`
`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 Elaine S. Gilmore, M.D., Ph.D.
`
`
`AMN1018
`
`

`

`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`TABLE OF CONTENTS
`
`Overview .......................................................................................................... 1
`I.
`Summary of Opinions ...................................................................................... 2
`II.
`III. My Background and Qualifications ................................................................. 3
`IV. List of documents I considered in formulating my opinions........................... 5
`V.
`Basis of my analysis with respect to obviousness ........................................... 6
`VI. The Person of Ordinary Skill in the Art .......................................................... 8
`VII. Claim Construction .......................................................................................... 9
`VIII. 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. ................................12
`IX. Garrett teaches methods for treatment of acne vulgaris and rosacea by
`administering to a patient having such a condition topical compositions containing
`7.5% w/w dapsone. ..................................................................................................15
`X.
`Topical dapsone compositions that did not include adapalene would have
`been obvious. ...........................................................................................................18
`XI. No clinical objective indicia of non-obviousness exist. ................................18
`XII. Conclusion .....................................................................................................21
`
`
`i
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`I, Elaine S. Gilmore, hereby declare as follows.
`
`I.
`
`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. 9,517,219
`
`(“the ’219 patent”), AMN1001, which resulted from U.S. Application No.
`
`14/885,805 (“the ’805 application”), filed on October 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 ’219 patent issued on December 13, 2016, from
`
`the ’805 application. The face of the ’219 patent states that it is assigned to
`
`Allergan, Inc., but I understand that, according to USPTO records, the ’219 patent
`
`is assigned to Almirall, LLC (“Almirall”).1
`
`
`1 Throughout this declaration, I will refer to both Allergan and Almirall as
`“Almirall.”
`
`- 1 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`The ’219 patent is generally directed to methods of treating acne
`
`3.
`
`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
`
`’219 patent are directed to this method 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 ’219 patent from a clinical perspective. Claim 1 is exemplary of the clinical
`
`issues I address in my declaration. Claim 1 reads:
`
`1. 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 adapalene.
`
`5.
`
`In my opinion, the treatment 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
`
`- 2 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`knowledge in the prior art.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
`I am an expert in the field of dermatology and in the treatment of
`6.
`
`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
`
`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.
`
`
`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 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`I earned a Bachelor of Science degree in Biology and a Bachelor of
`
`8.
`
`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.
`
`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
`
`(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.
`
`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
`
`- 4 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`on several clinical trials in cutaneous lymphoma, epidermolysis bullosa and
`
`cutaneous lupus.
`
`11.
`
`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.
`
`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.
`
`In view of my education, experience, and expertise described 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
`In formulating my opinions, I considered the following documents:
`14.
`
`- 5 -
`
`

`

`Exhibit or
`Paper No.
`
`1001
`
`1004
`
`1007
`
`1010
`1022
`
`1023
`
`1024
`1025
`
`1027
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`Description
`Warner et al., “Topical Dapsone and Dapsone/Adaplene
`Compositions and Methods for Use Thereof, U.S. Patent No.
`9,517,219 (filed October 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)
`Barclay, L., “Use of Topical Corticosteroids for Dermatologic
`Conditions Reviewed” Medscape - Jan 21, 2009, accessed from
`https://www.medscape.com/viewarticle/587159_print
`
`
`V. Basis of my analysis with respect to obviousness
`I understand from Counsel that, in considering obviousness of an
`15.
`
`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.
`
`- 6 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`I understand from Counsel that the relevant date of assessing the
`
`16.
`
`obviousness of the ’219 patent is November 20, 2012.
`
`17.
`
`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
`
`claimed range or ratio is proven to be critical to the performance or use of the
`
`claimed invention.
`
`18.
`
`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
`
`- 7 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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.
`
`VI. The Person of Ordinary Skill in the Art
`I am informed that a POSA may draw from the knowledge of a multi-
`19.
`
`disciplinary team. In my opinion, the relevant POSA would have the 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. 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. 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
`
`- 8 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`vulgaris and related conditions. (See AMN1001, 1:23-2:2) 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., 2:4-7) 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., 2:41-43) These concepts are restated in the
`
`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.
`
`VII. Claim Construction
`I have been asked to provide my opinion as to a POSA’s
`22.
`
`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
`
`- 9 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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.”
`
`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
`
`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 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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,”
`
`“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
`
`- 11 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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.
`
`VIII. 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. The sole active pharmaceutical ingredient recited in the claims is
`
`dapsone. (See AMN1001, 15:40-16:39 [claims 1-6].) Dapsone (4, 4’
`
`diaminodiphenylsulfone) was first synthesized in 1908. (AMN1022, 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. 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) 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, 1.)
`
`29.
`
`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
`
`- 12 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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)
`
`30.
`
`In 2007, it was shown that dapsone could be delivered in a topical
`
`composition effective for treating numerous skin conditions, including acne
`
`vulgaris and rosacea. (See, e.g., AMN1004, 3:13-15) 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, 2) Thus, topically administered dapsone is a much
`
`safer alternative to its oral counterpart.
`
`31. Before November 20, 2012, a topical 5% dapsone formulation had
`
`been approved by FDA for the treatment of acne vulgaris. (AMN1010) This 5%
`
`formulation was, and is, effective; I still prescribe it to my patients today.
`
`32. 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, 5-6) A
`
`- 13 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`POSA would have preferred these options to systemic ones due to the reduced
`
`likelihood of systemic side effects from topical therapy.
`
`33. Given the availability of several different drugs, “a suitable regimen
`
`for reducing [acne] lesions can be found for most patients.” (AMN1025, 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 potential adverse
`
`effects of all therapeutic options.” (AMN1024, 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. 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) 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.
`
`- 14 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`IX. Garrett teaches methods 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. WO 2009/061298 (“Garrett”) was filed on November 7, 2007,and
`
`published on May 14, 2009. (AMN1004, 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. Garrett discloses “methods to treat glucose-6-phosphate
`
`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, 3:9-12) 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., 3: 20-26) 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
`
`- 15 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`composition includes dapsone.” (Id., 4:32-5:1) 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,
`
`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.
`
`Indeed, by 2012, the FDA had already granted marketing approval to
`
`Almirall to market in the United States ACZONE Gel 5%, which was a topical
`
`- 16 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`dapsone composition containing 5% w/w dapsone, indicated for the treatment of
`
`acne vulgaris. (AMN1010)
`
`39. Garrett also discloses that topical dapsone compositions can contain
`
`from “about 5% to 10% dapsone” and identifies this amount of dapsone as being
`
`preferred.” (AMN1004, 4:2-5; 10:10-14; 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. 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. Beyond understanding that topical compositions containing about 5%
`
`to 10% w/w dapsone were useful, 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 2007, topical
`
`administration of dapsone, 5%, yields systemic exposure “100-fold less than those
`
`after oral dapsone at a therapeutic dose level.” (AMN1023, 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
`
`- 17 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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.
`
`X. Topical dapsone compositions that did not include adapalene would
`have been obvious.
`
`41.
`
`It would have been obvious to a POSA to not include adapalene in a
`
`topical dapsone composition.
`
`42. Dapsone was known to be an effective treatment for skin conditions
`
`as a monotherapy. (AMN1004; AMN1007) The prior art, including Garrett, taught
`
`that topical dapsone compositions did not require the presence of adapalene.
`
`(AMN1004) Indeed, the prior art FDA-approved ACZONE Gel 5% is a dapsone
`
`monotherapy and had been determined by FDA to be safe and effective as a
`
`monotherapy. (AMN1010) Accordingly, not including adapalene in a 7.5% w/w
`
`dapsone topical composition would have been obvious.
`
`XI. No clinical objective indicia of non-obviousness exist.
`I understand that a complete obviousness analysis requires
`43.
`
`consideration of objective indicia (or so called-secondary considerations) of non-
`
`obviousness, such as satisfaction of a long-felt but unmet need or unexpected
`
`- 18 -
`
`

`

`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`results. I understand, therefore, that I must consider any objective indicia as part of
`
`my analysis.
`
`44.
`
`I am not aware of any clinical objective indicia of non-obviousness. I
`
`understand that the patentee did not assert any clinical objective indicia during
`
`prosecution. For example, the patentee submitted evidence that particle size using
`
`the acrylamide copolymer was redu