`
`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.
`Patent Owner
`
`_____________________
`
`Case: IPR2018-00608
`
`U.S. Patent No. 9,161,926
`_____________________
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`
`
`AMN1018
`
`
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`
`TABLE OF CONTENTS
`
`I.
`Overview .......................................................................................................... 1
`Summary of Opinions ...................................................................................... 2
`II.
`III. My Background and Qualifications ................................................................. 2
`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 .......................................................... 7
`VII. Background: Dapsone was a well-known topical treatment for skin
`conditions. .................................................................................................................. 9
`VIII. Garrett teaches the use of topical compositions containing 7.5% w/w
`dapsone. .................................................................................................................... 11
`IX. Topical dapsone compositions that did not include adapalene would have
`been obvious. ........................................................................................................... 14
`X. No clinical objective indicia of non-obviousness exist. ................................ 15
`XI. Conclusion ..................................................................................................... 17
`
`
`i
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`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. 9,161,926
`
`(“the ’926 patent”), AMN1001, which resulted from U.S. Application No.
`
`14/082,955 (“the ’955 application”), filed on November 18, 2013, naming Kevin S.
`
`Warner, Ajay P. Parashar, Vijaya Swaminathan, and Varsha Bhatt as inventors.
`
`The ’926 patent issued on October 20, 2015, from the ’955 application. I further
`
`understand that, according to USPTO records, the ’926 patent is assigned to
`
`Allergan, Inc. (“the Patent Owner”).
`
`3.
`
`The ’926 patent is generally directed to 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 ’926 patent are
`
`- 1 -
`
`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`directed to this topical dapsone composition 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 ’926 patent from a clinical perspective. Claim 1 is exemplary of the clinical
`
`issues I address in my declaration:
`
`1. 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 use of 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 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.
`
`
`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.
`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`I am the medical director of Universal Dermatology, PLLC in
`
`7.
`
`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
`
`and rosacea. My curriculum vitae is provided as AMN1019.
`
`8.
`
`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.
`
`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
`
`- 3 -
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`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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
`
`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
`
`- 4 -
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`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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
`14.
`In formulating my opinions, I considered the following documents:
`
`Exhibit or
`Paper No.
`
`1001
`
`1004
`
`1007
`
`1010
`1022
`
`1023
`
`1024
`1025
`1027
`
`Description
`Warner et al., “Topical Dapsone and Dapsone/Adaplene
`Compositions and Methods for Use Thereof, U.S. Patent No.
`9,161,926 (filed November 18, 2013; issued October 20, 2015)
`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
`
`- 5 -
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`Conditions Reviewed” Medscape - Jan 21, 2009, accessed from
`https://www.medscape.com/viewarticle/587159_print
`
`
`V. Basis of my analysis with respect to obviousness
`15.
`I understand 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 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.
`
`I understand that the relevant date of assessing the obviousness of the
`
`’926 patent is November 20, 2012.
`
`17.
`
`I understand 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 that when a POSA would have reached the claimed
`
`invention through routine experimentation, the invention may be deemed obvious.
`
`I understand 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.
`
`- 6 -
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`I also understand that obviousness can be established by combining or
`
`18.
`
`modifying the teachings of various prior art references to achieve the claimed
`
`invention. It is also my understanding 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 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
`
`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 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
`19.
`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 knowledge of
`
`both a clinician and a formulator of topical pharmaceutical compositions. I am not
`
`a formulator, and I understand that another expert on behalf of Amneal will speak
`
`on those aspects.
`
`- 7 -
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`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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 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., 1:65-2:1.) 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., 2:33-35.) These concepts are restated in the
`
`claims, which recite a “topical pharmaceutical composition” comprising dapsone.
`
`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.
`
`- 8 -
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`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`VII. Background: Dapsone was a well-known topical treatment for skin
`conditions.
`22. The sole active pharmaceutical ingredient recited in the claims is
`
`dapsone. (See AMN1001, 15:21-16:23 [claims 1-6].) Dapsone (4, 4’
`
`diaminodiphenylsulfone) was first synthesized in 1908. (AMN1022, 599.) It falls
`
`within the class of “sulfones.” (Id.) In the 1950s, sulfones began receiving greater
`
`attention as their pharmacological properties became known. (Id.)
`
`23. 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, 599. )
`
`24.
`
`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
`
`- 9 -
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`hematologic side effects, including hemolysis and hemolytic anemia that are dose-
`
`dependent and occur more frequently with increasing dose.” (AMN1004, 1:13-15.
`
`25.
`
`In 2007, it was shown that dapsone could be delivered in a topical
`
`composition effective for treating numerous skin conditions, including acne and
`
`rosacea. (See, e.g., AMN1004, 2:13-15.) 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, 698.) Thus, topically administered dapsone is a much safer alternative
`
`to its oral counterpart.
`
`26. Before November 20, 2012, a topical 5% dapsone formulation had
`
`been approved by FDA for the treatment of acne. (AMN1010.) This 5%
`
`formulation was, and is, effective; I still prescribe it to my patients today.
`
`27. Before November 20, 2012, a number of other topical treatments were
`
`available, particularly for acne. Aside from dapsone, topical options included
`
`retinoids, benzoyl peroxide, and topical antibacterials. (AMN1024, 6.) A POSA
`
`would have preferred these options to systemic ones due to the reduced likelihood
`
`of systemic side effects from topical therapy.
`
`28. Given the availability of several different drugs, “a suitable regimen
`
`for reducing [acne] lesions can be found for most patients.” (AMN1025, 1.) In fact,
`
`- 10 -
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`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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.
`
`29. As a final point regarding the treatment of acne 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 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.
`
`VIII. Garrett teaches the use of topical compositions containing 7.5% w/w
`dapsone.
`30. 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 topical compositions containing dapsone.
`
`31. Garrett discloses “methods to treat glucose-6-phosphate
`
`dehydrogenase-deficient patients with dapsone. In one embodiment, the treatment
`
`- 11 -
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`is directed to dermatological conditions and the treatment is provided by a topical
`
`dapsone composition.” (AMN1004, 2:9-12.) 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., 2: 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
`
`composition includes dapsone.” (Id., 3:32-4:1.) From these disclosures, a POSA
`
`would understand that Garrett teaches topical pharmaceutical compositions
`
`containing dapsone.
`
`32.
`
`Indeed, by 2012, the FDA had already granted marketing approval to
`
`Allergan to market in the United States ACZONE Gel 5%, which was a topical
`
`dapsone composition containing 5% w/w dapsone. (AMN1010.)
`
`33. 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., 3:2-5; 10:10-14.) Although 7.5% w/w
`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`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.
`
`34. 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.
`
`35. 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.
`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`36. Beyond understanding that topical compositions containing about 5%
`
`to 10% dapsone were effective, 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
`
`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.
`37.
`
`It would have been obvious to a POSA to not include adapalene in a
`
`topical dapsone composition.
`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`38. 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.
`
`X. No clinical objective indicia of non-obviousness exist.
`39.
`I understand that a complete obviousness analysis requires
`
`consideration of objective indicia (or so called-secondary considerations) of non-
`
`obviousness, such as satisfaction of a long-felt but unmet need or unexpected
`
`results. I understand, therefore, that I must consider any objective indicia as part of
`
`my analysis.
`
`40.
`
`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 reduced as compared to a composition using
`
`Carbopol. But I further understand that Allergan made no assertion that this
`
`reduction in particle size was clinically meaningful, and I am not aware of any
`
`evidence that it is.
`
`- 15 -
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`41. To the extent that Allergan asserts that the once-daily administration
`
`of the 7.5% dapsone formulation is unexpected, or satisfied a long-felt need, as
`
`compared to the twice-daily administration required by the prior art 5% dapsone
`
`formulation, this result is neither unexpected nor needed.
`
`42. First, the reduction in number of daily applications is not unexpected,
`
`as dermatologists expected at the time of invention that the potency, or strength, of
`
`a given drug is related to both its duration of action and its side effects. A
`
`particularly apt analogy is that of topical steroids which, like dapsone, have anti-
`
`inflammatory activity and thus would be informative to a POSA. (See AMN1027
`
`[“The usefulness and side effects of topical steroids are a direct result of their anti-
`
`inflammatory properties.”].) Barclay (AMN1027) also explained that important
`
`factors for successful treatment include “potency, frequency of application,
`
`duration of treatment, and adverse effects” of a particular therapy. (AMN1027, 1.)
`
`Barclay further taught that “[m]ost preparations should be applied once or twice
`
`daily, with the optimal dosing schedule determined by trial and error.” (Id., 2.) A
`
`POSA would understand these teachings to mean that the optimal dosing schedule
`
`(generally meaning the most effective treatment with a tolerable side effect profile)
`
`could be once- or twice-daily, depending on the particular patient. Thus, while
`
`identifying the optimal dosing may require some “trial and error,” a POSA would
`
`- 16 -
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1018)
`have expected that an increased strength dapsone product could effectively treat
`
`some, if not many, patients on a once-daily dosing schedule.
`
`43. Second, a 7.5% formulation of dapsone does not meet any long-felt
`
`need. Given the availability of the prior art 5% Aczone predecessor product, I am
`
`not aware of any long-felt need for the 7.5% Aczone product that the commercial
`
`embodiment of the ’926 patent at issue in this IPR. Nor does the reduced daily
`
`dose meet a long-felt need. As Williams explained, the very public and visible
`
`nature of acne can have “detrimental effects on self-esteem”, which may translate
`
`into better adherence to recommended treatment regimens, whether they require
`
`once- or twice-daily application. (AMN1025.)
`
`44.
`
`I reserve the right to respond to any clinical objective indicia
`
`presented by Allergan or its experts.
`
`XI. Conclusion
`45.
`In signing this declaration, I recognize that the declaration will be
`
`filed as evidence in a contested proceeding before the Patent Trial and Appeal
`
`Board of the U.S. Patent & Trademark Office. I also recognize that I may be
`
`subject to cross-examination in the proceeding, and that cross-examination will
`
`take place in the United States. If cross-examination is required of me, I will
`
`appear for cross-examination, within the United States, during the time allotted for
`
`cross-examination.
`
`- 17 -
`
`
`
`Inter Partes Review of US. Patent No. 9,161,926
`Declaration ofElaine S. Gilmore, [M.D., Ph.D.
`(Exhibit 1018)
`I hereby declare that all statements made herein of my own knowledge are
`
`true and that all statements made on information and belief are believed to be true,
`
`and further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under § 1001 of title 18 of the United States Code.
`
`Dated: 31%‘Wlfi
`
`2 QtLAA“Ag EQE L4 4M\ VG
`
`Elaine S. Gilmore, M.D., Ph.D.
`
`-13-
`
`
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