IPR2018-00608
`Declaration of Alexander M. Klibanov
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC AND
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC,
`Petitioners,
`
`V.
`
`ALMIRALL, LLC,
`Patent Owner.
`
`Case IPR2018-00608
`Patent 9,161,926
`
`DECLARATION OF PROFESSOR ALEXANDER M. KLIBANOV
`IN SUPPORT OF PA TENT OWNER'S RESPONSE TO PETITION FOR
`INTERPARTESREVIEW
`
`1 of 108
`
`Almirall EXHIBIT 2003
`Amneal v. Almirall
`IPR2018-00608
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`

`

`IPR2018-00608
`Declaration of Alexander M. Klibanov
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION .......................................................................................... . 1
`
`A.
`
`Background and Qualifications ............................................................ . 1
`
`B. Materials Considered ............................................................................. 4
`
`II.
`
`SUMMARYOFOPINIONS ........................................................................... 8
`
`III. LEGAL STANDARDS ................................................................................. 10
`
`IV. THE '926 PATENT ....................................................................................... 11
`
`V.
`
`PROSECUTION HISTORY OF THE '926 PATENT .................................. 14
`
`VI. EFFECTIVE FILING DATE OF THE '926 PATENT ................................. 17
`
`VII. PERSON OF ORDINARY SKILL IN THE ART ........................................ 18
`
`VIII. BACKGROUND RELATING TO THE INVENTION OF
`THE '926 PATENT ....................................................................................... 18
`
`A. Dapsone ............................................................................................... 19
`
`B.
`
`General Principles of Pharmaceutical Formulation ............................ 21
`
`l.
`
`Considerations for Topical Products ....................................... .22
`
`C.
`
`D.
`
`E.
`
`F.
`
`Acne Treatments .................................................................................. 27
`
`Rosacea Treatments ............................................................................. 29
`
`Solvents ............................................................................................... 30
`
`Polymeric Viscosity Builders .............................................................. 33
`
`IX.
`
`PETITIONER'S PRIOR-ART REFERENCES ............................................ 36
`
`A. WO 2009/061298 ("Garrett") (Ex. 1004) ............................................ 37
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`IPR2018-00608
`Declaration of Alexander M. Klibanov
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`B.
`
`C.
`
`International Publ. No. WO 2010/072958 A2 ("Nadau-Fourcade")
`(Ex. 1005) ............................................................................................ 45
`
`Giulia Bonacucina et al., "Characterization and stability of emulsion
`gels based on acrylamide/sodium acryloyldimethyl taurate
`copolymer." AAPS PharmSciTech 10(2): 368-375 (2009)
`("Bonacucina") (Ex. 1015) ................................................................. .49
`
`D. U.S. Patent Publ. No. 2006/0204526 ("Lathrop") (Ex. 1007) ............ 50
`
`E.
`
`F.
`
`U.S. Patent Publ. No. 2010/0029781 ("Morris") (Ex. 1008) .............. 51
`
`David W. Osborne, "Diethylene glycol monoethyl ether: an emerging
`solvent in topical dermatology products." J. Cosmetic Dermatology
`10: 324-329 (2011) ("Osborne I") (Ex. 1009) .................................... 53
`
`G. Aczone® Gel 5% Package Insert (2005) ("2005 Aczone 5% PI")
`(Ex. 1010) ............................................................................................ 55
`
`H. U.S. Patent No. 7,820,186 ("Orsoni") (Ex. 1011) ............................... 55
`
`I.
`
`J.
`
`Epiduo® Prescribing Information (2008) ("Epiduo PI") (Ex. 1012) ... 56
`
`U.S. Patent Publ. No. 2007 /0190019 ("Guo") (Ex. 1013) .................. 56
`
`K. U.S. Patent No. 5,863,560 ("Osborne II") (Ex. 1016) ........................ 57
`
`L.
`
`M.
`
`Viscosity of Carbopol® Polymers in Aqueous Systems (2010)
`("Lubrizol Technical Data Sheet") (Ex. 1020) .................................... 59
`
`"Formulating Semisolid Products" (2008) ("Lubrizol Pharmaceutical
`Bulletin 21") (Ex. 1021) ...................................................................... 59
`
`N. Diane M. Thiboutot et al., "Pharmacokinetics of dapsone gel, 5% for
`the treatment of acne vulgaris." Clin. Pharmacokinet. 46: 697-712
`(2007) ("Thiboutot") (Ex. 1023) ......................................................... 59
`
`0.
`
`Sepineo™ P 600 Brochure (Ex. 1026) ................................................ 60
`
`P.
`
`Laurie Barclay, "Use of topical corticosteroids for dermatologic
`conditions reviewed." Medscape (2009) ("Barclay") (Ex. 1027) ....... 60
`
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`Declaration of Alexander M. Klibanov
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`Q.
`
`Jong-Yun Kim et al., "Rheological properties and microstructures of
`Carbopol gel network system." Colloid Polym. Sci. 281: 614-623
`(2003) ("Kim") (Ex. 1029) .................................................................. 60
`
`R. Neutralizing Carbopol® and Pemulen® Polymers in Aqueous and
`Hydroalcoholic Systems (2002) ("Noveon Technical Data Sheet")
`(Ex. 1030) ............................................................................................ 60
`
`S.
`
`Suleyman Piskin et al., "A review of the use of adapalene for the
`treatment of acne vulgaris." Therapeutics & Clinical Risk
`Management 3(4): 621-624 (2007) ("Piskin") (Ex. 1032) ................. 61
`
`X.
`
`THE CLAIMS OF THE '926 PATENT WOULD NOT HA VE BEEN
`OBVIOUS ...................................................................................................... 61
`
`A.
`
`The Combination of Garrett and Nadau-Fourcade Does Not Render
`the Claims of the '926 Patent Obvious ................................................ 62
`
`l.
`
`2.
`
`3.
`
`A POSA Would Not Have Been Motivated to Select the
`Dapsone of the Claimed Invention or Its Claimed
`Concentration of About 7.5% w/w ............................................ 64
`
`A POSA Would Not Have Increased the Concentration of
`DGME Above 25% w/w ............................................................ 71
`
`The Claimed Concentration Range of the Polymeric
`Viscosity Builder Comprising A/SA Copolymer Was Not
`Obvious ..................................................................................... 79
`
`B.
`
`The Combination of Garrett and Bonacucina Does Not Render the
`Claims of the '926 Patent Obvious ...................................................... 83
`
`l.
`
`2.
`
`3.
`
`A POSA Would Not Have Been Motivated to Select the
`Dapsone of the Claimed Invention or Its Claimed
`Concentration of About 7.5% w/w ............................................ 83
`
`A POSA Would Not Have Increased the Concentration of
`DGME Above 25% .................................................................... 87
`
`The Claimed Concentration Range of the Polymeric
`Viscosity Builder Comprising A/SA Copolymer Was Not
`Obvious ..................................................................................... 91
`
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`IPR2018-00608
`Declaration of Alexander M. Klibanov
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`C.
`
`Objective Indicia Further Support the Non-Obviousness of the Claims
`of the '926 Patent. ................................................................................ 95
`
`I.
`
`The Statements and Evidence in Dr. Kevin Warner's
`Declaration Show Unexpected Results of the Claimed
`Formulation .............................................................................. 96
`
`XI. CONCLUSION ............................................................................................ 103
`
`IV
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`IPR2018-00608
`Declaration of Alexander M. Klibanov
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`I, Alexander M. Klibanov, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by Patent Owner Almirall, LLC ("Almirall") as
`
`an expert witness in the above-captioned inter partes review ("IPR") of United
`
`States Patent No. 9,161,926 (the '"926 patent"). I understand that Amneal
`
`Pharmaceuticals LLC and Amneal Pharmaceuticals of New York, LLC
`
`( collectively, "Amneal") have petitioned the Patent Trial and Appeal Board ( the
`
`"Board") for IPR of the '926 patent and request that the United States Patent and
`
`Trademark Office ("PTO") cancel as unpatentable claims 1-6 of the '926 patent.
`
`2.
`
`This declaration sets forth my analyses and opinions based on the
`
`materials I have considered, as well as the bases for my opinions.
`
`A.
`
`3.
`
`Background and Qualifications
`
`I am a Professor of Chemistry and Bioengineering at
`
`the
`
`Massachusetts Institute of Technology ("M.I.T."), where I have been teaching and
`
`conducting research for over 39 years and currently hold the Novartis Endowed
`
`Chair Professorship (which I also held from 2007 to 2011). From 2012 to 2013, I
`
`held the Roger and Georges Firmenich Endowed Chair Professorship in Chemistry.
`
`Prior to that, I was a Professor of Chemistry and a Professor of Bioengineering at
`
`M.I.T., positions I held from 1988 and from 2000, respectively. From 1979 to
`
`1988, I was an Assistant Professor, then Associate Professor, and thereafter a Full
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`Professor of Applied Biochemistry in the Department of Applied Biological
`
`Sciences (formerly the Department of Nutrition and Food Science) at M.I.T.
`
`4.
`
`I obtained my M.S. degree in Chemistry from Moscow University in
`
`Russia in 1971 and Ph.D. in Chemical Enzymology from the same University in
`
`1974. Thereafter, I was a Research Chemist at Moscow University's Department of
`
`Chemistry for three years. From 1977 to 1979, following my immigration to the
`
`United States, I was a Post-Doctoral Associate at the Department of Chemistry,
`
`University of California in San Diego.
`
`5.
`
`Over the last 45+ years as a practicing chemist, I have extensively
`
`researched, published, taught, and lectured in many areas of biological, medicinal,
`
`organic, pharmaceutical formulation, and polymer chemistry.
`
`6.
`
`For my
`
`research accomplishments,
`
`I have earned numerous
`
`prestigious awards and honors. For example, I was elected to the U.S. National
`
`Academy of Sciences ( considered among the highest professional honors that can
`
`be given to an American scientist) and also to the U.S. National Academy of
`
`Engineering ( considered among the highest professional honors that can be given
`
`to an American engineer). I am also a Founding Fellow of the American Institute
`
`for Medical and Biological Engineering and a Corresponding Fellow of the Royal
`
`Society of Edinburgh (Scotland's National Academy of Science and Letters). In
`
`addition, I have received the Arthur C. Cope Scholar Award, the Marvin J. Johnson
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`Declaration of Alexander M. Klibanov
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`Award, the Ipatieff Prize, and the Leo Friend Award, all from the American
`
`Chemical Society, as well as the International Enzyme Engineering Prize.
`
`7.
`
`I currently serve on the Editorial Boards of 14 scientific journals,
`
`including several in the pharmaceutical area (as is the '926 patent), such as "Open
`
`Journal of Pharmacology," "Nanocarriers," "Journal of Biological Chemistry and
`
`Molecular Pharmacology," "Current Pharmaceutical Biotechnology," "Archives of
`
`Natural Products
`
`and Medicinal Chemistry,"
`
`"Archives of Medical
`
`Biotechnology," and "International Journal of Drug Design, Delivery and Safety."
`
`8.
`
`I have published over 315 scientific papers (nearly all of them in peer-
`
`reviewed journals), and I am a named inventor of 25 issued United States patents
`
`and of many foreign ones. I also have given over 370 invited lectures at
`
`professional conferences, universities, and corporations all over the world. A
`
`number of these publications, patents, and lectures have dealt specifically with the
`
`subject matters that are germane to those of the '926 patent, such as polymeric
`
`gels, surfactants, viscosity, solubility, acrylic polymers, and stability of
`
`pharmaceutical formulations.
`
`9.
`
`In addition to my research and teaching activities at M.I.T., I have
`
`consulted widely for pharmaceutical, medical device, chemical, and biotechnology
`
`companies. They have included both innovator and generic pharmaceutical
`
`companies. I have also founded six pharmaceutical companies and have been on
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`IPR2018-00608
`Declaration of Alexander M. Klibanov
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`the scientific advisory boards and/or boards of directors of those companies and of
`
`many others. A number of these entrepreneurial, consulting, advisory, and
`
`directorship activities have dealt specifically with the formulation, stability,
`
`delivery, and biological evaluation of pharmaceutically active compounds.
`
`10.
`
`I am being compensated at my customary rate of $950 per hour for
`
`my work on this case. My compensation is not contingent on the outcome of this
`
`case.
`
`11. My curriculum vitae, which includes a list of my publications, 1s
`
`attached as Exhibit 2004.
`
`12.
`
`In view of my experiences and expertise outlined above and provided
`
`in my curriculum vitae, I am an expert in the field of pharmaceutical formulations
`
`and medicinal chemistry. For this reason, I believe that I am qualified to provide an
`
`opinion as to what a person of ordinary skill in the art at the time of the invention
`
`("POSA") would have understood, known, or concluded as of the effective filing
`
`date of the '926 patent.
`
`B. Materials Considered
`
`13. The opinions expressed m this declaration are based on
`
`the
`
`information and evidence currently available to me. The following table lists the
`
`materials that I considered in forming my opinions set forth in this declaration. I
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`Declaration of Alexander M. Klibanov
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`have also relied on my education, knowledge, and professional experience that I
`
`have acquired over 45+ years as a practicing chemist.
`
`Exhibit
`No.
`
`Materials
`
`1001
`
`United States Patent No. 9,161,926
`
`1002
`
`Declaration of Bozena B. Michniak-Kohn, Ph.D., F AAPS,
`M.R.Pharm.S.
`
`1004 WO 2009/061298 ("Garrett")
`
`1005
`
`International Publ. No. WO 2010/072958 A2 ("Nadau-Fourcade")
`
`1007
`
`U.S. Patent Publ. No. 2006/0204526 ("Lathrop")
`
`1008
`
`U.S. Patent Publ. No. 2010/0029781 ("Morris")
`
`1009
`
`David W. Osborne, "Diethylene glycol monoethyl ether: an
`emerging solvent in topical dermatology products." J. Cosmetic
`Dermatology 10: 324-329 (2011)
`
`1010
`
`Aczone® Gel 5% Package Insert (2005) ("2005 Aczone 5% PI")
`
`1011
`
`U.S. Patent No. 7,820,186 ("Orsoni")
`
`1012
`
`Epiduo® Prescribing Information (2008) ("Epiduo PI")
`
`1013
`
`U.S. PatentPubl. No. 2007/0190019 ("Guo")
`
`1014
`
`1015
`
`Raymond C. Rowe et al. (Eds.), Handbook of Pharmaceutical
`Excipients 441--445, 6th edn., Pharmaceutical Press: London, UK
`(2009)
`
`Giulia Bonacucina et al., "Characterization and stability of emulsion
`gels based on acrylamide/sodium acryloyldimethyl taurate
`copolymer." AAPS PharmSciTech 10(2): 368-375 (2009)
`("Bonacucina")
`
`1016
`
`U.S. Patent No. 5,863,560 ("Osborne II")
`
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`Declaration of Alexander M. Klibanov
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`Exhibit
`No.
`
`Materials
`
`1017
`
`U.S. Patent No. 9,161,926 File History
`
`1018
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`Viscosity of Carbopol® Polymers in Aqueous Systems (2010)
`("Lubrizol Technical Data Sheet")
`
`"Formulating Semisolid Products" (2008) ("Lubrizol
`Pharmaceutical Bulletin 21 ")
`
`V.E. Gottfried Wozel, "Innovative use of dapsone." Dermatol. Clin.
`28: 599-610 (2010) ("Wozel")
`
`Diane M. Thiboutot et al., "Pharmacokinetics of dapsone gel, 5%
`for the treatment of acne vulgaris." Clin. Pharmacokinet. 46: 697-
`712 (2 007) ("Thiboutot")
`
`Rebecca Nguyen et al., "Treatment of acne vulgaris." Pediatrics &
`Child Health 21: 119-125 (2010) ("Nguyen")
`
`Hywel C. Williams et al., "Acne vulgaris." Lancet 379: 361-372
`(2012) ("Williams")
`
`Sepineo TM P 600 Brochure
`
`Laurie Barclay, "Use of topical corticosteroids for dermatologic
`conditions reviewed." Medscape (2009) ("Barclay")
`
`Remington: The Science and Practice of Pharmacy, 21st edn.,
`Lippincott Williams & Wilkins: Baltimore, MD (2005)
`("Remington")
`
`Jong-Yun Kim et al., "Rheological properties and microstructures
`of Carbopol gel network system." Colloid Polym. Sci. 281: 614-623
`(2003) ("Kim")
`
`1030
`
`Neutralizing Carbopol® and Pemulen® Polymers in Aqueous and
`Hydroalcoholic Systems (2002) ("Noveon Technical Data Sheet")
`
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`IPR2018-00608
`Declaration of Alexander M. Klibanov
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`Exhibit
`No.
`
`1032
`
`Materials
`
`Suleyman Piskin et al., "A review of the use of adapalene for the
`treatment of acne vulgaris." Therapeutics & Clinical Risk
`Management 3( 4 ): 621-624 (2007) ("Pi skin")
`
`1033
`
`Patent and Exclusivity for N207154, Orange Book: Approved Drug
`Products with Therapeutic Equivalence Evaluations, U.S. Food &
`Drug Administration
`
`2001
`
`Patent Assignment Agreement dated October 10, 2018
`
`2005
`
`WO 2011/014627 ("Ahluwalia")
`
`2006 WO 2009/108147 ("Garrett I")
`
`2007
`
`WO 2010/105052 ("Hani")
`
`2008
`
`U.S. Patent No. 4,829,058 ("Seydel I")
`
`2009
`
`U.S. Patent No. 4,912,112 ("Seydel II")
`
`2011
`
`S. Puavilai et al., "Incidence of anemia in leprosy patients treated
`with dapsone." J. Med. Assoc. Thailand 67(7): 404--407 (1984)
`("Puavilai ")
`
`2012 World Health Organization Alert No. 117, Antimalarial
`chlorproguanil-dapsone (LapDap™) withdrawn following
`demonstration of post-treatment haemolytic anaemia in G6PD
`deficient patients in a Phase III trial of chlorproguanil-dapsone-
`artesunate (Dacart™) versus artemether-lumefantrine (Coartem®)
`and confirmation of findings in a comparative trial ofLapDap™
`versus Dacart™ (Mar. 4, 2008)
`
`2013
`
`2014
`
`MaryAnn Steiner, "Dapsone topical gel for acne." J. Pharm. Soc.
`Wisc. 12(6):67-71 (2009) ("Steiner")
`
`ACZONE™ Gel, 5% Prescribing Information (2008) ("2008
`Aczone 5% PI")
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`Exhibit
`No.
`
`2015
`
`2016
`
`2017
`
`Materials
`
`Robert Lott et al., "Medication adherence among acne patients: a
`review." J. Cosmetic Dermatology 9: 160-166 (2010) ("Lott")
`
`Kirk A. James et al., "Emerging drugs for acne." Expert Opin.
`Emerging Drugs 14(4): 649-659 (2009) ("James I")
`
`Barry Coutinho, "Dapsone (Aczone) 5% Gel for the Treatment of
`Acne," American Family Physician (Dec. 2010) ("Coutinho")
`
`2018
`
`September 2012 Inactive Ingredient Database File
`
`2019
`
`H.C. Korting & C. Schollmann, "Current topical and systemic
`approaches to treatment of rosacea." JEADV23: 876-882 (2009)
`("Korting")
`
`2020
`
`European Commission's Scientific Committee on Consumer Safety,
`Opinion on Diethylene Glycol Monoethyl Ether (DEGEE) (2010)
`
`2021
`
`December 2012 Inactive Ingredient Database File
`
`II.
`
`SUMMARY OF OPINIONS
`
`14.
`
`I have reviewed the Declarations of Bozena B. Michniak-Kohn,
`
`Ph.D., F AAPS, M.R.Pharm.S., (the "Michniak-Kohn Declaration") and Elaine S.
`
`Gilmore, M.D., Ph.D., (the "Gilmore Declaration"), and Amneal's Petition for IPR
`
`of the '926 patent, as well as the specification, claims, and file history of the '926
`
`patent. I disagree with many of the opinions expressed in the Michniak-Kohn
`
`Declaration and the Gilmore Declaration, as well as with many of the positions
`
`taken in the Petition regarding the obviousness of the challenged claims of the '926
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`patent. It is my opinion that a POSA would not have found it obvious to arrive at
`
`the claims of the '926 patent for at least the following reasons:
`
`•
`
`A POSA would not have been motivated to formulate a dapsone
`
`composition using about 7 .5% w/w of the dapsone compound taught
`
`in the claims.
`
`•
`
`A POSA would have seen no reason to exceed a concentration of 25%
`
`w/w of the solvent, diethylene glycol monoethyl ether ("DGME"),
`
`and hence would not have been motivated to use the concentration
`
`ranges for DGME taught in the claims. A 25% DGME concentration
`
`was used in the ACZONE® Gel, 5%, ("Aczone 5%") formulation, and
`
`a POSA would have seen no benefit, and indeed potential harm, in
`
`increasing that concentration.
`
`•
`
`A POSA would have had no reason to select a polymeric viscosity
`
`builder, or a
`
`thickening agent, comprising acrylamide/sodium
`
`acryloyldimethyl taurate copolymer ("A/SA copolymer") or the
`
`concentration range of about 2% to about 6% w/w of the polymeric
`
`viscosity builder, as required by the claimed invention, based on the
`
`prior-art combinations that Amneal presents.
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`IPR2018-00608
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`III. LEGAL STANDARDS
`
`15.
`
`Since I am not an attorney, my understanding of the patent law and
`
`the legal standards set forth in this report is based on the following explanations
`
`provided to me by counsel for Almirall ("counsel").
`
`16. Even if a claimed invention is not identically disclosed or described in
`
`a single piece of prior art, the patent claim may still be unpatentable if the
`
`differences between the claimed invention and the prior art ( alone or m
`
`combination) are such that the claimed invention as a whole would have been
`
`obvious to a POSA when the invention was made. The level of ordinary skill in the
`
`pertinent art is evaluated as of the time of the invention, here the effective filing
`
`date of the '926 patent.
`
`17.
`
`In addressing obviousness, the following factors must be considered
`
`from the perspective of a hypothetical POSA: (1) the scope and content of the prior
`
`art; (2) the differences between the claimed invention and the prior art; (3) the
`
`level of ordinary skill in the art; and ( 4) any other indications ("objective indicia")
`
`of non-obviousness, such as commercial success, long-felt but unsolved needs,
`
`failure of others, industry acclaim, and unexpected results.
`
`18.
`
`If an experiment leads to unexpected results or a composition exhibits
`
`unexpected properties, that result or composition likely would not have been
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`IPR2018-00608
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`obvious to a POSA. In that instance, such unexpected results or properties suggest
`
`that the compound would not have been obvious.
`
`19.
`
`Prior-art references may be combined to render a claim obvious if a
`
`POSA would have been motivated to combine those teachings to derive the
`
`claimed subject matter with a reasonable expectation of success. However, the use
`
`of hindsight to select or combine prior-art references is improper for purposes of an
`
`obviousness analysis.
`
`20.
`
`In analyzing obviousness, it is relevant to consider whether the art
`
`includes references that "teach away" from the claimed invention. A reference
`
`teaches away from the claimed invention if a POSA reading the reference would be
`
`either discouraged from following the path of the claimed invention or led in a
`
`divergent direction.
`
`IV. THE '926 PATENT
`
`21.
`
`I understand that Amneal has petitioned for review and cancellation of
`
`claims 1-6 of the '926 patent ( collectively, the "challenged claims" or simply the
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`"claims").
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`22. The '926 patent is entitled "Topical Dapsone and Dapsone/Adapalene
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`Compositions and Methods for Use Thereof."
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`23. The
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`'926 patent claims certain topical pharmaceutical dapsone
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`compositions.
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`24. The
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`'926 patent "relate[s] generally to compositions useful for
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`treating a variety of dermatological conditions." '926 patent (Ex. 1001) at 1: 16-17.
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`25. The '926 patent describes acne in detail, but also pertains to "other
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`skin conditions exhibiting acne-like symptoms," including rosacea. Id. at 3:28-
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`5: 10 (Detailed Description); also at 1:23-2:2 (Background). The claimed invention
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`addresses "a continuing need for compositions ... used in a treatment of a variety
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`of skin conditions, such as acne, in which topical application is potentially
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`effective." Id. at 1 :65-2: 1.
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`26. Claims 1 and 5 of the '926 patent are independent claims. Claims 2, 3,
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`and 4 are dependent claims that depend from claim 1; claim 6 is a dependent claim
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`that depends from claim 5. I am informed by counsel that a dependent claim
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`includes all of the limitations of the claim from which it depends, as well as the
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`additional limitation(s) stated in the dependent claim itself.
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`27. Claims 1, 2, 3, and 4 of the '926 patent read as follows:
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`1.
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`A topical pharmaceutical composition comprising:
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`about 7 .5% w/w dapsone;
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`about 30% w/w to about 40% w/w diethylene glycol
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`monoethyl ether;
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`about 2% w/w to about 6% w/w of a polymeric viscosity
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`builder
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`consisting
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`of
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`acrylamide/ sodium
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`acryloyldimethyl taurate copolymer;
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`and water; wherein the composition does not comprise
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`adapalene.
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`2.
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`The composition of claim 1, wherein
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`the
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`diethylene glycol monoethyl ether 1s present at a
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`concentration of about 30% w/w.
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`3.
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`The composition of claim 1, wherein the polymeric
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`viscosity builder is present at a concentration of about
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`4%w/w.
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`4.
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`The composition of claim 1, further compnsmg
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`methyl paraben.
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`28. Claims 5 and 6 read as follows:
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`5.
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`A topical pharmaceutical composition comprising:
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`about 7 .5% w/w dapsone;
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`about 30% diethylene glycol monoethyl ether;
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`about 4% w/w of a polymeric viscosity builder consisting
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`of acrylamide/sodium acryloyldimethyl
`
`taurate
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`copolymer;
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`and water; wherein the composition does not comprise
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`adapalene.
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`6.
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`The composition of claim 5, further compnsmg
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`methyl paraben.
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`IPR2018-00608
`Declaration of Alexander M. Klibanov
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`V.
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`PROSECUTION HISTORY OF THE '926 PATENT
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`29.
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`I understand from counsel that the prosecution history of a U.S. patent
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`is comprised of the patent application and other submissions by the applicant( s) to
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`the PTO, as well as the PTO's responses ("Office Actions"). I also understand that
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`in reviewing a patent application for patentability, a PTO examiner considers,
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`among other things, the relevant prior art.
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`30. Having reviewed the prosecution history of the '926 patent, I provide
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`its brief summary below.
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`31. The application for the '926 patent, U.S. Patent Application No.
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`14/082,955 ("the '955 application") was filed on November 18, 2013.
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`32. The '955 application contained 20 original claims: 17 were directed to
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`compositions comprising dapsone, and 3 were directed to methods of treatment.
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`Application claim 1 was independent and recited: "A composition comprising
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`dapsone, a first solubilizing agent which is diethylene glycol monoethyl ether,
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`optionally at least one second solubilizing agent, a polymer viscosity builder, and
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`water, wherein the dapsone is present in the composition at a concentration of
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`about 3% w/w to about 10% w/w." Dependent application claims 2-16 specified
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`concentrations of the diethylene glycol monoethyl ether and identities and ranges
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`of concentrations of the other elements. Dependent application claims 18-20 were
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`directed to methods for treating dermatological conditions by administering the
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`claimed compositions. '926 prosecution history (Ex. 1017) at 21-22. In response to
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`a restriction/election requirement,
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`the applicants elected to prosecute
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`the
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`composition application claims (1-17). Id. at 63-64, 73.
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`33. The PTO examiner rejected the pending composition claims, among
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`other reasons, for obviousness over the combination of WO 2011/014627
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`("Ahluwalia"), citing to an online publication titled "Viscosity of CARBOPOL
`
`Polymers in Aqueous Systems" ("Lubrizol") and WO 2009/108147 ("Garrett I") to
`
`show facts, in view of WO 2010/105052 ("Hani"). '926 prosecution history (Ex.
`
`1017) at 82-85.
`
`34.
`
`In response, the applicants amended independent application claim 1
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`to recite: "A topical pharmaceutical composition comprising: about 7 .0% w/w to
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`about 8.0% w/w dapsone as the sole active agent; about 25% w/w to about 35%
`
`w/w diethylene glycol monoethyl ether; about 2% w/w to about 6% w/w of a
`
`polymer viscosity builder consisting of acrylamide/sodium acryloyldimethyl
`
`taurate copolymer; and water." Applicants also added a second independent
`
`application claim, reciting: "A topical pharmaceutical composition comprising:
`
`about 7 .5 % w/w dapsone as the sole active agent; about 30% w/w diethylene
`
`glycol monoethyl ether; about 4% w/w of a polymeric viscosity builder consisting
`
`of acrylamide/sodium acryloyldimethyl taurate copolymer; and water" ( application
`
`claim 22). Id. at 241-242. Applicants presented arguments against obviousness,
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`including distinguishing the primary reference, Ahluwalia, as only disclosing
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`dapsone in combination with adapalene, and not as a sole active agent as presently
`
`claimed. Id. at 249-251.
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`35. The PTO examiner rejected all pending application claims for
`
`obviousness over the new combination of Ahluwalia in view of Hani, citing to
`
`Garrett I and two additional references to show facts, finding that the claims as
`
`drafted did not exclude compositions containing adapalene. Id. at 260-270.
`
`36. After an interview with the PTO examiner in which applicants
`
`expressed a desire to exclude adapalene from
`
`the topical pharmaceutical
`
`composition as claimed, applicants submitted a request for continued examination.
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`Applicants amended the pending independent application claims to remove the
`
`"sole active agent" language, and add the recitation "wherein the composition does
`
`not comprise adapalene." Id. at 294, 305, 314. Applicants also added new
`
`application claims 26-30. New independent application claims 26 and 30 mirrored
`
`pending application claims 1 and 22 as amended, but recited
`
`topical
`
`pharmaceutical compositions "for the treatment of acne," further recited "wherein
`
`the dapsone is the sole active agent for the treatment of acne in the composition,"
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`and lacked the adapalene language. Id. at 315.
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`3 7.
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`The PTO withdrew its previous rejections in light of the amendments,
`
`but rejected all pending application claims, among other things, for obviousness
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`over the combinations of (1) Garrett I in view of Hani, and (2) U.S. Patent
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`Application Publication No. 2006/0204526 ("Lathrop") in view of Garrett I,
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`further in view ofHani, citing to Lubrizol to show a fact. Id. at 328-335.
`
`38.
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`In response, the applicants cancelled the new application claims 26-
`
`30 and amended the recited concentrations in application claim 1, bringing the
`
`latter to its present form. Id. at 345-346. Applicants also presented arguments
`
`against obviousness, including submission of a declaration from an inventor, Dr.
`
`Kevin S. Warner (the "Warner Declaration"), describing unexpected results. Id. at
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`347-356. The PTO then promptly allowed the claims without comment on March
`
`19, 2015. Id. at 359-372.
`
`39. After allowance, the applicants filed an additional request for
`
`continued examination to submit a further information disclosure statement. Id. at
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`377-378, 495-497. In response, the PTO indicated that the examiner had
`
`considered the cited references in the information disclosure statement and once
`
`again allowed the claims on July 7, 2015. Id. at 500, 504-505.
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`VI. EFFECTIVE FILING DATE OF THE '926 PATENT
`
`40. Counsel has informed me that the effective filing date of the '926
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`patent is November 20, 2012, and that references that were publicly available prior
`
`to this date hence qualify as prior art to the '926 patent. My opinions herein would
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`not differ, however, if I were to assume that the date of invention of the '926 patent
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`is February 28, 2013, or November 18, 2013.
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`VII. PERSON OF ORDINARY SKILL IN THE ART
`
`41.
`
`It is my view that a POSA in the case of the '926 patent would have
`
`had either (i) a bachelor- or master-level degree in chemistry, polymer science,
`
`pharmaceutics, or a related discipline, plus at least three years of experience in
`
`drug delivery, pharmaceutical formulations, or a related field; or (ii) a doctoral
`
`degree in chemistry, polymer science, pharmaceutics, or a related discipline, plus
`
`some experience in drug delivery, pharmaceutical formulations, or a related field.
`
`42. The '926 patent des