UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.
`Petitioners,
`v.
`ALMIRALL, LLC.
`Patent Owner
`
`______________________
`Case IPR2019-01095
`U.S. Patent No. 9,517,219
`_____________________
`Declaration of Marc Serota, M.D.
`
`US_139709686v1_391026-00295
`US_139709686v1_391026-00295
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`Mylan (IPR2019-01095) MYLAN1037, p. 001
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`
`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...........................................................7
`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
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota M.D.
`(Exhibit 1037)
`
`I.
`
`I, Marc Serota, 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 Petitioner
`
`Mylan Pharmaceuticals Inc. 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 $700/hr. I understand that the petition for IPR involves
`
`U.S. Patent No. 9,517,219 (“the ’219 patent”), MYLAN1001, 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
`
`3.
`
`The ’219 patent is generally directed to methods of treating acne
`
`vulgaris or rosacea, in patients with those conditions, by administering a topical
`
`
`1 Throughout this declaration, I will refer to both Allergan and Almirall as
`“Almirall.”
`
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`Mylan (IPR2019-01095) MYLAN1037, p. 003
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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 Mylan 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.
`In my opinion, the treatment of acne vulgaris or rosacea by
`
`5.
`
`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
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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
`6.
`I am an expert in the field of dermatology and in the treatment of
`
`patients suffering from dermatological disorders, including acne, atopic dermatitis,
`
`chronic urticaria, psoriasis, allergic contact dermatitis and many other skin
`
`conditions treated by a dermatologist.
`
`7.
`
`I am a supervising physician in Dermatology at the University of
`
`Colorado and a Physician and Attending/Supervising physician at the Veteran’s
`
`Affair Hospital in Denver and am in private practice at Peak Dermatology in
`
`Littleton, CO. Prior to holding these positions I was a physician with the Colorado
`
`Dermatology Specialists from 2015-2017. I have been practicing general medical
`
`dermatology for nearly 10 years and am triple Board Certified in Dermatology,
`
`Pediatrics, and Allergy/Immunology and am licensed to practice Dermatology and
`
`
`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.
`
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`

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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`Allergy/Immunology in 25 states. I am a national lecturer on dermatologic
`
`subjects, including acne. My curriculum vitae is provided as MYLAN1038.
`
`8.
`
`I earned a combined Bachelor of Science degree and Medicinae
`
`Doctor degree from the University of Missouri Kansas City in 2007. I completed
`
`a residency in pediatrics at Cohen’s Children Hospital in 2010 and a dermatology
`
`residency at the University of Colorado Denver in 2015. From 2010 to 2012, I
`
`attended an Allergy/Immunology Fellowship at the Children’s Mercy Hospital in
`
`Kansas City.
`
`9.
`
`I have received several honors and awards in my career, including the
`
`Academic All American Award, the Verizon Academic All-Midwest Award, and
`
`was nominated as the Snake Award Winner.
`
`10.
`
`In addition to my clinical practice, I have presented at numerous
`
`international meetings on topics related to dermatology and have been honored to
`
`be the keynote speaker and local, regional and national dermatologic and allergic
`
`society meetings. A complete list of my lectures and presentations can be found in
`
`my curriculum vitae (MYLAN1038).
`
`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 (MYLAN1038).
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`I am a member of or previously affiliated with a number of
`
`12.
`
`organizations and societies including Golden Key International Academic honor
`
`Society, American Medical Student Association (AMSA), American Medical
`
`Association (AMA), American Academy of Pediatrics (AAP), Fellow ACAAI,
`
`Fellow AAAAI, and Fellow FAAD.
`
`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
`
`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)
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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
`
`Basis of my analysis with respect to obviousness
`15.
`I understand from Counsel that, in considering obviousness of an
`
`1024
`1025
`
`1027
`
`V.
`
`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.
`
`I understand from Counsel that the relevant date of assessing the
`
`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
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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
`
`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
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`I am informed that a POSA may draw from the knowledge of a
`
`19.
`
`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 from Counsel that another
`
`expert on behalf of Mylan 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
`
`vulgaris and related conditions. (See MYLAN1001, 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
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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
`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
`
`
`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.
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`The specification includes substantial discussion that makes clear that
`
`23.
`
`“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 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).
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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
`
`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.
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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 MYLAN1001, 15:40-16:39 [claims 1-6].) Dapsone (4, 4’
`
`diaminodiphenylsulfone) was first synthesized in 1908. (MYLAN1022, 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.” (MYLAN1007, [0002]) These
`
`activities include antibacterial and anti-inflammatory activities. (Id.;
`
`MYLAN1004, 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. (MYLAN1022, 1.)
`
`29.
`
`Initially, dapsone was administered in an oral form. See, e.g.,
`
`MYLAN1004, 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 MYLAN1007, [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
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`with hematologic side effects, including hemolysis and hemolytic anemia that are
`
`dose-dependent and occur more frequently with increasing dose.” (MYLAN1004,
`
`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., MYLAN1004, 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.” (MYLAN1023, 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. (MYLAN1010) 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. (MYLAN1024, 5-
`
`6) A POSA would have preferred these options to systemic ones due to the
`
`reduced likelihood of systemic side effects from topical therapy.
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`33. Given the availability of several different drugs, “a suitable regimen
`
`for reducing [acne] lesions can be found for most patients.” (MYLAN1025, 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.” (MYLAN1024, 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.” (MYLAN1025, 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.
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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. (MYLAN1004, 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.” (MYLAN1004, 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
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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. (MYLAN1025, 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
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`dapsone composition containing 5% w/w dapsone, indicated for the treatment of
`
`acne vulgaris. (MYLAN1010)
`
`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.” (MYLAN1004, 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.” (MYLAN1023, 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
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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.
`
`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. (MYLAN1004; MYLAN1007) The prior art, including Garrett,
`
`taught that topical dapsone compositions did not require the presence of adapalene.
`
`(MYLAN1004) 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. (MYLAN1010) 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.
`43.
`I understand that a complete obviousness analysis requires
`
`consideration of objective indicia (or so called-secondary considerations) of non-
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Declaration of Marc Serota, M.D.
`(Exhibit 1037)
`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.
`
`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 ex