UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`MYLAN PHARMACEUTICALS INC,
`Petitioners,
`
`v.
`
`ALMIRALL, LLC
`Patent Owner
`
`_____________________________
`Case IPR2019-01095
`U.S. Patent No. 9,517,219
`_____________________________
`DECLARATION OF AUDRA L. STINCHCOMB, Ph.D.
`
`Mylan (IPR2019-01095) MYLAN1035, p. 001
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`
`TABLE OF CONTENTS
`Overview .........................................................................................................3
`I.
`II. My background and qualifications..................................................................4
`III. Basis for my opinion .......................................................................................8
`IV.
`Person of ordinary skill in the art ..................................................................11
`V.
`State of the art before November 20, 2012 ...................................................12
`VI.
`The ’219 patent and its claims.......................................................................20
`A.
`Independent claims 1 and 6.................................................................21
`B.
`Dependent claims 2-8..........................................................................23
`VII. Claims 1-4 and 6-7 would have been obvious over Garrett in view of
`Nadau-Fourcade.............................................................................................23
`A.
`Garrett (MYLAN1004) .......................................................................24
`B.
`Nadau-Fourcade (MYLAN1005)........................................................26
`C.
`Independent claims 1 and 6.................................................................26
`1.
`A POSA would have had reason to prepare a topical
`composition comprising “about 7.5% w/w dapsone,”
`“about 30% w/w to about 40% w/w diethylene glycol
`monoethyl ether,” and “water,” wherein “the composition
`does not comprise adapalene”...................................................30
`A POSA would have had a reason to prepare a topical
`composition comprising “about 2% w/w to about 6%
`w/w of a polymeric viscosity builder comprising
`acrylamide/sodium acryloyldimethyl taurate copolymer” .......34
`A POSA would have had reason to prepare a topical
`composition comprising “about 30% w/w diethylene
`glycol monoethyl ether” and “about 4% w/w of a
`polymeric viscosity builder comprising
`acrylamide/sodium acryloyldimethyl taurate copolymer” .......37
`The claimed compositional components are well-known
`for use in topical compositions and therefore a POSA
`would have had a reasonable expectation of successfully
`combining them ........................................................................38
`Dependent Claims 2-4 and 7...............................................................40
`1.
`Claim 2......................................................................................41
`2.
`Claim 3......................................................................................41
`
`D.
`
`2.
`
`3.
`
`4.
`
`1
`
`Mylan (IPR2019-01095) MYLAN1035, p. 002
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`Claims 4 and 7 ..........................................................................41
`3.
`VIII. Claims 1-4 and 6-7 would have been obvious over Garrett in view of
`Bonacucina ....................................................................................................42
`A.
`Bonacucina (MYLAN1015)................................................................43
`B.
`Independent claims 1 and 5.................................................................45
`1.
`A POSA would have had reason to prepare a topical
`composition comprising “about 7.5% w/w dapsone,”
`“about 30% w/w to about 40% w/w diethylene glycol
`monoethyl ether,” and “water,” wherein “the composition
`does not comprise adapalene”...................................................50
`A POSA would have had reason to prepare a topical
`composition comprising “about 2% w/w to about 6%
`w/w of a polymeric viscosity builder comprising
`acrylamide/sodium acryloyldimethyl taurate copolymer” .......53
`A POSA would have had reason to prepare a topical
`composition comprising “about 30% w/w diethylene
`glycol monoethyl ether” and “about 4% w/w of a
`polymeric viscosity builder comprising
`acrylamide/sodium acryloyldimethyl taurate copolymer” .......60
`The claimed compositional components are well-known
`for use in topical compositions and therefore a POSA
`would have had a reasonable expectation of successfully
`combining them ........................................................................61
`Dependent Claims 2-4 and 7...............................................................64
`1.
`Claim 2......................................................................................64
`2.
`Claim 3......................................................................................64
`3.
`Claims 4 and 7 ..........................................................................65
`IX. No objective indicia of non-obviousness exist..............................................66
`A.
`Incompatibility and smaller particle size would not have been
`unexpected...........................................................................................66
`There was no “teaching away” from combining the claimed
`components in the prior art. ................................................................71
`Conclusion.....................................................................................................72
`
`X.
`
`2.
`
`3.
`
`4.
`
`C.
`
`B.
`
`2
`
`Mylan (IPR2019-01095) MYLAN1035, p. 003
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`
`I, Audra L. Stinchcomb, do hereby declare as follows:
`Overview
`1.
`I am over the age of 18 and otherwise competent to make this
`
`I.
`
`declaration. I have been retained as an expert on behalf of Mylan Pharmaceuticals
`
`Inc. (“Mylan”). I understand from counsel this declaration is being submitted
`
`together with a petition for Inter Partes Review (“IPR”) of claims 1-8 of U.S. Patent
`
`No. 9,517,219 (“the ’219 patent”) (MYLAN1001).
`
`2.
`
`I am being compensated for my time in connection with this IPR at my
`
`standard legal consultant rate of $500/hr. I have no personal or financial interest in
`
`Mylan or in the outcome of this proceeding.
`
`3.
`
`In preparing this declaration, I have reviewed the ’219 patent
`
`(MYLAN1001) and considered each of the documents cited therein, in light of the
`
`general knowledge in the art before November 20, 2012. I have also relied upon my
`
`experience in the relevant art and considered the viewpoint of a person of ordinary
`
`skill in the art (“POSA”; defined in § IV) before November 20, 2012.
`
`4.
`
`As set forth below, claims 1-4 and 6-7 of the ’219 patent would have
`
`been obvious over the prior art. I understand from counsel that another expert on
`
`behalf of Mylan will address claims 5 and 8. Each of the claimed compositional
`
`components were known in the art for use in topical compositions. Specifically,
`
`each of the elements were known for use in dapsone compositions, many in the
`
`3
`
`Mylan (IPR2019-01095) MYLAN1035, p. 004
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`same amounts as claimed. Each element is performing the same function it is
`
`known for in the art, and the prior art teaches that modifications to these amounts
`
`were within the skill of the art and would result in predictable changes to the
`
`compositions.
`
`5.
`
`This declaration sets forth my opinion that a POSA would have had a
`
`reason to arrive at the subject matter recited in claims 1-4 and 6-7 of the ’219 patent,
`
`with a reasonable expectation of success, by combining either:
`
`the disclosures of Garrett (MYLAN1004), Nadau-Fourcade
`(1)
`(MYLAN 1005), and a POSA’s knowledge of the prior state of the art,
`or
`(MYLAN1004), Bonacucina
`the disclosures of Garrett
`(2)
`(MYLAN1015), and a POSA’s knowledge of the prior state of the art,
`as discussed in this declaration below.
`II. My background and qualifications
`6.
`My qualifications and credentials are fully set forth in my curriculum
`
`vitae, attached as MYLAN1036. I am an expert in the field of topical pharmaceutical
`
`compositions and transdermal drug delivery systems. Over almost 30 years, I have
`
`accumulated significant experience designing and testing novel formulations for
`
`topical and transdermal drug delivery systems including creams, gels, ointments, and
`
`patches.
`
`7.
`
`I received my Pre-Pharmacy Degree at the University of Southern
`
`Colorado, Pueblo, Colorado in 1986, and my B.S. in Pharmacy from the University
`
`4
`
`Mylan (IPR2019-01095) MYLAN1035, p. 005
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`of Colorado, Boulder/Denver, Colorado, in 1989. I received my Ph.D. in
`
`Pharmaceutics from The University of Michigan, Ann Arbor, Michigan, in 1995. I
`
`was a Research Fellow at the University of Southern Colorado from 1985-1986 and
`
`at the University of Colorado, Institute for Behavioral Genetics from 1987-1988. In
`
`addition, I held a Postdoctoral Fellowship at the University of California, San
`
`Francisco, School of Pharmacy: Biopharmaceutical Sciences and Pharmaceutical
`
`Chemistry from 1995-1996. Furthermore, I held several internships such as the NPC
`
`Research Intensive Internship in Semisolids at Ortho Pharmaceutical Corp., Raritan,
`
`NJ, in 1988, an Industrial Internship in Solid Dosage Forms at Geneva
`
`Pharmaceuticals, Inc., Broomfield, CO, in 1989 and an Industrial Internship in
`
`Ophthalmic Solutions at Lederle Laboratories, Inc., Pearl River, NY. I also worked
`
`as a Relief Pharmacist at Arbor Drugs, Michigan from 1989 to 1994.
`
`8.
`
`I was an Assistant Professor in the Department of Basic Pharmaceutical
`
`Sciences at the Albany College of Pharmacy from 1996-2001, an Assistant Professor
`
`at the University of Kentucky College of Pharmacy from 2001-2004, and an
`
`Associate Professor from 2005-2011. From 2006-2011, I worked as a Graduate
`
`Faculty Member in the Pharmacology and Nutritional Sciences Department at the
`
`University Of Kentucky and I became a full Professor in 2011. Since 2011, I have
`
`been a tenured Professor in the Department of Pharmaceutical Sciences at the
`
`University of Maryland School of Pharmacy, Baltimore.
`
`5
`
`Mylan (IPR2019-01095) MYLAN1035, p. 006
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`I am the Founder and Co-founder of several companies. From 2004-
`
`9.
`
`2014 I acted as the Chief Scientific Officer/Founder for AllTranz Inc., a transdermal
`
`cannabinoid company. Since 2014 I have acted as the Chief Scientific Officer/Co-
`
`Founder for F6Pharma Inc., a palliative care product company, and since 2017 I
`
`have acted as a Co-founder for Anti-Microbial Defense Solutions, LLC. I am also
`
`a member of the following Editorial Advisory Boards: Pharmaceutical Research
`
`(since 2006), Substance Abuse: Research and Treatment (2007), Recent Patents on
`
`Drug Delivery and Formulation (2017), Therapeutic Delivery (2009), Clinical
`
`Pharmacology: Current Research (2011), Medicinal Chemistry: Current Research
`
`(2011), Clinical and Experimental Pharmacology
`
`(2011), Advances
`
`in
`
`Pharmacoepidemiology and Drug Safety (2011); and previously served on the
`
`Editorial Boards of Transdermal (2009-2012). I was a USP Expert Consultant to
`
`General Chapters-Dosage Forms Expert Committee, Subcommittee B on Topical
`
`and Transdermal Drug Products (2012-2015) and a member of the Unites States
`
`Pharmacopeia (1997-2000). I have also been a member of various Peer Review
`
`Committees including the NIH: National Center for Advancing Translations
`
`Sciences (NCATS) (March 2018), NSF Phase I and II: Drug Delivery Panels (2017-
`
`2019), AAPS PPD Section Fellows Selection Committee Member (2016) and many
`
`others throughout my career.
`
`6
`
`Mylan (IPR2019-01095) MYLAN1035, p. 007
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`I have received several Honors throughout my career, such as the
`
`10.
`
`Biomedical Research Support Program Fellowship (1985-1986), the Dean’s
`
`Scholarship (University of Colorado; 1986-1989), the AACP Research Participation
`
`Program Fellowship (1987-1988), the Rho Chi Pharmacy Honor Society (1988), the
`
`National Pharmaceutical Council Research Intensive Internship (1988), the Lilly
`
`Endowment Fellowship (University of Michigan; 1989-1990), the Regent’s
`
`Fellowship, (The University of Michigan; 1989-1992), the Featured Company
`
`(Lexington Venture Club, Who got the Money; January 2010), the Springboard
`
`Portfolio Company (All Things Life Sciences; 2010), the Kentucky Entrepreneurs’
`
`Hall of Fame (2010), the AAPS Fellow (2011), Plenary Speaker at the Institute of
`
`Cannabis Research (Annual Conference, Pueblo, CO; 2018), and as Keynote
`
`Speaker for the 15th Annual Louis C. Littlefield Celebrating Pharmacy Research
`
`Excellence Day (University of Texas, Austin; 2019).
`
`11.
`
`I have published hundreds of peer-reviewed articles, book chapters, and
`
`abstracts related to the field of topical drug delivery and pharmaceutical
`
`compositions. I have also been invited to speak about the field of topical drug
`
`delivery and formulations at numerous industry conferences.
`
`12.
`
`In view of my experiences and expertise outlined above and provided
`
`in my CV, I am an expert in the field of topical pharmaceutical compositions and
`
`transdermal drug delivery. For this reason, I am qualified to provide an opinion as
`
`7
`
`Mylan (IPR2019-01095) MYLAN1035, p. 008
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`to what a person of ordinary skill in the art would have understood, known, or
`
`concluded as of November 20, 2012.
`
`III.
`
`Basis for my opinion
`13.
`In formulating my opinion, I have considered all documents cited
`
`herein, including the following:
`
`Mylan
`Exhibit #
`1001
`1036
`
`1004
`
`1005
`
`1007
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`U.S. Patent No. 9,517,219
`
`Description
`
`Curriculum Vitae for Audra L. Stinchcomb, Ph.D.
`
`International Patent Application Publication No. WO
`2009/061298 (“Garrett”)
`
`Publication No. WO
`International Application
`2010/072958 (“Nadau-Fourcade”)
`
`U.S. Patent Publication No. 2006/0204526 (“Lathrop”)
`
`U.S. Patent Publication No. 2010/0029781 (“Morris”)
`
`Osborne, D.W., “Diethylene glycol monoethyl ether: an
`emerging solvent in topical dermatology products,” J. Cosmetic
`Derm. 10:324-329 (2011) (“Osborne I”)
`
`Physician’s Desk Reference, 65th ed., pp. 599-602
`(2011) (ACZONE Gel 5% Label)
`
`U.S. Patent No. 7,820,186 (“Orsoni”)
`
`Epiduo Product Label, approved December 8, 2008
`(“Epiduo Label”)
`
`U.S. Patent Publication No. 2007/0190019 (“Guo”)
`
`8
`
`Mylan (IPR2019-01095) MYLAN1035, p. 009
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`
`Description
`Rowe, R.C. et al. (Eds.), Handbook of Pharmaceutical
`Excipients, 6th Ed., Pharmaceutical Press: London, UK (2009)
`
`Bonacucina, G. et al., “Characterization and Stability of
`Emulsion Gels Based on Acrylamide/Sodium Acryloyldimethyl
`Taurate Copolymer,” AAPS PharmaSciTech 10:368-375 (2009)
`(“Bonacucina”)
`
`U.S. Patent No. 5,863,560 (“Osborne II”)
`
`U.S. Patent No. 9,517,219 File History
`
`Affidavit of Christopher Butler
`
`Sepineo™ P 600 Brochure
`
`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”)
`
`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”)
`
`Mylan
`Exhibit #
`1014
`
`1015
`
`1016
`1017
`1020
`1026
`
`1028
`
`1029
`
`1032
`
`14.
`
`I understand from counsel that an obviousness analysis involves
`
`comparing a claim to the prior art to determine whether the claimed invention would
`
`have been obvious to a person of ordinary skill in the art in view of the prior art, and
`
`in light of the general knowledge in the art. I also understand from counsel that
`
`when a POSA would have reached the claimed invention through routine
`
`9
`
`Mylan (IPR2019-01095) MYLAN1035, p. 010
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`experimentation, the invention may be deemed obvious. I understand from counsel
`
`that a finding of obviousness for a specific range or ratio in a patent can be overcome
`
`if the claimed range or ratio is proven to be critical to the performance or use of the
`
`claimed invention.
`
`15.
`
`I also understand from counsel that obviousness can be established by
`
`combining or modifying the teachings of the prior art to achieve the claimed
`
`invention. It is also my understanding from counsel that where there is a reason to
`
`modify or combine the prior art to achieve the claimed invention, there must also be
`
`a reasonable expectation of success in so doing. I understand from counsel that the
`
`reason to combine prior art references can come from a variety of sources, not just
`
`the prior art itself or the specific problem the patentee was trying to solve. And I
`
`understand from counsel that the references themselves need not provide a specific
`
`hint or suggestion of the alteration needed to arrive at the claimed invention; the
`
`analysis may include recourse to logic, judgment, and common sense available to a
`
`person of ordinary skill that does not necessarily require explication in any reference.
`
`I understand from counsel further that when considering the obviousness of an
`
`invention, one should also consider whether there are any secondary considerations
`
`that support the nonobviousness of the invention.
`
`10
`
`Mylan (IPR2019-01095) MYLAN1035, p. 011
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`
`IV.
`
`Person of ordinary skill in the art
`16. Counsel has informed me that the critical date for assessing
`
`patentability of the ’219 patent is November 20, 2012. Counsel also informed me
`
`that a person of ordinary skill in the art (“POSA”) is a hypothetical person in
`
`November 2012 presumed to be aware of all pertinent art, who thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity.
`
`17.
`
`In my opinion, a POSA would work as part of a multi-disciplinary team
`
`and have access to and draw upon individuals with comparable levels of education
`
`and experience in relevant disciplines that lie outside his or her primary training. In
`
`particular, the relevant POSA for the ’219 patent would have the knowledge of both
`
`a clinician and a formulator of topical pharmaceutical compositions. I understand
`
`from counsel that another expert on behalf of Mylan will speak on those clinical
`
`aspects.
`
`18.
`
`For the formulator portion of a POSA, it is reasonable to think of a
`
`hypothetical POSA in 2012 as possessing a doctoral degree in pharmaceutics,
`
`chemistry or a related disciple such as pharmacology, or chemical engineering who
`
`also has practical experience (at least two years) of formulating topical drug delivery
`
`products, or someone possessing a Bachelors or Masters degree in one of the
`
`preceding disciplines but with a correspondingly greater level (at least four years) of
`
`formulating topical drug delivery products. That is, the person of ordinary skill
`
`11
`
`Mylan (IPR2019-01095) MYLAN1035, p. 012
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`would have knowledge and skill relating to the use, function, and formulation of
`
`pharmaceutical actives and excipients; knowledge and training regarding the
`
`equipment, processes and techniques used to analyze and test formulation materials;
`
`and an understanding of pharmacokinetic principles and how they relate to drug
`
`development and use.
`
`V.
`
`State of the art before November 20, 2012
`19. Before November 20, 2012, the state of the art included the teachings
`
`provided by the references discussed in this Declaration. Additionally, a POSA,
`
`based on then-existing literature, would also have had general knowledge of the
`
`development of topical pharmaceutical compositions, including dapsone topical
`
`compositions.
`
`20. Dapsone, a bis(4-aminophenyl)sulfone, was first synthesized in 1908.
`
`(MYLAN1004, 10.) Dapsone possesses “several beneficial medicinal activities”
`
`and has been used to treat leprosy, bacterial, protozonal, and plasmonic infections,
`
`and pneumocystis carinii. (MYLAN1007, [0002].) Dapsone was also known to be
`
`an anti-inflammatory agent and has been used to treat skin diseases characterized by
`
`the abnormal infiltration of neutrophils, such as Dermatisis herpetiformis, linear IgA
`
`dermatosis, pustular psoriasis, pyoderma gangrenosum, Sweet’s Syndrome, acne
`
`vulgaris, including inflammatory and non-inflammatory acne, and rosacea.
`
`(MYLAN1007, [0003]; MYLAN1004, 3:14-15.)
`
`12
`
`Mylan (IPR2019-01095) MYLAN1035, p. 013
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`21. Dapsone was originally administered orally, however, oral use of
`
`dapsone is associated with hemolysis and hemolytic anemia. (MYLAN1004,
`
`2:12-14.) Thus, topical dapsone compositions are needed which can deliver a
`
`drug to the pilosebaceous unit. (Id., 20:8-10.) Garrett teaches that topical dapsone
`
`formulations are advantageous because the hematologic effects associated with
`
`oral dapsone are minimized. (Id., 11:22-23.) Development of such topical
`
`compositions was known in the art. (MYLAN1004, generally; MYLAN1007,
`
`[0004]; MYLAN1008, generally.) Many of these compositions were aqueous-
`
`based compositions.
`
` (MYLAN1004, Abstract; MYLAN1008, generally,
`
`MYLAN1016, generally.) In 2005, the U.S. Food and Drug Administration
`
`(“FDA”) granted marketing approval for Aczone® 5% for the treatment of acne
`
`vulgaris, which was an aqueous topical gel composition containing 5% w/w
`
`dapsone. (MYLAN1010, 3.)
`
`22. Many of the topical dapsone compositions known in the art before 2012
`
`shared similar properties. Optimal compositions are those that contain both a
`
`dissolved portion of dapsone that crosses the stratum corneum of the skin and then
`
`passes into the epidermis/upper dermis to become systemically available, and an
`
`undissolved portion of dapsone that is retained in the stratum corneum to serve as a
`
`reservoir or to act in the supracorneum zone to reduce levels of Propionibacterium
`
`13
`
`Mylan (IPR2019-01095) MYLAN1035, p. 014
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`acnes. (MYLAN1004, 12:8-11; MYLAN1009, 4; MYLAN1016, 3:34-38.) In the
`
`5% dapsone gel, “approximately one-third of the dapsone is dissolved and two-thirds
`
`of
`
`the dapsone
`
`is suspended as uniformly dispersed drug particulates.”
`
`(MYLAN1009, 4.)
`
`23. An important aspect of the known dapsone compositions is a
`
`solubilizing agent. Dapsone is insoluble in water and oils, and is soluble in ethanol,
`
`methanol, and acetone. (MYLAN1007, [0005].) For this reason, topical dapsone
`
`compositions in water or oils were difficult to develop. (Id.) Solubilizing agents for
`
`dapsone include organic solvents that are moderately soluble to miscible with water,
`
`which are capable of partially or fully dissolving dapsone either alone or in
`
`combination with water.
`
` (MYLAN1007, [0048]-[0049].)
`
` One preferred
`
`solubilizing agent for dapsone is ethoxydiglycol (i.e., diethylene glycol monoethyl
`
`ether). (MYLAN1007, [0055]-[0057]; MYLAN1004, 14:13-14; MYLAN1010, 1;
`
`MYLAN1009, 3.)
`
`24.
`
`Ethoxydiglycol is used in hundreds of cosmetic products, as well as the
`
`FDA-approved 5% dapsone topical gel. (MYLAN1009, Abstract; MYLAN1010,
`
`3.) Garrett discloses that ethoxydiglycol is a preferred solvent for use in dapsone
`
`topical compositions. (MYLAN1004, 17:1-2.) Lathrop and Garrett specifically
`
`disclose
`
`topical
`
`dapsone
`
`compositions with
`
`10-30%
`
`ethoxydiglycol.
`
`14
`
`Mylan (IPR2019-01095) MYLAN1035, p. 015
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`(MYLAN1004, 4:3; MYLAN1007, claim 26.) The 5% dapsone topical gel contains
`
`25% ethoxydiglycol. (MYLAN1009, 2)
`
`25. Dapsone has a solubility profile in ethoxydiglycol/water mixtures that
`
`is favorable for formulating topical compositions. (MYLAN1009, 3, Figure 1.)
`
`Osborne I discloses dapsone solubility as a function of increasing percentage of
`
`ethoxydiglycol mixed with water:
`
`(MYLAN1009, 3, Figure 1). A POSA would understand from Figure 1 that
`
`the amount of dissolved dapsone dissolved increases as the amount of
`
`ethoxydiglycol increases, and that the rate of dapsone dissolution increases as the
`
`ethoxydiglycol:water ratio increases above 20:80.
`
`15
`
`Mylan (IPR2019-01095) MYLAN1035, p. 016
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`26. Another important aspect of dapsone topical compositions is a
`
`polymeric thickening agent.1 A POSA would understand that the rheological
`
`properties of a topical composition must be maintained to ensure a suitable shelf
`
`life of the product. (MYLAN1011, 3:7-12.) These rheological properties define
`
`“the behavior and texture of the composition during application, but also the
`
`active principle’s release properties [] and the homogeneity of the product when
`
`the active principles are present therein in dispersed form. (Id., 3:12-16.) Morris
`
`teaches that “[t]he rate of absorption of dapsone from the solid microparticulate
`
`state can be controlled, at least in part, by the specifics of the microparticulate
`
`form of the solid material, e.g., the size, size distribution, shape, surface/volume
`
`ratio, polymorphic crystalline form, and hydration or solvation of the dapsone
`
`microparticles. For example, as is well known in the art, larger particles tend to
`
`dissolve or disperse more slowly due to lower surface area/volume ratio in
`
`comparison with smaller but similarly shaped particulates.” (MYLAN1008,
`
`[0004].) Thus, a POSA would understand that the polymeric thickening agent
`
`played an important role in the rheological properties and homogeneity of topical
`
`dapsone compositions.
`
`
`1 The terms “polymeric thickening agent,” “gelling agent,” and “viscosity
`builder” are used interchangeably throughout this Declaration.
`
`16
`
`Mylan (IPR2019-01095) MYLAN1035, p. 017
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`Prior art dapsone compositions contained hydrophilic and
`
`27.
`
`hydroalcoholic thickening agents such as cross-linked acrylic acid polymers,
`
`commercially known as Carbopol®. (MYLAN1004, 13:17-18.) Other hydrophilic-
`
`phase thickening agents were also known to be suitable for dapsone, including
`
`acrylamide/sodium acryloyldimethyl taurate copolymer, such as Sepineo P 600® or
`
`Simulgel 600®. (MYLAN1005, 47:13-50:32 and 11:5-7; MYLAN1013, [0200].)
`
`Acrylamide/sodium acryloyldimethyltaurate copolymer in particular was approved
`
`by the FDA in 2008 in the Epiduo® product (adapalene/benzoyl peroxide topical
`
`gel.) (MYLAN1012, 6.)
`
`28. Bonacucina provides an extensive evaluation of Sepineo P 600 gels.
`
`According to Bonacucina, Sepineo P 600 “has self-gelling and thickening properties
`
`and the ability to emulsify oily phases, which make it easy to use in the formulation
`
`of gels and o/w emulsion gels.” (MYLAN1015, Abstract.) Gels prepared with 3%
`
`to 5% w/w Sepineo P 600 are characterized by “weak polymer-polymer interactions,
`
`an advantageous characteristic for topical administration, as the sample is thus easier
`
`to rub into the skin.” (Id.) Thus, a POSA would understand that acrylamide/sodium
`
`acryloyldimethyltaurate copolymer is a thickening agent useful for topical gel
`
`compositions, including dapsone topical compositions. Indeed, Bonacucina states
`
`that “Sepineo P 600 is a prime candidate for use in the formulation of gels and
`
`emulsion gels with rheological properties suitable for topical administration.”
`
`17
`
`Mylan (IPR2019-01095) MYLAN1035, p. 018
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`(MYLAN1015, 7.) And it was generally known by 2012, for example from the
`
`SEPPIC product brochure,2 that Sepineo P 600 was generally compatible with a
`
`variety of conditions: it was known to be compatible with a variety of solvents, such
`
`
`2 4. In my experience, companies that manufacturer pharmaceutical
`excipients typically create and publish product brochures that companies use to
`market their excipients, provide information about the product, and describe the
`product’s features, functions, abilities, and/or capacities. In my experience, these
`companies typically include a date on each edition of a given brochure, so that
`purchasers and the general public can review the latest information available for a
`given product. These brochures are typically published on or around the revision
`date whereby the brochures are made available on manufacturer’s websites,
`distributed by sales staff, including them with samples and purchases, or publishing
`them to the public in trade journals. MYLAN 1026 mirrors the standard leaflet setup
`for pharmaceutical excipient manufacturers’ product brochures. Although I do not
`specifically recall the Sepineo P 600 brochure, the context and content of this
`document is consistent with my experience with product brochures: MYLAN1026
`(1) identifies Sepineo P 600 as “belong[ing] to the SEPINEO™ new range [sic]
`specifically dedicated to your topical drug developments,” (2) provides technical
`details of the product (such as Sepineo™ P 600’s “benefits,” “thickening power,”
`“Emulsifying power,” and “formulation advice[].”), and (3) includes a date of “April
`2008” in the lower right corner of the second page. MYLAN1026, 1-2. Such
`information is often conveyed by excipient manufacturers in the ordinary course of
`advertising their products, and the information—including the date stated on the
`pamphlet—is a reliable indicator of the information contained within.
`I am familiar with Sepineo™ P 600, and the information contained in
`MYLAN1026 is consistent with the common knowledge, i.e., a POSA’s knowledge,
`of that product prior to the invention date. The fact that MYLAN1026 reflects the
`same information as a POSA would expect—i.e., the product name, technical
`information, and revision date—a POSA would find reliable the information
`contained on each point.
`
`18
`
`Mylan (IPR2019-01095) MYLAN1035, p. 019
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Audra L. Stinchcomb, Ph.D.
`(Exhibit 1035)
`as ethanol and propylene glycol, it thickens formulations over a large pH range, and
`
`it may be used in high shear mixing processes.3 (MYLAN1026, 4.)
`
`29. A final important aspect of the prior art dapsone compositions is a
`
`preservative. Preservatives are commonly used in topical compositions to maintain
`
`the potency, integrity, and safety of the compositions. (MYLAN1028, 20.) Garrett
`
`teaches using preservatives, such as methyl paraben, to prevent or diminish
`
`microorganism growth. (MYLAN1004, 13:29-30.) The working example disclosed
`
`in Garrett also contains methyl paraben, and Lathrop also discloses the use of methyl
`
`paraben as a preservative in topical dapsone compositions. (MYLAN1004, 24:30;
`
`MYLAN1007, [0082].) Mostly importantly, the prior art Aczone 5% commercial
`
`product contained methyl paraben. (MYLAN1010, 4.)
`
`
`3 This pre-2012 knowledge about the general compatibility of Sepineo P 600
`is further shown and corroborated by the December 2007 edition of Pharma &
`Healthcare News published by Alsiano. (MYLAN1034.) The face of MYLAN1034
`states that Pharma & Healthcare News is a periodical that “is published twic