`
`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 IPR2019-00207
`
`U.S. Patent No. 9,517,219
`_____________________
`
`DECLARATION OF BOZENA B. MICHNIAK-KOHN, Ph.D., FAAPS,
`M.R.Pharm.S.
`
`
`AMN1002
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`TABLE OF CONTENTS
`
`
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`
`2.
`
`3.
`
`Overview ....................................................................................................... 3
`My background and qualifications ............................................................... 4
`Basis for my opinion ..................................................................................... 7
`Person of ordinary skill in the art ................................................................. 9
`State of the art before November 20, 2012 ................................................ 11
`The ’219 patent and its claims .................................................................... 19
`A.
`Independent claims 1 and 6 .................................................................20
`B. Dependent claims 2-8 ..........................................................................21
`VII. Claims 1-4 and 6-7 would have been obvious over Garrett in view of
`Nadau-Fourcade .......................................................................................... 22
`A. Garrett (AMN1004) .............................................................................23
`B. Nadau-Fourcade (AMN1005) .............................................................25
`C.
`Independent claims 1 and 6 .................................................................25
`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” ............................. 31
`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 ................................................... 39
`D. Dependent Claims 2-4 and 7 ...............................................................41
`1
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`4.
`
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`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`
`
`2.
`
`3.
`
`4.
`
`1.
`Claim 2 ..................................................................................... 41
`Claim 3 ..................................................................................... 42
`2.
`Claims 4 and 7 .......................................................................... 42
`3.
`VIII. Claims 1-4 and 6-7 would have been obvious over Garrett in view of
`Bonacucina ................................................................................................. 43
`A. Bonacucina (AMN1015) .....................................................................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” ............................. 49
`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 ................................................... 62
`C. Dependent Claims 2-4 and 7 ...............................................................64
`1.
`Claim 2 ..................................................................................... 64
`2.
`Claim 3 ..................................................................................... 65
`3.
`Claims 4 and 7 .......................................................................... 65
`No objective indicia of non-obviousness exist ........................................... 66
`A.
`Incompatibility and smaller particle size would not have
`been unexpected. .................................................................................66
`B. There was no “teaching away” from combining the claimed
`components in the prior art. .................................................................72
`Conclusion .................................................................................................. 72
`
`IX.
`
`X.
`
`
`
`2
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`
`
`I, Bozena B. Michniak-Kohn, do hereby declare as follows:
`I.
`
`Overview
`
`1.
`
`I am over the age of 18 and otherwise competent to make this
`
`declaration. I have been retained as an expert on behalf of Amneal
`
`Pharmaceuticals LLC and Amneal Pharmaceuticals of New York, LLC
`
`(“Amneal”). 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”) (AMN1001).
`
`2.
`
`I am being compensated for my time in connection with this IPR at
`
`my standard legal consultant rate of $650/hr. I have no personal or financial
`
`interest in Amneal or in the outcome of this proceeding.
`
`3.
`
`In preparing this declaration, I have reviewed the ’219 patent
`
`(AMN1001) 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 Amneal will address claims 5 and 8. Each of the claimed compositional
`
`components were known in the art for use in topical compositions. Specifically,
`3
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`

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`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`each of the elements were known for use in dapsone compositions, many in the
`
`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:
`
`(1) the disclosures of Garrett (AMN1004), Nadau-Fourcade (AMN1005),
`and a POSA’s knowledge of the prior state of the art, or
`
`(2) the disclosures of Garrett (AMN1004), Bonacucina (AMN1015), 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 AMN1003. I am an expert in the field of topical pharmaceutical
`
`compositions and transdermal drug delivery systems. Over the past 37 years, I
`
`have accumulated significant experience designing and testing novel formulations
`
`for topical and transdermal drug delivery systems including creams, gels,
`
`emulsions, and micro- and nano-carrier systems.
`
`
`
`4
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`7.
`
`I received a B.S. in Pharmacy from DeMontfort University, Leicester,
`
`England, in 1977. I received my Ph.D. in Pharmacology from DeMontfort
`
`University in 1980. I held Postdoctoral Fellowships at the University of Florida’s
`
`College of Pharmacy from 1981-1983, and at the University of Bradford’s
`
`Postgraduate School of Studies in Pharmacy from 1983-1986. I am a member of
`
`the Royal Pharmaceutical Society of Great Britain (license #73637.)
`
`8.
`
`I was an Assistant Professor
`
`in
`
`the Department of Basic
`
`Pharmaceutical Sciences-Pharmaceutics (tenure-track) at the University of South
`
`Carolina’s College of Pharmacy from 1987-1993, an Associate Professor from
`
`1993-1998, and Full Professor with tenure from 1998-2000. From 2000-2005, I
`
`was an Associate Professor in the Department of Physiology and Pharmacology at
`
`the University of Medicine and Dentistry of New Jersey- NJ Medical School.
`
`Since 2005, I have been a tenured Professor in Pharmaceutics at Rutgers- The
`
`State University of New Jersey.
`
`9.
`
`Since 2000, I have acted as the Director of the Laboratory for Drug
`
`Delivery at the New Jersey Center for Biomaterials at Rutgers. In 2011, I founded
`
`the Center for Dermal Research at Rutgers and continue to act as its Director. I am
`
`currently a member of the Editorial Boards of several peer-reviewed journals
`
`including the Clinical Dermatology Research Journal (SciTechnol), Research and
`
`Reports in Transdermal Drug Discovery (Dove Medical Press, Ltd.), Journal of
`5
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`Drug Research and Development (Sciforshen), and the Journal of Drug Discovery
`
`(Hindawi Publishing Company).
`
`10. Since 2007, I have been a member of the Steering Committee of the
`
`Dermatopharmaceutics Focus Group of
`
`the American Association of
`
`Pharmaceutical Scientists. I have been an invited member of the College of NIH
`
`CSR reviewers since 2010. I have been a member of the Faculty of the National
`
`Institute for Pharmaceutical Technology and Education since 2014. Since 2014, I
`
`have acted as the Academic Chair of the Transdermal section of the Non-Invasive
`
`Macromolecule Consortium Working Group of the Catalent Applied Drug
`
`Delivery Institute. I have also organized numerous industry events and
`
`conferences.
`
`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
`
`to what a person of ordinary skill in the art would have understood, known, or
`
`concluded as of November 20, 2012.
`
`6
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`
`III. Basis for my opinion
`In formulating my opinion, I have considered all documents cited
`13.
`
`herein, including the following:
`
`Amneal
`Exhibit #
`1001
`
`1003
`
`1004
`
`1005
`
`1007
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`Description
`
`U.S. Patent No. 9,517,219
`Curriculum Vitae for 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
`(“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”)
`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”)
`
`
`
`7
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`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`Amneal
`Exhibit #
`1017
`1020
`1026
`
`1028
`
`1029
`
`1032
`
`Description
`
`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”)
`
`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 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
`
`8
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`

`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`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.
`
`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.
`
`
`
`9
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`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`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 Amneal
`
`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 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.
`
`10
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`State of the art before November 20, 2012
`
`
`V.
`
`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.
`
`(AMN1004, 10.) Dapsone possesses “several beneficial medicinal activities” and
`
`has been used to treat leprosy, bacterial, protozonal, and plasmonic infections, and
`
`pneumocystis carinii. (AMN1007, [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.
`
`(AMN1007, [0003]; AMN1004, 3:14-15.)
`
`21. Dapsone was originally administered orally, however, oral use of
`
`dapsone is associated with hemolysis and hemolytic anemia. (AMN1004, 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
`
`
`
`11
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`oral dapsone are minimized. (Id., 11:22-23.) Development of such topical
`
`compositions was known in the art. (AMN1004, generally; AMN1007, [0004];
`
`AMN1008, generally.) Many of
`
`these compositions were aqueous-based
`
`compositions.
`
`(AMN1004, Abstract; AMN1008, generally, AMN1016,
`
`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. (AMN1010, 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 acnes. (AMN1004, 12:8-11; AMN1009, 4; AMN1016, 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.” (AMN1009, 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. (AMN1007, [0005].) For this reason, topical
`12
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`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. (AMN1007, [0048]-[0049].) One
`
`preferred solubilizing agent for dapsone is ethoxydiglycol (i.e., diethylene glycol
`
`monoethyl ether). (AMN1007, [0055]-[0057]; AMN1004, 14:13-14; AMN1010,
`
`1; AMN1009, 3.)
`
`24. Ethoxydiglycol is used in hundreds of cosmetic products, as well as
`
`the FDA-approved 5% dapsone topical gel. (AMN1009, Abstract; AMN1010, 3.)
`
`Garrett discloses that ethoxydiglycol is a preferred solvent for use in dapsone
`
`topical compositions. (AMN1004, 17:1-2.) Lathrop and Garrett specifically
`
`disclose topical dapsone compositions with 10-30% ethoxydiglycol. (AMN1004,
`
`4:3; AMN1007, claim 26.) The 5% dapsone topical gel contains 25%
`
`ethoxydiglycol. (AMN1009, 2)
`
`25. Dapsone has a solubility profile in ethoxydiglycol/water mixtures that
`
`is favorable for formulating topical compositions. (AMN1009, 3, Figure 1.)
`
`Osborne I discloses dapsone solubility as a function of increasing percentage of
`
`ethoxydiglycol mixed with water:
`
`13
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`(AMN1009, 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.
`
`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
`
`1 The terms “polymeric thickening agent,” “gelling agent,” and “viscosity
`builder” are used interchangeably throughout this Declaration.
`
`
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`14
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`life of the product. (AMN1011, 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
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`teaches that “[t]he rate of absorption of dapsone from the solid microparticulate
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`state can be controlled, at least in part, by the specifics of the microparticulate
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`form of the solid material, e.g., the size, size distribution, shape, surface/volume
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`ratio, polymorphic crystalline form, and hydration or solvation of the dapsone
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`microparticles. For example, as is well known in the art, larger particles tend to
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`dissolve or disperse more slowly due to lower surface area/volume ratio in
`
`comparison with smaller but similarly shaped particulates.” (AMN1008, [0004].)
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`Thus, a POSA would understand that the polymeric thickening agent played an
`
`important role in the rheological properties and homogeneity of topical dapsone
`
`compositions.
`
`27. Prior art dapsone compositions contained hydrophilic and
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`hydroalcoholic thickening agents such as cross-linked acrylic acid polymers,
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`commercially known as Carbopol®. (AMN1004, 13:17-18.) Other hydrophilic-
`
`phase thickening agents were also known to be suitable for dapsone, including
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`acrylamide/sodium acryloyldimethyl taurate copolymer, such as Sepineo P 600®
`
`or Simulgel 600®. (AMN1005, 47:13-50:32 and 11:5-7; AMN1013, [0200].)
`15
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`Acrylamide/sodium acryloyldimethyltaurate copolymer
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`in particular was
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`approved by the FDA in 2008 in the Epiduo® product (adapalene/benzoyl
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`peroxide topical gel.) (AMN1012, 6.)
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`28. Bonacucina provides an extensive evaluation of Sepineo P 600 gels.
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`According to Bonacucina, Sepineo P 600 “has self-gelling and thickening
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`properties and the ability to emulsify oily phases, which make it easy to use in the
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`formulation of gels and o/w emulsion gels.” (AMN1015, Abstract.) Gels prepared
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`with 3% to 5% w/w Sepineo P 600 are characterized by “weak polymer-polymer
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`interactions, an advantageous characteristic for topical administration, as the
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`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
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`formulation of gels and emulsion gels with rheological properties suitable for
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`topical administration.” (AMN1015, 7.) And it was generally known by 2012, for
`
`example from the SEPPIC product brochure,2 that Sepineo P 600 was generally
`
`
`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
`
`
`16
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`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`compatible with a variety of conditions: it was known to be compatible with a
`
`variety of solvents, such as ethanol and propylene glycol, it thickens formulations
`
`over a large pH range, and it may be used in high shear mixing processes. 3
`
`(AMN1026, 4.)
`
`
`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. AMN 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:
`AMN1026 (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. AMN1026, 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
`AMN1026 is consistent with the common knowledge, i.e., a POSA’s knowledge,
`of that product prior to the invention date. The fact that AMN1026 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.
`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. (AMN1034.) The face of AMN1034 states
`that Pharma & Healthcare News is a periodical that “is published twice a year and
`distributed to customers and other interested parties.” Id., 1. It states that 650
`copies of this edition were circulated. Id. It further states that “SEPINEO™ P 600
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`29. A final important aspect of the prior art dapsone compositions is a
`
`
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`preservative. Preservatives are commonly used in topical compositions to
`
`maintain the potency, integrity, and safety of the compositions. (AMN1028, 20.)
`
`Garrett teaches using preservatives, such as methyl paraben, to prevent or
`
`diminish microorganism growth. (AMN1004, 13:29-30.) The working example
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`disclosed in Garrett also contains methyl paraben, and Lathrop also discloses the
`
`use of methyl paraben as a preservative in topical dapsone compositions.
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`(AMN1004, 24:30; AMN1007, [0082].) Mostly importantly, the prior art Aczone
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`5% commercial product contained methyl paraben. (AMN1010, 4.)
`
`VI. The ’219 patent and its claims
`I understand that the ’219 patent issued on October 20, 2015, and that
`30.
`
`the face page of the ’219 patent it states that the ’219 patent was assigned to
`
`Allergan, Inc. I understand that the ’219 patent is currently assigned to Almirall,
`
`LLC (“Almirall”).4
`
`
`is able to thicken formulations over a wide pH range (2 to 12) . . . . Its
`compatibility with solvents like ethanol, propylene glycol, etc. is an advantage that
`makes it possible to elaborate formulas containing actives with poor solubility
`(hydro-alcoholic gels including up to 60% ethanol) or water sensible actives
`(anhydrous formulations).” AMN1034, 4.
`4 Throughout this declaration, I will refer to both Allergan and Almirall as
`“Almirall.”
`
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`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS, M.R.Pharm.S.
`(Exhibit 1002)
`
`31. The face page of the ’219 patent cites several related U.S. patent
`
`applications including U.S. Application No. 14/082,955, filed on November 18,
`
`2013, which claims the benefit of U.S. Provisional Application Nos. 61/728,403,
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`filed on November 20, 2012, and 61/770,768, filed on February 28, 2013. I
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`understand that the ’219 patent is related to those applications. The earliest filing
`
`date of any of those listed applications is November 20, 2012. I understand that,
`
`based on that date, the earliest