`
`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
`_____________________
`
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`
`
`
`
`AMN1044
`Amneal v. Almirall, LLC
`IPR2019-00207
`
`
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`
`TABLE OF CONTENTS
`
`I.
`Overview .......................................................................................................... 1
`Scope of testimony and documents considered ............................................... 1
`II.
`III. The existence of other alternative acne treatments would not have led a
`POSA away from dapsone. ........................................................................................ 4
`A.
`POSAs, including three of Almirall’s experts, were motivated
`to select dapsone for the treatment of acne and rosacea. ...................... 4
`POSAs, including Almirall’s expert, were motivated to
`formulate a 7.5% w/w dapsone formulation. ...................................... 18
`Dr. Kircik’s opinions regarding adapalene are both unsupported
`with respect to acne and completely ignore rosacea in the
`claims. .................................................................................................. 19
`
`B.
`
`C.
`
`
`
`i
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`
`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, naming 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.
`
`3.
`
`To the extent that I have not responded to all of Dr. Kircik’s opinions,
`
`I understand that another expert may be responding to those opinions.
`
`II.
`
`Scope of testimony and documents considered
`4.
`
`Previously, I submitted a declaration in support of Amneal’s Petition.
`
`See AMN1018. I understand from Counsel for Amneal that Almirall submitted in
`
`support of its Patent Owner’s Response (“POR”) the declaration of Leon Kircik,
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`MD. EX2055 (“Kircik Decl.”). I have been asked to respond to the portions of Dr.
`
`Kircik’s declaration relied upon by Patent Owner Almirall.
`
`5.
`
`In formulating my opinions, I considered the following documents:
`
`Exhibit or
`Paper No.
`
`1001
`
`1004
`
`1007
`
`1008
`1010
`1018
`
`1023
`
`1024
`
`1025
`
`1035
`
`1047
`
`1048
`
`2001
`
`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, 2013; 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)
`U.S. Patent Publication No. 2010/0029781 (“Morris”)
`Physician’s Desk Reference, 65th ed., pp. 599-602 (2011)
`(ACZONE Gel 5% Label)
`Declaration of Elaine S. Gilmore, M.D., Ph.D.
`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)
`(“Williams”)
`Poster Abstracts for the Journal of the American Academy of
`Dermatology 2017 Annual Meeting
`Kircik, L.H., “Use of Dapsone 5% Gel as Maintenance
`Treatment of Acne Vulgaris Following Completion of Oral
`Doxycycline and Dapsone 5% Gel Combination Treatment,”
`Journal of Drugs in Dermatology 15(2):191-195 (2016)
`Tanghetti, E., et al., “The Efficacy and Tolerability of Dapsone
`5% Gel in Female vs. Male Patients With Facial Acne Vulgaris:
`Gender as a Clinically Relevant Outcome Variable,” Journal of
`Drugs in Dermatology 11:1417-1421 (2012)
`International Patent Application Publication No. WO
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`
`2009/108147 (“Garrett II”)
`International Patent Application Publication No. WO
`2011/014627 (“Ahluwalia”)
`Dina Anderson, Finding a Place for Topical Anti-inflammatory
`Acne Therapy, Practical Dermatology 17 (July 2009)
`(“Anderson”)
`Barry Coutinho, Dapsone (Aczone) 5% Gel for the Treatment of
`Acne, Am. Family Physician (2010) (“Coutinho”)
`Michael Ghods et al., The Role of Dapsone Gel in the Acne
`Armamentarium, The Dermatologist (June 10, 2010) (“Ghods”)
`Kirk A. James et al., Emerging Drugs for Acne, 14 Expert
`Opinions on Emerging Drugs 649 (2009) (“James 2009”)
`Leon H. Kircik, Harnessing the Anti-inflammatory Effects of
`Topical Dapsone for Management of Acne, 9 J. Drugs Dermatol.
`667 (2010) (“Kircik 2010”)
`H.C. Korting & C. Schöllmann, Current topical and systemic
`approaches to treatment of rosacea, 23 J. Eur. Acad. of
`Dermatology and Venereology 876, 876 (2009) (“Korting”)
`John Kraft & Anatoli Freiman, Management of acne, 183
`Canadian Med. Assoc. J. E430 (2011) (“Kraft”)
`MaryAnn Steiner, Dapsone Topical Gel for Acne, 12 J Pharm
`Soc. Wisc. 67 (2009) (“Steiner”)
`Emil Tanghetti et al., Clinical Evidence for the Role of a Topical
`Anti-Inflammatory Agent in Comedonal Acne: Findings From a
`Randomized Study of Dapsone Gel 5% in Combination With
`Tazarotene Cream 0.1% in Patients With Acne Vulgaris, 10 J.
`Drugs Dermatol. 783 (2011) (“Tanghetti”)
`Diane Thiboutot et al., New insights into the management of
`acne: An update from the Global Alliance to Improve Outcomes
`in Acne Group, 60 J. Am. Acad. Dermatol. S1 (2009)
`(“Thiboutot 2009”)
`Stephen Titus & Joshua Hodge, Diagnosis and Treatment of
`Acne, 86 Am. Family Physician 734 (2012) (“Titus”)
`2005 Aczone 5% approval letter
`Declaration of Leon H. Kircik, M.D.
`
`2008
`
`2009
`
`2012
`
`2017
`
`2019
`
`2020
`
`2024
`
`2025
`
`2031
`
`2034
`
`2036
`
`2038
`2045
`2055
`
`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`III. The existence of other alternative acne treatments would not have led a
`POSA away from dapsone.
`6.
`
`After reading the Kircik Declaration, I understand Dr. Kircik to offer
`
`essentially the following opinions, as summarized by Dr. Kircik: (1) “a POSA
`
`would not have been motivated to treat patients for acne and rosacea with any
`
`novel topical formulation of dapsone, and less motivated still to treat with such a
`
`formulation having a design as described in … Garrett”; and (2) “had a POSA
`
`selected dapsone for an improved acne or rosacea treatment, it would only have
`
`been obvious [to] combine adapalene in, not exclude adapalene from, the
`
`composition.” EX2055, ¶15. As I explain below, these opinions are inconsistent
`
`with the art—including art authored by Almirall’s current experts, Dr. Kircik and
`
`Dr. David Osborne, as well as Almirall’s expert in a related IPR, Dr. Julie Harper.
`
`A.
`
`7.
`
`POSAs, including three of Almirall’s experts, were motivated to
`select dapsone for the treatment of acne and rosacea.
`
`Dr. Kircik opines that a POSA would not have been motivated to
`
`select dapsone. See EX2055, § VII.A, ¶¶90-98. Dr. Kircik breaks his analysis
`
`down into three sub-categories: use of dapsone to treat acne, to treat rosacea, and
`
`to treat both acne and rosacea. For clarity, I will use the same structure. And, as
`
`shown below, the bases for Dr. Kircik’s opinions are not only incorrect—they
`
`contradict his own statements at the time of invention regarding the value of
`
`dapsone.
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`For acne. I do not disagree with Dr. Kircik that, in 2012, there were
`
`8.
`
`several treatment options for acne. See EX2055, ¶91. But, Dr. Kircik’s overall
`
`conclusion—that a second-line treatment was not an obvious one—is flatly
`
`incorrect. In fact, I understand from Amneal’s counsel that Dr. Kircik testified
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`during deposition that before 2012 he often used dapsone along with other drugs,
`
`and that is precisely the point: dapsone was an obvious drug to use for the
`
`treatment of acne. Its status as a second-line acne treatment does not matter,
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`because its use with any number of other treatments, or on its own, was obvious
`
`and reasonable to a POSA in 2012.
`
`9.
`
`As I explain below, Dr. Kircik’s opinions are refuted by four different
`
`sets of art. First, Garrett itself refutes Dr. Kircik’s claims that a POSA would not
`
`have considered dapsone. Second, Dr. Kircik’s reliance on dapsone as a second-
`
`line therapy is misplaced in light of substantial art (including FDA approval) that
`
`described dapsone as effective. Third, Dr. Kircik’s testimony is inconsistent with
`
`his own statements before 2012, as well as those of Almirall’s formulation expert,
`
`Dr. David Osborne, and Dr. Julie Harper, Almirall’s clinical expert in IPR2018-
`
`00608 regarding the related U.S. Patent No. 9,161,926. All three of these Almirall
`
`witnesses were motivated to consider dapsone around the time of invention.
`
`10. First, I have already explained that the use of dapsone was obvious in
`
`2012. AMN1018, ¶¶27-42. Dr. Kircik’s attempt to minimize the teachings of
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`Garrett is misplaced. Dr. Kircik opines that Garrett “clearly reported that vehicle
`
`alone ‘resulted in a better reduction in non-inflammatory [acne] lesion counts,’ and
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`that the overall (inflammatory and non-inflammatory) percentage reduction of acne
`
`lesions ‘was similar between Aczone™ [5%] and vehicle.” EX2055, ¶80 (citing
`
`AMN1004, 29:20-24) (all modifications Dr. Kircik’s). From this, Dr. Kircik claims
`
`that “nothing in Garrett itself … would motivate a POSA to use dapsone in a new
`
`or improved method for treating acne.” EX2055, ¶95.
`
`11. But, as Dr. Kircik recognizes, dapsone 5% had already been approved
`
`by FDA as efficacious for the treatment of acne before Garrett was published, but
`
`FDA “required an additional, post-approval study of at least 50 G6PD-deficient
`
`patients to further evaluate the risk of anemia or other hematological adverse
`
`events with Aczone 5% use.” EX2055, ¶69 (citing EX2045, 2). Dr. Kircik then
`
`goes on to explain the safety study described in Garrett. EX2055, ¶¶70-73.
`
`12. What Dr. Kircik misses is that the efficacy of dapsone had already
`
`been established, as shown by the FDA approval letter. See EX2045, 1.
`
`Accordingly, the goal of Garrett was not to again show efficacy, but to establish
`
`dapsone’s safety for administration to patients with G6PD deficiency. See EX2055,
`
`¶80 (Garrett’s study “did not report statistical tests on efficacy,” and “was not
`
`designed [to show] efficacy.”); Id. (explaining that “the ‘unexpected result’
`
`common to all methods and compositions described in Garrett [including a 7.5%
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`dapsone, 30% DGME formulation] is that ‘treatment of G6PD-deficient patients
`
`with the Aczone™ gel, 5%, formulation does not result in adverse hematological
`
`effects.”) Id.,¶71 (citing AMN1004, 10:22-25).
`
`13. Even though Garrett’s study was not powered to show the efficacy of
`
`dapsone to treat acne (as that has already been established), it nevertheless reported
`
`dapsone’s efficacy. Here, Dr. Kircik ignores the plain teachings of both Garrett and
`
`the ’219 patent in an effort to cast doubt on dapsone’s efficacy. But Garrett
`
`explained that:
`
`[T]he term “treat”, “treatment”, or “treating” refers to the reduction in
`number and/or severity of symptoms, including individual skin lesions,
`prevention of the development of symptoms, including skin lesions, or
`global improvement in the appearance of symptoms, including skin lesions.”
`
`AMN1004, 9:33-10:2. That definition is practically identical to the definition used
`
`in the ’219 patent:
`
`“the terms ‘treatment’ or treating’ in reference to a skin condition generally
`mean ‘having a positive effect on a skin condition’ and encompass
`alleviation of at least one symptom of a skin condition, a reduction in the
`severity of the skin conditions, or delay, prevention, or inhibition of the
`progression of the skin condition. … A composition or a product useful for
`treatment of a skin condition, or a method of treating a skin condition, needs
`only to reduce the severity of a skin condition…
`
`AMN1001, 5:22-35.
`
`14. Garrett plainly teaches such treatment by disclosing that “[i]n all
`
`lesion categories [inflammatory, noninflammatory, and total], Aczone™-treated
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`subjects experienced larger absolute reductions in lesions than vehicle-treated
`
`subjects after 12 weeks in the first treatment period.” AMN1004, 28:11-29:2; Id.,
`
`29:24-25. It appears that Dr. Kircik ignores how a POSA would have interpreted
`
`“treating” in Garrett—which is the same way a POSA would have interpreted it in
`
`the ’219 patent.
`
`15.
`
`Second, I understand that Almirall cited a portion of my deposition in
`
`which I testified that I did not use dapsone as a first-line treatment. In my opinion,
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`that fact is irrelevant to the obviousness of selecting dapsone as an acne treatment.
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`The simple fact of the matter is that before the ’219 patent, dermatologists (myself
`
`included) were prescribing topical dapsone for the treatment of acne vulgaris—as
`
`instructed by the ACZONE Gel, 5% label. AMN1010, 3. That it was second-line
`
`means only that it was not typically used as the very first drug on a given patient.
`
`However, in my experience, the first drug prescribed to a patient is rarely the last.
`
`16. As reflected even in the treatment paradigms cited by Dr. Kircik, the
`
`treatment of acne is cyclic—it involves diagnosing a patient and then developing a
`
`treatment regimen for that particular patient. Each patient presents with a unique
`
`combination of factors, including severity of acne, tolerability to acne treatments,
`
`gender and genetic considerations, and patient finances that impact the patient’s
`
`treatment regimen. Accordingly, the treatment of acne is often a cycle of trial-and-
`
`error: what works for one patient may not work for another. That is why even the
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`treatment guidelines cited by Dr. Kircik show multiple treatment regimens, without
`
`a single one-size-fits-all therapy. See, e.g., EX2055, ¶¶44-45 (citing AMN1025, 4;
`
`EX2036, 7; EX2025, 4). Each of these references describes either the signs of acne
`
`or the severity of it, and which drug(s) to use in each scenario. AMN1025, 4;
`
`EX2036, 7; EX2025, 4.1 As I did before 2012, a POSA would have understood that
`
`any of the well-known drugs—first- or second-line—was obvious to use to treat
`
`acne, and would have rotated through drugs—including dapsone—until arriving at
`
`a satisfactory treatment. I understand from counsel that Dr. Kircik testified at his
`
`deposition that his approach to the treatment of acne is similar.
`
`
`1 Although dapsone is not present in any of these guidelines, that absence is easily
`
`explained: each table relies on review articles published before Aczone 5% was
`
`launched in 2008. Each of the tables Dr. Kircik includes in this section of his
`
`declaration were created before dapsone was even on the market. The basis for the
`
`table from Williams (AMN1025, 4) appears to be the four articles cited as
`
`footnotes 76-79, by Lehmann, Gollnick, Strauss, and Dréno. AMN1025, 10. The
`
`latest of these—Strauss—was published in 2007, after dapsone gained approval but
`
`before it launched. Likewise, the Thiboutot reference (EX2036) is reprinted from
`
`the same Gollnick article published in 2003. And finally, Kraft (EX2025) relies on
`
`Gollnick and Strauss.
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`17. Third, ACZONE Gel, 5% was approved by the U.S. Food and Drug
`
`Administration for the treatment of acne vulgaris as a monotherapy. AMN1010, 3.
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`Thus, regardless of whether it was first-line or second-line, the FDA had already
`
`determined by 2012 that topically applied dapsone was effective at treating acne
`
`vulgaris as a monotherapy, so a POSA would have had a reason to select dapsone
`
`as an acne treatment based on its FDA-approved indication. This is consistent with
`
`the fact that Dr. Kircik and I actually used topical dapsone to treat acne before and
`
`after 2012. In addition, I understand that Almirall’s prior dermatologist expert, Dr.
`
`Julie Harper, testified at her deposition that she frequently used dapsone to treat
`
`acne. Our experiences are consistent with one another and demonstrate the
`
`obviousness of using dapsone to treat acne.
`
`18. Besides FDA approval and my agreement with Drs. Kircik and Harper
`
`that dapsone was used before the invention date, the art was full of other references
`
`demonstrating that topical dapsone compositions were effective acne treatments—
`
`further confirming a POSA’s selection—including:
`
` AMN1008: “One topical formulation for the treatment of acne that
`
`has found wide acceptance is Aczone®, a topical formulation of the
`
`bioactive drug dapsone that is in the physical form of an aqueous gel
`
`containing dapsone both in solution and in the solid phase.”
`
`AMN1008, ¶[0004].
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
` EX2008: “These effects [of dapsone] result[s] in reduction of
`
`inflammatory acne lesions. In addition to its anti-inflammatory
`
`activity, dapsone is also effective against P. acnes.” EX2008, 3:22-24.
`
` EX2031: “Dapsone-treated patients were more likely to have
`
`treatment success [versus vehicle] at 12 weeks (p<0.001).” EX2031,
`
`3-4.
`
` EX2009: “two recent studies have shown that a 5% dapsone topical
`
`gel solution is effective in reducing the amount of both non-
`
`inflammatory and inflammatory acne lesions when used as a
`
`monotherapy and applied twice a day for 12 weeks. The most
`
`pronounced effect was in treating the inflammatory lesions, which
`
`decreased by 47.5% after 12 weeks of treatment”. EX2009, 5.
`
` EX2012: “Studies show that dapsone gel has modest effectiveness in
`
`the treatment of moderately severe inflammatory and
`
`noninflammatory acne.” EX2012, 1.
`
` EX2025: “A large multicentre randomized controlled trial in
`
`adolescents with acne found that when the gel was applied twice daily
`
`on the affected areas, 40% of the treatment group and 28% of the
`
`placebo group (p < 0.001) achieved the desired outcome at 12 weeks.
`
`The same trial, and an additional study, found that topical dapsone 5%
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`gel is a safe treatment option in patients with a deficiency in glucose-
`
`6-phosphate dehydrogenase.” EX2025, 5.
`
` EX2009: “Several publications have presented and reviewed the
`
`efficacy of topical dapsone gel 5% in treating mild to moderately
`
`severe acne. In 12-week clinical trials comparing topical dapsone to
`
`vehicle, treated patients had greater improvements in investigator’s
`
`global acne assessment and mean percentage reduction in
`
`inflammatory, non-inflammatory, and total lesion counts, compared to
`
`controls. Statistically significant improvement in lesion counts was
`
`evident by week four.” EX2009, 1.
`
` EX2017: “Clinical trials have demonstrated reductions in acne lesions
`
`with 5% dapsone gel use, particularly for inflammatory lesions.”
`
`EX2017, 1-2.
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`19. Fourth, Dr. Kircik’s testimony that a POSA would not have been
`
`motivated to select dapsone (EX2055, ¶¶91-95) is inconsistent with publications
`
`authored by him, and by Almirall’s other experts, Dr. Osborne and Dr. Harper. In
`
`2010, Dr. Kircik—as sole author of a paper entitled “Harnessing the Anti-
`
`Inflammatory Effects of Dapsone for Management of Acne”—described “topical
`
`dapsone 5% gel [as] a worthwhile anti-inflammatory treatment for many patients
`
`with mild-to-moderate acne.” EX2020, Abstract. In that same paper, he said
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`“Aczone gel 5% represents a valuable treatment option for patients with acne
`
`vulgaris.” Id., 4. A POSA would certainly have been interested in using a “valuable
`
`treatment option” to treat acne.
`
`20. Likewise, a 2011 article co-authored by Dr. Kircik studied the
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`coadministration (i.e., the administration of two separate drug products) of dapsone
`
`and the retinoid tazarotene. EX2034. In this paper, Dr. Kircik and his colleagues
`
`said that “[c]ombination therapy with dapsone gel 5% plus tazarotene cream 0.1%
`
`was more effective than tazarotene monotherapy for treatment of comedonal acne.”
`
`Id., Abstract. They concluded that the “combination of topical tazarotene cream
`
`0.1% with dapsone 5% gel appears to be useful in patients with comedonal acne
`
`and offers a BPO- and oral antibiotic-free treatment alternative for patients with
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`moderate to severe inflammatory acne.” Id., 9.
`
`21. Dr. Kircik’s interest in dapsone did not end in 2012. In 2016, he
`
`published an article on dapsone 5% that described the use of oral doxycycline with
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`topical dapsone 5% for 12 weeks, at which time the doxycycline was removed
`
`from the regimen and dapsone was administered alone. AMN1047, Abstract. I
`
`understand that Dr. Kircik testified that he used this regimen prior to November
`
`2012. I also used this combination. The fact that four years after the invention date
`
`Dr. Kircik was still studying dapsone serves to confirm the value of the drug.
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`22. Dr. Harper, Almirall’s clinical expert in the related IPR2018-00608
`
`proceeding similarly praised the 5% dapsone formulation. In an article published in
`
`December 2012, just weeks after the earliest possible filing date for the ’219
`
`patent, Dr. Harper declared that “[d]apsone is an anti-inflammatory agent that, in
`
`the 5% gel formulation, is an effective topical treatment for patients with acne
`
`vulgaris.” AMN1048, 1. Dr. Harper assessed the clinical efficacy of dapsone and
`
`concluded that “[f]emale patients experienced a significantly better response to
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`dapsone 5% gel than male patients.” Id., 5. Even if only treating females, a POSA
`
`like Dr. Harper was motivated to treat female patients with dapsone.
`
`23. Like Almirall’s other experts, Dr. Osborne was also motivated to
`
`select dapsone before 2012. Dr. Osborne is one of two named inventors on the
`
`Lathrop patent application. AMN1007, 1. In this application, Dr. Osborne
`
`explained that dapsone could be used to treat several skin conditions, including
`
`acne vulgaris. AMN1007, ¶[0003]. While it appears that he was referring to oral
`
`dapsone in this paragraph, it is clear that he sought to make a topical dapsone
`
`formulation. Id., ¶[0007] (“Therefore, there is a need to formulate a stable, aqueous
`
`based, emulsive Dapsone composition that will not dry or crack the skin.”).
`
`24.
`
`In short, three different experts retained by Almirall published articles
`
`or filed patent applications that showed that they were motivated to investigate
`
`- 14 -
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`dapsone’s use for the treatment of acne. Their claims to the contrary are simply not
`
`credible.
`
`25. For rosacea. Dr. Kircik next attempts to belittle the use of dapsone to
`
`treat rosacea. EX2055, ¶96. He points to Garrett II in an effort to claim that
`
`dapsone 5% was no more effective than vehicle. EX2055, ¶81. I disagree for two
`
`reasons.
`
`26. First, I understand that Dr. Kircik testified that he frequently used
`
`dapsone to treat rosacea if other FDA-approved treatments, such as metronidazole
`
`or azelaic acid, failed for a particular patient or otherwise, Dr. Kircik used dapsone
`
`in combination with those other approved treatments to treat rosacea. Some
`
`physicians followed this practice in 2012, because rosacea was known to be an
`
`inflammatory disease and dapsone to be an anti-inflammatory drug. EX2024, 2
`
`(“What is known is that the pathophysiology of rosacea likely is inflammatory, and
`
`that most interventions appear to modulate the inflammatory process.”). Even
`
`though dapsone was viewed as something of a last-line option for rosacea
`
`treatment, there were not many drugs approved to treat rosacea, so it was one of
`
`only a few known drugs used to treat rosacea that a POSA would have envisioned
`
`in 2012.
`
`27.
`
`Second, as I explained above, Dr. Kircik’s testimony plainly
`
`misunderstands the meaning of the term “treating” in the challenged claims. The
`
`- 15 -
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`’219 patent’s specification unambiguously defines the terms “treatment” or
`
`“treating” to mean “‘having [a] positive effect on a skin condition.’” AMN1001,
`
`5:22-35. And that definition is similar to the one stated in Garrett II. See EX2001,
`
`8:20-23 (“As used herein, the term ‘treat’, ‘treatment’, or ‘treating’ refers to the
`
`reduction in number and/or severity of individual rosacea lesions, prevention of the
`
`development of rosacea symptoms including papulopustular lesions, or global
`
`improvement in the appearance of rosacea.”). Almirall and Dr. Kircik’s contention
`
`that dapsone formulations were not known to be effective for the treatment of
`
`rosacea is contrary to the published art at the time of invention. Garrett is clear:
`
`dapsone treats “inflammatory acne, non-inflammatory acne or rosacea.”
`
`AMN1004, 3:13-15. Dr. Kircik cites the Garrett II reference as proof that dapsone
`
`is not effective in treating rosacea (see, e.g., EX2055, ¶81), but then ignores what
`
`Garrett II teaches: “[a]ll treatment groups experienced a mean decrease from
`
`baseline in lesion counts.” EX2001, 35:16-17. Both dapsone once-daily and twice-
`
`daily achieved a reduction in lesions. Id., 17-23. Similarly, when measured in the
`
`Investigator’s Global Assessment scale, the success rate was greater in the dapsone
`
`+ MetroGel® arm than the MetroGel®-only treatment arm. Id., 35:24-29. All told,
`
`these improvements with dapsone formulations qualify as “treatment” as defined in
`
`each of Garrett, Garrett II, and the ’219 patent.
`
`- 16 -
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`28. For acne and rosacea. Dr. Kircik appears to interpret the claims of
`
`the ’219 patent to include three options for the claimed methods—treatment of
`
`acne, treatment of rosacea, and treatment of both together. EX2055, ¶97. To the
`
`extent the claims encompass use of topical dapsone compositions that can be used
`
`to treat both acne and rosacea, dapsone would have been one of a very limited set
`
`of drugs a POSA would have considered at the time of invention, and thus would
`
`have been obvious. I understand that Dr. Kircik testified that dapsone was one of
`
`the products he used to treat both rosacea and acne. I further understand that he
`
`testified, and I agree, that the only other product known to be useful for treating
`
`both conditions was azelaic acid.2 Thus, it is my opinion that it would have been
`
`obvious for a POSA to endeavor to use dapsone as a rosacea treatment. Further, to
`
`the extent that a POSA seeking to treat rosacea wanted to develop a combination
`
`therapy to treat both acne and rosacea, as Dr. Kircik opines, the most obvious
`
`combination would have been dapsone and azelaic acid.
`
`
`2 I understand that Dr. Kircik testified that adapalene was occasionally used to treat
`
`rosacea. But I understand that he testified that such use was “very, very” rare—
`
`retinoids like adapalene are known to be irritating to the skin, and patients with
`
`rosacea are extremely susceptible to irritability.
`
`- 17 -
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`POSAs, including Almirall’s expert, were motivated to formulate
`a 7.5% w/w dapsone formulation.
`29. Dr. Kircik next opines that a POSA would not have been motivated to
`
`B.
`
`select a 7.5% w/w concentration of dapsone. I disagree for at least the reasons
`
`below.
`
`30. First, Dr. Kircik’s claim that no POSA would have been motivated to
`
`develop a 7.5% w/w formulation of dapsone is directly inconsistent with Dr.
`
`Osborne’s pre-invention publications. As it turns out, Dr. Osborne was motivated
`
`to develop a 7.5% w/w dapsone formulation. Not only was he motivated, but he
`
`told the public that “7.5 [% w/w dapsone is] especially preferred.” AMN1007,
`
`[0014].
`
`31.
`
`Second, the result of shifting from twice-daily to once-daily dapsone
`
`administration was one reason a POSA would have had to increase the
`
`concentration of dapsone from 5% to 7.5% w/w. That was established in Garrett,
`
`which explained that the compositions described therein could be applied “once or
`
`twice daily.” See, e.g., AMN1018, ¶46 (citing AMN1004, 23:8-10). Although
`
`dapsone 5% was sometimes prescribed for once-daily administration, typically in
`
`co-administration regimens, I am not aware of any data to suggest that once-daily
`
`5% dapsone had any meaningful clinical effect.
`
`32. The expectation that effective once-daily administration of dapsone
`
`could be expected when the dapsone concentration was increased to 7.5% is
`
`- 18 -
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Elaine S. Gilmore, M.D., Ph.D.
`(Exhibit 1044)
`confirmed by Dr. Kircik himself. AMN1035, AB7 (“once-daily dapsone gel 7.5%
`
`(DAP) was developed to simplify topical anti-inflammatory acne treatment relative
`
`to twice-daily Aczone® Gel 5%.”). Dr. Kircik’s backward-looking explanation of
`
`why the 7.5% product was developed meshes well with what a POSA would have
`
`anticipated from the Garrett reference: that some concentration of dapsone between
`
`5% and 10% would be expected to show efficacy against acne vulgaris with once-
`
`daily administration. AMN1004, 23:8-10.
`
`C. Dr. Kircik’s opinions regarding adapalene are both unsupported
`with respect to acne and completely ignore rosacea in the claims.
`33. Dr. Kircik’s opinion that a POSA looking at dapsone would only have
`
`done so if the product combined dapsone and adapalene into a single formulation is
`
`plainly inconsistent with the prior art and the clinical practice before 2012.
`
`34. Before turning to the issues I take with Dr. Kircik’s opinions, it is
`
`important to clarify the nomenclature I use below. Two drugs can be administered
`
`together in two ways: they can either be administered as two separate products,
`
`which I refer to as co-administration; or the two drugs can be formulated into a
`
`single product, which I refer to as co-formulation. As I sho
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