Committee of
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`the Product Quality Research Institute (PQRI) where, in order to improve drug
`
`quality, we discussed three main areas: (1) specifications, (2) particle size, and
`
`(3) chemical impurities.
`
`14.
`
`I am also past Chair of the Chemistry 5 Expert Committee at the USP
`
`(United States Pharmacopeia), where my work involved monographs of
`
`pharmaceutical formulations and a past member of the Council of Experts at the
`
`USP. I continue to serve as Purdue University’s delegate to the USP. I also served
`
`on the USP dissolution and bioavailability subcommittee and the Excipients 2
`
`subcommittee.
`
`15.
`
`I was a member of the Controlled Substances Advisory Committee of
`
`the State of Indiana from 1982-1998. I was Secretary of the committee from 1987-
`
`1994 and Chair from 1994-1998. This committee dealt with and still deals with, a
`
`wide range of issues relating to controlled substances, including abuse of
`
`controlled substances by professional medical personnel.
`
`16.
`
`I have received numerous awards including the AAPS David Grant
`
`Research Achievement Award in Physical Pharmacy. In 2010, a Special Issue of
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`the Journal of Pharmaceutical Sciences was dedicated to me based on my work as
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`a “Scientist, Educator and Visionary.”
`
`17.
`
`I have received numerous grants as the Principal Investigator for
`
`research relating to the chemistry of pharmaceutical drugs and medicinal
`
`chemistry. The grants I have received during my tenure at Purdue University total
`
`roughly $44 million and have been sponsored by government research
`
`organizations and pharmaceutical companies, including the National Institutes of
`
`Health, the U.S. FDA, Eli Lilly & Co., Merck & Co., Bristol-Myers Squibb,
`
`Boehringer, Pfizer, Sandoz, Glaxo, and Upjohn.
`
`18. Specifically, I was one of the key investigators on an FDA grant to
`
`study failure modes of abuse-deterrent products, including OxyContin®, Opana®
`
`ER, and two immediate-release generic products. This grant evaluated various
`
`strategies used by abusers to extract or remove the opioid from these products. We
`
`utilized a range of analytical methods, including high-pressure liquid
`
`chromatography. We are in the process of publishing our research.
`
`19. After completing the research related to that grant, we continued
`
`working extensively with PEO-based formulations of several different model drugs
`
`to develop and improve understanding of how the structure of the drug affects the
`
`performance of PEO-based formulations. We are in the process of publishing this
`
`research as well. I presented this research at an open FDA meeting, entitled
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`“Development and Regulation of Abuse-Deterrent Opioid Medications,” on
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`October 30, 2014. I was an invited expert speaker at that meeting.
`
`20.
`
`I have served as a consultant for many pharmaceutical companies in
`
`the United States and abroad. Among the companies for which I have consulted
`
`are Purdue Pharma, Pfizer, GlaxoSmithKline, Merck, Genentech, Bristol-Myers
`
`Squibb, Johnson & Johnson, Wyeth, Eli Lilly, Roche, and Abbott. In addition, I
`
`served as the head of the Scientific Advisory Board for Aptuit.
`
`21. With respect to Purdue Pharma, I was previously retained as an expert
`
`in litigations, including Purdue Pharma LP et al. v. Acura Pharmaceuticals, Inc. et
`
`al., 1-15-cv-00292 (D. Del.), which involved, among other patents, U.S. Patent No.
`
`8,389,007. I was also retained as an expert in Alpharma Inc. v. Purdue Pharma
`
`L.P., 08-cv-00050 (W.D. Va.), relating to the extended-release opioid Embeda,
`
`which also contained an opioid antagonist for abuse deterrence. I was also retained
`
`as an expert in inter-partes reviews, including IPR2016-01027 and IPR2016-
`
`01028, which involved U.S. Patent No. 9,060,976, and IPR2016-01412 and
`
`IPR2016-01413, which involved U.S. Patent No. 9,034,376. While at SSCI, Inc.,
`
`we did solid-state chemistry research for Purdue Pharma.
`
`22.
`
`I have attached as Exhibit 1 to this declaration a current copy of my
`
`CV and as Exhibit 2 a list of testimony I have provided in the last four years.
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`B. Materials Considered
`I have considered the Petition and certain exhibits accompanying that
`23.
`
`Petition, including the ’392 and ’393 patents and Dr. Omidian’s Declaration. I
`
`have also considered certain materials attached to Purdue Pharma’s Preliminary
`
`Patent Owner Response and all materials cited in this declaration. Finally, I further
`
`considered the prosecution histories of the ’392 and ’393 patents.
`
`II.
`
`SUMMARY OF OPINIONS
`
`24.
`
`I understand that the ’392 patent is the subject of IPR2018-00625, in
`
`which Kashiv alleges that the ’392 patent is invalid as: (1) obvious over
`
`Bartholomaus in view of McGinity, Oshlack 2, and Oshlack 1; (2) obvious over
`
`Wright in view of Royce, Moroni, and Shao; and (3) obvious over Oshlack 1 in
`
`view of Bartholomaus, McGinity, and Oshlack 2.
`
`25.
`
`I also understand that the ’393 patent is the subject of IPR2018-00717,
`
`in which Kashiv alleges that the ’393 patent is invalid as: (1) obvious over Oshlack
`
`1 (Ex. 1016) in view of Bartholomaus (Ex. 1024), McGinity (Ex. 1025), and
`
`Oshlack 2 (Ex. 1026); or (2) obvious over Wright (Ex. 1017) in view of Royce
`
`(Ex. 1027), Moroni (Ex. 1028), and Shao (Ex. 1029). I understand that prior to
`
`evaluating the validity, the claims need to be construed.
`
`26.
`
`I have been asked to provide my opinions on claim construction, as
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`discussed further in Section VII.
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`I explain these opinions below. I was not asked to evaluate all of the
`
`27.
`
`arguments and opinions set forth in the petitions or in Dr. Omidian’s declaration. I
`
`understand that in the event that the petitions are instituted, I will have an
`
`opportunity to address those arguments and opinions, and I reserve the right to do
`
`so. For the arguments and opinions that I have considered, I explain various
`
`disagreements I have with Dr. Omidian. My silence on particular opinions of Dr.
`
`Omidian does not mean that I agree.
`
`III. TECHNICAL BACKGROUND
`
`A.
`
`OxyContin®
`
`28. Original OxyContin®, approved and launched in the United States in
`
`1995 and 1996 respectively, was widely abused. (See generally Ex. 1019 ¶¶ 7, 12).
`
`Original OxyContin® was a groundbreaking treatment for patients suffering
`
`chronic pain. Original OxyContin®’s medical success is attributed to its unique
`
`extended-release profile providing for twelve hours of therapeutic relief, allowing
`
`for optimum treatment of chronic pain. OxyContin distinguished itself from other
`
`short-acting oxycodone formulations by providing long-lasting, controlled release
`
`dose of oxycodone that acted for 12 hours. (Ex. 1019 ¶ 13).
`
`29. But many of the features that made it so effective, including its
`
`strength, duration, and known dosage, also made it attractive to abusers.
`
`30.
`
`Seeking an instant and powerful “high,” abusers would crush the 12-
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`hour tablet, reducing it to an immediate-release fine powder, and then either snort
`
`it or, after adding water and drawing it into a syringe, inject it. (Ex. 2020 at 3).
`
`The consequences of that abuse included addiction, overdose, and death. (Ex.
`
`2021 at 2571-73). By at least 2001, original OxyContin® was widely abused.
`
`31.
`
`In response to this abuse, Purdue Pharma created new OxyContin®
`
`that uses several patented technologies to deter abuse without sacrificing original
`
`OxyContin®’s intended benefits. OxyContin® now incorporates as one of its
`
`abuse-deterring mechanisms gelling to impede snorting and injecting of any
`
`powder resulting from crushed tablets, but without disrupting the extended-release
`
`profile allowing for a 12-hour therapeutic effect. (Ex. 1003 at 30-31).
`
`IV. THE ’392 AND ’393 PATENTS
`32. The ’392 and ’393 patents were filed as U.S. Application No.
`
`14/729,634 and U.S. Application No. 14/729,660, respectively, on June 3, 2015.
`
`The patents issued on November 15, 2016 to William H. McKenna, Richard O.
`
`Mannion, Edward P. O’Donnell, and Haiyong H. Huang, entitled “Tamper
`
`Resistant Dosage Forms.”
`
`33. The patents are listed in the Orange Book as covering OxyContin®.
`
`34. The ’392 and ’393 patents and its patent family were the first to
`
`disclose tamper resistant formulations, which display reduced density of the final
`
`dosage forms, manufactured by a process comprising compression shaping
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`followed by air curing without compression.
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`V. LEGAL UNDERSTANDINGS
`Claim Construction
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`Case IPR2018-00625
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`35.
`
`I have been informed by counsel that, in this proceeding, the Patent
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`Trial and Appeal Board (“the Board”) will construe a claim term, in light of the
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`claim language, specification, and prosecution history, as it would be interpreted
`
`by a POSA at the time of the invention.
`
`36.
`
`I understand that this is a meaning consistent with the ordinary and
`
`customary meaning of the term (unless the term has been given a special definition
`
`by the patentee) and consistent with the use of the claim term in the specification.
`
`I understand that in construing the meaning of claim terms, the Board will look
`
`first to the claim language, specification, and prosecution history, and also to
`
`outside evidence such as dictionaries.
`
`VI. PERSON OF ORDINARY SKILL IN THE ART
`I have been informed by counsel that, to determine the level of
`37.
`
`ordinary skill in the art, I should consider factors such as the educational level of
`
`those in the relevant industry and the sophistication of the technology involved.
`
`38. A POSA in the art of abuse-deterring dosage forms as of August 25,
`
`2006 had a degree in one or more fields of medicine, chemical engineering,
`
`chemistry, pharmaceutical science, polymer chemistry, pharmaceutics,
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`pharmaceutical technology, pharmacokinetics, and/or pharmacology and/or a
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`number of years of industry training or experience in one or more of those fields,
`
`particularly with controlled-release formulations.
`
`39.
`
`I understand that Dr. Omidian and Kashiv have proposed a different
`
`definition of a POSA that is slightly different than what I have proposed.
`
`Regardless, my opinions and analysis remain the same.
`
`40. Under any of the proposed definitions of a POSA, I believe I was at
`
`least a POSA as of the relevant date of August 2006. I understand who a person of
`
`ordinary skill in the art was as of August 25, 2006, and what such a person would
`
`know. Moreover, the differences in the parties proposed definitions would not
`
`affect any of the opinions set forth herein.
`
`VII. CLAIM CONSTRUCTIONS
`
`A.
`
`41.
`
`“Compression Shaped” And “Compression”
`
`“Compression Shaped” And “Compression” are well-known terms of
`
`art. A POSA would understand what those terms meant and, in my opinion, no
`
`construction of those terms are necessary. Petitioner hasn’t explained how
`
`compaction is different than compression or provides any additional meaning. The
`
`Dictionary of Pharmacy provides the following definition of compression, which
`
`confirms that the terms compression and compaction are not different: a “process
`
`of rendering a discrete quantity of substance more dense or more compact;
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`examples: solid granules to tablets, gases to liquids; synonym: compaction.” (Ex.
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`2022 at 78).
`
` “Curing”
`
`B.
`42. The claims of the ’392 and ’393 Patents require “at least a first
`
`compression shaped and then air cured matrix, wherein said curing is without
`
`compression ….” (Ex. 1001, e.g. claim 1)1. I disagree with Petitioner’s proposed
`
`construction of this term “heating to an elevated temperature that is at least as high
`
`as the softening temperature or melting point for a few minutes.” (IPR625 Pet. 20;
`
`IPR717 Pet. 21). (emphasis added.)
`
`43. Petitioner acknowledges that the specification defines the “curing
`
`temperature” as being “at least the softening temperature” of the PEO (Ex. 1001,
`
`3:10-15, 17:10-14) and “curing” as heating to a point where the PEO “at least
`
`partially melts” (id. 17:28-30). Moreover, the specification makes this clear and
`
`describes curing as subjecting the extended release matrix “to an elevated
`
`temperature” (id. at 17:58), “where[] the high molecular weight polyethylene oxide
`
`
`1 Throughout this declaration, unless otherwise noted, specific citations to Ex. 1001
`
`refer to Ex. 1001 in IPR2018-00625. However, the specifications for the ’392 and
`
`’393 patents are substantively the same, thus the citations support my opinion for
`
`both patents and both IPR proceedings.
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`in the extended release matrix formulation at least partially melts” (id. at 17:42-
`
`45), and where the extended release matrix “has reached it softening temperature”
`
`(id. at 22:49). Furthermore, the claims make clear that the curing takes place
`
`without compression. (Id. at claim 1).
`
`44. A POSA reading the specification would understand that “Curing”
`
`means heating the compression shaped matrix, without compression, until the high
`
`molecular weight PEO present in the matrix has at least partially softened or
`
`melted.
`
`45. Furthermore, the claim language recites a specific temperature and
`
`duration of the curing step, e.g. “for a duration of at least about 5 minutes.” (Ex.
`
`1001, e.g. claim 1). Therefore, I do not understand the basis for Petitioner’s
`
`addition of the phrase “for a few minutes” and, in my opinion, a POSA would not
`
`read that additional term into the meaning.
`
`C.
`
`“Selected From The Group Consisting of 4,000,000; 7,000,000;
`And A Combination Thereof”
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`46. The claims of the ’392 and ’393 Patents require a “cured shaped
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`pharmaceutical tablet comprising” “polyethylene oxide having, based on
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`rheological measurements, an approximate molecular weight selected from the
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`group consisting of 4,000,000, 7,000,000, and a combination thereof.”
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`47.
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`I have been informed by counsel that the term has been previously
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`construed in a district court case to mean, “one or a combination of polyethylene
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`Declaration of Stephen Byrn, Ph.D.
`Case IPR2018-00717
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`oxides having an overall weight average molecular weight of approximately
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`4,000,000 daltons, 7,000,000 daltons, or a combination thereof based on
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`rheological measurements.” (Ex. 2019). I agree with this construction.
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`48. The claim language is clear that the PEO can have a molecular weight
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`of “4,000,000; 7,000,000; and a combination thereof.” A POSA would understand
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`that to mean the PEO molecular weight can be either 4 million, 7 million, or
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`combination of a PEO with a molecular weight of 4 million and a PEO with a
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`molecular weight of 7 million.
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`49. Petitioner’s proposed meaning does not conform to the claim terms.
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`Petitioner asserts that a “POSA would appreciate that reference to PEO in whole
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`numbers reflects standard grades.” (IPR625 Pet. 22; IPR717 Pet. 23). That a
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`POSA would understand that Dow has PEO grades of 4,000,000 and 7,000,000
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`molecular weight does not mean a POSA would understand the claim terms to
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`include “any molecular weight in between” these molecular weights. The claim
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`elements at issue require a choice between, either 4 million, 7 million, or
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`combination of a PEO with a molecular weight of 4 million and a PEO with a
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`molecular weight of 7 million.
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`D.
`50.
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`Product-By-Process Limitations
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`I have been informed by counsel that a process step in a product-by-
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`process claim must be considered in an anticipation or obviousness analysis if the
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`Declaration of Stephen Byrn, Ph.D.
`Case IPR2018-00717
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`process makes the product structurally and functionally different. In my opinion,
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`the curing elements clearly impart structural and functional differences to the
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`claimed tablets.
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`51. As stated in the specification, “it is believed that the curing at a
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`temperature that is at least as high as the softening temperature of the high
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`molecular polyethylene oxide causes the polyethylene oxide particles to at least
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`adhere to each other or even to fuse.” (E.g., Ex. 1001, 17:47-51). The melting of
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`PEO, and subsequent adhering or fusing of the particles contributes to the hardness
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`and crush resistance of the tablets.
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`52. Furthermore, the claimed curing without compression imparts an
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`unexpected decrease in density. The decrease in density corresponds to greater
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`tablet porosity, and/or a greater percentage of amorphous character, leading to
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`faster tablet gelling and increased potential to reduce intravenous abuse, as
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`discussed in more detail in Section VIII.
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` In contrast, Opana ER®
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`was manufactured using hot-melt extrusion (i.e., simultaneous heat and pressure).
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`(Ex. 2024 at 1). The FDA granted OxyContin abuse-deterrent labeling recognizing
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`its reduced potential for intravenous abuse. (Ex. 2025 at 20-21). The FDA,
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`Declaration of Stephen Byrn, Ph.D.
`Case IPR2018-00717
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`however, refused to grant Opana ER® such labeling, and Opana ER®’s tendency
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`to be abused via injection led the FDA to request that it be withdrawn from the
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`market. (Ex. 2024 at 1-3).
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`53. As a result, in my Opinion, it is clear that the curing elements of the
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`patents impart structural differences to the tablets, e.g., increased abuse deterrence.
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`VIII. UNEXPECTED DENSITY RESULTS
`A POSA would have expected curing to increase the density
`1.
`I have reviewed, and agree with, the Examiner’s Reasons for
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`54.
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`Allowance of the ’392 and ’393 patents. Specifically, that the curing process leads
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`to an unexpected result of a decrease in density. The decrease in density
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`corresponds to greater tablet porosity, and/or greater percentage of amorphous
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`character. A person of skill would expect tablets with decreased density to exhibit
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`a faster rate of gelling and an increased potential to reduce intravenous abuse.
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`55. At the time of the invention, however, it was well-understood in the
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`art that heating a polymeric matrix to at least its softening point, such as during the
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`claimed curing process, causes polyethylene oxide to fuse together. That process
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`is expected to increase the density of a dosage form, which corresponds to
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`decreased tablet porosity and/or a decreased percentage of amorphous character.
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`56. A POSA would expect that for polymer matrices specifically, such as
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`those claimed in the patents, the natural result of curing was known to be an
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`Declaration of Stephen Byrn, Ph.D.
`Case IPR2018-00717
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`increase in polymer density. (See, e.g., Ex. 1041 at 253 (teaching that heat
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`treatment of polypropylene increases polymer density); Ex. 1042 at 99 (teaching
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`that heat exposure increased the density of neat polymeric compacts); Ex. 1043 at
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`145 (teaching that the adsorbed polymer density of PEO and polyacrylamide
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`(“PAM”) increased significantly with increasing temperature)).
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`57. For example, Mai studied the effect of cold extrusion and subsequent
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`heat treatment on polypropylene, a widely used polymer that is similar in many
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`aspects to polyethylene, especially with regard to solubilities. The study results
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`included effects on dimensional changes, density changes, and mechanical
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`properties. Prior to Mai, it was generally known that for cold-extruded crystalline
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`polymers, annealing at sufficiently high temperatures so as to cause partial melting
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`followed by recrystallization of the polymer, results in an increase in density for
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`the cold-worked polymer. Mai’s study confirmed that for polypropylene,
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`“[a]nnealing tends to increase the density (and crystallinity) and the improvement
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`is higher the higher the annealing temperature.” (Ex. 1041 at 101).
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`58. Similarly, Mpofu investigated the effect of temperature on
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`conformation and adsorption of PEO and PAM flocculants, noting that “an
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`increase in adsorption density with increasing temperature is expected ….” (Ex.
`
`1043 at 149). Mpofu found that “[a] decrease in solvency as temperature increases
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`is indicated, hence the adsorption density increased.” (Id.; emphasis added.)
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`Case IPR2018-00717
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`59. AlKhatib investigated the effect of dry and humid thermal curing
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`conditions on the physical and drug-release properties of polyvinyl acetate-
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`polyvinyl pyrrolidone (“PVAc-PVP”) matrices. AlKhatib notes that heating a
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`polymer matrix at “temperatures above the glass transition temperature (Tg) of the
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`polymeric component for a determined period of time … lead[s] to coalescence of
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`polymeric particles producing a more homogenous, less porous system” (Ex. 1042
`
`at 254; emphasis added). Upon curing, AlKhatib observed that the “density of neat
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`polymeric compacts increased upon exposure to heat.” (Ex. 1042 at 253).
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`60. Moreover, I have reviewed certain references cited in Kashiv’s
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`Petitions, specifically, Omelczuk (Ex. 1050), which further confirm that the
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`expectation in the art that density would increase, not decrease, with curing.
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`Omelczuk states, “[i]n general, annealing increases the density within the polymer.
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`. . .” (Ex. 1050 at 542). A POSA would expect that density would increase as a
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`polymeric matrix was cured. Therefore, in my opinion, a decrease in density upon
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`curing was clearly unexpected.
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`Purdue’s data establishes an unexpected density decrease
`2.
`I have reviewed the data prese