UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SLAYBACK PHARMA, LLC
`Petitioner,
`v.
`EYE THERAPIES, LLC
`Patent Owner
`
`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
`
`DECLARATION OF PAUL LASKAR, PH.D IN SUPPORT OF
`PETITIONER’S REPLY
`
`
`
`Slayback Exhibit 1048
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SLAYBACK PHARMA, LLC
`Petitioner,
`v.
`EYE THERAPIES, LLC
`Patent Owner
`
`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
`
`DECLARATION OF PAUL LASKAR, PH.D IN SUPPORT OF
`PETITIONER’S REPLY
`
`
`
`Slayback Exhibit 1048
`Slayback v. Eye Therapies - IPR2022-00142
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`B.
`
`INTRODUCTION ........................................................................................ 1
`I.
`II. MATERIALS CONSIDERED .................................................................... 2
`III. ABOUT 0.025% INCLUDES 0.03% .......................................................... 2
`A.
`FDA Acceptance Criteria and the U.S. Pharmacopoeia Are
`Not the Proper References for Interpreting the ’742 Patent ......... 3
`“About 0.025%” Cannot be Distinguished From “About
`0.03%” ................................................................................................. 6
`IV. A POSA WOULD HAVE BEEN MOTIVATED TO
`FORMULATE A BRIMONIDINE EYE DROP AT A pH OF
`ABOUT 5.5 TO 6.5 ....................................................................................... 8
`A.
`Eye Drops Are Comfortable at a Range of pH Values ................... 9
`B.
`There Was No “Progression in the Art” from Alphagan® to
`Alphagan P® ..................................................................................... 15
`The Countervailing Considerations Here Would Have
`Motivated a POSA to Use a pH in the Claimed Range................. 17
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`C.
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`Case No. IPR2022-00142
`U.S. Patent No. 8,293,742
`I, Paul Laskar Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION
`I am the same Paul Laskar, Ph.D., who submitted a declaration dated
`1.
`
`November 4, 2021, in support of Petitioner’s inter partes review of U.S. Patent
`
`8,293,742 (EX-1001, “the ‘742 patent”). I understand that the Board has instituted
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`inter partes review of claims 1–6 of the ’742 patent, and that the Patent Owner has
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`filed a Patent Owner’s Response (“POR”), together with Dr. Noecker’s
`
`Declaration (EX-2020, “the Noecker Declaration”), Dr. Williams’ Declaration
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`(EX-2021, “the Williams Declaration”), and Dr. Davies’ Declaration in support of
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`the POR (EX-2022, “the Davies Declaration”). I submit this reply Declaration in
`
`support of Petitioner’s reply to the POR and to respond to the arguments made by
`
`Dr. Noecker, Dr. Williams, and Dr. Davies.
`
`2.
`
`I am being compensated at my standard rate for my time spent
`
`preparing this declaration, and my compensation is not contingent on the outcome
`
`of any matter or on any of the opinions provided below. I have no financial interest
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`in the outcome of this proceeding.
`
`3.
`
`In my Opening Declaration, I provided a summary of my background,
`
`qualifications and expertise, together with a copy of my curriculum vitae. I also
`
`provided my understanding of the relevant legal principles. My understanding of
`
`these principles has not changed since I wrote my Opening Declaration.
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`1
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`U.S. Patent No. 8,293,742
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`II. MATERIALS CONSIDERED
`In preparing this Reply Declaration, I considered the Board’s
`4.
`
`Institution Decision, the POR, the Williams Declaration (Ex. 2021), the Noecker
`
`Declaration (Ex. 2020), the Davies Declaration (Ex. 2022), the materials cited in
`
`those declarations that are relevant to my opinions, and materials identified in
`
`Exhibit D to this declaration. I also considered my first declaration and the
`
`materials listed in Exhibit C that I considered in preparing my first declaration.
`
`III. ABOUT 0.025% INCLUDES 0.03%
`I have reviewed and considered Dr. Williams’s and Dr. Noecker’s
`5.
`
`opinions that “about 0.025%” does not include 0.03%. For the reasons I explain in
`
`more detail below, the opinions by Dr. Williams and Dr. Noecker do not change
`
`my opinion that a POSA would understand “about 0.025%” to include a
`
`brimonidine concentration of 0.03%.
`
`6.
`
`Dr. Williams opines that 0.025% does not include 0.03% because,
`
`according to Dr. Williams, a POSA would have understood “about” to mean ±
`
`10% due to “typical” FDA acceptance criteria and statements in the U.S.
`
`Pharmacopoeia (“USP”). EX-2021 (Williams Decl.), ¶¶ 39, 44–50. Dr. Williams
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`also disagrees that typical rounding principles should apply to “about 0.025%.”
`
`Id., ¶¶ 39, 46. Dr. Noecker states that a POSA would have understood that 0.025%
`
`and 0.03% do not overlap because they are listed separately in the ’742 patent.
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`EX-2020 (Noecker Decl.),¶ 109. I disagree with the conclusions that Dr. Williams
`
`and Dr. Noecker draw, and I address each of these in turn below.
`
`A. FDA Acceptance Criteria and the U.S. Pharmacopoeia Are Not the
`Proper References for Interpreting the ’742 Patent
`I disagree with Dr. Williams that a POSA would turn to “typical”
`
`7.
`
`FDA acceptance criteria and a definition in the USP to determine the meaning of
`
`“about” in the context of the ’742 patent. EX-2021 (Williams Decl.), ¶ 43. At the
`
`outset, there is no indication in the ’742 patent that the inventors intended to define
`
`the “about” using manufacturing tolerance levels set by United States “regulatory
`
`authorities” such as FDA and USP. The ’742 patent does not direct a POSA to
`
`FDA acceptance criteria or limitations imposed by the USP. Neither document is
`
`cited or otherwise referred to in the specification.
`
`8.
`
`I also disagree with Dr. Williams’ reliance on the manufacturing
`
`tolerances set by U.S. regulatory authorities for the separate reason that the
`
`tolerances set by USP and FDA serve different purposes than the use of “about
`
`0.025%” in the claims of the ’742 patent. Id., ¶¶ 44-45. The claims of the ’742
`
`patent are directed toward “method[s] for reducing eye redness,” without regard to
`
`the many additional factors used by FDA and USP when setting manufacturing
`
`tolerances. EX-1001 (ʼ742 patent), claims 1, 3. For example, FDA does not limit
`
`itself to the efficacy of products when setting acceptance criteria. Rather,
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`acceptance criteria are used to define acceptable test result ranges to meet product
`
`quality and consistency standards during or after manufacturing. See Ex. 2026 (65
`
`Fed. Reg. 83,041 (Dec. 29, 2000)), p.83042 (“Specifications are one part of a total
`
`control strategy for the drug substance and drug product designed to ensure
`
`product quality and consistency.”).
`
`9.
`
`In addition, FDA does not universally require products to have a ±
`
`10% acceptance criteria for any particular test. While I agree that many acceptance
`
`criteria are set at ± 10%, there also are many instances where this is not an
`
`appropriate or necessary restriction. As Dr. Williams points out, the FDA advises
`
`pharmaceutical manufacturers that they must justify each acceptance criteria
`
`proposed, taking into account testing and manufacturing variabilities. EX-2021
`
`(Williams Decl.), ¶ 42; EX-2026 (65 Fed. Reg. 83,041 (Dec. 29, 2000)), p.83042.
`
`As a result, a POSA would understand that even FDA-required acceptance criteria
`
`can and do vary from product to product.
`
`10. For the same reasons, I disagree that a POSA would turn to the
`
`definition of “about” in the U.S. Pharmacopeia. See EX-2025 (USP 32), p.8
`
`(Section 8.20). Notably, the definition from the U.S. Pharmacopeia relied on by
`
`Dr. Williams is used to define the quality attributes of compendial articles, such as
`
`identity, strength, quality and purity. Both the U.S. Pharmacopoeia and the FDA
`
`acceptance criteria are designed to account for variability and experimental error in
`
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`manufacturing, test results, and product stability.
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`11. By contrast, a POSA would understand the term “about” as used in
`
`the claimed formulation as referring to a range of concentrations that are
`
`acceptable in the formulation. The amount of brimonidine included in the claimed
`
`formulation would not need to factor in experimental error or manufacturing
`
`variability. Instead, the range encompassed by the claims in the ’742 patent are
`
`directed toward a range of concentrations that are acceptable in the claimed
`
`brimonidine formulation—i.e., methods of reducing eye redness.
`
`12. U.S. Pharmacopeia standards also reflect a wide variety of acceptance
`
`criteria for ready-to-use ophthalmic solutions. As shown in the 2005 USP, 20
`
`ready-to-use ophthalmic solutions had percent label claim specifications wider than
`
`± 10%, including apraclonidine, dexamethasone phosphate, epinephrine bitartate,
`
`epinephryl borate, gentamicin sulfate, hypromellose, suprofen, and tobramycin.
`
`See EX-1055 (U.S. Pharmacopeia 28-National Formulary 23 (2005)), pp. 175, 744,
`
`897, 990, 1842, 1941-42. Therefore, a POSA would not have assumed there to be
`
`a “typical” FDA or U.S. Pharmacopeia acceptance criteria to apply to any specific
`
`product through the use of the term “about.”
`
`13. For those reasons and given the additional, stricter considerations that
`
`go into setting acceptance criteria by FDA and USP, I do not agree that a POSA
`
`would rely on FDA acceptance criteria or the definition of “about” in the U.S.
`
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`Pharmacopoeia to interpret “about 0.025%” in the ’742 patent, absent an express
`
`indication by the inventors that they intended to impose those strict numerical
`
`ranges to their claims. I agree with Dr. Williams that a POSA would have been
`
`familiar with FDA regulatory requirements and the standards set by the USP.
`
`Those requirements are well known concepts in the pharmaceutical industry and to
`
`POSAs. If anything, a POSA would have expected the inventors to expressly refer
`
`to those strict numerical limitations if they had intended to define “about”
`
`specifically and numerically. Because they did not do so, a POSA would
`
`understand that the inventors did not intend “about” to have precise numerical
`
`ranges.
`
`“About 0.025%” Cannot be Distinguished From “About 0.03%”
`B.
`14. Dr. Noecker states that a POSA would have understood 0.025% and
`
`0.03% to be different based on the inventors’ separate recitation of these numbers
`
`in the ’742 patent. EX-2020 (Noecker Decl.), ¶ 109. I disagree with Dr.
`
`Noecker’s conclusion on its face because a person of ordinary skill in the art would
`
`have understood that the patent repeatedly recited overlapping ranges. See, e.g.,
`
`EX-1001 (ʼ742 patent), 3:61 (disclosing a range between about 0.0001% to about
`
`0.05%), 7:53 (disclosing a range between about 0.001% to about 0.05%), 3:63
`
`(disclosing a range between about 0.001% to about 0.025%), 7:7 (same), 7:17
`
`(same), 7:25 (same), 8:8 (same), 8:15 (same), 8:41-42 (same), 9:23 (same), 9:31
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`(same), 9:39 (same), 9:55 (same), 9:66 (same), 10:6 (same), 10:15 (same), 11:9
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`(same), 16:22 (same), 16:33 (same), 16:40 (same), 3:62-63 (disclosing a range
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`between about 0.01% to about 0.025%), 13:44 (disclosing a range between about
`
`0.001% to about 0.05%), 14:16-18 (same), 11:2 (disclosing a range between about
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`0.005% to about 0.05%), 8:63 (disclosing a range between about 0.01% to about
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`0.03%), 9:16 (disclosing a range between about 0.001% to about 0.035%), 8:62
`
`(disclosing a range of about 0.001% and about 0.07%), 10:62-63 (disclosing a
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`range between about 0.01% and about 0.04% and a range between about 0.01%
`
`and about 0.07%), 12:11-12 (disclosing a range of 0.01% to about 0.04% and a
`
`range from 0.02% to about 0.035%), 12:63-64 (disclosing a range from about
`
`0.015% to about 0.05% and a range from about 0.020% to about 0.025%). There
`
`is nothing in the patent that indicates that the recited ranges were separate and
`
`distinct embodiments of the invention.
`
`15. Additionally, if a POSA relied on the discussion of “about” in the
`
`USP, as Dr. Williams asserts, the POSA would have understood that “about
`
`0.025%” would overlap with “about 0.03%” as recited in the ’742 patent. Using a
`
`± 10% range for about 0.025% corresponds to 0.0225%–0.0275%, and ± 10% of
`
`0.03% corresponds to 0.027%–0.033%. A POSA would have recognized that
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`these ranges overlap, indicating that the ranges identified in the patent are
`
`overlapping and not distinct from one another.
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`16.
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` The prosecution history of the ʼ742 patent also recognizes overlapping
`
`ranges and indicates that “about 0.025%” includes “0.03%.” The ʼ742 patent claims
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`priority to the ’481 provisional application. EX-1001 (ʼ742 patent), p.1 The ’481
`
`provisional application includes Figure 4, which is a prior version of Figure 2 in the
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`ʼ742 patent. Compare EX-1011 (’481 provisional application), p.111 (FIG.4) with
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`EX-1001 (ʼ742 patent), p.4 (FIG.2). Figure 4 discloses that “[t]he net
`
`vasoconstrictive effect curve (vasoconstriction - rebound) is shown by the thicker
`
`light gray curve, and peaks at ~ 0.025% +/- 0.01% (intersecting dashed lines).” EX-
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`1011 (’481 provisional application), p.111 (FIG.4). The range disclosed in Figure 4
`
`is not ±10% of the 0.025% concentration itself, but rather a range from 0.025%-
`
`0.01%, which is 0.015%, to 0.025% +0.01%, which is 0.035%. Id. In summary, the
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`’481 provisional application explains in words what Figure 2 would convey to a
`
`POSA—that the maximum net vasoconstriction benefit occurs in the range of
`
`0.015% to 0.035%. Id. Therefore, a POSA would not have understood the patent to
`
`define “about 0.025%” separately from “about 0.03%.”
`
`IV. A POSA WOULD HAVE BEEN MOTIVATED TO FORMULATE A
`BRIMONIDINE EYE DROP AT A pH OF ABOUT 5.5 TO 6.5
`I also considered Dr. Williams’ opinions that a POSA would not have
`17.
`
`been motivated to formulate at a pH of 5.5 to 6.5, but his opinions do not change
`
`my opinion that a POSA would have been motivated to target a pH in the range of
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`about 5.5 to 6.5.
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`18. Dr. Williams takes the position that a POSA would have targeted a pH
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`that is closest to “physiological pH.” EX-2021 (Williams Decl.),¶ 96. In addition,
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`Dr. Williams states that a POSA would not have been motivated to target a pH of
`
`5.5 to 6.5 because of the “progression in the art” from Alphagan®, which
`
`contained 0.5% or 0.2% brimonidine, to Alphagan P®, which contained 0.15% or
`
`0.1% brimonidine. Id., ¶ 98. I disagree, and I address each of these arguments in
`
`turn.
`
`A. Eye Drops Are Comfortable at a Range of pH Values
`19. To begin, I agree with Dr. Williams’s statement that “a POSA would
`
`have recognized that it is preferable to formulate a topical eye drop at or around the
`
`physiological pH (approximately 7.4).” Id., ¶ 96. But this does not mean that
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`every eye drop must be formulated essentially exactly at pH 7.4 to be comfortable
`
`for the patient. As Dr. Williams admits, a POSA would have been aware of
`
`countervailing considerations that necessitate using a higher or lower pH. Id., ¶ 59.
`
`20. First, a POSA would have understood there is a pH range around 7.4
`
`that has acceptable ocular tolerability. Looking first at studies specifically
`
`examining pH, a POSA would have understood that a range of pH 6 to 8 would
`
`have been tolerable. For example, Conrad et al., published a 1978 study examining
`
`the effect of solutions of pH 1, 4, 7, and 9 on lacrimation. EX-1056 (Conrad et
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`al.), p.152. The study showed that the “eye was more tolerant of acidic than
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`alkaline solutions as evidenced by the substantial increase in lacrimation constant
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`when comparing pH 7 to pH 9.0 and the lesser change that occur[red] when going
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`from pH 7.0 to pH 4.0.” Id. Conrad et. al. concluded that “[t]his relative tolerance
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`of the eye to acidic solutions is in accord with findings for other body tissues.” Id.,
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`pp.152-53.
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`21.
`
`In another example, Gonnering et al’s 1979 study on the pH tolerance
`
`of rabbit and human corneal epithelium showed that “the least amount of swelling
`
`occurs within the range of pH 6.5 to 8.5” in the rabbit experiments, (EX-1057,
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`(Gonnering et al.), p.375), which was further confirmed by the human experiments
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`(Id., pp.381, 385). The results of Gonnering et al.’s study indicated that “no
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`deleterious effects upon the corneal endothelium w[ould] result from exposure to
`
`intraocular solution, vehicles, and drugs if they have a pH from 6.5 to 8.5, with the
`
`necessary ions for maintenance of endothelial function . . . .” (Id., p.385).
`
`22. Additionally, a POSA would have understood that the commercially
`
`available eye drop products ranged in pH, and included products with pH well
`
`below 7.4.1 Alphagan® 0.2% brimonidine was reported to have a pH of 6.3 to 6.5,
`
`
`1 Dr. Williams’ conclusions regarding Pasquali 2013 (EX-1025) are overreaching.
`
`Dr. Williams states that “a contributing factor to the lack of burning and pain upon
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`(Ex-1008 (Alphagan Label® 1998), p.487) or 5.6-6.6 (Ex. 2012 (Alphagan®
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`(0.5%, 0.2%) Label (2001), p.1)). Allergan represented to the FDA that
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`Alphagan® 0.2% was “safe and comfortable.” Ex. 1031 (Ctr. For Drug Evaluation
`
`& Res., NDA 20-613 AlphaganTM), p.13. Naphcon A has a pH around 6, and was
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`FDA approved for over-the-counter (OTC) use. EX-1058 (Naphcon A Insert).
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`The pH ranges of other well-known ophthalmic solutions are included below2:
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`administration of brimonidine may have been the pH of the solution,” (EX-2021
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`(Williams Decl.), ¶72), but Pasquali tested three solutions: brimonidine, which had
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`a pH 7.4 to 8; Naphcon A, which had a pH of 6 (EX-1058 (Naphcon A Insert));
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`and Systane Ultra, which had a pH of 7.9 (EX-1059 (Srinivasan et al.), p.2423).
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`EX-1025 (Pasquali 2013), p.470. Pasquali 2013 concluded that both “dilute
`
`brimonidine or naphazoline/pheniramine [Naphcon A] were markedly more
`
`comfortable” than Systane Ultra. EX-1025 (Pasquali 2013), p.471. Therefore, Dr.
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`Williams is incorrect to conclude that a lower pH would have led to burning and
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`pain upon administration of brimonidine. EX-2021 (Williams Decl.), ¶72.
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`2 Data from this table is based on EX-1055 (U.S. Pharmacopeia 26-National
`
`Formulary 23 (2005)), pp. 175, 201-202, 226-27, 253-54, 341, 363, 376-77, 429,
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`479-80. 551, 557-58, 596, 673, 729, 741, 743-44, 805-806, 845-46, 867-68, 897-
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`98, 948, 976-77, 997-98, 990, 1119, 1258, 1334-35, 1345, 1352, 1357-58, 1334-35,
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`
`pH Specification
`USP Monograph Name
`4.4-7.8
`Apraclonidine Ophthalmic Solution (OS)
`3.5-6.0
`Atropine Sulfate OS
`3.0-6.0
`Benoximate HCl OS
`4.0-8.0
`Betaxolol OS
`5.0-7.0
`Carbachol OS
`6.0-8.0
`Carteolol HCl OS
`4.5-6.0
`Cefazolin Sodium OS
`7.0-7.5; unbuffered: 3.0-6.0
`Chloramphenicol OS
`3.5-5.5
`Ciprofloxacin OS
`4.0-7.0
`Cromolyn Sodium OS
`3.0-5.5
`Cyclopentolate HCl OS
`6.6-7.8
`Dexamethasone Sodium Phosphate OS
`2.5-3.5
`Dipivefrin HCl OS
`5.0-8.0
`Emedastine OS
`2.2-4.5
`Epinephrine OS
`3.0-3.8
`Epinephrine Bitartrate OS
`5.5-7.6
`Epinephryl Borate OS
`4.0-5.0
`Eucatropine HCl OS
`4.3-5.3
`Fluorescein & Benoxinate HCl
`4.0-5.2
`Fluorescein Sodium & Proparacaine HCl OS
`6.0-7.0
`Flurbiprofren Sodium OS
`6.5-7.5
`Gentamicin Sulfate OS
`Gentamicin Sulfate & Betamethasone Acetate OS 5.5-7.0
`Homatropine HBr OS
`2.5-5.0
`Hydroxyamphetamine HBr OS
`4.2-6.0
`Hypromellose OS
`6.0-7.8
`Idoxuridine OS
`4.5-7.0
`Levobunolol HCl OS
`5.5-7.5
`Methylcellulose OS
`6.0-7.8
`Naphazoline HCl OS
`5.5-7.0
`
`
`1400, 1414, 1445, 1542-43, 1556, 1561, 1578-79, 1613, 1646-47, 1757, 1768,
`
`1781-82, 1842, 1883, 1934, 1941-42, 1998, 2057.
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`
`Naphazoline HCl & Pheniramine Maleate OS
`Neomycin Sulfate & Dexamethasone Sodium
`Phosphate OS
`Neomycin Sulfate & Polymyxin B Sulfates OS
`Neomycin Sulfate, Polymyxin B Sulfate, &
`Gramicidin OS
`Norfloxacin OS
`Ofloxacin OS
`Oxymetazoline HCl OS
`Phenylephrine HCl OS
`
`Physostigmine Salicylate OS
`Pilocarpine HCl OS
`Pilocarpine Nitrate OS
`Polymyxin B Sulfate & Trimethoprim OS
`Prednisolone Sodium Phosphate OS
`Proparocaine HCl OS
`Scopolamine HBr OS
`Silver Nitrate OS
`Sodium Chloride OS
`Suprofen OS
`Tetracaine HCl OS
`Tetrahydozoline HCl OS
`Timolol Maleate OS
`Tobramycin OS
`Tropicamide OS
`Zinc sulfate OS
`
`
`
`
`
`5.7-6.3
`6.0-8.0
`
`5.0-7.0
`4.7-6.0
`
`5.0-5.4
`6.0-6.8
`5.8-6.8
`Buffered: 4.0-7.5;
`unbuffered: 3.0-4.5
`2.0-4.0
`3.5-5.5
`4.0-5.5
`4.0-6.2
`6.2-8.2
`3.5-6.0
`4.0-6.0
`4.5-6.0
`6.0-8.0
`6.5-8.0
`3.7-6.0
`5.8-6.5
`6.5-7.5
`5.5-6.5
`4.0-5.8
`5.8-6.2; if with sodium
`citrate: 7.2-7.8
`
`23. The variation in the pH of FDA-approved eye drop formulations
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`demonstrates that a POSA would have been able to make a tolerable ocular
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`formulation in a wide pH range. A POSA would have understood how to adjust
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`various factors to formulate brimonidine at a lower pH, such as using buffers that
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`were known to ophthalmic formulators to optimize patient safety and comfort
`
`without adversely affecting drug stability and efficacy. The 2005 USP
`
`Monograph, for example, shows that various ophthalmic solutions that were used
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`for other conditions, such as chloramphenicol, phenylephrine HCl, and zinc sulfate
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`had different pH levels in buffered and unbuffered solutions. See EX-1055 (U.S.
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`Pharmacopeia 26-National Formulary 23 (2005), pp. 429, 1543, 2057.
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`Alphagan®, with 0.5% or 0.2% brimonidine, also contained a known citrate
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`buffer—citric acid and sodium citrate—to maintain Alphagan® at its pH level of
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`6.3-6.5 or 5.6-6.6. See EX-1008 ((Alphagan® Label 1996), p.487); Ex. 2012
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`(Alphagan® (0.5%, 0.2%) Label (2001)), pp.1, 6.
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`24. A POSA would have further understood that buffers were extensively
`
`used ophthalmic formulations to prevent discomfort, to allow concentrations of
`
`other ophthalmic ingredients to be delivered at different pH ranges, and ensure
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`acceptable stability of active drug(s). Remington’s Pharmaceutical Sciences
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`(RPS), 19th edition (1995), a widely used publication for POSAs including those
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`specializing in ophthalmic formulations, discusses how buffers mediate the
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`interplay between tolerability, functionality, and stability in ophthalmic drugs.
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`RPS notes that the type of buffer, buffer capacity, pH, and tonicity must be
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`collectively considered. See EX-1064 (Remington (1995)), pp.1570-71. The
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`buffer system needs to be considered together with pH, tonicity and comfort in
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`mind. See id., p.1571.
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`25. Additionally, after an eye drop formulation is administered to a
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`patient’s eye, it is highly desirable that the patient’s tears equilibrate back to tear
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`pH quickly. See id. A buffer in the formulation can act to slow this equilibration,
`
`with buffers having high buffer capacity maintaining a non-physiological pH for a
`
`longer time, and conversely unbuffered or buffers with low buffer capacity
`
`enabling tear pH to equilibrate to baseline pH quickly. See id. A POSA would
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`have understood if, when, and how to use a wide range of buffering systems to
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`balance the targeted pH with patient comfort. See id.
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`B.
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`There Was No “Progression in the Art” from Alphagan® to
`Alphagan P®
`26. Dr. Williams suggests that a POSA would have been motivated to use
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`a higher pH because Alphagan® was discontinued in favor of Alphagan® P. EX-
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`2021 (Williams Decl.), ¶98. I disagree. Alphagan® 0.2% brimonidine, with a pH
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`of 6.3 to 6.5, (Ex-1008 (Alphagan Label® 1998), p.487), was FDA approved, and I
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`am not aware of any reports (other than in connection with this proceeding) that
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`suggest the pH of Alphagan® to have been problematic. In fact, I understand
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`Allergan did tolerability studies in development of Alphagan® 0.2% brimonidine,
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`and reported to the FDA that the formulation was safe and comfortable for
`
`patients. EX-1031 (Ctr. For Drug Evaluation & Res., NDA 20-613 AlphaganTM),
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`pp.13-14.
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`27. Dr. Williams refers to the earlier Alphagan® products containing
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`0.5% or 0.2% brimonidine with a pH between 5.6 and 6.6 being discontinued in
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`favor of Alphagan® P products (EX-2021 (Williams Decl.), ¶ 98). The earlier
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`Alphagan® 0.5% and 0.2% products were discontinued for commercial reasons or
`
`reasons having to do with life cycle management; they were not discontinued for
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`reasons of safety or efficacy. See EX-1060, p.1 (Drugs@FDA website).3
`
`28.
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`Indeed, a POSA would have understood that the pH change in the
`
`Alphagan P® products was due to the change in preservative. Alphagan®
`
`products, with 0.5% or 0.2% brimonidine, contain the preservative, BAK, whereas
`
`Alphagan® P products contain the preservative, Purite. EX-2014 (Alphagan® P
`
`(0.1%, 0.15%), p.1 The increased pH of the Alphagan® P products, as compared
`
`to the Alphagan® products, was most likely motivated by the stability of Purite,
`
`not by any property of brimonidine. Purite (or sodium chlorite) requires a higher
`
`pH because it less stable in acidic solutions. See EX-1061 (Aieta et al.), p.787
`
`(stating that in “acid[ic] solutions, chlorous acid rapidly disproportionates to from
`
`
`3 EX-1060 is an accurate copy of the information I accessed at Drugs@FDA. Drug
`
`information, such as those that are available on Drugs@FDA, is the type of
`
`information on which I routinely rely in my work as an eye drop formulator.
`
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`ClO2, chlorate ion, and chloride ion”); EX-1063 (NDA-21-770), p.2 . Thus, a
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`POSA would have understood that the higher pH of the Alphagan® P products was
`
`based on the need to ensure the stability of Purite. Absent a choice to use Purite in
`
`the formulation, the pH of Alphagan P® would not have persuaded a POSA to use a
`
`higher pH in a brimonidine formulation.
`
`C. The Countervailing Considerations Here Would Have Motivated
`a POSA to Use a pH in the Claimed Range
`29. As Dr. Williams recognized, there are often “countervailing
`
`consideration[s],” (EX-2021,¶¶ 95-96), that would direct a POSA to a pH higher or
`
`lower than “physiological pH,” which is approximately 7.4. Here, I understand
`
`from Dr. Sher that POSA would have understood that ocular redness occurs at the
`
`surface of the eye. Therefore, a POSA would have sought to keep brimonidine at
`
`the surface and avoid or delay penetration of the drug into the deeper layers of the
`
`eye. As I explained in my Opening Declaration, a lower pH would reduce the rate
`
`of diffusion of brimonidine into the sclera and cornea of the eye and would keep
`
`the drug near its desired site of action for longer. See EX-1003 (Laskar Op.
`
`Decl.),¶ 99. The pKa of brimonidine is 7.78. EX-1033 (ʼ873 patent), 13:59. That
`
`means that at pH below 7.78, brimonidine will be more protonated, making it
`
`ionized. The further below pH 7.78, the more brimonidine will be ionized. For
`
`example, at pH 6.5, approximately 95% of the brimonidine would be ionized,
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`while at pH 7.4, approximately 73% would be ionized. EX-1101 (Remington
`
`(2000)), pp.241-42. This can be illustrated using the well-known Henderson-
`
`Hasselbalch equation:
`
`conjugate acid�
`pH=pKa+ log�conjugate base
`
`Id. Using Henderson-Hasselbalch, an estimate of the percent ionization can be
`
`made. Id. This equation can be rearranged as presented below to provide an
`
`estimate of percent ionization (as any POSA would well know & understand). Id.
`
`(% Ionization)=(100)[
`
`1
`
`1+ 10(pH-pKa) ]
`
`See id.
`
`30. Because ocular permeability is reduced when brimonidine is ionized,
`
`less of the drug will be in its unionized form which is the form that migrates more
`
`readily across the ocular membrane and therefore remain near the superficial
`
`vasculature. EX-1033 (ʼ873 patent), 8:11-19. Therefore, a POSA would have
`
`been motivated to formulate a redness reducing brimonidine eye drop at a pH that
`
`retained more brimonidine near the parts of the eye that impact eye redness, e.g., in
`
`the pH range of 6.5 or below.
`
`31. A POSA would have recognized that there would have been no
`
`barriers to formulating brimonidine at this lower pH. As explained above, eye
`
`drop formulations were known to be well tolerated in the range of pH 6-8. A
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`POSA would have recognized that the solubility of brimonidine is not impacted by
`
`this pH range, as demonstrated by the Alphagan® products which included
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`brimonidine at much higher concentrations. Additionally, as Dr. Williams
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`admitted, Alphagan®, with 0.2% brimonidine, is shelf stable at 15°–25° C,
`
`confirming to a POSA that brimonidine has no stability issues at this pH. See EX-
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`2012, p.7; EX-1054 (Williams Dep.), 39:12-15. Therefore, a POSA would have
`
`had no reservations or difficulties formulating a brimonidine eye drop at a pH
`
`around 6.5.
`
`32. Dr. Williams’s statements about the alleged difficulties and
`
`complexities of formulating an eye drop do not reflect the knowledge of a POSA.
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`While it is true that any general formulator will “consider numerous factors” when
`
`developing a product (EX-2021 (Williams Decl.), ¶ 95), whether a solid dosage
`
`form or liquid formulation, the POSA here is a pharmaceutical formulator with a
`
`doctorate in pharmaceutics or a related degree and at least three to five years of
`
`experience developing eye drops for clinical trial and regulatory approval. See
`
`EX-1003 (Laskar Decl.), ¶ 29. An eye drop formulator would understand the
`
`interaction of factors such as “tolerability, solubility, stability, and permeability” as
`
`they relate to formulations for ophthalmic administration and would have the skills
`
`and experience to routinely address and account for these factors. See EX-2021
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`(Williams Decl.), ¶ 95.
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`Case No. IPR2022-00142
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`I declare that all statements made herein of my knowledge are true, that all
`
`statements made herein on information and belief are believed to be true, and
`
`that these statements were made with the knowledge that willful false statements
`
`and the like so made are punishable by fine or imprisonment, or both, under
`
`Section 1001 of Title 18 of the United States Code.
`
`Dated: December 16, 2022
`
`Respectfully submitted,
`
`Paul Laskar, Ph.D.
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`
`EXHIBIT D
`
`List of Materials Considered
`
`Exhibit
`1001
`
`1002
`1003
`1008
`
`1033
`
`Description
`U.S. Patent No. 8,293,742 (filed July 27, 2009) (issued Oct. 23, 2012)
`(’742 Patent)
`Expert Declaration of Neal A. Sher, M.D. (Sher)
`Expert Declaration of Paul A. Laskar, Ph.D. (Laskar)
`“ALPHAGAN® (brimonidine tartrate ophthalmic solution) 0.2%.”
`Physicians’ Desk Reference, 52th ed., Medical Economics Company,
`Inc., 1998, p. 487 (Alphagan® Label 1998)
`U.S. Patent No. 6,562,873 (filed July 10, 2001) (issued May 13, 2003)
`(’873 patent)
`Declaration of Paul Laskar, Ph.D In Support of Petitioner’s Reply
`Declaration of Neal A. Sher, M.D. in Support of Petitioner’s Reply
`(Sher Reply)
`Deposition Transcript of Robert O. Williams, III, Ph.D., dated
`November 15, 2022
`U.S. Pharmacopeia 28-National Formulary 23, 2005
`Conrad, J.M., Reay, W.A., Polcyn, R.E., and Robinson, J.R., Influence
`of Tonicity and pH on Lacrimation and Ocular Drug Availability,
`Journal of the Parenteral Drug Association, vol. 32, no. 4, pp. 149-161,
`July-August 1978 (Conrad 1978)
`1057 Gonnering, R., Edelhauser, H.F., Van Horn, D.L., and Durant, W., The
`pH Tolerance of Rabbit and Human Corneal Endothelium,
`
`1048
`1049
`
`1054
`
`1055
`1056
`
`
`
`
`
`-21-
`
`
`
`1058
`1059
`
`1060
`
`1061
`
`1063
`
`1064
`
`Investigative Ophthalmology & Visual Science, vol. 18, no. 4, pp.
`373-390, April 1979 (Gonnering 1979)
`Naphcon A, Alcon Laboratories, Inc.
`Srinivasan, S. and Venkiteshwar, M., A Decade of Effective Dry Eye
`Disease Management with Systane Ultra (Polyethylene
`Glycol/Propylene Glycol with Hydroxypropyl Guar) Lubricant Eye
`Drops, Clinical Ophthalmology, vol. 15, pp. 2421-2435, June 9, 2021
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