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 BOZENA B. MICHNIAK-KOHN, Ph.D.,
`FAAPS, M.R.Pharm.S.
`
`
`AMN1043
`Amneal v. Almirall, LLC
`IPR2019-00207
`
`
`
`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 BOZENA B. MICHNIAK-KOHN, Ph.D.,
`FAAPS, M.R.Pharm.S.
`
`
`AMN1043
`Amneal v. Almirall, LLC
`IPR2019-00207
`
`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`I, Bozena B. Michniak-Kohn, do hereby declare as follows:
`I.
`
`I am over the age of 18 and otherwise competent to make this
`
`Introduction
`1.
`
`declaration. I have been retained as an expert on behalf of Amneal
`
`Pharmaceuticals LLC and Amneal Pharmaceuticals of New York, LLC
`
`(“Amneal”). I understand this declaration is being submitted in an Inter Partes
`
`Review (“IPR”) proceeding concerning claims 1-8 of U.S. Patent No. 9,517,219
`
`(“the ’219 patent”) (AMN1001). I am being compensated for my time in
`
`connection with this IPR at my standard legal consultant rate of $650/hr. I have no
`
`personal or financial interest in Amneal or in the outcome of this proceeding.
`
`2.
`
`I have previously submitted a declaration in this IPR.
`
`II. Basis for my opinion
`3.
`In arriving at my opinion below, I considered Dr. Osborne’s
`
`Declaration (EX2057) as well as certain documents cited in Dr. Osborne’s
`
`declaration, and the documents cited herein.
`
`III. A POSA would have considered the referenced prior art
`4. Dr. Osborne argues that a POSA would not have considered Garrett,
`
`Nadau-Fourcade, Bonacucina to arrive at the inventions claimed in the ‘219
`
`patent. EX2057, ¶¶110-111. I disagree. A POSA would have understood that
`
`Garrett’s dapsone formulations referenced the previously FDA-approved 5%
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`1
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`ACZONE formulation. I understand that Dr. Osborne has also admitted that John
`
`Steven Garrett, the inventor of the Garrett reference, was heavily involved in the
`
`development of the 5% ACZONE formulation. I also disagree that a POSA would
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`have viewed the FDA Review Package to be the richest source of information
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`about a drug after it is approved. I understand from counsel that a POSA would
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`have been aware of all of the prior art and would not have given any particular
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`reference “priority” as Dr. Osborne argues.
`
`IV. Garrett does not teach away, or otherwise dissuade, a POSA from
`topical dapsone compositions.
`A. A POSA would not have avoided topical compositions containing
`undissolved dapsone.
`5. Dr. Osborne argues that a POSA had no reason to select Garrett as a
`
`prior art reference because of its formulation design where some dapsone was
`
`dissolved in the composition and some dapsone was undissolved. EX2057, ¶¶112-
`
`115. I disagree. Importantly, the challenged claims are not limited to any
`
`particular dissolution state and so the claimed dapsone can be in any form:
`
`dissolved, undissolved, a mixture of the two. Similarly, I disagree with Dr.
`
`Osborne’s premise that a POSA would have avoided Garrett, especially since
`
`Garrett disclosed that “the dapsone may exist as a microparticulate form, a
`
`dissolved form, or both.” AMN1004, 3:12-13, 4:29-31.
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`2
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`6. Dr. Osborne has also argued that “suspending a drug in undissolved
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`solid particulate form for topical administration was loathed by artisans, and
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`generally avoided as a formulation design choice.” EX2057, ¶¶42, 115. This
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`argument is contradicted by Dr. Osborne’s own patented dapsone formulation,
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`U.S. Patent No. 5,863,560, which describes its invention as “a pharmaceutical
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`carrier system comprising…a semi-solid aqueous gel, wherein a pharmaceutical is
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`dissolved…and wherein the composition also contains pharmaceutical in a
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`microparticulate state….” AMN1016, 2:57-65. That is, Dr. Osborne’s own patent
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`disclosed the exact formulation design he argues is “loathed” by artisans.
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`Furthermore, Dr. Osborne himself was also actively pursuing and patenting other
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`suspension formulations prior to 2012. AMN1042.
`
`7.
`
`In addition, a POSA would have known that the FDA-approved
`
`ACZONE 5% formulation already contained this dual-state formulation design.
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`AMN1009, 4. Dr. Osborne’s opinion is inconsistent with the fact that he asserts
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`that ACZONE 5% Gel was “optimized” “[d]espite a relatively high amount of
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`dispersed dapsone.” EX2057, ¶¶44, 154, 186-187; AMN1009, 4. Indeed, Dr.
`
`Osborne agrees
`
`that Garrett discloses only one single
`
`topical dapsone
`
`embodiment, which is the commercially-available ACZONE 5%. EX2057, ¶53.
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`And despite the dual-state design where some dapsone was dissolved and other
`
`dapsone was undissolved, FDA evaluated the ACZONE 5% Gel and assessed its
`
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`3
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`safety, efficacy, and stability and determined that it was safe and effective to treat
`
`acne. AMN1010, 1; AMN1004, 4; EX2042, 4. Therefore, a POSA would not have
`
`disregarded Garrett or otherwise been dissuaded from considering Garrett.
`
`8. Dr. Osborne also argues that Ahluwahlia (EX2008) taught that the
`
`efficacy of ACZONE 5% was low because of poor absorption caused by the
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`undissolved dapsone in the formulation. EX2057, ¶114. A POSA would not have
`
`avoided a suspended formulation with undissolved dapsone just from reading this
`
`reference. First, Garrett expressly taught that dapsone can be in dissolved form,
`
`undissolved form, or a mixture of both. AMN1004, 4:29-31. Therefore, a POSA
`
`would understand that poor absorption could be solved by adjusting the amount of
`
`undissolved dapsone in the formulation, which is expressly taught in Garrett and
`
`was within the skill of a POSA. Second, as stated above, a POSA would have
`
`been aware that the ACZONE 5% formulation contained undissolved dapsone and
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`would not have avoided such a suspension formulation. Third, Ahluwalia doesn’t
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`mention undissolved dapsone so a POSA would not understand the reference to
`
`criticize or discredit the use of undissolved dapsone in a topical composition.
`
`9.
`
`In sum, a POSA’s consideration of topical dapsone compositions with
`
`undissolved dapsone would not have been the product of hindsight nor would a
`
`POSA have been dissuaded considering such compositions.
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`4
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`B. ACZONE Gel 5% could have been optimized to once-daily dosing
`by increasing the amount of dapsone to 7.5% w/w.
`10. Dr. Osborne argues that Garrett would not have motivated a POSA
`
`seeking to select the dapsone in a concentration of about 7.5%. EX2057, ¶¶126-
`
`130. I disagree. A POSA would not have disregarded Garrett’s teachings in view
`
`of the fact that it is directed to treating glucose-6-phosphate dehydrogenase
`
`(G6PD) deficiency. While it may have been Garrett’s purpose to arrive at methods
`
`of treating G6PD-deficient patients with topical dapsone compositions “without
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`the adverse hematologic effects associated with oral dapsone administration,”
`
`Garrett taught multiple topical dapsone compositions that achieved this purpose.
`
`AMN1004, 3:4-6. In addition, Garrett taught that 5% to 10% dapsone
`
`compositions “do[] not induce hemolytic anemia” or “adverse hematologic
`
`events.” AMN1004, 4:2-5; 6:5-8; 42:25-32. Indeed, Garrett shows that one
`
`preferred embodiment is a topical composition containing “about 5% to 10%
`
`dapsone” and “about 10% to 30% ethoxydiglycol”. AMN1004, 4:2-5. Garrett
`
`contained an extensive teaching as to different topical dapsone compositions (gels,
`
`creams, lotions, solutions, suspensions), different excipients that may be used to
`
`prepare such compositions, and methods of preparing such compositions. Id.,
`
`11:15-18:22. All of this information would have been of interest to a POSA.
`
`11. A POSA would also not have disregarded Garrett because it showed a
`
`“similar” percent reduction in total acne lesions to treatment with vehicle alone.
`
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`5
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`EX2057, ¶126. Garrett’s Example 1 compared ACZONE Gel, 5% to vehicle and
`
`found that “[i]n all lesion categories, ACZONE™-treated subjects experienced
`
`larger absolute reductions in lesions than vehicle-treated subjects after 12 weeks
`
`in the first treatment period. There was a higher percentage reduction in
`
`inflammatory lesion counts in ACZONE™-treated subjects than vehicle-treated
`
`subjects (44% compared with 29%).” AMN1004, 28:11-29:5. Although the
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`primary purpose of the clinical study shown in Example 1 was to “evaluate
`
`safety,” this would not detract from its results. It simply means that “no statistical
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`tests were planned for comparisons of the efficacy variable.” Id., 29:7-9. And
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`although no statistical tests were conducted to assess the statistical significance of
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`the differences in efficacy of ACZONE Gel, 5% and vehicle, Garrett says that its
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`clinical results were “consistent with the result from the pivotal phase 3 studies.”
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`Id., 29:16-27. Given that the phase 3 studies were sufficient for FDA to approve
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`ACZONE Gel, 5% for the treatment of acne vulgaris, Garrett’s disclosure of
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`“consistent” clinical data would be sufficient for a POSA.
`
`12.
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`In addition, Dr. Osborne is wrong to claim that Garrett discloses 5%
`
`dapsone compositions having similar efficacy to vehicle. EX2057, ¶126. Not only
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`is that conclusion incongruous with ACZONE Gel, 5%’s FDA-approved treatment
`
`indication, Garrett also states that “the absolute reduction in lesion counts was
`
`numerically better with ACZONE™ treatment for all lesion categories.”
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`6
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`AMN1004, 29:20-27. Dr. Osborne also appears to ignore the explicit teachings of
`
`Garrett that: (1) dapsone performed better than vehicle in absolute reductions of
`
`lesion counts for all categories, (2) dapsone resulted in a larger number of
`
`reductions in lesions than vehicle, (3) dapsone resulted in a higher percentage
`
`reduction in inflammatory lesions than vehicle, and (4) that Garrett’s clinical
`
`results were consistent with the phase 3 studies that resulted in FDA approval. Id.,
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`28:11-29:5. Moreover, the ACZONE Gel, 5% label shows that dapsone usage
`
`resulted in a greater percentage reduction in acne lesions compared to vehicle.
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`AMN1010, 2-3. In addition, Garrett says that topical dapsone compositions are
`
`used to treat rosacea. AMN1004, 3:13-15. 4:23-24, 18:25-29.
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`13. Further, a POSA would have known that the ACZONE 5%
`
`formulation was FDA-approved to treat acne vulgaris. It is clear from the art that
`
`Garrett disclosed a post-approval study of ACZONE 5% Gel, so a POSA would
`
`have already known that FDA had determined ACZONE 5% Gel to be effective
`
`against acne. AMN1004, 28:10-29:27; EX2042, 4; EX2043, 3-4; EX2057, ¶¶48-
`
`49, 111. In addition, clinical study results showed that the ACZONE 5% was more
`
`efficacious than vehicle. AMN1010, 2:57-59, 2:81 (Table 1), 3:87 (Table 2);
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`EX2042, 4; EX2057, ¶48. A POSA would have understood that the ACZONE 5%
`
`formulation demonstrated efficacy beyond the clinical disclosures shown in
`
`Garrett.
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`7
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`14. Garrett also cites to two clinical studies that are disclosed in the
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`Draelos reference. EX2015, 4-5, 8. Draelos discloses that dapsone was effective
`
`against inflammatory lesions and non-inflammatory lesions. Id. Since Garrett cites
`
`to Draelos, a POSA would understand that Garrett discloses the efficacy results
`
`shown in Draelos.
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`15. Dr. Osborne also argues that a POSA would not have chosen a
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`dapsone concentration of about 7.5% because Garrett does not disclose an
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`embodiment containing 7.5% dapsone specifically. EX2057, ¶¶127, 130. As an
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`initial matter, I understand Dr. Osborne admitted at his deposition that 7.5%
`
`dapsone is within the range of 5-10% dapsone disclosed in Garrett. Moreover, a
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`POSA considering all of Garrett’s teachings in addition to the prior art would not
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`be limited to the one “preferred” embodiment disclosed in Garrett. AMN1004,
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`4:2-5. A POSA would not have been dissuaded from using a 7.5% dapsone
`
`concentration just because Garrett did not disclose a specific embodiment
`
`containing a 7.5% concentration of dapsone, especially when a range
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`encompassing 7.5% is disclosed as “preferred.”
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`16. Similarly, Dr. Osborne argues that ACZONE Gel, 5% was optimal so
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`there was no reason to use 7.5% w/w. EX2057, ¶¶113, 131-133. I disagree. A
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`POSA would not have been dissuaded from using 7.5% w/w dapsone in a topical
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`
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`8
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`composition due to some fear of deviating from the allegedly “optimal” 5% w/w
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`composition.
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`17. As an initial matter, a POSA would not have believed that all topical
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`dapsone compositions had been investigated and optimized into ACZONE Gel,
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`5%, as Dr. Osborne assumes. As support, Dr. Osborne cites to another of his
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`patent applications (EX2053) to argue that there was no reason to increase the
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`dapsone concentration above 5%. Ex. 2057, ¶134. The data in EX2053 is flawed.
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`Not only was it based on very small sample sizes (less than 20 for each of
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`Example 2 and Example 3 of EX2053), but there is no information in EX2053 to
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`inform a POSA of how much dapsone was dissolved (as opposed to undissolved)
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`in the 1%, 3%, and 5% formulations. As explained below, the amount of dissolved
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`dapsone would impact the anti-acne effect. AMN1009, 3-4.
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`18. A POSA, however, does know that by the time Allergan sought
`
`approval for ACZONE 5% Gel, only the 1% and the 5% dapsone formulations
`
`were submitted and considered by FDA. EX2043, 6. Additionally, before 2012,
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`Osborne explained that he had adjusted the ratio of dissolved dapsone to
`
`undissolved dapsone so that the amount of dissolved dapsone “was optimized with
`
`regard to the amount of active agent targeted to remain within the follicle
`
`(particulate dapsone).” AMN1009, 4 (emphasis added). This would have been
`
`understood to mean that Osborne “targeted” an amount of dapsone to remain
`
`
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`9
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`undissolved and then optimized a formulation to achieve that target. This does not
`
`mean that all dapsone amounts had been investigated and discarded. Osborne
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`further reported that “[f]or the 5% dapsone gel” the ratio was one-third dissolved
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`to two-thirds undissolved. Id. (emphasis added). This, again, would not have been
`
`understood to mean that all possible dapsone amounts had been investigated and
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`then discarded in view of a 5% composition. Far from it: Osborne simply reported
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`that “for the 5% dapsone gel” he had optimized the ratio of dissolved-to-
`
`undissolved dapsone. A POSA would have known that this ratio could be
`
`optimized for compositions containing other amounts of dapsone, including a
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`7.5% w/w dapsone composition; indeed, Garrett teaches modifying the amount of
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`ethoxydiglycol and dapsone depending on “the desired ratio of microparticulate to
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`dissolved dapsone.” AMN1004, 18:17-20.
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`19. A POSA would have also understood that the prior art below and Dr.
`
`Warner’s own declaration show that the amount of dapsone could be increased to
`
`achieve optimized dosing. AMN1017, 290, ¶4. According to the ACZONE Gel,
`
`5% label, the 5% composition was administered twice daily. AMN1010, 5. Based
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`on Garrett’s teachings, increasing the amount of dapsone in the composition, and
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`optimizing the ratio of any dissolved-to-undissolved dapsone, would have been
`
`expected to result in once-daily administration. A POSA would have preferred
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`once-daily dosing because Garrett
`
`teaches
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`that “dapsone dermatological
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`
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`10
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`composition[s] [are] typically applied to affected skin once or twice daily.”
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`AMN1004, 23:8-10. Given that ACZONE Gel, 5% was already administered
`
`twice-daily, it would have been obvious to optimize the composition for once-
`
`daily dosing.
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`20. And a POSA would have known how to optimize the composition to
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`achieve once-daily dosing: Garrett teaches that, in a composition containing 5% to
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`10% dapsone, modifying the ratio of dissolved-to-undissolved dapsone can result
`
`in, on the one hand, compositions that provide “minimum reservoir capacity” that
`
`may not maintain sustained delivery, or, on the other hand, compositions that
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`provide “maximum reservoir capacity” and maintains sustained delivery. Id.,
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`12:20-13:2. Garrett further teaches that some conditions are best treated by pulsed
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`or spiked drug delivery, while a “cosmetic, topical, or transdermal product that
`
`provides steady state active pharmaceutical delivery” will be best for other
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`conditions. Id., 22:28-23:7.
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`21. Further, Dr. Osborne’s own patent on the ACZONE 5% formulation,
`
`the ’560 patent, confirmed that a dapsone formulation with a higher concentration
`
`of the active ingredient could still maintain a reservoir of undissolved dapsone.
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`AMN1016, 3:52-64. In the disclosed examples of the ’560 patent, when the ratio
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`of dapsone to ethoxydiglycol was less than 1:20, the formulation contained both
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`microparticulate and dissolved dapsone. Id., Examples 1, 5-6. However, when the
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`11
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`ratio of dapsone to ethoxydiglycol is at or above 1:33, the formulation contained
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`only dissolved dapsone. Id., Examples 2-4. A POSA would have already been
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`familiar with the FDA-approved ACZONE 5% formulation, which had a dapsone
`
`to ethoxydiglycol ratio of 1:5. Therefore, a POSA reading the ’560 patent would
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`have understood that the concentration of dapsone could still increase and still be
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`optimized to contain a reservoir of undissolved dapsone. To suggest otherwise
`
`would be contrary to the prior art teachings disclosed in Dr. Osborne’s own
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`patent.
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`22. Moreover, the ’560 patent also disclosed that “at concentrations above
`
`0.3% [dapsone], the amount of dissolved drug did not increase, and the amount of
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`drug delivered remained the same.” Id., 13:24-28. Dr. Osborne then goes on to
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`state that the “excess drug (above 0.3 weight percent) was retained in the stratum
`
`corneum or supracorneum zone.” Id. Morris also confirmed that “higher levels of
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`active agent to the supracorneum zone” build up when “10-fold increases in the
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`amount of pharmaceutical [is] applied to the skin.” AMN1008, [0054]. Thus,
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`increasing the concentration of dapsone will increase the amount of drug reservoir
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`available for sustained delivery.
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`23. Additionally, a POSA would also have understood that increasing the
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`concentration of dapsone would also increase the amount of dissolved dapsone
`
`that can penetrate and become absorbed into the skin. Ahluwalia (EX2008)
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`12
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`disclosed that an increased concentration of dissolved dapsone with the use of
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`additional solubilizers in combination with DGME “increase the rate of skin
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`penetration” of dapsone into and through the skin. EX2008, 8:24-26. And a POSA
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`would know that dapsone needs to penetrate across the barrier of the skin, the
`
`stratum corneum and pass into the lower skin layers in order to exert its anti-acne
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`effect. AMN1009, 3-4. From these disclosures, a POSA would have understood
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`that increasing the concentration of dapsone would lead to a concomitant increase
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`in both dissolved and undissolved dapsone. Thus, a POSA would have known
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`how to optimize the composition to achieve the optimal ratio of dissolved to
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`microparticulate dapsone with an increased concentration of dapsone.
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`24. Next, Dr. Osborne misunderstands my testimony to argue that a
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`POSA would not have increased the concentration of dapsone because dose-
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`ranging studies showed that 5% dapsone was no more efficacious in lesion
`
`reduction than lower doses. EX2057, ¶134. Dr. Osborne missed the point: a POSA
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`would know that the commercialized 5% dapsone formulation disclosed in Garrett
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`had only been approved with twice-daily dosing, so it would have been obvious
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`(and within the skill in the art) to adjust the amount of dapsone in the formulation,
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`and the ratio of dissolved/undissolved dapsone, to arrive at a once-daily
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`formulation as instructed by Garrett. Moreover, according to Dr. Osborne the
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`dose-ranging studies show that the 1% dapsone formulation was better at treating
`
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`13
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`inflammatory lesions than the 5% dapsone formulation, which would contradict
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`Dr. Osborne’s conclusion that the 5% dapsone formulation was optimized to treat
`
`acne. EX2053, ¶134, Table 1, 2, cf. ¶113 (saying that the 5% composition in
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`AMN 1009 was “optimized”).
`
`25. Moreover, even if 1% or 3% dapsone compositions were effective at
`
`treating acne, a POSA would know that ultimately the 5% formulation was
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`submitted for FDA approval and was indeed approved by FDA, and therefore a
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`POSA would not have been dissuaded from using amounts of dapsone greater
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`than 1% or 3%, as Dr. Osborne suggests.
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`26. Finally, Dr. Osborne argues that in view of Garrett and other prior art,
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`a POSA would not have viewed Lathrop’s express preference for 7.5% dapsone as
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`relevant because the prior art reflected an understanding that 5% dapsone was
`
`optimal and Lathrop preferred formulations where the dapsone was dissolved.
`
`EX2057, ¶135. I disagree. First, Dr. Osborne appears to be saying that a POSA
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`would not have taken at face value Lathrop’s explicit statement that 7.5% dapsone
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`was a “preferred” amount. I am not aware of any art before or after Lathrop that
`
`would discourage, dissuade, or discredit a POSA from using this amount of
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`dapsone for any reason, including the presence of side effects. Nor am I aware that
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`Dr. Osborne, as a named co-inventor of the Lathrop reference, has retracted his
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`statement. Notably, I understand Dr. Osborne admitted during his deposition that a
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`14
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`POSA reading Lathrop would have understood 7.5% dapsone to be a preferred
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`embodiment. Second, a POSA would not have viewed Osborne II’s disclosure as
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`inconsistent with Lathrop. Osborne II does not mention a 7.5% dapsone
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`formulation and therefore would not have been viewed by a POSA as somehow
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`trumping Lathrop’s explicit teaching that 7.5% dapsone was a “preferred” amount.
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`And, as explained above, a POSA would not have viewed the 5% dapsone
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`formulation as optimal. A POSA, therefore, would not have somehow viewed
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`Osborne II as discrediting Lathrop’s disclosure, or otherwise dissuading or
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`discouraging use of 7.5% dapsone. Third, Garrett expressly taught that dapsone
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`can be in dissolved form, undissolved form, or a mixture of both. AMN1004,
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`4:29-31. Therefore, a POSA reading Lathrop and Garrett together would have
`
`understood that a 7.5% dapsone concentration was preferred in a formulation
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`where all of the dapsone is dissolved.
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`V. Garrett discloses topical dapsone compositions containing about 30%
`ethoxydiglycol, so the art does not teach away from, or otherwise
`dissuade, a POSA from using ethoxydiglycol amounts above 25%.
`27. Dr. Osborne argues that a POSA would not have used more than 25%
`
`w/w of ethoxydiglycol. EX2057, ¶¶136-151. I disagree. A POSA would not have
`
`been dissuaded from using the amount of ethoxydiglycol recited in the challenged
`
`claims due to (1) a concern of deviating from the allegedly “optimized” amount of
`
`
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`15
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`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`ethoxydiglycol (25%) in ACZONE Gel, 5%, or (2) purported safety concerns with
`
`using amounts greater than 25%.
`
`28. As an initial matter, the challenged claims require only “about 7.5%
`
`w/w dapsone.” As stated above in more detail, a POSA would have been
`
`motivated to increase the concentration of dapsone to 7.5%. A POSA would also
`
`understand that the claimed dapsone is not limited to any particular dissolution
`
`state and can be in any form: dissolved, undissolved, a mixture of the two. In that
`
`context, I disagree with Dr. Osborne’s premise that a POSA would not have
`
`wanted to deviate from 25% w/w ethoxydiglycol because it would upset the
`
`allegedly “optimized” ratio of dissolved-to-undissolved dapsone.
`
`29. Dr. Osborne does not appear to dispute that Garrett’s disclosure of
`
`“about” 10% to 30% ethoxydiglycol would encompass amounts greater than 30%.
`
`AMN1004, 4:2-5. It is undisputed that Garrett’s disclosure overlaps with the
`
`claimed ethoxydiglycol range. Moreover, another prior art Garrett reference
`
`(EX2001) discloses a preferred concentration of glycol ethers, including
`
`ethoxydiglycol, in a range of 20-40% w/w. EX2001, 16:34-17:5.
`
`30.
`
`In any event, Garrett unambiguously taught that one of its preferred
`
`embodiments was a composition containing “about” 30% of ethoxydiglycol and
`
`about 5% to 10% w/w dapsone. AMN1004, 4:2-5. So, a POSA would not have
`
`been dissuaded from using amounts of ethoxydiglycol above 25%, as Dr. Osborne
`
`
`
`16
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`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`claims. Garrett taught a POSA how to optimize the ratio of dissolved-to-
`
`undissolved dapsone
`
`in a
`
`topical composition
`
`that: (1)
`
`the “ratio of
`
`microparticulate to dissolved dapsone is adjustable,” (2) ethoxydiglycol “allows
`
`for an optimized ratio of microparticulate drug to dissolved drug,” and (3) the
`
`amount of ethoxydiglycol in the composition can be modified depending on “the
`
`desired ratio of microparticulate to dissolved dapsone.” AMN1004, 3:26-27,
`
`12:20-13:2, 14:29-31, 18:17-20. Nor would the non-linear solubility curve of
`
`dapsone in ethoxydiglycol have caused any concern. Although it was found to be
`
`non-linear, Osborne informed a POSA what the solubility curve of dapsone in
`
`ethoxydiglycol in water was, as reproduced below:
`
`
`
`17
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`
`
`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`
`
`
`AMN1009, Figure 1.
`
`Although this particular solubility curve was non-linear, as many solubility curves
`
`are, a POSA would not have been confused by the non-linear solubility curve for
`
`dapsone, nor would a POSA have been dissuaded from adjusting the amount of
`
`ethoxydiglycol as Garrett teachings. That is, a POSA would have been able to use
`
`this information in Osborne, along with Garrett, to arrive at a new optimized ratio
`
`of dissolved-to-undissolved dapsone. Regardless, if a POSA was put off by the
`
`non-linear solubility curve she could have converted the graph to logarithmic scale
`
`to generate a straight line.
`
`
`
`18
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`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`In addition, although a POSA could have been able to arrive at a new
`
`31.
`
`optimized ratio of dissolved-to-undissolved dapsone for a 7.5% formulation, a
`
`POSA could have also sought to maintain the same ratio of dissolved-to-
`
`undissolved dapsone that Dr. Osborne claims was “optimized”—one-third
`
`dissolved to two-thirds undissolved. AMN1009, 4. Seeking to keep one-third of
`
`7.5% w/w dapsone dissolved, a POSA would have looked to Osborne’s solubility
`
`curve to see how much ethoxydiglycol was needed to dissolve 2.5% dapsone (i.e.,
`
`1/3 of 7.5%). As shown by the annotated solubility curve below (AMN1009,
`
`Figure 1), an amount of ethoxydiglycol between 30% and 40% would have been
`
`needed to maintain the “optimized” ratio for 7.5% w/w—the same amount of
`
`ethoxydiglycol recited in the challenged claims.
`
`
`
`19
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`
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`
`
`
`AMN1009, Figure 1 (annotated).
`
`32. Additionally, Dr. Osborne is wrong to claim that the range of 10% to
`
`30% DGME in Garrett would not have motivated a POSA to use a DGME range
`
`of 30-40% with a reasonable expectation of success given the substantial
`
`difference in the ranges. EX2057, ¶¶146, 149. In any event, Garrett informs a
`
`POSA to vary the amount of ethoxydiglycol to achieve the desired ratio of
`
`dissolved-to-undissolved dapsone. AMN1004, 18:17-23. Dr. Osborne also argues
`
`that a 25% DGME was preferred when dapsone is used at a concentration of 5%.
`
`EX2057, ¶148. Again, a POSA considering all of Garrett’s teachings in addition
`
`
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`20
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`to the prior art would not be limited to the one “preferred” embodiment disclosed
`
`in Garrett.
`
`33. Dr. Osborne next argues that it would have been difficult for a POSA
`
`to adjust the concentrations of the other components in the formulation (i.e.,
`
`water) if the concentrations of DGME and dapsone were increased. EX2057,
`
`¶147. I disagree. First, I understand Almirall in its Patent Owner Response, but
`
`not Dr. Osborne specifically, argued that it was difficult to adjust the
`
`concentration of water. Second, Garrett informs a POSA that “[t]he relative
`
`percentages for each of the reagents used in the present invention may vary.”
`
`AMN1004, 18:17-20. The dapsone formulations disclosed by Garrett contain
`
`dapsone, a solvent (preferably ethoxydiglycol), a thickening agent, a preservative,
`
`and water. Id., 4. A POSA would read Garrett as confirming the skill set already
`
`possessed by a POSA: that the amounts of each of the components in Garrett’s
`
`dapsone formulations could be routinely adjusted. A POSA would therefore know
`
`that increasing the weight percentages of some components would cause a
`
`decrease in the weight percentages of other components, but this was an everyday
`
`occurrence in formulation development work, which a POSA was well-equipped
`
`to resolve.
`
`34. Third, I disagree that a POSA would have a specific concern with
`
`decreasing the amount of water in the formulation. Garrett discloses wide weight
`
`
`
`21
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`Inter Partes Review of U.S. Patent No. 9,517,219
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1043)
`percentages of water (53.8% to 84.2%), so a POSA knew that a wide variance in
`
`the amount of water in the formulation was possible. Knowing this, a POSA
`
`would not be concerned with decreasing the concentration of water. I understand
`
`Almirall has argued that less water means a higher ratio of DGME to water, which
`
`would decrease the ratio of undissolved to dissolved dapsone in product spread on
`
`the skin. Even if that were the case, a POSA would have understood that
`
`decreasing the amount of water would only increase the amount of dissolved
`
`dapsone that could penetrate the stratum corneum. A POSA would have
`
`understood that an increase in the amount of dissolved dapsone could increase
`
`efficacy. EX2008, 8:16-26. This adjustment in the delivery and behavior of the
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`formulation would have been expected by a POSA
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