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.
`
`ALLERGAN, INC.ALMIRALL, LLC.
`Patent Owner
`
`Case: IPR2018-006082019-00207
`U.S. Patent No. 9,161,9269,517,219
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`
`AMN1018
`
`Almirall, LLC
`Exhibit 2005
`Page 1
`
`

`

`Inter Partes Review of U.S. Patent No. 9,161,9269,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`I.
`
`I, Elaine S. Gilmore, hereby declare as follows.
`
`Overview
`1.
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Petitioners
`
`Amneal Pharmaceuticals LLC and Amneal Pharmaceuticals of New York, LLC for
`
`the above-captioned inter partes review (“IPR”). I am being compensated for my
`
`time in connection with this IPR at my standard consulting rate, which is $500/hr. I
`
`understand that the petition for IPR involves U.S. Patent No. 9,161,9269,517,219
`
`(“the ’926219 patent”), AMN1001, which resulted from U.S. Application No.
`
`14/082,955885,805 (“the ’955805 application”), filed on November 18, 2013,
`
`namingOctober 16, 2015, and is a divisional application derived from the
`
`application that issued as U.S. Patent No. 9,161,926. The ’219 patent names Kevin
`
`S. Warner, Ajay P. Parashar, Vijaya Swaminathan, and Varsha Bhatt as inventors.
`
`The ’926219 patent issued on October 20, 2015,December 13, 2016, from the
`
`’955805 application. The face of the ’219 patent states that it is assigned to
`
`Allergan, Inc., but I further understand that, according to USPTO records, the
`
`’926219 patent is assigned to Allergan, Inc. (“the Patent OwnerAlmirall, LLC
`
`1
`
`Almirall, LLC
`Exhibit 2005
`Page 2
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`(“Almirall”).1
`
`3.
`
`The ’926219 patent is generally directed to methods of treating acne
`
`vulgaris or rosacea, in patients with those conditions, by administering a topical
`
`pharmaceutical composition comprising 7.5% w/w dapsone and various excipients,
`
`including: diethylene glycol monoethyl ether; a polymeric viscosity builder
`
`comprising acrylamide/sodium acryloyldimethyl taurate copolymer; water; and
`
`wherein the composition does not include adapalene. Some of the claims of the
`
`’926219 patent are directed to this topical dapsone compositionmethod of
`
`treatment, but also include methyl paraben as a preservative.
`
`II.
`
`Summary of Opinions
`4.
`I have been asked by Counsel for Amneal to assess the obviousness of
`
`the ’926219 patent from a clinical perspective. Claim 1 is exemplary of the clinical
`
`issues I address in my declaration. Claim 1 reads:
`
`A1. A method for treating a dermatological condition selected from
`the group consisting of acne vulgaris and rosacea comprising
`administering to a subject having the dermatological condition
`selected from the group consisting of acne vulgaris and rosacea a
`topical pharmaceutical composition comprising:
`about 7.5% w/w dapsone;
`about 30% w/w to about 40% w/w diethylene glycol monoethyl
`ether; about 2% w/w to about 6% w/w of a polymeric viscosity
`builder consistent of acrylamide/sodium acryloyldimethyl taurate
`copolymer; and water; wherein the composition does not comprise
`
`1 Throughout this declaration, I will refer to both Allergan and Almirall as
`“Almirall.”
`
`
`
`2
`
`Almirall, LLC
`Exhibit 2005
`Page 3
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`
`
`
`adapalene.
`
`5.
`
`In my opinion, the use oftreatment of acne vulgaris or rosacea by
`
`administering a pharmaceutical composition comprising 7.5% w/w dapsone in a
`
`topical composition would have been obvious in view of Garrett and the general
`
`knowledge in the prior art.1 2 In addition, in view of Garrett and the general
`
`knowledge in the art, topical dapsone compositions that did not contain adapalene
`
`would have been obvious. Finally, in my opinion, there are no clinical objective
`
`indicia of nonobviousness.
`
`III. My Background and Qualifications
`6.
`I am an expert in the field of dermatology and in the treatment of
`
`patients suffering from dermatological disorders.
`
`7.
`
`I am the medical director of Universal Dermatology, PLLC in
`
`Fairport, NY, a former Assistant Professor of Dermatology and Medical Director
`
`of University Dermatology Associates (Henrietta, NY), and former Director of the
`
`Medical Student Dermatology Course and Clerkship at the University of Rochester
`
`
`1 I understand “prior art” to mean the store of knowledge, including scientific,
`clinical, and patent literature, and other publically available information and
`disclosures that are relevant to the subject matter claimed in the ’926 patent.
`2 I understand from Counsel that “prior art” means the store of knowledge,
`including scientific, clinical, and patent literature, and other publically available
`information and disclosures that are relevant to the subject matter claimed in the
`’219 patent.
`
`
`
`3
`
`Almirall, LLC
`Exhibit 2005
`Page 4
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`School of Medicine and Dentistry, Department of Dermatology. I am Board
`
`Certified in Dermatology by the American Board of Dermatology. I have worked
`
`and taught extensively in the fields of cell and molecular physiology and
`
`dermatology. I have a full-time private practice in which I treat patients with
`
`general dermatological disorders, including numerous patients suffering from acne
`
`vulgaris and rosacea. My curriculum vitae is provided as AMN1019.
`
`8.
`
`7. I earned a Bachelor of Science degree in Biology and a Bachelor of
`
`Arts degree in Chemistry from Providence College, summa cum laude, in 1996. I
`
`earned an M.D. and Ph.D. from the University of North Carolina at Chapel Hill in
`
`2003 and 2001, respectively. My doctoral research focused on cell and molecular
`
`physiology, specifically on ion channel regulation in the lungs and kidneys. I
`
`completed a residency in dermatology at Yale-New Haven Hospital in 2006 and a
`
`research fellowship in dermatology at Yale in 2008.
`
`9.
`
`8. I have received several honors in my career, including the Brian P.
`
`Flanagan Faculty Teaching Award at the University of Rochester (2013); Wilmot
`
`Cancer Research Fellowship Grant (2011); Wilmot Cancer Center Lymphoma
`
`SPORE Career Development Award (2011); Dermatology Foundation Fellowship
`
`Grant (2007); Medical Scientist Training Program (MSTP) Scholarship (1996-
`
`2003); University of North Carolina Travel Grant (2000); Renaissance Physiology
`
`Department Travel Award (2000); John B. Graham Research Society Travel Grant
`
`
`
`4
`
`Almirall, LLC
`Exhibit 2005
`Page 5
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`(1999); John B. Graham Research Society (Inducted) (1999); Howard Holderness
`
`Fellowship (1997-1998); NIH Summer Research Training Grant (1997); and the
`
`Roddy Foundation Scholarship (1992-1996).
`
`10.
`
`9. In addition to my clinical practice, I am also actively involved in
`
`scientific research programs. I have presented my work at national and
`
`international dermatological meetings. I have served as a co-clinical investigator
`
`on several clinical trials in cutaneous lymphoma, epidermolysis bullosa and
`
`cutaneous lupus.
`
`11.
`
`10. I am the author or co-author of many medical publications
`
`involving dermatology and related sciences. A complete list of my publications can
`
`be found in my curriculum vitae (AMN1019). I have served as a peer reviewer for
`
`the British Journal of Dermatology, the Journal of the American Academy of
`
`Dermatology and the JAAD Case Reports.
`
`12.
`
`11. I am a member of or previously affiliated with a number of
`
`organizations dedicated to dermatology, including the American Academy of
`
`Dermatology, American Contact Dermatitis Society, International Forum for the
`
`Study of Itch, International Society of Cutaneous Lymphoma, Society for
`
`Investigative Dermatology, and the American Academy of Dermatology Diversity
`
`Mentorship Program.
`
`13.
`
`12. In view of my education, experience, and expertise described
`
`
`
`5
`
`Almirall, LLC
`Exhibit 2005
`Page 6
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`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`above, I am an expert in the field of dermatology and in the treatment of patients
`
`suffering from dermatological disorders. Accordingly, I am an expert in the field of
`
`the invention.
`
`IV. List of documents I considered in formulating my opinions
`14.
`13. In formulating my opinions, I considered the following
`
`documents:
`
`Exhibit or
`Paper No.
`
`1001
`
`1004
`
`1007
`
`1010
`1022
`
`1023
`
`1024
`
`1025
`
`
`
`
`
`
`
`
`
`
`
`Description
`Warner et al., “Topical Dapsone and Dapsone/Adaplene
`Compositions and Methods for Use Thereof, U.S. Patent
`No. 9,161,9269,517,219 (filed November 18, 2013; issued
`October 20,16, 2015; issued December 13, 2016)
`Garrett et al., “Topical Treatment With Dapsone in G6PD-
`Deficient Patients” WO 2009/061298 (filed November 7,
`2007;
`published May 14, 2009)
`Lathrop, “Emulsive Composition Containing Dapsone” U.S.
`Pat. Appl. Publ. No. 2006/0204526 (filed February 13,
`2006; published September 14, 2006)
`ACZONETM Gel 5% Package Insert
`Wozel, D., “Innovative Use of Dapsone” Dermatol. Clin. 28:
`599–610 (2010)
`Thiboutot, D., et al., “Pharmacokinetics of Dapsone Gel,
`5% for the Treatment of Acne Vulgaris” Clin.
`Pharmacokinet. 46:
`697-712 (2007)
`Nguyen, R. and Su, J., “Treatment of Acne Vulgaris”
`Pediatrics
`and Child Health 21: 119-125 (2010)
`Williams, H., et al., “Acne vulgaris” Lancet 379: 361–72
`(2012)
`
`6
`
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`Exhibit 2005
`Page 7
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`Barclay, L., “Use of Topical Corticosteroids for
`Dermatologic Conditions Reviewed” Medscape - Jan 21,
`2009, accessed from https://www.medscape.com
`https:/viewarticle/587159_print/www.medscape.com/viewarti
`cle/587159_print
`
`
`
`
`
`1027
`
`
`
`I.
`
`V. Basis of my analysis with respect to obviousness
`15.
`14. I understand from Counsel that, in considering obviousness of an
`
`invention, I am required to look back to the understanding that a hypothetical
`
`person of ordinary skill in the art (“POSA”) would have had prior to the date of
`
`invention. In determining the hypothetical POSA, I understand from Counsel that I
`
`should consider: (i) the level of ordinary skill in the art; (ii) the scope and content
`
`of the prior art; (iii) the differences between the prior art and the claims at issue;
`
`and (iv) the applicable objective indicia of nonobviousness.
`
`16.
`
`15. I understand from Counsel that the relevant date of assessing the
`
`obviousness of the ’926219 patent is November 20, 2012.
`
`17.
`
`16. I understand from Counsel that an obviousness analysis involves
`
`comparing a patent claim to the prior art to determine whether the claimed
`
`invention would have been obvious to a POSA in view of the prior art, and in light
`
`of the relevant 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 only if the
`
`
`
`7
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`Exhibit 2005
`Page 8
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`claimed range or ratio is proven to be critical to the performance or use of the
`
`claimed invention.
`
`18.
`
`17. I also understand from Counsel that obviousness can be
`
`established by combining or modifying the teachings of various prior art references
`
`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 teaching 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 an explicit teaching, suggestion, or motivation in any
`
`reference. I understand further from Counsel 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.
`
`V. VI. The Person of Ordinary Skill in the Art
`19.
`18. I am informed that a POSA may draw from the knowledge of a
`
`multi- disciplinary team. In my opinion, the relevant POSA would have the
`
`
`
`8
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`Exhibit 2005
`Page 9
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`knowledge of both a clinician and a formulator of topical pharmaceutical
`
`compositions. I am not a formulator, and I understand from Counsel that another
`
`expert on behalf of Amneal will speak on those aspects.
`
`20.
`
`19. For the clinical portion of a POSA, it is reasonable to think of a
`
`POSA as possessing an M.D. with a board certification in dermatology with at
`
`least two years of experience in dermatology, or otherwise treating skin conditions.
`
`It is also possible that an M.D. without a certification in dermatology (i.e., a
`
`primary care physician, or a pediatrician) may qualify as a clinical POSA,
`
`assuming that they have more than two years of knowledge and experience treating
`
`skin conditions.
`
`21.
`
`20. My view of the clinical POSA is rooted in the intrinsic record.
`
`First, the “background” portion of the specification begins with a description of
`
`acne vulgaris and related conditions. (See AMN1001, 1:23-2:2.2) This section
`
`concludes by explaining the purport of the invention: “there is a continuing need
`
`for compositions and methods used in a treatment of a variety of skin conditions,
`
`such as acne, in which topical application is potentially effective.” (Id., 1:65-2:1.4-
`
`7) The first active ingredient discussed in the “summary” portion of the
`
`specification is dapsone, (See Id., 2:6-7), and even states that “[t]he present
`
`dapsone and dapsone/adapalene compositions can be useful for treating a variety of
`
`dermatological conditions.” (Id., 2:3341-35.43) These concepts are restated in the
`
`
`
`9
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`Exhibit 2005
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`claims, which recite a “topical pharmaceutical composition” comprising dapsone.
`
`In addition, I have considered the type of problems encountered in the art, prior art
`
`solutions to those problems, the rapidity with which innovations are made in the
`
`field, the sophistication of the technology, and the education level of active
`
`workers in the field. Accordingly, it is my opinion that the claims are directed to
`
`topical pharmaceutical compositions for treating dermatological conditions, and
`
`the clinically relevant factors here are most accurately adjudged by a
`
`dermatologist.
`
`VI. Claim Construction
`22.
`I have been asked to provide my opinion as to a POSA’s
`
`understanding of the term “acne vulgaris,” as used in the claims. I have been
`
`informed by Counsel that the proper construction of the claims in this proceeding
`
`is the “broadest reasonable interpretation” in light of the patent’s specification. I
`
`further understand that it is important to consult the patent’s prosecution history.3
`
`23. The specification includes substantial discussion that makes clear that
`
`“acne vulgaris” means “acne consisting of inflammatory or non-inflammatory
`
`lesions.”
`
`
`3 I further understand that there is a different claim construction standard which
`will be employed by the Board in future cases. Because I understand that this
`alternative construction standard likewise looks primarily to the intrinsic record,
`my interpretation of the claims would be the same under this alternative standard.
`
`
`
`10
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`Almirall, LLC
`Exhibit 2005
`Page 11
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`
`24. First, the specification sets out a detailed description of the types of
`
`“lesions” associated with acne and acne-like conditions. The relevant portion of the
`
`specification is reproduced below:
`
`The term “lesion” is generally used to denote an infected or
`diseased patch of skin. A lesion can involve an infected sebaceous
`gland. Some lesions are more severe than others. Examples of
`skin lesions are comedones, macules, papules, pustules, nodules
`and cysts. The term “comedo” (plural “comedones”) is used to
`describe a sebaceous follicle plugged with dirt, other cells, tiny
`hairs, or bacteria. Comedones include the so-called “blackheads,”
`which can also refer to as “open comedones,” which have a spot
`or a surface that appears black. Comedones also include slightly
`inflamed, skin colored bumps, as well as “whiteheads,” which
`have a spot or a surface that appears white. The term “macule”
`generally refers to a flat spot or area of the skin with a changed
`color, such as a red spot. The term “pustule” is generally used to
`refer to an inflamed, pus-filled lesion, or a small inflamed
`elevation of the skin that is filled with pus. The term “papule” is
`generally used to refer to a small, solid, usually inflammatory
`elevation of the skin that does not contain pus. The term “nodule”
`is generally used to refer to an elevation of a skin that is similar to
`a papule but is white and dome-shaped. Colloquially, a papule, a
`pustule or a nodule can be referred to as “a pimple” or “a zit.” The
`term “cyst” generally refers to an abnormal membranous sac
`containing a liquid or semi-liquid substance containing white
`blood cells, dead cells, and bacteria. Cysts can be painful and
`extend to deeper layers of skin.
`
`’219 patent, 4:2-28 (emphasis added).
`
`25. After describing these lesions, the specification goes on to describe
`
`
`
`
`
`specific acne types, including whether the lesions associated with each acne type is
`
`inflammatory or non-inflammatory. Id., 4:38-45 (describing “comedonal acne,”
`
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`“localized cystic acne,” “diffuse cystic acne,” “nodular acne,” and “nodulocystic
`
`acne”). For example, “comedonal acne” is characterized by the appearance of non-
`
`inflammatory lesions, such as blackheads. Id., 4:7-12, 4:38-40. “Nodular acne,” on
`
`the other hand, is characterized by the appearance of nodules, which are generally
`
`larger and more inflamed than papules and involve “inflammatory elevations” of
`
`the skin. Id., 4:19-23, 4:43-44.
`
`26.
`
`In contrast to these specific forms of acne, the specification states that
`
`“[a]cne vulgaris is a common form of acne characterized by the appearance of
`
`several types of lesions, which may appear together or separately.” Id., 4:45-48
`
`(emphasis added). Unlike the other specific forms of acne described in the
`
`specification, “acne vulgaris” is not limited to any particular lesion type, but is
`
`instead characterized by the appearance of multiple types of lesions, including non-
`
`inflammatory lesions like open- and closed-comedones, as well as inflammatory
`
`lesions such as pustules and papules. Id. A POSA would understand that the
`
`broadest reasonable interpretation of the term “acne vulgaris” means acne
`
`consisting of inflammatory or non-inflammatory lesions.
`
`VII. Background: Dapsone was a well-known topical treatment for skin
`conditions, including acne vulgaris and rosacea, and methods of using
`topical dapsone to treat these conditions were well-known in the art.
`27.
`21. The sole active pharmaceutical ingredient recited in the claims is
`
`dapsone. (See AMN1001, 15:2140-16:2339 [claims 1-6].) Dapsone (4, 4’
`
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`diaminodiphenylsulfone) was first synthesized in 1908. (AMN1022, 599.1) It falls
`
`within the class of “sulfones.” (Id.) In the 1950s, sulfones began receiving greater
`
`attention as their pharmacological properties became known. (Id.)
`
`28.
`
`22. For decades before 2012, dapsone was “a well-known medicament
`
`possessing several beneficial medicinal activities.” (AMN1007, [0002].) These
`
`activities include antibacterial and anti-inflammatory activities. (Id.; AMN1004,
`
`1:7-8.8) Indeed, in 2010, dapsone was declared a “unique and essential agent” in
`
`the therapeutic armamentarium thanks to its efficacy across a broad spectrum of
`
`conditions. (AMN1022, 599.1.)
`
`29.
`
`23. Initially, dapsone was administered in an oral form. See, e.g.,
`
`AMN1004, 1:8-15. As Garrett explains, “[t]he oral formulation of [dapsone] is
`
`used to treat leprosy, dermatitis herpetiformis, and malaria, … but historically, it
`
`was also used to treat severe acne in doses ranging from 50 mg/day to 300
`
`mg/week.” (Id., 1:8-11; see also AMN1007, [0003] [explaining that dapsone can
`
`be used to treat acne, rosacea, and other “skin diseases characterized by the
`
`abnormal infiltration of neutrophils.”].) Oral dapsone, however, is “associated with
`
`hematologic side effects, including hemolysis and hemolytic anemia that are dose-
`
`dependent and occur more frequently with increasing dose.” (AMN1004, 1:13-
`
`15.15)
`
`30.
`
`24. In 2007, it was shown that dapsone could be delivered in a topical
`
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`composition effective for treating numerous skin conditions, including acne
`
`vulgaris and rosacea. (See, e.g., AMN1004, 23:13-15.15) Thiboutot, a 2007 article
`
`cited by Garrett, reported that “total systemic exposure to dapsone and its
`
`metabolites were approximately 100-fold less for [topical] dapsone gel than for
`
`oral dapsone,” and further that “there were no reports of any haemotological
`
`adverse events.” (AMN1023, 698.2) Thus, topically administered dapsone is a
`
`much safer alternative to its oral counterpart.
`
`31.
`
`25. Before November 20, 2012, a topical 5% dapsone formulation had
`
`been approved by FDA for the treatment of acne vulgaris. (AMN1010.1010) This
`
`5% formulation was, and is, effective; I still prescribe it to my patients today.
`
`32.
`
`26. Before November 20, 2012, a number of other topical treatments
`
`were available, particularly for acne vulgaris. Aside from dapsone, topical options
`
`included retinoids, benzoyl peroxide, and topical antibacterials. (AMN1024, 6.5-6)
`
`A POSA would have preferred these options to systemic ones due to the reduced
`
`likelihood of systemic side effects from topical therapy.
`
`33.
`
`27. Given the availability of several different drugs, “a suitable
`
`regimen for reducing [acne] lesions can be found for most patients.” (AMN1025,
`
`1.1) In fact, combinations of topical treatments “usually improve control of mild to
`
`moderate acne.” (Id.) But the art also taught that “[t]reatment regimens should
`
`accommodate individual patient considerations, duly noting limitations and
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`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`potential adverse effects of all therapeutic options.” (AMN1024, 1.1) A POSA
`
`would understand from these teachings that each drug should be kept separately
`
`formulated from the other drugs so that an ideal treatment could be reached for
`
`each patient.
`
`34.
`
`28. As a final point regarding the treatment of acne vulgaris and
`
`rosacea, I note that, in my experience, treatment of these conditions is often subject
`
`to patient compliance. These conditions, which between them occur most often on
`
`the face, back, and shoulders, are generally visible in public and, in the case of
`
`acne vulgaris in particular, can lead to facial scarring and eventually, “detrimental
`
`effects on self- esteem.” (AMN1025, 1.1) Accordingly, patients are particularly
`
`motivated to comply with the therapies prescribed by their physicians as the
`
`patients seek to resolve these issues as quickly and effectively as possible.
`
`VIII. Garrett teaches the use ofmethods for treatment of acne vulgaris and
`rosacea by administering to a patient having such a condition topical
`compositions containing 7.5% w/w dapsone.
`35.
`29. WO 2009/061298 (“Garrett”) was filed on November 7, 2007,and
`
`published on May 14, 2009. (AMN1004, 1.1) A POSA in 2012 would understand
`
`that Garrett teaches methods of treating both rosacea and acne consisting of
`
`inflammatory and non-inflammatory lesions by applying topical compositions
`
`containing dapsone to a patient’s affected areas.
`
`36.
`
`30. Garrett discloses “methods
`
`to
`
`treat glucose-6-phosphate
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`dehydrogenase-deficient patients with dapsone. In one embodiment, the treatment is
`
`directed to dermatological conditions and the treatment is provided by a topical
`
`dapsone composition.” (AMN1004, 23:9-12.12) Garrett further discloses “a
`
`pharmaceutical carrier system comprising a dermatological composition that is a
`
`semi-solid aqueous gel, wherein dapsone is dissolved in the gel such that the dapsone
`
`has the capacity to cross the stratum corneum layer of the epidermis and become
`
`available systemically, and wherein the composition also contains dapsone in a
`
`microparticulate state that does not readily cross the stratum corneum of the
`
`epidermis.” (Id., 23: 20-26.26) Finally, Garrett also teaches that “[i]n a preferred
`
`embodiment, the invention provides a method to treat a dermatological condition in
`
`a glucose-6-phosphate dehydrogenase-deficient patient by
`
`applying
`
`a
`
`dermatological composition
`
`to
`
`the condition, wherein
`
`the dermatological
`
`composition includes dapsone.” (Id., 34:32-4:1.5:1) From these disclosures, a POSA
`
`would understand that Garrett teaches methods of using topical pharmaceutical
`
`compositions containing dapsone.
`
`37.
`
`In addition, a POSA would understand from Garrett that topical
`
`dapsone compositions are useful treat skin conditions. (Id.) Garrett discloses a
`
`“dermatological composition for use in the methods of treating [G6PD-deficient]
`
`patients. (Id., 3:32-33) Garrett teaches that “[t]he present invention provides
`
`methods to treat . . . patients with dapsone” and specifies that “in one embodiment,
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`the treatment is directed to dermatological conditions and the treatment is provided
`
`by a topical dapsone composition.” (Id., 3:9-12). Garrett also teaches that “the
`
`dermatological condition to be treated is inflammatory acne, non-inflammatory
`
`acne or rosacea.” (Id., 3:13-15, 19:27-29). As explained above, POSA would
`
`understand that acne vulgarus consists of inflammatory acne and non-inflammatory
`
`lesions. AMN1025, 1). Consequently, it would have been obvious to a POSA that
`
`Garrett teaches methods of treating dermatological conditions—inflammatory
`
`acne, non-inflammatory acne, and rosacea—by administering topical compositions
`
`containing dapsone.
`
`38.
`
`31. Indeed, by 2012, the FDA had already granted marketing approval
`
`to AllerganAlmirall to market in the United States ACZONE Gel 5%, which was a
`
`topical dapsone composition containing 5% w/w dapsone, indicated for the
`
`treatment of acne vulgaris. (AMN1010.1010)
`
`39.
`
`32. Garrett also discloses that topical dapsone compositions can
`
`contain from “about 5% to 10% w/w dapsone. (AMN1004, 3:4; 14:5.) Moreover,
`
`Garrett discloses that this range is “preferred.” (Id., 3dapsone” and identifies this
`
`amount of dapsone as being preferred.” (AMN1004, 4:2-5; 10:10-14.14; 15:5)
`
`Although 7.5% w/w is not specifically identified in Garrett, it falls squarely in the
`
`middle of the preferred range. It is my opinion that using 7.5% w/w dapsone in a
`
`topical composition would have been obvious.
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`
`33. Moreover, a POSA would understand from Garrett that topical
`
`compositions containing 5% to 10% w/w dapsone were effective in treating skin
`
`conditions. (Id.) For example, Garrett teaches that “[t]he present invention provides
`
`methods to treat glucose-6-phosphate dehydrogenase-deficient [(“G6PD-
`
`deficient”)] patients with dapsone. In one embodiment, the treatment is directed to
`
`dermatological conditions and the treatment is provided by a topical dapsone
`
`composition,” (Id., 2:9-12), and also that “the dermatological condition to be
`
`treated is inflammatory acne, non-inflammatory acne or rosacea.” (Id., 2:13-15.)
`
`Garrett further discloses a “dermatological composition for use in the methods of
`
`treating [G6PD-deficient] patients. (Id., 2:32-33.) Garrett discloses that a
`
`“preferred embodiment” of this composition includes “about 5% to 10% dapsone.”
`
`(Id., 3:2-5.) From this disclosure, a POSA would have understood Garrett to teach
`
`that dapsone formulations containing 5% to 10% dapsone to be effective for the
`
`disclosed method of treating acne or rosacea.34.
`
` This is consistent with the fact
`
`that ACZONE Gel 5%, containing 5% w/w dapsone, was FDA-approved by 2012
`
`and is also within Garrett’s “preferred” range.
`
`40.
`
`35. Beyond understanding that topical compositions containing about
`
`5% to 10% w/w dapsone were effectiveuseful, a POSA would have additionally
`
`understood that using amounts within that range would not be likely to yield any of
`
`the known, and significant hematological adverse reactions. As Thiboutot taught in
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`
`2007, topical administration of dapsone, 5%, yields systemic exposure “100-fold
`
`less than those after oral dapsone at a therapeutic dose level.” (AMN1023, 2.2)
`
`More importantly, Thiboutot reported that “concentrations of dapsone and its
`
`metabolites reached steady state [in the blood] and did not increase during
`
`prolonged treatment.” (Id.) From Thiboutot, a POSA would have understood that
`
`topical application of 5% w/w dapsone did not result in the systemic
`
`concentrations of dapsone that were known to result from oral dapsone
`
`administration and were also known to cause significant adverse effects.
`
`Consequently, a POSA would have understood that the 5% to 10% w/w dapsone
`
`range in Garrett would have exhibited similar exposure levels and would also not
`
`result in the significant adverse effects known with oral administration. According,
`
`it is my opinion that it would have been obvious for a POSA in 2012 to use 7.5%
`
`w/w dapsone in a topical composition.
`
`IX. Topical dapsone compositions that did not include adapalene would
`have been obvious.
`41.
`36. It would have been obvious to a POSA to not include adapalene in
`
`a topical dapsone composition.
`
`42.
`
`37. Dapsone was known to be an effective treatment for skin
`
`conditions as a monotherapy. (AMN1004; AMN1007.1007) The prior art,
`
`including Garrett, taught that topical dapsone compositions did not require the
`
`
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`Inter Partes Review of U.S. Pate