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: IPR2018-00608
`
`U.S. Patent No. 9,161,926
`_____________________
`
`SECOND DECLARATION OF BOZENA B. MICHNIAK-KOHN, Ph.D.,
`FAAPS, M.R.Pharm.S.
`
`
`AMN1050
`Amneal v. Almirall, LLC
`IPR2016-00608
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`AMNEAL PHARMACEUTICALS LLC and AMNEAL
`PHARMACEUTICALS OF NEW YORK, LLC,
`Petitioners,
`
`v.
`
`ALMIRALL, LLC
`Patent Owner
`
`_____________________
`
`Case: IPR2018-00608
`
`U.S. Patent No. 9,161,926
`_____________________
`
`SECOND DECLARATION OF BOZENA B. MICHNIAK-KOHN, Ph.D.,
`FAAPS, M.R.Pharm.S.
`
`
`AMN1050
`Amneal v. Almirall, LLC
`IPR2016-00608
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`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 1-6 of U.S. Patent No. 9,161,926
`
`(“the ’926 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. Klibanov’s
`
`Declaration (Ex. 2003) as well as certain documents cited in Dr. Klibanov’s
`
`declaration, and the documents cited herein.
`
`III. A construction of “dapsone” is not necessary as Garrett discloses the
`claimed “dapsone” and a POSA would understand the amounts of
`dapsone shown in Garrett would apply to 4-4’diaminodiphenyl sulfone.
`4. Dr. Klibanov argues that the challenged claims are limited to a
`
`specific “dapsone” chemical name: 4,4’-diaminodiphenyl sulfone. Ex. 2003,
`
`¶¶142-43.
`
`
`
`1
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`5. A POSA would have understood from the prior art that dapsone has
`
`the chemical formula C12H12N2O2 and can be referred to as 4,4’-diaminodiphenyl
`
`sulfone or 4,4’-sulfonyldianiline or bis (4-aminophenyl)sulfone. AMN1007,
`
`[0022]; AMN1004, 8:17-22; AMN1010, 1. The fact that the ’926 patent says
`
`“[d]apsone (4,4’-diaminophenyl sulfone)” (AMN1001, 2:6) would simply be
`
`understood by a POSA to refer to dapsone generally, and would not have been
`
`understood to exclude synonymous chemical names for dapsone.
`
`6. Next, Dr. Klibanov argues that (1) Garrett does not disclose the
`
`claimed “dapsone” structure and (2) a POSA would not understand Garrett’s
`
`teaching of using about 5% to 10% w/w dapsone in a topical composition would
`
`apply to the claimed “dapsone.” Ex. 2003, ¶¶79, 82-85, 142, 148. I disagree.
`
`Regardless of whether the claimed “dapsone” was limited to the compound 4-
`
`4’diaminodiphenyl sulfone, Garrett discloses this compound and teaches that the
`
`amount taught in Garrett would apply to this compound.
`
`7.
`
`First, Garrett says that “’dapsone’ refers to the chemical compound
`
`dapsone having
`
`the chemical formula C12H12N2O2S as well as bis(4-
`
`aminophenyl)sulfone, 4’4’-diaminodiphenyl sulfone, and its hydrates … dapsone
`
`analogs, and dapsone related compounds.” AMN1004, 8:18-22 (emphasis added).
`
`From this disclosure a POSA would understand that 4’4’-diaminodiphenyl sulfone
`
`is the claimed compound that Dr. Klibanov seeks to limit the claimed “dapsone”
`
`
`
`2
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`to.1 Moreover, Garrett discloses the chemical structure of dapsone “C12H12N2O2S”
`
`and then identifies several different ways of identifying that structure using
`
`different naming conventions
`
`(“bis(4-aminophenyl)sulfone” versus “4’4’-
`
`diaminodiphenyl sulfone”) but a POSA would understand these chemical names
`
`to be synonyms because they are referring to the same chemical structure. It
`
`appears that Dr. Klibanov agrees. AMN1004, 8:18-27, 10:28-31; Ex. 2003, ¶47.
`
`And the “dapsone analogs” and “dapsone related compounds” in Garrett are
`
`derived from that same basic chemical structure, so if a POSA were considering
`
`“dapsone analogs” or “dapsone related compounds” she would additionally
`
`envisage the 4,4-diaminodiphenyl sulfone structure. AMN1004, 8:22-27.
`
`
`1 The only difference between the “4’4’-diaminodiphenyl sulfone” structure in
`
`Garrett and Almirall’s proposed construction is the first apostrophe which is
`
`bolded for emphasis: 4’4’-diaminodiphenyl sulfone. Dr. Klibanov does not appear
`
`to argue that this difference is meaningful, and a POSA would not consider it so,
`
`because the apostrophe in the chemical name merely conveys that each phenyl ring
`
`contains an amino group at the 4-position. Because both amino groups in the
`
`structure could not be located at the same 4-position, a POSA would be able to
`
`understand the chemical structure regardless of the added apostrophe.
`
`
`
`3
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`Second, a POSA would understand that the amount of dapsone
`
`8.
`
`disclosed by Garrett would apply to the 4,4’-diaminodiphenyl sulfone compound.
`
`Throughout Garrett, it distinguishes between “dapsone” and “dapsone analogs and
`
`related compounds.” Garrett says that ACZONE Gel, 5% is “a topical formulation
`
`of dapsone” and that it is approved by Food and Drug Administration (“FDA”) to
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`treat acne vulgaris. AMN1004, 10:6-9 (emphasis added). Garrett also says that
`
`“dapsone” was first synthesized in 1908. AMN1004, 10:27-28. Conversely,
`
`Garrett later describes “dapsone analogs and related compounds” and discusses
`
`activity and toxicity comparison testing against dapsone. AMN1004, 11:1-12.
`
`From these disclosures, and notwithstanding Garrett’s definition of “dapsone,” a
`
`POSA would have understood that when Garrett simply refers to “dapsone,” it
`
`means the 4,4’-diaminodiphenyl sulfone compound. Accordingly, a POSA would
`
`consider Garrett’s disclosure of compositions containing about 5% to 10% w/w
`
`dapsone to apply to the 4,4’-diaminodiphenyl sulfone structure.
`
`9.
`
`Third, of the compounds encompassed by Garrett’s definition of
`
`“dapsone,” the 4,4’-diaminodiphenyl sulfone compound was the only one
`
`approved by FDA for the treatment of acne, thus Garrett’s disclosure of using
`
`topical compositions containing “about 5% to 10% dapsone,” which encompasses
`
`the FDA-approved amount of 4,4’-diaminodiphenyl sulfone, would have been
`
`understood by a POSA to apply to the 4,4’-diaminodiphenyl sulfone compound.
`
`
`
`4
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`AMN1004, 10:6-12; AMN1010, 1. In any event, Garrett says that “dapsone
`
`analogs and related compounds” have “activity similar to dapsone and would be
`
`expected to have similar treatment efficacy.” AMN1004, 11:10-12. So, a POSA
`
`would also understand that Garrett’s disclosure of using topical compositions
`
`containing “about 5% to 10% dapsone” could apply to dapsone analogs and
`
`related compounds, in addition to the 4,4’-diaminodiphenyl sulfone compound.
`
`10. For the same reasons, I disagree with Dr. Klibanov’s assertion (see
`
`Ex. 2003, ¶¶105, 154) that Lathrop’s disclosure that 7.5% w/w dapsone was a
`
`“preferred” amount would have been ambiguous. Lathrop says that “dapsone is
`
`4,4’-diaminodiphenyl sulfone.” AMN1007, [0022]. Next, Lathrop says that
`
`“dapsone derivatives” “have a similar chemical structure and thus similar
`
`therapeutic potential to Dapsone.” AMN1007, [0023]. Thus, a POSA would have
`
`no problem understanding that Lathrop’s disclosure of 7.5% w/w dapsone as a
`
`preferred amount applied to the 4,4’-diaminodiphenyl sulfone structure.
`
`IV. Garrett does not teach away, or otherwise dissuade, a POSA from
`topical compositions of dapsone.
`11. Dr. Klibanov argues that a POSA had no reason to select dapsone. Ex.
`
`2003, ¶¶142-154. I disagree. Dapsone was known for the treatment of acne via
`
`oral administration, and had been used as an anti-inflammatory and antibiotic.
`
`AMN1004, 10:28-29. Additionally, topical compositions containing dapsone had
`
`been “developed to deliver therapeutic concentrations of dapsone to the skin”
`
`
`
`5
`
`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`which led to FDA approval of topical dapsone compositions for the treatment of
`
`acne vulgaris. AMN1004, 10:6-9; AMN1010, 1, 3. Topical dapsone compositions
`
`were FDA-approved in view of clinical data, submitted to FDA and disclosed on
`
`the ACZONE Gel, 5% label, showing that more acne patients achieved “no” or
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`“minimal” acne when using
`
`topical dapsone compositions
`
`than vehicle
`
`(containing the same excipients but no dapsone). AMN1010, 2-3. Further, the
`
`ACZONE Gel, 5% label shows that dapsone usage resulted in a greater percentage
`
`reduction in acne lesions compared to vehicle. AMN1010, 2-3. Garrett also says
`
`that topical dapsone compositions are used to treat rosacea. AMN1004, 3:13-15.
`
`4:23-24, 18:25-29.
`
`12. Moreover, a POSA would not have been dissuaded from using topical
`
`dapsone compositions in view of the clinical results shown in Garrett Example 1.
`
`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 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 tests were planned for comparisons
`
`
`
`6
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`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`of the efficacy variable.” AMN1004, 29:8-9. And although no statistical tests were
`
`conducted to assess the statistical significance of the differences in efficacy of
`
`ACZONE Gel, 5% and vehicle, Garrett says that its clinical results were
`
`“consistent with the result from the pivotal phase 3 studies.” AMN1004, 29:16-27.
`
`Given that the phase 3 studies were sufficient for FDA to approve ACZONE Gel,
`
`5% for the treatment of acne vulgaris, Garrett’s disclosure of “consistent” clinical
`
`data would be sufficient for a POSA.2
`
`13.
`
`In addition, Dr. Klibanov is wrong to claim that Garrett discloses 5%
`
`dapsone compositions having similar efficacy to vehicle. Ex. 2003, ¶144. Not only
`
`is that conclusion incongruous with ACZONE Gel, 5%’s FDA-approved treatment
`
`indication, the sentence following from the one Almirall cites reads: “However,
`
`
`2 Dr. Klibanov also cites to Ex. 2008 (U.S. Patent No. 4,829,058) and Ex. 2009
`
`(U.S. Patent No. 4,912,112) to say that analogs of dapsone were better targets than
`
`dapsone itself. Ex. 2003, ¶¶86, 145. But Ex. 2008 discloses only in vitro cell
`
`culture results and would not have caused a POSA to ignore the FDA-endorsed in
`
`vivo clinical results obtained for dapsone. Ex. 2008, 9:1-43. Similarly, Ex. 2009
`
`discloses that dapsone in combination with its analogs showed synergistic activity.
`
`EX. 2009, 4:33-52, Example 1. This also would not have caused a POSA to ignore
`
`dapsone in favor of its analogs.
`
`
`
`7
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`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`the absolute reduction in lesion counts was numerically better with Aczone™
`
`treatment for all lesion categories.” AMN1004, 29:20-27. Dr. Klibanov 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. AMN1004, 28:11-29:5.
`
`14. Nor would a POSA have disconsidered Garrett’s teachings in view of
`
`the fact that FDA had determined that administration of ACZONE Gel, 5% did
`
`not require screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency
`
`or blood monitoring. Ex. 2003, ¶144. While it may have been Garrett’s purpose to
`
`arrive at methods of treating G6PD-deficient patients with topical dapsone
`
`compositions “without the adverse hematological effects associated with oral
`
`dapsone administration,” Garrett taught multiple topical dapsone compositions
`
`that achieved this purpose. AMN1004, 3:5-6. 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
`
`
`
`8
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`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`prepare such compositions, and methods of preparing such compositions.
`
`AMN1004, 11:15-18:22. All of this information would have been of interest to a
`
`POSA regardless of whether FDA had determined that no G6PD or blood
`
`monitoring was necessary after administration of ACZONE Gel, 5%.
`
`15.
`
`In sum, a POSA’s consideration of topical dapsone compositions
`
`would not have been the product of hindsight nor would a POSA have been
`
`dissuaded considering such compositions.
`
`A. There is no teaching away from topical compositions containing
`7.5% w/w dapsone.
`
`16.
`
`I understand from Counsel that Patent Owner Almirall argues in its
`
`Patent Owner Response that a POSA would not have used 7.5% w/w dapsone due
`
`to alleged increased risk of hematological side effects. Dr. Klibanov also argues
`
`the same. Ex. 2003, ¶153. I disagree. A POSA would not have been dissuaded
`
`from using a concentration of 7.5% w/w dapsone due to alleged concerns that
`
`such a concentration would increase the risk of hematologic effects that were
`
`associated with oral dapsone.
`
`17.
`
`I understand that Almirall relies on the statement in the ACZONE
`
`Gel, 5% label that “some subjects with G6PD deficiency using ACZONE Gel
`
`developed laboratory changes suggestive of mild hemolysis.” Ex. 2014, 1. This
`
`statement is too general to lead a POSA away from a 7.5% w/w dapsone
`
`composition. This statement from the ACZONE Gel, 5% label (1) does not
`
`
`
`9
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`mention the 7.5% amount, (2) says laboratory changes occurred in only “some,”
`
`but not all, G6PD-deficient patients, (3) says there is no evidence of clinically
`
`relevant hemolysis or anemia in patients treated with ACZONE Gel, 5%, and (4)
`
`says the changes merely “suggest[],” but not demonstrate, “mild hemolysis. ” Ex.
`
`2014, 2 (emphasis added).
`
`18. Regardless, Garrett apparently set out to arrive at methods to treating
`
`dermatological conditions in patients “without the adverse hematologic effects
`
`associated with oral dapsone administration.” AMN1004, 3:4-6. Garrett then
`
`disclosed “a method to treat a dermatological condition in a [G6PD]-deficient
`
`patient by applying a dermatological composition to the condition, wherein the
`
`dermatological composition includes dapsone, wherein the method results in
`
`blood plasma levels of dapsone . . . below the levels associated with hemolysis.”
`
`AMN1004, 4:32-5:3. Still other disclosures show that Garret arrived at methods of
`
`using topical dapsone compositions that “do[] not induce hemolytic anemia” or
`
`“adverse hematologic events.” AMN1004, 6:5-8. Garrett then disclosed that a
`
`preferred embodiment of the invention was a topical pharmaceutical composition
`
`containing “about 5% to 10% dapsone”. AMN1004, 4:2-4. In that context, a
`
`POSA would not have been dissuaded from using 7.5% w/w dapsone due to any
`
`alleged safety or side effect concerns. Indeed, Garrett was not dissuaded from
`
`explicitly claiming as his invention methods of administering 5% to 10% dapsone
`
`
`
`10
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`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`(as well as compositions potentially containing greater amounts) that “do[] not
`
`induce hemolytic anemia” and “do[] not induce adverse hematologic events.”
`
`AMN1004, claims 5, 16-18, and 24-26.
`
`19. Moreover, the clinical data shown in Garrett confirms that there was
`
`no safety or side effect concerns with using 7.5% w/w dapsone. Garrett found that
`
`systemic exposure
`
`to dapsone was approximately 5 ng/ml (mean) and
`
`approximately 37 ng/ml (maximum) which was “low” and “substantially lower
`
`than the levels associated with oral dosing that would be expected to cause
`
`hematological changes.” AMN1004, 39:2-15. Although these plasma levels were
`
`generated for a 5% w/w topical dapsone composition, a POSA would not have
`
`expected using slightly more dapsone (7.5%) in a topical composition to result in
`
`plasma levels significantly above those reported for the 5% composition such that
`
`the plasma levels of the 7.5% composition would be on par with oral
`
`administration.3
`
`
`3 For these same reasons, Dr. Klibanov’s rebuttal to Thiboutot is misguided.
`
`Contrary to Dr. Klibanov’s assertion (Ex. 2003. ¶153 footnote 10) that there is “no
`
`basis” to extrapolate from Thiboutot’s teaching, Thiboutot informs a POSA that
`
`topical administration will result in lower systemic absorption generally compared
`
`to oral administration, and specific to dapsone, that “it was expected that systemic
`
`
`
`
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`11
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`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`Indeed, Garrett conducted pharmacokinetic modeling and reported
`
`20.
`
`that “systemic dapsone levels after topical dapsone gel treatment would still be
`
`approximately 35-fold (Cmax) to 63-fold (AUC) lower than the systemic levels of
`
`dapsone following a single 50 mg oral dose.” AMN1004, 39:2-15. Consistent with
`
`a POSA’s understanding, when ACZONE Gel, 5% and ACZONE Gel, 7.5% were
`
`put into clinical practice, the 5% composition generated an area under the curve
`
`(“AUC”) from zero to 24 hours of 415 ± 224 ng*h/mL, while for that same time
`
`period the 7.5% composition generated an AUC of 282 ± 146 ng*h/mL.
`
`AMN1010, 1; Ex. 2039, 5. That is, the systemic dapsone levels from a 7.5%
`
`composition were similar to—and in fact less than—the systemic dapsone levels
`
`of a 5% composition. And the ACZONE Gel, 7.5% label says that its systemic
`
`dapsone levels were “expected to be about 1% of that from a 100 mg oral dose,”
`
`so the plasma levels of both a 5% composition and a 7.5% dapsone composition
`
`would have expected to be well below the levels generated from oral
`
`administration. Ex. 2039, 5.
`
`absorption would be considerably lower than that observed with oral dapsone
`
`therapy, thereby avoiding any adverse hematological effects.” Thus, Thiboutot
`
`confirms a POSA’s expectation that topical administration will result in lower
`
`systemic absorption, regardless of the amount of dapsone administered.
`
`
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`12
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`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`B. ACZONE Gel 5% could have been optimized to once-daily dosing
`by increasing the amount of dapsone to 7.5% w/w.
`
`21.
`
`I understand that Patent Owner Almirall argues in its Patent Owner
`
`Response that a POSA would not have had a reason to deviate from the 5% w/w
`
`amount of dapsone used in ACZONE Gel, 5%. Similarly, Dr. Klibanov argues
`
`that ACZONE Gel, 5% was optimized so there was no reason to use 7.5% w/w.
`
`Ex. 2003, ¶¶150-153. I disagree. A POSA would not have been dissuaded from
`
`using 7.5% w/w dapsone in a topical composition due to some fear of deviating
`
`from the allegedly “optimized” 5% w/w composition.
`
`22. As an initial matter, a POSA would not have believed that all topical
`
`dapsone compositions had been investigated and optimized into ACZONE Gel,
`
`5%, Almirall and Dr. Klibanov posit. Dr. Klibanov as cited to no evidence that the
`
`developers of ACZONE Gel, 5% actually investigated other amounts of dapsone.4
`
`Before 2012, Osbourne explained that he had adjusted the ratio of dissolved
`
`4 Dr. Klibanov speculates that because Osbourne I (AMN1016) discloses an
`
`amount of dapsone from 0.5% to 10% w/w in a composition, that the makers of
`
`ACZONE Gel, 5% must have investigated all amounts within that range. Dr.
`
`Klibanov’s speculation is undercut in view of the fact that AMN1016 does not
`
`disclose that compositions containing greater than 5% w/w dapsone were prepared
`
`and evaluated.
`
`
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`13
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`
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`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`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 Osbourne “targeted” an amount of dapsone to
`
`remain undissolved and then optimized a formulation to achieve that target. This
`
`does not mean that all dapsone amounts had been investigated and discarded.
`
`Osbourne further reported that “[f]or the 5% dapsone gel” the ratio was one-third
`
`dissolved to two-thirds undissolved. AMN1009, 4 (emphasis added). This again
`
`would not have been understood to mean that all possible dapsone amounts had
`
`been investigated and then discarded in view of a 5% composition. Far from it:
`
`Osbourne simply reported 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 7.5% w/w dapsone composition; indeed, Garrett teaches modifying the
`
`amount of ethoxydiglycol and dapsone depending on “the desired ratio of
`
`microparticulate to dissolved dapsone.” AMN1004, 18:17-20.
`
`23. Next, a POSA would have understood that the 5% dapsone
`
`composition in the prior art could be optimized. Dr. Klibanov appears to speculate
`
`that a POSA would believe the researchers had already optimized dapsone’s
`
`dosing. Ex. 2003, ¶151. But the record belies that speculation as the prior art
`
`
`
`14
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`below and Dr. Warner’s own declaration show that the amount of dapsone could
`
`be increased to achieve optimized dosing. AMN1017, 353, ¶4.
`
`24. As I previously stated at my deposition, a POSA would have known
`
`that the dosing of the 5% w/w composition could have been optimized. Ex. 2053,
`
`139:17-141:3. According to the ACZONE Gel, 5% label, the 5% composition was
`
`administered twice daily. AMN1010, 8-9. Increasing the amount of dapsone in the
`
`composition, and optimizing the ratio of any dissolved-to-undissolved dapsone,
`
`would have been expected to result in once-daily administration. A POSA would
`
`have preferred once-daily dosing because Garrett
`
`teaches
`
`that “dapsone
`
`dermatological compositions [are] typically applied to affected skin once or twice
`
`daily.” AMN1004, 23:8-9. Given
`
`that ACZONE Gel, 5% was already
`
`administered twice-daily, it would have been obvious to optimize the composition
`
`for once-daily dosing.
`
`25. And a POSA would have known how to optimize the composition to
`
`achieve once-daily dosing: Garrett teaches that, in a composition containing 5% to
`
`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
`
`provide “maximum reservoir capacity” and maintains sustained delivery.
`
`AMN1004, 12:20-13:2. Garrett further teaches that some conditions are best
`
`
`
`15
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`treated by pulsed or spiked drug delivery, while a “cosmetic, topical, or
`
`transdermal product that provides steady state active pharmaceutical delivery”
`
`will be best for other conditions. AMN1004, 22:28-23:7.
`
`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%.
`26. Dr. Klibanov argues that a POSA would not have used more than 25%
`
`w/w of ethoxydiglycol. Ex. 2003, ¶¶155-169. I disagree. A POSA would not have
`
`been dissuaded from using the amount of ethoxydiglycol recited in the challenged
`
`claims due to a concern of deviating from the allegedly “optimized” amount of
`
`ethoxydiglycol (25%) in ACZONE Gel, 5%.
`
`27. As an initial matter, the challenged claims require only “about 7.5%
`
`w/w dapsone.” A POSA would 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. Klibanov’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.
`
`28.
`
`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, 4:2-4. So, a POSA would not have
`
`been dissuaded from using amount of ethoxydiglycol above 25%, as Dr. Klibanov
`
`
`
`16
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`claims. Ex. 2003, ¶¶159, 162. As I explained above (§ V.B), 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, Osbourne informed a POSA what the
`
`solubility curve of dapsone in ethoxydiglycol in water was, as reproduced below:
`
`
`
`17
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`
`
`
`AMN1009, Figure 1. Although non-linear (as many solubility curves are), a POSA
`
`would have been able to use this information, 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.
`
`29.
`
`In addition, although a POSA could have been able to arrive at a new
`
`optimized ratio of dissolved-to-undissolved dapsone, a POSA could have also
`
`sought to maintain the same ratio of dissolved-to-undissolved dapsone Dr.
`
`Klibanov claims was “optimized”—one-third dissolved to two-thirds undissolved.
`
`
`
`18
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`AMN1009, 4. Seeking to keep one-third of 7.5% w/w dapsone dissolved, a POSA
`
`would have
`
`looked
`
`to Osbourne’s solubility curve
`
`to see how much
`
`ethoxydiglycol was needed. 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.
`
`30. Additionally, Dr. Klibanov is wrong to claim that Garrett does not
`
`disclose ethoxydiglycol amounts up to 40% w/w. Ex. 2003, ¶167. Dr. Klibanov
`
`does not appear to challenge that Garrett’s teaching of “about” 30% encompasses
`
`
`
`
`
`19
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`amounts between 30% to 40%, which overlap with the claimed range. In any
`
`event, Garrett informs a POSA to vary the amount of ethoxydiglycol to achieve
`
`the desired ratio of dissolved-to-undissolved dapsone. AMN1004, at 18:17-23.
`
`31. Nor would a POSA have been led away from ethoxydiglycol amounts
`
`greater than 25% w/w in view of the FDA’s Inactive Ingredient Database, as Dr.
`
`Klibanov argues. Ex. 2003, ¶162. Although amounts over 25% ethoxydiglycol
`
`had not been used in an FDA-approved product, this simply meant that the FDA
`
`had not yet had the opportunity to review and approve a product containing
`
`greater amounts. Indeed, as Sullivan noted in 2014 concerning the regulatory
`
`status of ethoxydiglycol in 2012, “[i]t is important to note that the approved
`
`maximum potency is not a limit for inactive ingredients, as higher levels may be
`
`approved with justification, but merely lists the amount of such ingredients that
`
`are currently approved for use in drug products.” AMN1053, 3. As of 2012 (or
`
`even today), I am not aware of any prohibition from FDA on using amounts
`
`greater than 25%. In any event, the challenged claims do not require an FDA-
`
`approved (or approvable) product. Thus, a POSA would not have been dissuaded
`
`by whether FDA had approved amounts of ethoxydiglycol greater than 25%.
`
`32.
`
`In addition, I disagree with Dr. Klibanov that a POSA would have
`
`been dissuaded from using amounts of ethoxydiglycol above 25% due to alleged
`
`
`
`20
`
`
`
`Inter Partes Review of U.S. Patent No. 9,161,926
`Second Declaration of Bozena B. Michniak-Kohn, Ph.D., FAAPS,
`M.R.Pharm.S. (Exhibit 1050)
`safety concerns. Ex. 2003, ¶¶161, 163.5 Dr. Klibanov relies on the European
`
`Union’s 2010 Scientific Committee on Consumer Safety’s “Opinion on
`
`Diethylene Glycol Monoethyl Ether” (“Opinion”) (Ex 2020) to support his
`
`testimony, but this Opinion actually undercuts his argument. First, this committee
`
`and this Opinion were concerned with “non-food consumer products (for example:
`
`cosmetic, products and their ingredients, toys, textiles, clothing, personal care and
`
`household products such as detergents, etc.)”—this Committee and this Opinion
`
`were not directed to pharmaceutical compositions that deliver drugs, like the
`
`subject matter of
`
`the challenged claims. The safety of pharmaceutical
`
`compositions that deliver drugs is evaluated by the European Medicines Agency
`
`in Europe and by FDA in the US. That is, the safety of any topical dapsone
`
`composition would not be assessed by the European Union’s Scientific Committee
`
`on Consumer Safety and would not be governed by the Opinion of Ex. 2020.
`
`
`5 Dr. Klibanov argues that using amounts above 25% would also exacerbate the
`
`safety concerns of dapsone itself. Ex. 2003, ¶163. For the reasons above, a POSA
`
`would not have expected the increased amount of dapsone ostensibly ma
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