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 JULIE HARPER, M.D. IN SUPPORT OF PATENT
`OWNER'S RESPONSE TO PETITION FOR INTER PARTES REVIEW
`
`1 of94
`
`Almirall EXHIBIT 2022
`Amneal v. Almirall
`IPR2018-00608
`
`

`

`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`A.
`
`Background and Qualifications ............................................................. 1
`
`B. Materials Considered ............................................................................. 4
`
`II.
`
`SUMMARY OF OPINIONS ......................................................................... 11
`
`III. LEGAL STANDARDS ................................................................................. 14
`
`IV. THE '926 PATENT ....................................................................................... 16
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 19
`
`VI. EFFECTIVE FILING DATE OF THE '926 PATENT ................................. 20
`
`VII. BACKGROUND RELATING TO THE INVENTION ................................ 20
`
`A. Acne ..................................................................................................... 22
`
`1.
`
`2.
`
`Causes of Acne ........................................................................ .. 23
`
`Prior Art Acne Treatments ...................................................... .. 28
`
`B.
`
`Rosacea ................................................................................................ 39
`
`VIII. Petitioner's Prior Art References .................................................................. .43
`
`A. WO 2009/061298 ("Garrett") (Ex. 1004) ........................................... .44
`
`B.
`
`C.
`
`International Publ. No. WO 2010/072958 A2 ("Nadau-Fourcade")
`(Ex. 1005) ............................................................................................ 46
`
`Giulia Bonacucina et al., Characterization and stability of emulsion
`gels based on acrylamide/sodium acryloyldimethyl taurate copolymer,
`10 Am. Assoc. of Pharmaceutical Scientists PharmSciTech 368 (2009)
`("Bonacucina") (Ex. 1015) .................................................................. 47
`
`D. U.S. Patent Publ. No. 2006/0204526 ("Lathrop") (Ex. 1007) ........... .47
`
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`E.
`
`F.
`
`U.S. Patent Publ. No. 2010/0029781 ("Morris") (Ex. 1008) ............. .48
`
`David W. Osborne, Diethylene glycol monoethyl ether: an emerging
`solvent in topical dermatology products, 10 J. Cosmetic Dermatology
`324 (2011) ("Osborne I") (Ex. 1009) ................................................. .48
`
`G. Aczone Gel 5% Package Insert (2005) ("2005 Aczone 5% PI")
`(Ex. 1010) ............................................................................................ 50
`
`H. U.S. Patent No. 7,820,186 ("Orsoni") (Ex. 1011) ............................... 52
`
`I.
`
`J.
`
`Epiduo Gel Prescribing Information (2008) ("Epiduo PI") (Ex. 1012)
`............................................................................................................. 53
`
`U.S. Patent Publ. No. WO 2007 /0190019 ("Guo") (Ex. 1013) .......... 54
`
`K. U.S. Patent No. 5,863,560 ("Osborne II") (Ex. 1016) ........................ 55
`
`L.
`
`M.
`
`N.
`
`Viscosity of Carbopol® Polymers in Aqueous Systems ("Lubrizol
`Technical Data Sheet") (Ex. 1020) ...................................................... 55
`
`Formulating Semisolid Products ("Lubrizol Pharmaceutical Bulletin
`21") (Ex. 1021) .................................................................................... 56
`
`V. E. Gottfried Wozel, Innovative use of Dapsone, 28 Dermatol Clin
`599 (2010) ("Wozel") (Ex. 1022) ........................................................ 56
`
`0. Diane M. Thiboutot et al., Pharmacokinetics of Dapsone Gel, 5% for
`the Treatment of Acne Vulgaris, 46 Clin Pharmacokinet 697 (2007)
`("Thiboutot") (Ex. 1023) ..................................................................... 56
`
`P.
`
`Rebecca Nguyen and John Su, Treatment of acne vulgaris, 21
`Pediatrics and Child Health 119 (2010) ("Nguyen") (Ex. 1024) ........ 57
`
`Q. Hywel C. Williams et al., Acne vulgaris, 379 The Lancet 361 (2012)
`("Williams") (Ex. 1025) ...................................................................... 57
`
`R.
`
`S.
`
`Seppic Sepineo™ P 600 Brochure (2008) (Ex. 1026) ........................ 58
`
`Laurie Barclay, Use of Topical Corticosteroids for Dermatological
`conditions Reviewed, www.medscape.com (January 21, 2009)
`("Barclay") (Ex. 1027) ........................................................................ 58
`
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`Declaration of Julie Harper, M.D.
`
`T.
`
`Jong-Yun Kim et al., Rheological properties and microstructures of
`Carbopol gel network system, 281 Colloid Polym Sci 614 (2003)
`(''Kim'') (Ex. 1029) .............................................................................. 58
`
`U. Neutralizing Carbopol® and Pemulen® Polymers in Aqueous and
`Hydroalcoholic Systems (2002) ("Noveon Technical Data Sheet")
`(Ex. 1030) ............................................................................................ 58
`
`V.
`
`Suleyman Piskin and Erol Uzunali, A review of the use of adapalene
`for the treatment of acne vulgaris, 3 Therapeutics & CLincial Risk
`Management 621 (2007) ("Piskin") (Ex. 1032) .................................. 59
`
`IX. The Claims of the '926 Patent Would Not Have been Obvious ................... 59
`
`A. A Person of Ordinary Skill in the Art at the Time of the '926 Patent
`Would Not Have Selected Dapsone .................................................... 60
`
`B. A Person of Ordinary Skill Would Not Have Selected a Dapsone
`Concentration of About 7 .5% .............................................................. 70
`
`C.
`
`D.
`
`If a Person of Ordinary Skill Had Sought to Use Dapsone as Part of an
`Improved Acne Product, that Person Would Have Done So in
`Combination with Adapalene .............................................................. 75
`
`The Combinations Asserted by Amneal Would Not Have Rendered
`the Claims Obvious ............................................................................. 80
`
`1.
`
`2.
`
`Garrett in view of Nadau-Fourcade ......................................... 80
`
`Garrett in view of Bonacucina .................................................. 85
`
`X.
`
`Conclusion ..................................................................................................... 90
`
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`I, Julie Harper, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1. My name is Julie Harper, M.D. I am a practicing dermatologist and
`
`head of the Dermatology & Skin Care Center of Birmingham, Alabama-a practice
`
`that provides thousands of patients with dermatological care every year. I am also a
`
`Clinical Associate Professor in the Department of Dermatology at the University of
`
`Alabama-Birmingham.
`
`I have been asked by Patent Owner Almirall, LLC
`
`("Almirall") to offer my opinions in the above-captioned inter partes review 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 for inter partes review 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 practicing dermatologist and the head of the Dermatology and
`
`Skin Care Center of Birmingham, a practice
`
`in Alabama that provides
`
`comprehensive dermatology services to patients. I am also a Clinical Associate
`
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`Professor in the Department of Dermatology at the University of Alabama(cid:173)
`
`Birmingham.
`
`4.
`
`As a dermatologist at the Dermatology and Skin Care Center, I see
`
`thousands of patients every year with a variety of skincare conditions and needs. I
`
`diagnose and treat patients with a range of dermatological issues, including acne,
`
`skin cancer, dry skin, eczema, dermatitis, keratosis pilaris, psoriasis, and rosacea to
`
`name a few. I opened this practice in 2007.
`
`5.
`
`Before opening my own dermatology practice, I was a full-time
`
`member of the faculty of the Department of Dermatology at the University of
`
`Alabama-Birmingham, holding positions as Associate Professor and Residency
`
`Program Director from 2005 to 2007, and Assistant Professor and Assistant
`
`Residency Program Director from 2000 to 2005.
`
`In those positions, I taught
`
`residents and medical students, as well as saw patients for a range of dermatological
`
`conditions.
`
`I maintain a clinical appointment with the University, in which I
`
`continue to train residents and lecture students.
`
`6.
`
`Through these positions, I have been practicing as a dermatologist since
`
`2000, during which time I have treated tens of thousands of patients for various skin
`
`conditions. One of the common conditions I treat is acne. I have treated thousands
`
`of patients with acne and throughout my years as a dermatologist have been
`
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
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`knowledgeable about the causes of acne, as well as the treatments for them. I have
`
`prescribed several acne medications, including topical medications.
`
`7.
`
`During my eighteen years of practice, I have also treated numerous
`
`patients with rosacea, and am and have been knowledgeable about treatments for
`
`rosacea.
`
`8.
`
`In addition to running a private practice and serving as a Clinical
`
`Associate Professor of Dermatology, I have written and spoken on the subject of
`
`acne and rosacea extensively. I have authored or co-authored over 40 publications
`
`or posters in the field of dermatology, most of which pertain to acne and/or rosacea,
`
`and have given nearly 100 presentations, nationally, about acne and/or rosacea.
`
`Additionally, I have been an Investigator or Principal Investigator on several clinical
`
`trials relating to acne and rosacea treatments.
`
`9.
`
`I am also a founding director and the current president of the American
`
`Acne and Rosacea Society.
`
`I was also previously a member of the American
`
`Academy of Dermatology's Acne Work Group, and served as the President and
`
`Treasurer/Secretary of the Alabama Dermatological Society. In 2016, I won the
`
`American Academy of Dermatology Presidential Citation Award.
`
`I was also a
`
`former Contributing Editor to Practical Dermatology. I have been certified by the
`
`American Board of Dermatology since October 2000.
`
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`Declaration of Julie Harper, M.D.
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`10.
`
`I obtained my Bachelor of Science from Southeast Missouri State
`
`University in 1991. I subsequently earned my M.D. from the University of Missouri(cid:173)
`
`Columbia School of Medicine in 1996.
`
`I completed an internship in internal
`
`medicine from 1996 to 1997 and a residency in dermatology from 1997 to 2000,
`
`both at the University of Missouri-Columbia.
`
`11. My background and qualifications are more fully set forth m my
`
`curriculum vitae, attached as Exhibit 2023.
`
`12.
`
`I am being compensated at my customary rate of $600 per hour for my
`
`work on this case. My compensation is not contingent on the outcome of this case.
`
`B. Materials Considered
`
`13. The opinions that I express 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
`
`have also relied on my education, knowledge, and experience that I have acquired
`
`over eighteen years practicing, teaching, conducting clinical research, and consulting
`
`in the areas of dermatology.
`
`Exhibit
`No.
`
`Materials
`
`1001
`
`United States Patent No. 9,161,926
`
`4
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`Exhibit
`No.
`
`1002
`
`1004
`
`1005
`
`Materials
`
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S.
`
`International Patent Application Publication No. WO 2009/061298
`("Garrett")
`
`International Application Publication No. WO 2010/072958
`("N adau-F ourcade")
`
`1007
`
`U.S. Patent Publication No. 2006/0204526 ("Lathrop")
`
`1008
`
`U.S. Patent Publication No. 2010/0029781 ("Morris")
`
`1009
`
`Osborne, D.W., "Diethylene glycol monoethyl ether: an emerging
`solvent in topical dermatology products," J. Cosmetic Derm.
`10:324-329 (2011) ("Osborne I")
`
`1010
`
`Aczone® Gel 5% Product Label, approved July 7, 2005 ("Aczone®
`Gel 5% Label")
`
`1011
`
`U.S. Patent No. 7,820,186 ("Orsoni")
`
`1012
`
`Epiduo Product Label, approved December 8, 2008 ("Epiduo
`Label")
`
`1013
`
`U.S. Patent Publication No. 2007/0190019 ("Guo")
`
`1014
`
`Rowe, R.C. et al. (Eds.), Handbook of Pharmaceutical Excipients,
`6th Ed., Pharmaceutical Press: London, UK (2009)
`
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`Exhibit
`No.
`
`1015
`
`Materials
`
`Bonacucina, G., et al., "Characterization and Stability of Emulsion
`Gels Based on Acrylamide/Sodium Acryloyldimethyl Taurate
`Copolymer," AAPS PharmaSciTech 10:368-375 (2009)
`("Bonacucina")
`
`1016
`
`U.S. Patent No. 5,863,560 ("Osborne II")
`
`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
`
`Viscosity of Carbopol® Polymers in Aqueous Systems, published
`August 13, 2010 ("Lubrizol Technical Data Sheet")
`
`"Formulating Semisolid Products," published October 29, 2008
`("Lubrizol Pharmaceutical Bulletin 21 ")
`
`Wozel, D., "Innovative Use of Dapsone" Dermatol. Clin. 28: 599-
`610 (2010) ("Wozel")
`
`Thiboutot, D., et al., "Pharmacokinetics of Dapsone Gel, 5% for the
`Treatment of Acne Vulgaris" Clin. Pharmacokinet. 46: 697-712
`(2007) ("Thiboutot")
`
`Nguyen, R. and Su, J., "Treatment of Acne Vulgaris" Pediatrics
`and Child Health 21: 119-125 (2010) ("Nguyen")
`
`Williams, H., et al., "Acne vulgaris" Lancet 379: 361-72 (2012)
`("Williams")
`
`6
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`Exhibit
`No.
`
`Materials
`
`1026
`
`Sepineo TM P 600 Brochure
`
`1027
`
`1028
`
`1029
`
`1030
`
`1032
`
`1033
`
`2005
`
`2006
`
`Barclay, L., "Use of Topical Corticosteroids for Dermatologic
`Conditions Reviewed" Medscape - Jan 21, 2009, accessed from
`https://www.medscape.com/viewarticle/5 87159 _print ("Barclay")
`
`Remington: The Science and Practice of Pharmacy, 21st Ed.,
`Lippincott Williams & Wilkins: Baltimore, MD (2005)
`("Remington")
`
`Kim, J-Y., et al., "Rheological properties and microstructures of
`Carbopol gel network system," Colloid. Polym. Sci. 281:614-623
`(2003) ("Kim")
`
`Neutralizing Carbopol® and Pemulen® Polymers in Aqueous and
`Hydroalcoholic Systems, published January 2002 ("Noveon
`Technical Data Sheet")
`
`Piskin, S. et al. "A review of the use of adapalene for the treatment
`of acne vulgaris," Therapeutics and Clinical Risk Management 3 ( 4):
`621-624 (2007) ("Piskin")
`
`Orange Book: Approved Drug Products with Therapeutic
`Equivalence Evaluations, Patent and Exclusivity for: N207 l 54
`
`International Patent Application Publication No. WO 2011/014627
`("Ahluwalia")
`
`International Patent Application Publication No. WO 2009/108147
`("Garrett I")
`
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`Exhibit
`No.
`
`Materials
`
`2010
`
`2013
`
`2014
`
`2016
`
`2017
`
`2019
`
`2024
`
`2025
`
`2026
`
`Wayback Machine Results for Pascoe Article, available at
`https://web.archive.org/web/20120801225046/http:/rosacea-
`support. org: 80/ aczone-fails-to-im press-for-rosacea.html
`
`MaryAnn Steiner, "Dapsone Topical Gel for Acne," J. Pharm. Soc.
`Wisc. 12(6):67-71 (2009) ("Steiner")
`
`ACZONE1
`M Gel, 5% Prescribing Information (2008) ("2008
`Aczone 5% PI")
`
`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")
`
`H.C. Korting & C. Schollmann, "Current topical and systemic
`approaches to treatment of rosacea," JEADV 23: 876-882 (2009)
`("Korting")
`
`John Kraft & Anatoli Freiman, Management of acne, 183 Canadian
`Med. Assoc. J. E430-E435 (2011) ("Kraft")
`
`Meghan I. Dubina & Alan B. Fleisher Jr., Interaction of Topical
`Sulfacetamide and Topical Dapsone with Benzoyl Peroxide, 145
`JAMA Dermatology 1027-1029 (2009) ("Dubina")
`
`Stephen Titus & Joshua Hodge, Diagnosis and Treatment of Acne,
`86 Am. Family Physician 734-740 (2012) ("Titus")
`
`8
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`Exhibit
`No.
`
`Materials
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`John S. Strauss, Biology of the Sebaceous Gland and the
`Pathophysiology of Acne Vulgaris, Chapter 13 in Pathophysiology
`of Dermatologic Diseases, Second Edition, N. A. Soter and H.
`Baden eds., McGraw-Hill, New York 195-210 (1991) ("Strauss")
`
`William D. James, Acne, 352 New Eng. J. Medicine 1463-1472
`(2005) ("James II")
`
`Ayumi Naito et al., Topical retinoids for acne vulgaris (Protocol), 3
`The Cochrane Library (John Wiley & Sons 2008) ("Naito")
`
`Physicians' Desk Reference 2967 (2011) (excerpt)
`
`Physicians' Desk Reference 2765 (2012) ( excerpt)
`
`Gabriella Fabbrocini et al., Resveratrol-Containing Gel for the
`Treatment of Acne Vulgaris, 12 Am. J. of Clinical Dermatology
`131-141 (2011) ("Fabbrocini")
`
`James Q. Del Rosso, The Use of Sodium Sulfacetamide 10%-Sulfur
`5% Emollient Foam in the Treatment of Acne Vulgaris, 2 J. Clinical
`and Aesthetic Dermatology 26-29 (2009) ("Del Rosso")
`
`Janusz Marcinkiewicz et al., Topical taurine bromamine, a new
`candidate in the treatment of moderate inflammatory acne
`vulgaris-A pilot study, 18 Eur J. Dermatology 433-439 (2008)
`(''Marcinkiewicz'')
`
`Yuko Takenaka et al., Glycolic acid chemical peeling improves
`inflammatory acne eruptions through its inhibitory and bactericidal
`effects on Propionibacte-rium acnes, 39 J. Dermatology 350-354
`(2012) ("Takenaka")
`
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`Declaration of Julie Harper, M.D.
`
`Exhibit
`No.
`
`Materials
`
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`P. Marazzi et al., Clinical evaluation of Double Strength
`JsotrexinTM versus Ben-zamycin® in the topical treatment of mild
`to moderate acne vulgaris, 13 Journal of Dermatological Treatment
`111-117 (2002) ("Marazzi")
`
`N. Kellett et al., Conjoint analysis: a novel, rigorous tool for
`determining patient preferences for topical antibiotic treatment for
`acne. A randomized controlled trial, 154 British Journal of
`Dermatology 524-532 (2006) ("Kellett")
`
`Frank C. Powell, Rosacea, 352 New Eng. J. Med. 793-803 (2005)
`("Powell")
`
`Aczone 7.5% PI ("Aczone 7.5% PI")
`
`Dina Anderson, Finding a Place for Topical Anti-inflammatory
`Acne Therapy, Practical Dermatology 17-18 (July 2009)
`("Anderson")
`
`Michael Ghods et al., The Role of Dapsone Gel in the Acne
`Armamentarium, The Dermatologist (June 10, 2010), available at
`https: //www.the-dermatologist.com/ content/role-dapsone-gel-acne-
`armamentarium ("Ghods")
`
`David Pascoe, Aczone Fails to Impress for Rosacea, Rosacea
`Support Group (July 23, 2012), available at https://rosacea-
`support. org/ aczone-fails-to-impress-for-rosacea.html ("Pascoe")
`
`A Phase II, Randomized, Partial-Blind, Parallel-Group, Active- and
`Vehicle-Controlled, Multi center Study of the Safety and Efficacy of
`AczoneTM (Dap-sone) Gel, 5% in Subjects With Papulopustular
`Rosacea (QLT Inc. publ., Feb. 5, 2007)
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`Exhibit
`No.
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`Materials
`
`AZC ROS 01 Web Results Summary, A Phase II, Randomized,
`Partial-Blind, Parallel-Group, Active- and Vehicle-Controlled,
`Multi center Study of the Safety and Efficacy of Aczone TM
`( dapsone) Gel, 5% in Subjects with Papulopustular Rosacea,
`available at http://www. all erganclini caltrials. com/
`pdfs/medical _aesthetics/Results_ Web_ PostingACZ-ROS-0 l .pdf
`
`Otto H. Mills et al., Comparing 2.5%, 5%, and 10% Benzoyl
`Peroxide on Inflammatory Acne Vulgaris, 25 Int'l J. Dermatology
`664-667 (1986) ("Mills")
`
`John V. Ashurst et al., Pathophysiological Mechanisms, Diagnosis,
`and Management of Dapsone-Jnduced Methemoglobinemia, 110 J.
`Am. Osteopathic Assoc. 16-20 (2010) ("Ashurst")
`
`J.S. Chun et al., Dapsone hypersensitivity syndrome with circulating
`190-kDA and 230-kDA autoantibodies, 34 Clinical and
`Experimental Dermatology e798-e801 (2009) ("Chun")
`
`U.S. Patent Publication No. 2011/0135584 ("Mallard")
`
`U.S. Patent Publication No. 2011/0003894 ("Louis")
`
`II.
`
`SUMMARY OF OPINIONS
`
`14.
`
`I have reviewed the Declarations of Dr. Bozena B. Michniak-Kohn (the
`
`"Michniak-Kohn Declaration") and Elaine S. Gilmore (the "Gilmore Declaration"),
`
`Amneal's Petition for inter partes review of the '926 patent, and the specification,
`
`claims, and file history of the '926 patent. I disagree with a number of the opinions
`
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`IPR2018-00608
`Declaration of Julie Harper, M.D.
`
`expressed in the Michniak-Kohn Declaration and the Gilmore Declaration and the
`
`positions taken in the Petition regarding the obviousness of the challenged claims of
`
`the '926 patent. I offer my opinion that a person of skill in the art would not have
`
`found it obvious to arrive at the asserted claims of the '926 patent for at least the
`
`following reasons:
`
`• A person of ordinary skill in the art seeking to make an improved
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`treatment for acne or rosacea at the time of the invention would
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`not have selected dapsone as the active ingredient. There were
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`numerous potential starting points for an improved acne or rosacea
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`treatment, and a person of ordinary skill in the art would not have
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`seen a reason to select, or reasonably expected success with
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`choosing, dapsone as an active agent. As an acne treatment,
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`dapsone had been relegated to second line status and was
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`perceived as being less effective than other agents. As a rosacea
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`treatment, it was understood to be a disappointing agent that was
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`no more effective than vehicle alone.
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`•
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`Second, even assuming a person of ordinary skill would have
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`contemplated using dapsone as part of a topical product, that
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`person would not have sought to use dapsone in a concentration of
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`about 7 .5%. A person of ordinary skill, aware of prior art
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`including the recently launched Aczone 5% product, would have
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`understood that the concentration of dapsone had already been
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`optimized at 5%. A person of ordinary skill therefore would have
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`seen no benefit in increasing the concentration of dapsone above
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`5%, nor expected success in doing so, as that person would have
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`believed that increasing the concentration could only raise
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`tolerability and potential safety concerns, without increased
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`efficacy.
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`If such a person had sought to make an improved
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`treatment with dapsone, that person would instead have gone in a
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`different direction-combining it with another active agent(cid:173)
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`while keeping the concentration of dapsone at 5%.
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`•
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`Third, the asserted claims prohibit the inclusion of adapalene.
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`Assuming a person of ordinary skill had decided to start with
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`dapsone in seeking to make an improved dermatologic treatment,
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`that person would have sought to improve the formulation by
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`combining it with another active ingredient. In my opinion, that
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`agent would have been adapalene.
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`III. LEGAL STANDARDS
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`15.
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`I am not an attorney, and therefore, my understanding of patent law and
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`the legal standards set forth in this declaration is based on explanations provided by
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`counsel.
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`16.
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`I have been informed that a patent claim is obvious in view of the prior
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`art if the differences between the patented claims and the prior art are such that, at
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`the time of the claimed invention, the subject matter as a whole would have been
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`obvious to a person of ordinary skill in the art.
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`17.
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`I have been informed that the factors to be considered in analyzing
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`whether a claim was obvious are: (i) the scope and content of the prior art; (ii) the
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`differences between the prior art and the claims; (iii) the level of ordinary skill in the
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`art; and (iv) any asserted objective indicia of non-obviousness.
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`18.
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`I have been
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`informed
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`that objective
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`indicia, or secondary
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`considerations, of non-obviousness must be considered when determining
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`obviousness. I understand these objective indicia of non-obviousness include a long(cid:173)
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`standing and unmet problem or need, prior failures, unexpected benefits or results,
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`teaching away, industry skepticism, and industry praise for the invention. It is my
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`understanding that these factors, when present, are intended to serve as a real-world
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`check against "hindsight bias"-the inclination after a problem has been solved to
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`see the solution as obvious or predictable even when it was not.
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`19.
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`I have been informed that, to be relevant to an obviousness inquiry,
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`evidence of objective indicia must be attributable to the claimed invention, and that
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`this may also be referred to as a requirement of a "nexus." I have been informed
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`that there is a rebuttable presumption of nexus when the objective indicia are tied to
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`a specific product and the product is the invention disclosed and claimed in the
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`patent.
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`20.
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`I have been informed that if obviousness is based on a combination of
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`prior art references, then some teaching, suggestion, or motivation to combine the
`
`references may be considered to determine whether the combination would have
`
`been obvious. I understand that a motivation to combine prior art references can
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`come from the references themselves or from the understanding of a person of
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`ordinary skill in the art.
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`I understand that hindsight is impermissible, and that
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`references must be considered in their entirety, and in the context of the prior art as
`
`a whole, from the view of a person of ordinary skill in the art at the time of the
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`claimed invention.
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`21.
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`I understand that when a modification of one reference or disclosure is
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`nothing more than a simple substitution of one known element for another, and when
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`that substitution would yield a predictable result, that the substitution may be
`
`considered obvious. I also understand that a person of skill in the art must have a
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`reasonable expectation of success when combining prior art references at the time
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`of the claimed invention.
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`22.
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`I understand that a prior art reference may be said to teach away when
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`a person of ordinary skill, upon reading the reference, would be discouraged from
`
`following the path set out in the reference, or would be led in a direction divergent
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`from the path that was taken by the inventor.
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`IV. THE '926 PA TENT
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`23.
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`I understand that Amneal has petitioned for review and cancellation of
`
`claims 1-6 of the '926 patent ( collectively, the "challenged claims").
`
`24.
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`The '926 patent is entitled "Topical Dapsone and Dapsone/Adapalene
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`Compositions and Methods for Use Thereof' and pertains to topical pharmaceutical
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`dapsone compositions useful for treating dermatological conditions.
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`25. Claims 1 and 5 are independent claims. Claims 2, 3, and 4 are
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`dependent claims that depend from claim 1. Claim 6 is a dependent claim that
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`depends from claim 5. I am informed by counsel that a dependent claim includes all
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`of the limitations of the claim from which it depends, as well as the additional
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`limitation(s) stated in the dependent claim itself.
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`26. Claim 1 recites:
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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
`
`builder consisting of acrylamide/sodium
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`acryloyldimethyl taurate copolymer;
`
`and water; wherein the composition does not comprise
`
`adapalene.
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`Ex. 1001, '926 patent at 15:20-16:5. I therefore understand that Claim 1 claims a
`
`pharmaceutical topical formulation that:
`
`•
`
`•
`
`includes dapsone in a concentration of about 7 .5% by weight;
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`contains about 30 to about 40% by weight of diethylene glycol
`
`monoethyl ether ("DGME");
`
`•
`
`contains about 2 to about 6% by weight of acrylamide/sodium
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`acryloyldimethyl taurate copolymer ("A/SA") as a polymeric
`
`viscosity builder;
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`contains water; and
`
`does not contain adapalene.
`
`•
`
`•
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`27. Claim 2 recites the composition of claim 1, wherein the DGME is
`
`present at a concentration of about 30% w/w. Ex. 1001, '926 patent at 16:6-8. It
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`therefore narrows the range of DGME used in Claim 1.
`
`28. Claim 3 recites the composition of claim 1, wherein the polymeric
`
`viscosity builder (A/SA) is present at a concentration of about 4% w/w. Ex. 1001,
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`'926 patent at 16:9-11. It therefore narrows the range of A/SA used in Claim 1.
`
`29. Claim 4 recites the composition of claim 1, further comprising methyl
`
`paraben. Ex. 1001, '926 patent at 16:12-13.
`
`30. Claim 5 recites:
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`A topical pharmaceutical composition comprising:
`
`about 7.5% w/w dapsone;
`
`about 30% diethylene glycol monoethyl ether;
`
`about 4% w/w of a polymeric viscosity builder consisting
`
`of acrylamide/sodium acryloyldimethyl taurate
`
`copolymer;
`
`and water; wherein the composition does not comprise
`
`adapalene.
`
`Ex. 1001, '926 patent at 16:14-21. I therefore understand that Claim 5 claims a
`
`topical pharmaceutical formulation that:
`
`•
`
`•
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`includes dapsone in a concentration of about 7 .5% by weight;
`
`contains about 30% by weight of DGME;
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`•
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`contains about 4% by weight A/SA as a polymeric viscosity
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`builder;
`
`contains water; and
`
`does not contain adapalene.
`
`•
`
`•
`
`31. Claim 6 recites the composition of claim 5, further comprising methyl
`
`paraben. Ex. 1001, '926 patent at 16:22-23.
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`32. Counsel has informed me that the effective filing date of the '926 patent
`
`is November 20, 2012.
`
`33.
`
`I understand that Dr. Klibanov offers a definition of a person of
`
`ordinary skill in the art as someone with either:
`
`(i) a bachelor- or master-level degree in chemistry,
`
`polymer science, pharmaceutics, or a related discipline,
`
`plus at least three years' experience in drug delivery,
`
`pharmaceutical formulations, or a related field; or
`
`(ii) a doctoral degree in chemistry, polymer science,
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`pharmaceutics, or a related discipline, plus some
`
`experience in drug delivery, pharmaceutical formulations,
`
`or a related field.
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`34.
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`I will use this definition, with the clarification and understanding that a
`
`person of ordinary skill in the art as defined would consult with a person having
`
`clinical experience treating skin conditions including acne and rosacea.
`
`35.
`
`I have reviewed Dr. Gilmore's definition of the clinical portion of the
`
`person of ordinary skill in the art. Dr. Gilmore appears to agree with my
`
`understanding, acknowledging that the clinical person of ordinary skill in the art
`
`would be either an M.D. with a board certification in dermatology or at least two
`
`years of experience treating skin conditions. See Ex. 1018, Gilmore Deel. at ,r 21.
`
`VI. EFFECTIVE FILING DATE OF THE '926 PATENT
`
`36.
`
`I have been informed that the date of the invention of the '926 patent is
`
`November 20, 2012, and used that date for purposes of my opinions. I have been
`
`informed that references that were publicly available prior to this date therefore
`
`qualify as prior art to the '926 patent.
`
`37. None of my opinions would differ if I were to assume that