Declaration of Metin Çelik, Ph.D.
`Patent No. 8,475,832
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`
`
`Attorney Docket No. 117744-00048
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`Paper No._______
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`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
` BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
`
`v.
`
`RB PHARMACEUTICALS LIMITED
`Patent Owner
`
`
`Patent 8,475,832
`
`_______________
`
`Mailed: June 20, 2014
`
`
`DECLARATION OF METIN ÇELIK, PH.D.
`UNDER 37 CFR § 1.132
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`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`Paper No._______
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
` BIODELIVERY SCIENCES INTERNATIONAL, INC.
`Petitioner
`
`v.
`
`RB PHARMACEUTICALS LIMITED
`Patent Owner
`
`
`Patent 8,475,832
`
`_______________
`
`Mailed: June 20, 2014
`
`
`DECLARATION OF METIN ÇELIK, PH.D.
`UNDER 37 CFR § 1.132
`
`
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`Declaration of Metin Çelik, Ph.D.
`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`
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`I, Metin Çelik, Ph.D., do hereby make the following declaration:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am currently the President of Pharmaceutical Technologies
`
`International, Inc. (“PTI”), a company that I founded in 1997. PTI develops
`
`management tools, databases and expert systems for the pharmaceutical industry
`
`worldwide and provides expert consultant services to various international
`
`pharmaceutical, food, excipient and equipment companies and to law firms
`
`throughout North America.
`
`2.
`
`Since 2008, I am also a Research Professor of Pharmaceutical
`
`Technology at the College of Pharmacy, Near East University in Cyprus where I
`
`have established a tableting research center.
`
`3.
`
`Over the past thirty years, working in industry, academia, and as a
`
`consultant, I have been continuously involved in the development and formulation
`
`of pharmaceutical products. I have also provided expert consultant services to the
`
`Food and Drug Administration (“FDA”).
`
`4. My involvement in the formulation and process of pharmaceutical
`
`products has given me specialized expertise in the areas of solid dosage forms,
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`integrated compaction research systems, the theory and practice of pharmaceutical
`
`compaction, excipient functionality testing, multiunit dosage form development,
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`artificial neural networks, design and development of pharmaceutical formulation
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`Attorney Docket No. 117744-00048
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`and processing expert systems, preformulation and compaction databases and the
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`development of Management Information Systems for FDA inspection
`
`preparations and general project management purposes.
`
`5. With respect to formulation and process of oral dosage forms, my
`
`practical experience began at Novartis (formerly known as Sandoz) – Switzerland
`
`in 1984. My knowledge in this area continued to develop during my time at
`
`Novartis, in Switzerland and Turkey, and then as a professor in the College of
`
`Pharmacy at Rutgers University in Piscataway, New Jersey. As a member of the
`
`faculty at the latter institution, I lectured in this field (within and outside the
`
`University) and conducted research both as an advisor to a Ph.D. project and as a
`
`consultant to the pharmaceutical industry.
`
`A. Education and Work Experience
`
`6.
`
`I earned my B.Sc. (Hons.) degree in Pharmacy from Hacettepe
`
`University in Turkey in 1979.
`
`7.
`
`I was awarded a Ph.D. degree in Pharmaceutical Technology by the
`
`Department of Pharmaceutical Technology, School of Pharmacy, De Montfort
`
`University (formerly known as Leicester Polytechnic), the United Kingdom, in
`
`1984.
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`8.
`
`After completing my Ph.D. in 1984, I took a position in the Galenical
`
`R&D Department at Novartis in Switzerland, where I was involved in
`
`pharmaceutical technology research and development. I was then promoted to
`
`Development Co-ordinator, Galenical R&D at Novartis in Turkey, where I was
`
`responsible for establishing a pharmaceutical research department.
`
`9.
`
`In 1986, I joined Smith Kline & French Laboratories (presently
`
`known as GlaxoSmithKline) in Swedeland, Pennsylvania, where I developed and
`
`established the first state-of-the-art Compaction Simulator System in the Western
`
`hemisphere.
`
`10.
`
`In 1988, I joined the faculty at the College of Pharmacy, Rutgers
`
`University, where I stayed until 1997. During my tenure at Rutgers, I taught
`
`various courses to both undergraduate and graduate students that focused on the
`
`theory and practice of pharmaceutical formulation and process development. Such
`
`courses included Drug Delivery, Problems in Pharmaceutics, and Pharmaceutical
`
`Processes and Equipment.
`
`11. At Rutgers, in my position as Director of Pharmaceutical Compaction
`
`Research Laboratory & Information Center, I developed a second Compaction
`
`Simulator System. The Compaction Simulator System at Rutgers was the first to
`
`be developed in academia in the U.S.A., and consequently established Rutgers as
`
`an internationally recognized pharmaceutical research centre.
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`12. Between 2004 and 2008, I was a Pharmaceutical Processing Research
`
`Professor at the Department of Industrial Engineering (2004-2008) at Rutgers
`
`where I was involved in the development of a Process Analytical Technology
`
`(PAT) program at Rutgers.
`
`B.
`
`13.
`
`Professional Affiliations, Activities and Awards
`
`I am or have been a member of the following professional
`
`organizations: the American Association of Pharmaceutical Scientists (AAPS), the
`
`New Jersey Pharmaceutical Association of Science and Technology (NJPhAST),
`
`the American Association of Colleges of Pharmacy (AACP), and the Ankara
`
`Chamber of Pharmacists (ACP).
`
`14.
`
`I have been extensively involved with several groups in the AAPS.
`
`For example, from 1995 to 1998, I held the position of chair of the AAPS Process
`
`Development Focus Group. I am also a founder and the former chair of the AAPS
`
`Excipients Focus Group and a founder and the former chair of the AAPS Expert
`
`Systems Focus Group. I have also served as a member of the Pharmaceutical
`
`Technology Section Programming Committee.
`
`15.
`
`In 1991, 1993, and 1994, I received the Faculty Academic Service
`
`Increment Program Award in recognition of my service at Rutgers.
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`16.
`
`I am also listed in the Who’s Who in Science and Engineering (1995).
`
`In 1996, I received the Commission of Science & Technology of New Jersey
`
`Award.
`
`17. While at Rutgers, I also received more than fifty grants from a wide
`
`variety of pharmaceutical companies, including Glaxo and SmithKline Beecham,
`
`totalling more than $1.1 million.
`
`C.
`
`18.
`
`Publications and Educational Involvement
`
`I have organized over thirty national and international symposia and
`
`short courses. I have published a book, nine book chapters, and more than thirty
`
`articles relating to pharmaceutical formulation and processing issues, along with
`
`numerous abstracts and papers presented at scientific conferences.
`
`19.
`
`I have also served as an editorial board member and/or reviewer for
`
`journals such as Pharmaceutical Technology, Drug Development and Industrial
`
`Pharmacy, the European Journal of Pharmaceutical Sciences, and the
`
`International Journal of Pharmaceutics. In addition, I have made over 200
`
`presentations at industry, academic, national and international meetings, and
`
`conferences, most of which by invitation.
`
`20. Attached to this Declaration as Appendix A is a copy of my
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`curriculum vitae detailing my professional expertise in relation to the fields of
`
`pharmaceutical formulation and process development.
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`STUDY AND COMPENSATION
`
`II.
`
`Attorney Docket No. 117744-00048
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`21.
`
`I have been asked by counsel for BioDelivery Sciences, Incorporated
`
`(BDSI) to provide opinions relating to U.S. Patent 8,475,832 (“the ‘832 Patent”)
`
`22.
`
`In addition to my general level of knowledge derived from my
`
`academic studies, my teaching, and over 30 years of practical experience in
`
`pharmaceutical formulation and process development, in forming my opinions
`
`expressed below, I have also relied upon the following documents:
`
`Exhibit
`Ex. 1001
`
`Ex. 1013
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1018
`
`Ex. 1030
`
`Ex. 1031
`
`Ex. 1032
`Ex. 1034
`
`Reference
`U.S. Patent No. 8,475,832 (“the ‘832 patent”)
`
` Suboxone® tablet label, Revised September 2006 (“Suboxone
`Tablet Label”)
`European Medicines Agency (EMEA) Study Report on Suboxone®
`tablets, 2006 (“EMEA Study Report”)
`U.S. Patent No. 7,357,891, “Process for Making an Ingestible Film,”
`issued on April 15, 2008 to Yang, et al. (“Yang”)
`International Patent Publication No. WO 2008/025791, to Applicant
`Euro-Celtique S.A., published March 6, 2008 (“Euro-Celtique”)
`International Patent Publication No. WO 2005/079750, “Films for
`Use as Dosage Forms,” published September 1, 2005
`International Patent Publication No. WO 03/030883, “Uniform
`Films for Rapid Dissolve Dosage Form Incorporating Taste-
`Masking Compositions,” published April 17, 2003
`U.S. Patent No. 4,582,835, issued April 15, 1986, to Lewis, et al.
`Excerpts from Ansel, H., et al., PHARMACEUTICAL DOSAGE FORMS
`AND DRUG DELIVERY SYSTEMS, 7TH ED., Lippincott Williams &
`Wilkins (1999)
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`Declaration of Metin Çelik, Ph.D.
`Patent No. 8,475,832
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`Ex. 1035
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`Attorney Docket No. 117744-00048
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`Excerpt from MERRIAM-WEBSTER’S COLLEGIATE DICTIONARY, 10TH
`ED., Merriam-Webster, Inc. (2000)
`FDA, “Guidance for Industry: Bioavailability and Bioequivalence
`Studies for Orally Administered Drug Products—General
`Considerations,” March 2003
`Print-out from www.accessdata.fda.gov, last viewed June 12, 2014
`
`Ex. 1036
`
`Ex. 1037
`
`23.
`
`I have been asked to provide my opinions regarding (a) the person of
`
`ordinary skill in that art relevant to the ‘832 patent, (b) the appropriate construction
`
`of the claim term “provides an in vivo plasma profile,” (c) the appropriate
`
`construction of the claim term “film formulation,” (d) the background of the art
`
`relevant to the ‘832 patent at its identified filing date, (e) whether claims 15-19 are
`
`obvious over Euro-Celtique, (f) whether claims 15-19 are obvious over Euro-
`
`Celtique in view of the EMEA Study Report, (g) whether claims 15-19 are obvious
`
`over Euro-Celtique in view of the EMEA Study Report and WO 2005/079750 A2,
`
`and (h) whether claims 15-19 are obvious over Euro-Celtique in view of the EMEA
`
`Study Report and U.S. Patent No. 7,357,891. My opinions are provided in Section
`
`V below.
`
`24.
`
`I am being compensated for my time spent on this matter at my usual
`
`consulting rate of $550.00 per hour. My compensation does not depend on the
`
`outcome of this matter. I have no financial interest in BDSI or the outcome of this
`
`proceeding.
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`Patent No. 8,475,832
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`III. LEGAL PRINCIPLES
`
`Attorney Docket No. 117744-00048
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`A. Person of Ordinary Skill in the Art
`
`25.
`
`I have been informed that the hypothetical “person of ordinary skill in
`
`the art” (POSITA) is presumed to be aware of all of the pertinent art and is a
`
`person of ordinary creativity.
`
`B. Claim Construction
`
`26.
`
`I have been informed that, in inter partes review, a claim is given its
`
`broadest reasonable construction in light of the specification of the patent in which
`
`it appears, and that the broadest reasonable construction is the broadest reasonable
`
`interpretation of the claim language.
`
`27.
`
`I have further been informed that, under this legal standard, the claim
`
`language is read in light of the specification, as it would be interpreted by the
`
`POSITA. I have also been informed that the words in a claim are generally given
`
`their ordinary and accustomed meaning, unless the inventor has provided a specific
`
`definition in the specification or the file history of the patent.
`
`C. Obviousness
`
`28.
`
`I have been informed that obviousness involves construing a claim
`
`and comparing it to the prior art to determine whether the claimed method would
`
`have been obvious in light of the prior art. I have also been informed that in order
`
`to assess whether a claim is obvious in light of the prior art, one must analyze the
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`claims from the perspective of the POSITA when the invention was unknown and
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`Attorney Docket No. 117744-00048
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`just before it was made.
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`29.
`
`I have been informed that the factual bases for an obviousness
`
`analysis are: the scope and content of the prior art; any differences between the
`
`claimed subject matter and the prior art; the level of ordinary skill in the art; and
`
`objective evidence of nonobviousness. I have been informed that in an inter partes
`
`review, a prior art reference must be construed in its entirety, including portions
`
`that would teach away from the claimed invention.
`
`30.
`
`I have been informed that hindsight is impermissible and the
`
`obviousness or non-obviousness of a claim must be determined on the basis of the
`
`facts gleaned from the prior art and the knowledge of a person of ordinary skill at
`
`the relevant time. I have been informed that when considering the obviousness of
`
`a patent claim, one should consider whether a teaching, suggestion, or motivation
`
`to combine the references existed at the relevant time.
`
`31.
`
`I have further been informed that a combination of familiar elements
`
`according to known methods is likely to be obvious when it does no more than
`
`yield predictable results. I have also been informed that when there is a design
`
`need or a market pressure to solve a problem and there are a finite number of
`
`identified, predictable solutions, the POSITA has good reason to pursue the known
`
`options within his technical grasp. If this leads to the anticipated success, it is
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`likely the product is not one of innovation, but instead is one of ordinary skill and
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`Attorney Docket No. 117744-00048
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`common sense, and thus is obvious.
`
`
`IV. CLAIMS 15-19
`
`A.
`
`Independent Claim 15
`
`32.
`
`Independent claim 15 recites:
`
`An orally dissolving film formulation comprising buprenorphine and
`
`naloxone,
`
`wherein said formulation provides
`
`an in vivo plasma profile having a Cmax of between about
`
`0.624 ng/ml and about 5.638 ng/ml for buprenorphine
`
`and an in vivo plasma profile having a Cmax of between about
`
`41.04 pg/ml to about 323.75 pg/ml for naloxone.
`
`
`B. Dependent Claims 16 and 17
`
`33. Dependent claims 16 and 17 recite the formulation of claim 15
`
`wherein the formulation provides a mean AUC within broad ranges for
`
`buprenorphine (between about 5.431 hr·ng/ml to about 56.238 hr·ng/ml) (claim
`
`16) and for naloxone (between about 102.88 hr·pg/ml to about 812.00 hr·pg/ml)
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`(claim 17).
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`C. Dependent Claims 18 and 19
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`Attorney Docket No. 117744-00048
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`34. Dependent claims 18 and 19 recite the formulation of claim 15,
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`wherein the formulation comprises about 2 to about 16 mg of buprenorphine or a
`
`salt thereof (claim 18), and about 0.5 to about 4 mg of naloxone or a salt thereof
`
`(claim 19).
`
`V. OPINIONS
`
`A. Relevant Field and Person of Ordinary Skill in the Art
`
`35.
`
`In my opinion, the POSITA as of August 2009 would have a degree in
`
`the pharmaceutical sciences, chemistry, or a related field, and several years of
`
`practical experience in pharmaceutical formulation and processing, namely, a
`
`Ph.D. and 2-3 years of such experience; or a master’s degree and 4-5 years of such
`
`experience; or a bachelor’s degree and 6-7 years of such experience.
`
`B. Claim Construction
`
`1.
`
`“provides an in vivo plasma profile”
`
`36. The POSITA would have readily understood that a “film formulation”
`
`cannot “provide an in vivo plasma profile” by itself. Instead, the POSITA would
`
`understand that an “in vivo” plasma profile is a characteristic of a living organism.
`
`See, e.g., Ex. 1035, MERRIAM-WEBSTER’S COLLEGIATE DICTIONARY, 10TH ED.
`
`(2000), at 616 (defining “in vivo” as “in the living body of a plant or animal”).
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`37.
`
`I note that the ‘832 specification describes film formulations being
`
`prepared so the resulting film could be tested in vivo to determine whether the
`
`profiles would be bioequivalent to Suboxone tablets. See, e.g., Ex. 1001, ‘832
`
`patent, at Examples 6-8 & 13:57-14:15
`
`38. Therefore, I agree that under the legal standards set forth above in
`
`Section III, the broadest reasonable interpretation of the term “provides an in vivo
`
`plasma profile” in light of the ‘832 specification is “results in an in vivo plasma
`
`profile after a resulting film is administered to a human subject.”
`
`2.
`
`“film formulation”
`
`39.
`
`In my opinion, the POSITA would understand that “film formulation”
`
`may refer to the combination of components, or ingredients, that may be processed
`
`into a film. See Ex. 1034, Ansel, H., et al., PHARMACEUTICAL DOSAGE FORMS AND
`
`DRUG DELIVERY SYSTEMS, 7TH ED., Lippincott Williams & Wilkins (1999)
`
`(“PHARMACEUTICAL DOSAGE FORMS”), at 62 (“[V]arious initial formulations of the
`
`product are developed and examined for desired features … [t]he formulation that
`
`best meets the goals for the product is selected and represents its master formula.”)
`
`(emphasis in original).
`
`40.
`
`I note that the specification of the ‘832 patent uses the term
`
`“formulation” to describe a list of components. See, e.g., Ex. 1001, ‘832 patent, at
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`18:41-42 (“The formulations are set forth in Table 5.”), and at Table 5 (disclosing
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`Attorney Docket No. 117744-00048
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`three different “formulations” only by identifying the components of each).
`
`41. Therefore, under the legal standards set forth above in Section III, I
`
`agree that the broadest reasonable interpretation of “film formulation” in light of
`
`the specification includes a “combination of components capable of being used to
`
`prepare a single film.”
`
`42. Nonetheless, as explained in detail below, I have provided opinions
`
`applying alternative constructions of the claim term “film formulation.”
`
`C. Background of the Technology
`
`1.
`
`Pharmaceutical Products Containing Buprenorphine and
`Naloxone Were Known in the Art Before August 2009.
`
`43. Oral administration of pharmaceutical products containing both
`
`buprenorphine and naloxone has been known in the art for many years. See, e.g.,
`
`Ex. 1032, U.S. Patent No. 4,582,835, issued in 1986, at Abstract (disclosing “[a]
`
`method of treating pain which comprises the administration to a patient of a
`
`parenterally or sublingually effective dose of buprenorphine together with an
`
`amount of naloxone sufficient to prevent substitution in an opiate dependent
`
`subject.”).
`
`44. Suboxone tablets, which contain both buprenorphine and naloxone,
`
`were approved by the FDA for oral administration in 2002. See Ex. 1037, print-out
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`from www.accessdata.fda.org (identifying approval date for NDA 20733 for
`
`Attorney Docket No. 117744-00048
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`Suboxone tablet as October 8, 2002).
`
`2.
`
`Pharmaceutical Film Technology was Known and Widely Used
`in the Art Before August 2009
`
`45. As the ‘832 patent acknowledges, pharmaceutical film was known in
`
`the prior art and the film described in the ‘832 specification could be “formed via
`
`any desired process.” See Ex. 1001, ‘832 patent, at 15:29-30. Many such
`
`processes were known and used by those skilled in the art. Several references
`
`teaching techniques for making films are identified in Euro-Celtique, including Ex.
`
`1030, WO 2005/079750 (“Films for Use as Dosage Forms”) and Ex. 1031, WO
`
`03/030883 (“Uniform Films for Rapid Dissolve Dosage Form Incorporating Taste-
`
`Masking Compositions”).
`
`3.
`
`Absorption, Therapeutic Range, Cmax, and AUC
`
`46. The POSITA would have been aware that, for a drug to provide a
`
`therapeutic effect, that the drug must be absorbed into the body at a suitable rate,
`
`be distributed in adequate concentration to the relevant receptor sites, and remain
`
`at the relevant sites for a sufficient period of time. Ex. 1034, PHARMACEUTICAL
`
`DOSAGE FORMS, at 49.
`
`47. The POSITA would have been aware that “[f]or a drug to be
`
`absorbed, it must first be dissolved in the fluid at the absorption site.” Id. at 106.
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`48. One common way to measure absorption characteristics is to measure
`
`blood serum concentration at various time intervals following administration
`
`during clinical studies. Id. at 49. The figure below illustrates a blood serum
`
`concentration curve for a hypothetical drug as a function of time.
`
`
`
`
`From Ex. 1034, PHARMACEUTIC DOSAGE FORMS, at 49.
`
`
`
`49. The POSITA would have been aware that for certain drugs, one can
`
`make a correlation between the drug’s blood serum concentration and the effects of
`
`the drug. See id. The POSITA would have been aware that, for these drugs, there
`
`is a minimum blood serum concentration at which a drug is expected to produce a
`
`therapeutic effect in a patient. Id. at 49. This concentration is known as the
`
`Minimum Effective Concentration (MEC). Id. Because a dosage form that does
`
`not provide at least the MEC will not produce a therapeutic effect, the POSITA
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`developing a new dosage form would be motivated to develop a dosage form that
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`Attorney Docket No. 117744-00048
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`would provide at least the MEC for the drug.
`
`50. A second critical piece of data is the Minimum Toxic Concentration
`
`(MTC). See id. Above this level, the average individual would be expected to
`
`suffer dose-related toxic effects. Id.
`
`51. A goal of pharmaceutical formulation is to provide a serum drug
`
`concentration that is maintained between the MEC and the MTC—known as the
`
`therapeutic window—for the period during which the therapeutic effects of the
`
`drug are desired. Id. This therapeutic range is determined during clinical studies.
`
`See id. at 48-49.
`
`52. There are several different measurements of blood serum
`
`concentration, such as Cmax and AUC. The POSITA would understand Cmax to
`
`refer to the maximum, or peak, concentration of a drug observed in the blood
`
`plasma (or serum) following a dose of the drug. See id. at 114. I note the ‘832
`
`patent states, “[a]s used herein, the term Cmax refers to the mean maximum
`
`plasma concentration after administration of the composition to a human subject.”
`
`Ex. 1001, ‘832 patent, at 3:9-11. Later, however, the ‘832 patent also refers to “a
`
`mean maximum plasma concentration (Cmax).” Id. at 13:45-47.
`
`53. The POSITA would understand AUC to refer to the area under the
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`concentration-time curve, and that AUC is “considered representative of the total
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`amount of drug absorbed into the circulation following the administration of a
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`Attorney Docket No. 117744-00048
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`single dose of that drug.” Ex. 1034, PHARMACEUTICAL DOSAGE FORMS, at 116.
`
`The POSITA would further have understood that “[e]quivalent doses of a drug,
`
`when fully absorbed, would produce the same AUC.” Id.
`
`54. There are different ways to calculate AUC. In some cases, AUC is
`
`calculated from the point of administration throughout the entire concentration
`
`curve. This is sometimes referred to as AUC 0-∞ (or AUCinf). See, e.g., Ex. 1036,
`
`FDA, Guidance for Industry (2003), at 9. In other cases, AUC may be calculated
`
`from the point of administration until t, indicated as AUC0-t,, where t is the last time
`
`point with measurable concentration for an individual formulation. Id. at 9. For
`
`example, an AUC calculated for the first 48 hours after administration could be
`
`identified as AUC0-48. The FDA Guidance provides the calculation for determining
`
`AUC0-∞ from AUC0-t. Id.
`
`55.
`
`I note that the ‘832 patent states “[a]s … used herein, the term AUC
`
`refers to the mean area under the plasma concentration-time curve value after
`
`administration of the compositions formed herein.” Ex. 1001, ‘832 patent, at 3:11-
`
`14. The ‘832 patent also refers to “the mean area under the curve (AUC) value.”
`
`Id. at 14:4-6. I further note that the ‘832 patent reports values for “AUC,”
`
`“AUCinf,” and “AUClast.” See id. at Tables 2-4, 6-11.
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`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`4.
`
`Safety and Efficacy Testing
`
`56.
`
`In order to gain the FDA’s approval for marketing a drug, the
`
`POSITA would have known that a drug’s sponsor would need to provide evidence
`
`demonstrating that the new drug or drug product is safe and effective for its
`
`intended use. Ex. 1034, PHARMACEUTICAL DOSAGE FORMS, at 23.
`
`57. After a new drug is discovered, the drug agent is tested for
`
`pharmacological and toxicological effects and possible therapeutic uses. Id. at 24.
`
`Pre-formulation studies are conducted to identify the physical and chemical
`
`properties of the drug agent. Id. After pre-formulation studies, formulation studies
`
`are conducted to determine features of the proposed product or dosage form. Id.
`
`58. The drug is tested for safety and efficacy through a series of
`
`preclinical and, later, clinical studies. Id. A showing of safety and efficacy is
`
`critical to the FDA’s approval of a drug. See id. An important goal of any clinical
`
`study is to determine the drug’s safe and effective dose. Id. at 48. One can think
`
`of a dose of a drug as “enough but not too much”; i.e., the goal is “to achieve the
`
`drug’s optimum therapeutic effect with safety but at the lowest possible dose.” Id.
`
`59. The POSITA would understand that a pharmaceutical product that has
`
`been approved by the FDA has been determined by the FDA to be safe and
`
`effective. Id. at 23 (“To gain approval for marketing, a drug’s sponsor … must
`
`demonstration, through supporting scientific evidence, that the new drug/drug
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`product is safe and effective for its proposed use.”) A POSITA developing a new
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`Attorney Docket No. 117744-00048
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`dosage form for an existing, FDA-approved drug would and does want to mimic
`
`the pharmacokinetic profile of the approved dosage form in order to better ensure
`
`the new dosage form will be safe and effective. See, e.g., id. at 118. In particular,
`
`targeting the pharmacokinetic profile, including Cmax and AUC, of the FDA-
`
`approved dosage form would better ensure that the serum concentration reaches the
`
`Minimum Effective Dose but does not reach the Minimum Toxic Dose. See
`
`Paragraph 46-58 above.
`
`5.
`
`Dosage Form Development
`
`60. Pharmaceutical formulation and process development is a
`
`multidisciplinary field. Because the development of any drug product requires a
`
`multi-disciplinary approach, the POSITA may work as part of a multi-disciplinary
`
`team and draw upon not only his or her own skills, but also take advantage of
`
`certain specialized skills of others in the team to solve a problem. For example, the
`
`team may include a pre-formulation scientist and/or a clinician.
`
`61. The first step in developing a dosage form for a drug is preformulation
`
`testing. Data collected during preformulation include physical descriptions,
`
`solubility, including pH solubility, dissolution, chemical stability, and buffering
`
`capacity of the drug substance. Ex. 1034, PHARMACEUTICAL DOSAGE FORMS, at
`
`64-87.
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`Attorney Docket No. 117744-00048
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`62. Formulation scientists use the preformulation data in identifying
`
`acceptable dosage forms. In addition, the POSITA would have been aware that
`
`various other considerations go into choosing a preferred dosage form, including
`
`characteristics of the intended patient population. See id. at 62-64.
`
`63. Once a dosage form is chosen, the POSITA would have been aware
`
`that “various initial [i.e., candidate] formulations of the product are developed and
`
`examined for desired features (e.g., drug release profile, bioavailability, clinical
`
`effectiveness) and for pilot plant studies and production scale-up.” Id. at 62. At
`
`this stage, the formulation scientist may conduct in vitro studies and/or may team
`
`up with clinicians to conduct in vivo tests to collect data relating to, among other
`
`things, the concentration of the drug in the body, including the AUC and Cmax data
`
`described above at Paragraphs 46-54.
`
`64. The POSITA would understand that these candidate formulations
`
`would include excipients (i.e., components other than the active drug substance(s)).
`
`Id. at 87-100. Examples of excipients include solvents, polymers, flavors,
`
`colorants, preservatives, stabilizers, diluents, fillers, lubricants, and disintegrating
`
`agents; the POSITA would have been aware of the effects of each when added to
`
`pharmaceutical dosage forms. See id. The POSITA would understand that
`
`formulation scientists routinely adjust these formulations to optimize the drug
`
`release of the dosage form, and thus optimize the Cmax and AUC values described
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`above at Paragraphs 46-54. See id. The formulation that best achieves the goals
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`Attorney Docket No. 117744-00048
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`for the drug product would ultimately represent the drug product’s “master
`
`formula.” Id. at 62.
`
`
`
`D. Claims 15-19 Would Have Been Obvious to the POSITA as of
`August 7, 2009.
`
`65.
`
`In my opinion, there is nothing new or non-obvious recited in claims
`
`15-19 of the ‘832 patent. The two drugs recited in claim 15, buprenorphine and
`
`naloxone, had been known in the art for decades, both alone and in combination.
`
`Although the claims recite “an orally dissolving film formulation,” the claims do
`
`not recite all of the components of a formulation, instead merely reciting that the
`
`film formulation comprises two well-known drugs and providing several
`
`pharmacokinetic target ranges. The recited orally dissolving film formulation
`
`providing Cmax ranges and AUC values within the recited target ranges for
`
`buprenorphine were explicitly disclosed before August 7, 2009. The recited orally
`
`dissolving film formulation providing Cmax and AUC values within the recited
`
`ranges for naloxone would have been obvious to the POSITA before August 7,
`
`2009.
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`Declaration of Metin Çelik, Ph.D.
`Patent No. 8,475,832
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`Attorney Docket No. 117744-00048
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`1.
`
`Ground 1: Claims 15-19 are Obvious over Euro-Celtique
`
`a)
`
`Explicit disclosure in Euro-Celtique.
`
`66. As explained in Table 1 below, Euro-Celtique explicitly discloses
`
`every element of claims 15-19 except the recited Cmax and AUC ranges for
`
`naloxone.
`
`Claim
`15. An orally
`dissolving film
`formulation
`comprising
`buprenorphine
`and naloxone,
`
`Table 1
`Euro-Celtique Disclosure
`Euro-Celtique discloses and claims orally dissolving film
`formulations containing buprenorphine and naloxone. See,
`e.g., Ex. 1018, Euro-Celtique, at Title (“Buprenorphine-Wafer
`for Drug Substitution Therapy”), Abstract (“The present
`invention relates to oral pharmaceutical dosage forms
`comprising buprenorphine with the dosage form releasing
`buprenorphine instantly upon oral, preferably sublingual,
`application of the dosage form.”); claim 7 (reciting an “[o]ral
`pharmaceutical dosage form ... compris[ing] buprenorphine ...
`and naloxone ....”). See also id. at 17:3-6 (“Such film-type …
`dosage forms in accordance with the present invention are
`characterised in that they comprise a matrix which is formed
`from at least one matrix-forming polymer and in which
`buprenorphine and preferably an opioid antagonist such as
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