Declaration of David W. Feigal, MD MPH Attorney Docket No. 117744-00041
`IPR2014-00325
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`Paper No._______
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
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` BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
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`v.
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`RB PHARMACEUTICALS LIMITED
`Patent Owner
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`Case No. IPR2014-00325
`Patent 8,475,832
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`DECLARATION BY DAVID W. FEIGAL, MD MPH
`IN SUPPORT OF PETITIONER’S REPLY
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`IPR2014-00325
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`Paper No._______
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
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` BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
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`v.
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`RB PHARMACEUTICALS LIMITED
`Patent Owner
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`Case No. IPR2014-00325
`Patent 8,475,832
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`
`
`DECLARATION BY DAVID W. FEIGAL, MD MPH
`IN SUPPORT OF PETITIONER’S REPLY
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`I. QUALIFICATIONS
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`1.
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`I am a physician, am board certified in Internal Medicine, and have a
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`Master’s Degree in Public Health (M.P.H.) in the fields of epidemiology and
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`biostatistics. I graduated from Stanford University Medical School in 1976;
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`completed my internship and residency at the University of California, Davis in
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`1979; and earned an M.P.H from the University of California, Berkeley in 1983.
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`2.
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`From 1982-1989, I held several positions at the University of
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`California, San Francisco, including Associate Director of the Clinical
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`Epidemiology program and Assistant Professor of Medicine with joint
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`appointments in Epidemiology and Biostatistics, and was a member of the Clinical
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`Pharmacology faculty. I was also Director of the Data Center at the AIDS Clinical
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`Research Center. From 1989 to 1991, I was a Clinical Associate Professor of
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`Clinical Medicine at the University of California, San Diego.
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`3.
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`During my career, I have practiced medicine as a general internist in
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`faculty practices at the University of California, as well as taught medical students,
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`interns, residents and fellows, and cared for patients on the in-patient services at
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`several university hospitals. As an internist-epidemiologist, I designed and
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`conducted clinical trials. My responsibilities for clinical trials included monitoring
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`and reporting adverse drug reactions to FDA and to the trials’ data safety and
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`monitoring boards, as well as to Institutional Review Boards (IRBs). Clinical trials
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`that I designed and conducted led to the approval of new drugs and devices. I
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`presented to and served on FDA Advisory Committees, as well as National
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`Institutes of Health and Public Health Service Consensus Task Forces on disease
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`prevention and treatment that included evaluation of the quality of evidence from
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`epidemiology and clinical trials.
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`4.
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`From 1992 to 2004, I held a number of senior positions at FDA. From
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`1992-1997, I held positions in FDA’s Center for Drug Evaluation and Research
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`(CDER). This Center has the responsibility for the review and approval of all new
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`drugs, and the ongoing assessment of the quality, safety and effectiveness of
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`marketed drugs. It has the authority to take actions through its compliance
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`programs to assure that drugs meet standards defined in law. At CDER, I held the
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`positions of Director of the Division of Anti-Viral Drug Products and Acting
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`Director of the Anti-Infective Drug Products, and in addition from 1994 to 1997, I
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`was Director of the Office of Drug Evaluation IV.
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`5.
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`I had the direct authority to approve investigational studies of new
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`drugs for various indications, including the clinical pharmacology studies, to halt
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`such studies for safety reasons, to approve the protocols for studies that would be
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`the evidence to demonstrate effectiveness, to approve new indications and new
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`formulations for approved drugs in these areas, and to approve the manufacturing
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`methods and take compliance actions through the CDER Office of Compliance and
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`FDA field staff. My responsibilities included the supervisions of the review
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`disciplines, including the pharmaceutical chemists, pharmacologists, toxicologists,
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`statisticians and medical reviewers. Based on my review of the reports of the
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`review disciplines and my own assessments, I had the decision-making authority
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`for the approval of new drug indications, new formulations, and product labeling.
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`Approval of generic drugs that required clinical trials were also among my
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`responsibilities. As an Office Director, I supervised the directors of the Divisions
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`of Antiviral Drug Products, Anti-Infective Drug Products, and Special Pathogens
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`and was one of five people at FDA with the authority for the initial approval of
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`new drugs. I also shared responsibility for policy development including drafting
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`FDA Guidance documents, many on the FDA requirements for drug approval.
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`6.
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`From 1997-1999, I served as the Medical Deputy Director of the
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`Center for Biologics Evaluation and Research (CBER). I directly supervised the
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`Biostatistics and Epidemiology Division, among others, as well as the Advisory
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`Committee Staff and served as the Center Ombudsman.
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`7.
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`From 1999-2004, I served as Director of the Center for Devices and
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`Radiological Health (CDRH). Many medical devices are used as drug delivery
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`devices, including the combination products designed for novel delivery methods.
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`Whether approved as drugs or medical devices, these products involved CDRH
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`and CDER or CBER.
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`8. My career has included extensive experience in the evaluation of
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`safety and effectiveness of pharmaceutical drugs and biologics, as well as medical
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`devices. At FDA, I was responsible for the evaluation of safety and efficacy of
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`new drugs within my Divisions, including the initial approval process and
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`continuing oversight of the safety and effectiveness of those drugs after approval,
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`and as new dosage forms were developed and approved. This involved extensive
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`interactions with sponsors about their study design and product development
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`programs, evaluating the results of those programs, and analyzing the adequacy
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`and completeness of product labeling.
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`9.
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`As a CDER Division Director and Office Director, I had direct
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`responsibility for evaluating the adequacy of the preclinical, the pharmacology and
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`the clinical outcome studies that were the basis for investigational studies of new
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`drugs (INDs) and New Drug Applications (NDAs), and I had direct sign-off
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`authority, known as “signatory authority,” for their approval. In addition to direct
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`review of applications, I participated in policy and guidance efforts at FDA and
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`participated in many meetings of several different FDA Advisory Committees. I
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`presented safety evaluations to Committees of the Institute of Medicine, in
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`congressional testimony, and published invited commentaries on product safety. I
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`understand fully the process and criteria utilized by FDA in assessing safety and
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`efficacy, pharmaceutical product labeling and pharmaceutical manufacturing
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`quality, and I participated directly in that process for years.
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`10. Since leaving FDA, I have taught and participated in research grants
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`at Arizona State University (ASU), where I am currently an Adjunct Professor in
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`the School of Law; I have taught a course on Food and Drug Law for the last ten
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`years. In the research area, I have assisted my colleagues in the Biodesign Institute
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`at ASU in developing a scientifically sound regulatory path for products, often
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`“start-up” medical product companies develop research plans that will comply with
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`FDA standards.
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`11.
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`I have also held senior positions at two biotech-pharmaceutical
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`companies. At Élan Pharmaceuticals, I was the Senior Vice President for Global
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`Regulatory, Global Safety and Biostatistics.
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`12. From May 2008 through July 2010 I was the Vice President for
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`Global Regulatory at Amgen, Inc. based in Thousand Oaks, California. The
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`regulatory team was responsible for all products in development and on the market.
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`I participated in the preparation of the application to FDA and European Medicines
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`Agency (EMA), including the labeling discussions and agreements about post-
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`marketing commitments, as well as the preparation of applications.
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`II. LEGAL BACKGROUND
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`13.
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`I have been informed that, in inter partes review, a claim is given its
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`broadest reasonable construction, in light of the specification of the patent in which
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`it appears. The broadest reasonable construction is the broadest reasonable
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`interpretation of the claim language.
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`14.
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`I further understand that under this legal standard, the claim language
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`is read in light of the specification of the patent, as would be interpreted by a
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`hypothetical “person of ordinary skill in the art. I also understand that the words in
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`a claim are generally given their ordinary and accustomed meaning, unless the
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`inventor has provided a specific definition in the specification or the file history of
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`the patent.
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`15.
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`I understand that the scope of the invention is defined by the patent
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`claims. I have been informed that it is improper to import limitations from the
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`specifications into the claims.
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`16.
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`I have been informed that anticipation of a claim requires that every
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`element of a claim is disclosed expressly or inherently in a single prior art
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`reference, arranged as in the claim.
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`17.
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`I have been informed that in order to assess whether a claim is
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`obvious in light of the prior art, I must analyze the claims from the perspective of
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`the hypothetical “person of ordinary skill in the art” when the invention was
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`unknown and just before it was made.
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`18.
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`I have been informed that when considering the obviousness of a
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`patent claim, one may consider whether there existed at the relevant time a
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`teaching, suggestion, or motivation that would have led one of ordinary skill in the
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`art to modify the prior art or to combine prior art teachings to arrive at the claimed
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`invention.
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`III. ASSIGNMENT AND MATERIALS
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`19.
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` I have been asked to respond to opinions set forth in the Declaration
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`of Dr. Thomas P. Johnston filed in support of the Patent Owner’s Corrected
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`Response.
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`20.
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`In forming my opinions, I have reviewed and relied upon the Petition
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`for Inter Partes Review filed by BioDelivery Sciences International, Inc., exhibits
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`cited in the Petition, Patent Owner’s Corrected Response filed by RB
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`Pharmaceuticals Limited, exhibits to the Corrected Response, the November 7,
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`2014 Declaration of Dr. Thomas Johnston, documents cited in Dr. Johnston’s
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`Declaration, the transcript of the January 23, 2015 Deposition of Dr. Johnston, and
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`exhibits to that deposition. This material includes Ex. 1001, U.S. Patent No.
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`8,475,832 (“‘832 patent”), Ex. 1017 WO 2008/040534 (“Labtec”), and other
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`references cited below. In addition, I rely on my 35 years of experience in
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`pharmaceutical product development and review from my career in academics, as a
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`medical doctor, as a senior FDA official, as a consultant to industry, and from the
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`positions I have held in pharmaceutical companies.
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`IV. RESPONSE TO DR. JOHNSTON’S OPINIONS
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`A. Response to Dr. Johnston’s Opinions Regarding Claims 15-19 and
`the ‘832 Patent
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`i. “Bioequivalence” and “Substantial Bioequivalence” in the ‘832
`Patent
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`21. The ‘832 patent defines “bioequivalent” at column 3:
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`The term “bioequivalent” means obtaining 80% to 125% of the Cmax
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`and AUC values for a given active in a different product. For
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`example, assuming Cmax and AUC values of buprenorphine for a
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`commercially-available Suboxone
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`tablet
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`(containing
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`2 mg
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`buprenorphine and 0.5 mg naloxone) are 0.780 ng/ml and 6.789
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`hr*ng/ml, respectively, a bioequivalent product would have a Cmax of
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`buprenorphine in the range of 0.624-0.975 ng/ml, and an AUC value
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`of buprenorphine of 5.431-8.486 hr*ng/ml.
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`Ex. 1001, ‘832 patent, at 3:47-56. The ranges in the second sentence in the quote
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`above represent 80% and 125% of the Cmax and AUC values for the specific
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`reference dose identified, i.e., the 2 mg/0.5 mg Suboxone tablet.
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`22. The ranges in Claims 15-17 of the ‘832 patent do not represent
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`“bioequivalent” ranges, as the term “bioequivalent” is understood in the field or as
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`it is defined in the ’832 patent. Instead, the ranges in Claims 15-17 actually
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`represent the “brackets” of PK values, from the 80% of the Cmax and AUC values
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`for the 2 mg/0.5mg Suboxone ODT product to 125% of the Cmax and AUC values
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`for the 16 mg/4mg Suboxone ODT product. See Ex. 1001, ‘832 patent, at Table 3.
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`The bracket between 80% to 125% of an approved reference product is often used
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`by FDA to identify the bracket of PK values which have been found to be safe and
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`effective for a given drug. However, not all products with Cmax and AUC values
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`in this range will be “bioequivalent” to any of the approved Suboxone ODT
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`products.
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`23. Within each of the wide brackets in claims 15-17, there are multiple
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`bioequivalence ranges, corresponding to each of the different approved doses of
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`Suboxone tablets. Compare Ex. 1001, ‘832 patent, at claims 15-17 with Ex. 1013
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`at 1. Using the definition of bioequivalence in the ‘832 patent, it is not accurate to
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`say that every film that provides a Cmax and AUC for buprenorphine and naloxone
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`within the respective ranges in claims 15-17 would be “bioequivalent” to anything.
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`24. The authors of the ‘832 patent appear to have recognized this fact in
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`column 23, stating “[a]s can be seen, the in vivo data indicated that the absorption
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`of buprenorphine was substantially bioequivalent to that of the one dose tablet
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`when the film composition pH was lowered to about 3-3.5.” Ex. 1001, ‘832 patent,
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`at 23:1-4 (emphasis added). When comparing the test film to a specific reference
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`product, the authors of the ‘832 patent recognized that their test film was not
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`bioequivalent, and instead used the term “substantial bioequivalence.” See id.
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`25. Dr. Johnston, too, seems to recognize this, stating that the inventors of
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`the ‘832 patent were trying to “make an improved oral transmucosal formulation
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`containing buprenorphine and naloxone that would have substantial
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`bioequivalence with the well-established Suboxone sublingual tablet.” Ex. 2003,
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`Johnston Decl., at Para. 66 (emphasis added); see also id. at Para. 23 (“The subject
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`to which the ʼ832 patent is directed is an oral transmucosal film dosage that is
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`substantially bioequivalent to Suboxone® tablets, a drug product containing two
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`actives, buprenorphine and naloxone, used to treat opioid dependence.”) (emphasis
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`added). If Dr. Johnston believed that the ‘832 patent was limited to
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`bioequivalence, I do not see any reason why he would have used the term
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`“substantially bioequivalent.”
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`26. The term “substantially bioequivalent” is not defined in the ‘832
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`patent, and is only used in the first paragraph of column 23. Ex. 1001, ‘832 patent,
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`at 23:1-11. In my 35 years of experience with the term “bioequivalence” at the
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`FDA and in my other positions, I am unfamiliar with any use of the term
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`“substantially bioequivalent.” “Substantially bioequivalent” is not a term of art
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`used at FDA. Using the definition of bioequivalence given in the ‘832 patent, a
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`particular product is either bioequivalent to another product or it is not. Without a
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`specific definition or numeric range, it is not possible to know what would be
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`“substantially bioequivalent” and what would not.
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`27.
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`In his deposition, Dr. Johnston testified that “substantial
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`bioequivalence” means that there is “very close agreement between the mean
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`values of the pharmacokinetic parameters between the reference listed drug and the
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`test versus the reference.” Ex. 1028, Johnston Dep. Tr., at 190:7-14. However, Dr.
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`Johnston would not attach any numeric value to what would constitute “very
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`close.” See, e.g., id., at 190:15-18; 253:12-20. Instead, Dr. Johnston offered the
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`following definition of “substantially bioequivalent”:
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`We use statistics to compare whether a referenced product, PK
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`parameters, the tablet, is different from the new dosage form. In this
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`case, the sublingual film, and I have looked at that, and they are not
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`statistically different. So for buprenorphine, those films, the AUCs
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`and Cmaxs, are not significantly different from a statistical ·perspective
`between the tablets and the film or between the films and the tablets.
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`To me, that's substantially bioequivalent.
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`Ex. 1028, Johnston Dep. Tr., at 188:8-22. However, Dr. Johnston offers no basis
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`for what why this would be the definition of “substantial bioequivalence” in the
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`context of the ‘832 patent. Indeed, this is not even the correct statistical definition
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`of bioequivalence, which tests whether the PK values (i.e., AUC and Cmax), are
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`both statistically significantly larger than 80% of the value from the reference
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`formulation and statistically significantly smaller than 125% of the value from the
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`reference formulation.1
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`28. Throughout his declaration and deposition, Dr. Johnston uses the
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`terms “bioequivalent” and “substantially bioequivalent” inconsistently and, at
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`times, apparently interchangeably. Compare Ex. 2003, Johnston Decl., at Para. 72
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`(“…the specification’s focus on: … producing effects bioequivalent to Suboxone®
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`sublingual tablets…”), with id. Para. 86 (“…the ʼ832 patent is directed to providing
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`a rapidly orally dissolving mucoadhesive film … with the objective of producing
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`effects that are substantially bioequivalent to those produced by the commercial
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`product Suboxone® sublingual tablets.”); see also Ex. 2018, Johnston Dep. Tr., at
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`253:23-254:7:
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`Q. Does Claim 15 not require bioequivalence to a suboxone tablet?
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`… I’m not using the word substantially, just to be absolutely clear.
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`A. Well, I believe it does, and that’s the whole goal of the FDA
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`instituting bioequivalency ranges…
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`1 Instead of determining that differences are “not statistically significant” as Dr.
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`Johnston suggests, bioequivalence studies demonstrate whether a mean Cmax (and
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`AUC) of one drug is statistically larger than 80% and statistically less than 125%
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`the mean Cmax (and AUC) of another drug.
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`29.
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` In my opinion, Dr. Johnston appears to be glossing over the meaning
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`of bioequivalence as defined in the ‘832 patent. As explained above, per the
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`definition of “bioequivalent” in the ‘832 patent, something is either bioequivalent
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`or it is not.
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`ii. Response to Dr. Johnston’s opinions regarding absorption with
`respect the ‘832 patent
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`30. Dr. Johnston’s does not provide any basis for his statement in footnote
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`11 of his Declaration, that:
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`I note for clarity that this understanding does not exclude the
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`possibility that some very small fraction of buprenorphine could be
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`absorbed in the gut, such as could, but not necessarily, occur if some
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`is unintentionally swallowed.
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`Dr. Johnston contradicted this statement at his deposition, stating the obvious: the
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`buprenorphine that is not absorbed across the mucous membranes is swallowed.
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`Ex. 1028, Johnston Dep. Tr., 237:9-18:
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`[I]f you give an orally dissolving film, and if the drug is not absorbed
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`across the oral mucosa, sublingual, buccal, whatever, then it has to be
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`swallowed, because the patient – where else would it go? The patient
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`doesn’t expectorate [i.e., spit] the saliva drug solution. So to answer
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`your question, it has to be swallowed. If it isn’t absorbed, it has to go
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`somewhere.
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`31.
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`In light this admission, it follows that, even using Dr. Johnston’s
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`stated figure for “oral transmucosal absorption” of buprenorphine—i.e., 30-50%
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`(Ex. 2003, Johnston Decl., at Para. 61)2—at least half of the buprenorphine is not
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`absorbed in the mouth and is swallowed. Further, given Dr. Johnston’s opinion
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`that the bioavailability of buprenorphine from what Dr. Johnston calls “peroral
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`administration”3 is 10-15% (id. at Para. 46), it follows that the bioavailability of
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`2 As explained below at Paragraphs 54-60, I believe Dr. Johnston’s “30-50%”
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`figure overstates the bioavailability of buprenorphine from administration of the
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`relevant dosage form.
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`3 I note that Dr. Johnston uses the term “peroral,” which does not appear in either
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`the ‘832 patent or in Labtec, to mean drug products such as compressed tablets and
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`capsules that are intended to be swallowed for gastrointestinal (“GI”) absorption.
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`Ex. 1028, Johnston Dep. Tr., at 3:23-25 (“Peroral to me means a dosage
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`form is swallowed for subsequent absorption in the gastrointestinal tract.”); see
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`also id. at 8:3-9. Prescription instructions for such products are often labeled
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`“P.O.”, an abbreviation for per oral, meaning “to take by mouth.” As a medical
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`doctor, I note that ODTs and films are usually not prescribed “P.O.,” but instead
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`are prescribed with additional instructions, such as to place the drug sublingual
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`(i.e., under the tongue) or on top of the tongue. For the purposes of considering
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`Dr. Johnston’s opinions, I will understand that Dr. Johnston uses the term “peroral”
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`to mean that the entire drug product is swallowed whole.
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`buprenorphine from an orally-dissolving dosage form results from absorption in
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`both the mouth and the GI tract.
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`B. Response to Dr. Johnston’s Opinion that Labtec’s Disclosure is a
`Mistake
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`i. The Evidence Does Not Support Dr. Johnston’s Opinion that the
`Inclusion of Suboxone in Table A of Labtec was a “Mistake”
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`32. Dr. Johnston offers the opinion that the POSITA would know that “it
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`is evident that Labtec’s inclusion of Suboxone tablets (and Subutex) in Table A’s
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`laundry list of brand name products was a mistake.” Ex. 2003, Johnston Decl., at
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`Para. 82. Dr. Johnston states “the dosage forms of Labtec are meant to be taken
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`perorally and absorbed through the GI tract.” Id. at Para. 75. Dr. Johnston further
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`states that:
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`Labtec lists such peroral existing GI-absorbed “drugs of interest” to
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`mimic through proposed oral films designed to provide GI absorption
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`in Table A. Id. at 20. Of the 19 brand-name drugs in Table A, 17 are
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`indeed intended and routinely given for peroral administration and
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`gastrointestinal absorption. These 17 drugs fit Labtec’s model, in that
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`the active of the named branded product is intended to be absorbed in
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`the GI tract. But the remaining two brand-name drugs in Table A, i.e.,
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`Suboxone® and Subutex® sublingual tablets, are of course oral-
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`transmucosal drugs, not peroral drugs for GI absorption.
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`Id. at Para. 80.
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`33. However, I have seen no evidence that the disclosure of Suboxone is
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`in a “laundry list” or is a mistake.
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`34. Labtec is generally directed to orally-disintegrating films. See, e.g.,
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`Ex. 1017, Labtec at Page 3. Labtec teaches that an object of its invention is to
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`provide a bioequivalent version of an orally-dissolving tablet. Ex. 1017, Labtec, at
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`Page 4.
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`35. Labtec states:
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`The prior art has not appreciated that an innovator’s drug product, be
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`it a tablet, capsule, or other oral dosage form, has already proven itself
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`effective through rigorous clinical testing, and that the innovator’s
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`product may already provide
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`the optimum bioavailability of
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`pharmaceutical agent. What is needed is a film product that mimics
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`the pharmacokinetics of an innovator’s product, and that follows the
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`same metabolic and bioabsorption pathways as the innovator’s
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`product, to ensure that the dosage form achieves the proven clinical
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`efficacy of the innovator product.
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`Ex. 1017, Labtec, at Page 3.
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`36. Therefore, the POSITA would understand that the goal of Labtec is to
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`create an orally-dissolving film that gets close to the reference product’s
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`pharmacokinetics. The goal is not to maximize or minimize absorption, but rather
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`to “mimic” absorption.
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`ME1 19765305v.1
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`17
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`Page 17
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`37. The general teaching of Labtec is how to reduce absorption through
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`the oral mucosa in order to achieve bioequivalence to a reference dosage tablet,
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`whether the reference tablet is swallowed whole (i.e., “peroral,” to use Dr.
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`Johnston’s term) or is dissolved or disintegrated in the mouth. See, e.g., Ex. 1017,
`
`Labtec, at Page 3 (“it is an object of the present invention to provide non-
`
`mucoadhesive orally disintegrating film dosage forms that mimic the
`
`pharmacokinetic profile of orally administered drug products such as tablets,
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`capsules … and orally dissolving/dispersing tablet (ODT)”); id. at Page 4 (“another
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`object of the present invention is to provide techniques and methodologies for
`
`retarding the absorption of drugs from orally disintegrating films through the oral
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`mucosa”); see also id. (“said film is bioequivalent to an immediate release tablet or
`
`an orally dissolving/dispersing tablet (ODT)…”).
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`38. Dr. Johnston’s opinion that the disclosure of Suboxone in Labtec is a
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`“mistake” therefore contradicts: (i) the general teachings of Labtec, i.e., of orally
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`dissolving films that mimic the pharmacokinetics of orally dissolving tablets
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`(“ODTs”) (Ex. 2017, Labtec, at Page 3), (ii) the description of film versions of
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`ODTs in Table A of Labtec (id. at Pages 21-24), and (iii) the examples in Labtec,
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`which teach films that mimic the pharmacokinetics of these ODTs (id. at Pages 29-
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`47).
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`ME1 19765305v.1
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`18
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`Page 18
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`39.
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`In my opinion, the only way the disclosure of Suboxone could be
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`considered a “mistake” would be if Labtec only taught how to eliminate all
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`transmucosal absorption. Labtec does not teach this. See Paragraph immediately
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`below. Instead, Labtec teaches reducing transmucosal absorption in order to
`
`achieve bioequivalence. Id. at Page 4 (“another object of the present invention is
`
`to provide techniques and methodologies for retarding the absorption of drugs from
`
`orally disintegrating films through the oral mucosa”); see also id. at Page 4 (“said
`
`film is bioequivalent to an immediate release tablet or an orally
`
`dissolving/dispersing tablet (ODT)…”).
`
`40. Labtec explicitly says that it does not require the elimination of all
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`oral transmucosal absorption. For example, Labtec states “the means should be
`
`able to deliver greater than 60 … and up to 100 wt.% of the active ingredient to the
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`gastrointestinal tract.” Ex. 1017, Labtec, at Page 15. Because Labtec describes
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`films in which about 60% of the drug is “delivered” to the GI tract, the POSITA
`
`would understand that Labtec describes films in which up to about 40% of the drug
`
`is absorbed in the mouth.4
`
`
`
`4 Dr. Johnston gave his opinion that “transmucosal oral bioavailability of
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`buprenorphine” is between 30-50%. Ex. 2003, Johnston Decl., at Para. 61. (As
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`explained below at Paragraphs 54-60, this figure is overstated, but I will assume it
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`is true for the purpose of this footnote.) As Dr. Johnston admitted in his
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`ME1 19765305v.1
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`19
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`Page 19
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`41. Finally, I note that Labtec never suggests that it would be harmful to
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`the patient if the drugs listed in Table A were to be absorbed by the oral mucosa.
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`Rather, the purpose of Labtec is “to meet exacting bioavailability requirements, or
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`to be bioequivalent to existing orally administered dosage forms.” Ex. 1017,
`
`Labtec, at Page 4. This is a typical goal in formulating a new version of an
`
`existing drug product and would be readily understood by the audience of Labtec.
`
`ii. Labtec Describes the Same Dosage Form as the ‘832 Patent, i.e.,
`an Orally-Dissolving Film that Mimics the PK profile of Suboxone
`Tablets
`
`42. Dr. Johnston states that “[i]t is my opinion that as [of] 2009 Labtec
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`would not enable a person of ordinary skill in the art to practice the invention of
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`claims 15-19 of the ‘832 patent.” Ex. 2003, Johnston Decl., at Para. 78.
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`43. Labtec teaches achieving bioequivalence between an orally dissolving
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`film and an orally dissolving tablet. See, e.g., Ex. 1017, Labtec, at Pages 3-4.
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`Labtec teaches achieving this goal by reducing oral transmucosal absorption in
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`order to achieve bioequivalence to a reference orally-dissolving tablet. Id. Labtec
`
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`deposition, whatever drug is not absorbed in the oral cavity is subsequently
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`swallowed. Ex. 1028, Johnston Dep. Tr., at 237:9-18. Therefore, according to Dr.
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`Johnston’s own reasoning, “transmucosal oral bioavailability of buprenorphine”
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`would result in up to 50-70% of the drug being “delivered” to the GI tract.
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`ME1 19765305v.1
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`20
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`Page 20
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`
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`teaches that reducing oral transmucosal absorption can be achieved by modifying
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`pH. Id. at Pages 16-17.
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`44. As I understand the ‘832 patent, the inventors were trying to do the
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`same thing and faced precisely the same problem: the inventors sought to
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`approximate the buprenorphine and naloxone PK values of the reference tablet
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`with those of the film. See, e.g., Ex. 1001, ‘832 patent, at 1:8-12; see also id. at
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`Tables 6-10. The inventors tested three test film formulations, each having a
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`different pH, in order to find the film formulation(s) that produced PK values
`
`within the bracket between 80% of the lowest approved dose of Suboxone ODT
`
`and 125% of the highest approved dose of Suboxone ODT. See, e.g., Ex. 1001,
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`‘832 patent, at 18:25-23:55.
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`45.
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`If the inventors of the ‘832 patent used techniques taught in Labtec to
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`reduce oral mucosal absorption to mimic PK values of a reference orally-
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`dissolving tablet, how could Labtec’s disclosure of the same be a mistake?
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`46. Both Labtec’s films and the films described in the ‘832 patent are
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`dissolved in the mouth and ultimately swallowed. Therefore, I find Dr. Johnston’s
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`use of the word “peroral” to distinguish the administration and/or absorption
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`described in Labtec from that described in the ‘832 patent to be unhelpful and
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`misleading.
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`ME1 19765305v.1
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`21
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`Page 21
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`47. Similarly, the films in both Labtec and the ‘832 patent, once
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`dissolved, allow absorption of the drug through the oral mucosa and, once
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`swallowed, through the GI tract. See discussion above. Therefore, the
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`bioavailability observed after administration of either the films of Labtec or the
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`films of the ‘832 patent would result from absorption in the mouth and the GI tract.
`
`48. Dr. Johnston seems to focus on the description of films in Labtec as
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`“non-mucoadhesive.” See, e.g., Ex. 2003, Johnston Decl., at Para. 73. To the
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`extent this is the basis for his opinions that listing Suboxone in Labtec is a mistake,
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`I disagree for at least two reasons. First, I understand this Board has already
`
`declined to “read those unrecited features [i.e., “muco-adhesiveness or mucosal
`
`absorption of buprenorphine”] into the challenged claims.” Second, Dr. Johnston
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`admitted that the Suboxone tablet was not mucoadhesive. Ex. 1028, Johnston Dep.
`
`Tr., at 106:10-12. A non-mucoadhesive orally-dissolving tablet is exactly
`
`comparable to a non-mucoadhesive orally-dissolving film: both dosage forms
`
`deliver the drug in exactly the same way, i.e., by dissolving in the mouth and
`
`subsequently being swallowed. It is common sense that it would be just as easy to
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`hold a non-mucoadhesive film in your mouth and let it dissolve as it would be to
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`hold a non-mucoadhesive tablet in your mouth and let it dissolve.
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`49. Finally, the Patent Owner did not invent absorption by the oral
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`mucosal of buprenorphine (or naloxone). Instead, the Patent Owner merely took
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`ME1 19765305v.1
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`22
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`Page 22
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`advantage of the fact that buprenorphine (and, to a much lesser extent, naloxone) is
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`absorbed by the oral mucosa. It is an inherent property of the drugs. See, e.g., Ex
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`2014, Chiang, at 540 (“Buprenorphine is a very lipophilic compound, which
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`readily permeates the gastrointestinal and oral mucosal membrane.). Dr. Johnston
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`admitted that the difference in administration between “the films in the ‘832
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`Patent” and the administration “of the films in Labtec” is that the former is
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`dissolved und
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