UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`EYENOVIA, INC.,
`Petitioner,
`
`v.
`
`SYDNEXIS, INC.,
`Patent Owner.
`
`Case No. IPR2022-00384, U.S. Patent No. 10,842,787
`Case No. IPR2022-00414, U.S. Patent No. 10,940,145
`Case No. IPR2022-00415, U.S. Patent No. 10,888,557
`
`DECLARATION OF PAUL A. LASKAR, PH.D.
`
`SYDNEXIS - EXHIBIT 2001
`Eyenovia, Inc. v. Sydnexis, Inc.
`IPR2022-00384, IPR2022-00414, & IPR2022-00415
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`EYENOVIA, INC.,
`Petitioner,
`
`v.
`
`SYDNEXIS, INC.,
`Patent Owner.
`
`Case No. IPR2022-00384, U.S. Patent No. 10,842,787
`Case No. IPR2022-00414, U.S. Patent No. 10,940,145
`Case No. IPR2022-00415, U.S. Patent No. 10,888,557
`
`DECLARATION OF PAUL A. LASKAR, PH.D.
`
`SYDNEXIS - EXHIBIT 2001
`Eyenovia, Inc. v. Sydnexis, Inc.
`IPR2022-00384, IPR2022-00414, & IPR2022-00415
`
`
`
`TABLE OF CONTENTS
`INTRODUCTION AND QUALIFICATIONS .................................................. 1
`I.
`II. STATE OF THE ART OF OPHTHALMIC AQUEOUS SOLUTIONS
`OF ATROPINE SULFATE ................................................................................ 6
`III. CONCLUSIONS ...............................................................................................18
`
`-i-
`
`
`
`I, Dr. Paul A. Laskar, declare as follows:
`
`I.
`1.
`
`INTRODUCTION AND QUALIFICATIONS
`I am over the age of eighteen (18) and otherwise competent to make
`
`this Declaration.
`
`2.
`
`I have been retained on behalf of Patent Owner Sydnexis, Inc.
`
`(“Sydnexis”) for the above-captioned inter partes reviews (IPRs). I am being
`
`compensated for my time in connection with these IPRs at my standard consulting
`
`rate, which is $300.00 per hour for consulting; $375.00 per hour for deposition and
`
`testimony, including preparation; and $150.00 per hour for non-working travel
`
`time. My compensation does not depend in any way on the outcome of the IPRs. I
`
`have been asked to describe briefly the state of the art before April 23, 2015, for
`
`formulating ophthalmic aqueous solutions of active ingredients that are weak
`
`bases, specifically atropine sulfate. I have been asked what that state of the art
`
`would have indicated to a person of ordinary skill in the art regarding solution pH
`
`during storage and regarding the use of a buffering agent in that solution. I also
`
`have been asked to evaluate whether the disclosure of EX1004 is consistent with
`
`the state of the art.
`
`3.
`
`I am an expert in the field of formulations and drug delivery,
`
`specifically pharmaceutical formulations for ophthalmic administration, including
`
`topical aqueous liquid preparations, and I have been an expert in this field since
`
`-1-
`
`
`
`well before 2015, which I understand is the priority date of the patent. Throughout
`
`the remainder of this Declaration, I will refer to the field of ophthalmic
`
`formulations, and specifically pharmaceutical formulations for ophthalmic
`
`preparations, as the relevant field or the relevant art. In formulating my opinions, I
`
`have relied upon my training, knowledge, and experience in the relevant art. A
`
`copy of my current curriculum vitae is attached to this declaration as EX2002, and
`
`it provides a comprehensive description of my academic and employment history.
`
`4.
`
`I had a Ph.D. in Pharmaceutical Sciences (which is sometimes called
`
`pharmaceutics) and several years of experience preparing and testing pharmaceutical
`
`formulations by 2015. I was familiar with common inactive ingredients (excipients)
`
`used in aqueous pharmaceutical formulations and the basic characteristics of
`
`aqueous formulations, including stability, before 2015. I also had knowledge about
`
`drug degradation kinetics. I understand that this is how the Petitioner in this matter
`
`has defined the level of skill of the person of ordinary skill in the art (“POSA” or
`
`“skilled artisan”). I satisfy this definition. Moreover, as an expert in the field of
`
`Pharmaceutical Sciences for ophthalmic solutions before 2015, I am qualified to
`
`provide an opinion as to what a POSA would have understood, known, or concluded
`
`as of 2015. Indeed, since 1965, I have accumulated significant training and
`
`experience
`
`in
`
`the
`
`field of pharmaceutical
`
`formulations
`
`for ophthalmic
`
`administration.
`
`-2-
`
`
`
`5.
`
`I have a Ph.D. in Pharmaceutical Sciences from Oregon State
`
`University with a Minor in Biostatistics; an M.B.A. in General Management,
`
`International Management and Marketing from the University of California at
`
`Irvine; a M.S. in Pharmacy and a B.S. in Pharmacy from the University of Illinois;
`
`and a B.A. in General Science (Chemistry, Biology) from the University of
`
`Rochester.
`
`6.
`
`I am currently, and have been since October 2006, the President of
`
`Paul Laskar Associates, Inc., a pharmaceutical development consulting firm that I
`
`founded. My client base consists of start-up and established pharmaceutical
`
`companies with whom I consult in the areas of pharmaceutical development,
`
`including formulation, development, and evaluation. A significant fraction of my
`
`work on my clients’ behalf focuses on ophthalmic products and preparations. From
`
`2003 to 2006, I was Senior Director, Pharmaceutical Development at Dey LP, at
`
`that time owned by Merck KGaA. In that capacity, I supervised the formulation
`
`development, clinical supply, technology transfer, pilot operations, and preclinical
`
`functions. While most of Dey’s projects were for inhalation, I worked on two
`
`generic ophthalmic projects.
`
`7.
`
`From 1994 to 2003, I was initially Director, then Vice President,
`
`Pharmaceutical Development, and subsequently Principal Director, Pharmaceutics
`
`and Technology, at Santen Inc., the U.S. subsidiary of the Japanese ophthalmic
`
`-3-
`
`
`
`pharmaceutical company, Santen Ltd. My responsibilities included directing
`
`ophthalmic formulation development, stability assessment, technology transfer,
`
`preparation of internal reports and regulatory documents, and review of in-license
`
`candidates. The areas I supervised included: formulation development, analytical
`
`chemistry and stability assessment, clinical supplies, and non-clinical development.
`
`During my tenure with Santen Inc., three ophthalmic projects, Quixin, Betimol,
`
`and Alamast, resulted in successful New Drug Applications (“NDAs”) by the Food
`
`and Drug Administration (“FDA”) and commercial launch. A fourth NDA, Iquix,
`
`and a prostaglandin compound, taflutan (now marketed in the U.S. as Zioptan®),
`
`to which I contributed to its formulation as well as chemistry, manufacturing and
`
`control (“CMC”) development strategy, were approved subsequent to my leaving
`
`Santen.
`
`8.
`
`From 1993 to 1994, I was Director, Pharmaceutical Development, at
`
`CoCensys, Inc., a start-up pharmaceutical company. During this time, I directed
`
`CMC development of two new chemical entities (“NCE”), one for oral use as a
`
`suspension and solid drug product, and the second as a parenteral. The oral NCE was
`
`successfully formulated as a suspension and submitted as an investigational new
`
`drug (“IND”) application to the FDA.
`
`9.
`
`From 1982 to 1993, I was employed by Allergan, Inc., an ophthalmic
`
`specialty company. Initially, I was a Scientist, Product Development, then I became
`
`-4-
`
`
`
`a Section Manager and eventually Manager in the same area, and, finally, Director,
`
`Product Development. While at Allergan, I was involved in the formulation and
`
`subsequent development of a number of ophthalmic and dermatological drug
`
`products, many of which were approved as NDAs by the FDA and their equivalents
`
`in other countries/jurisdictions. From 1973 to 1982, I was Assistant Professor of
`
`Pharmacy at the College of Pharmacy, University of Illinois Medical Center (now
`
`University of Illinois-Chicago Campuses) and then Associate Professor of Pharmacy
`
`at the School of Pharmacy at Creighton University. During this time, among the
`
`courses I taught were those in dosage form development including oral solids,
`
`ophthalmics, and dermatologicals.
`
`10. At present, I provide consulting services to start-up and established
`
`pharmaceutical companies for pharmaceutical projects. The nature of the projects
`
`include ophthalmics, sterile parenterals, dermatologicals, and liquid and solid oral
`
`drug products. The areas in which I consult include active pharmaceutical
`
`ingredient (API) manufacture and qualification, formulation development, stability
`
`assessment, analytical development, manufacturing process development and
`
`transfer, contract laboratory and drug product manufacturer identification and their
`
`management, and preparation of regulatory documents.
`
`11.
`
`Prior to being engaged on behalf of Sydnexis regarding these IPRs, I
`
`have not previously worked with Sydnexis in any capacity.
`
`-5-
`
`
`
`II.
`
`STATE OF THE ART OF OPHTHALMIC AQUEOUS SOLUTIONS
`OF ATROPINE SULFATE
`12.
`I have been asked to explain briefly the state of the art before April
`
`23, 2015, for formulating ophthalmic aqueous solutions of active ingredients that
`
`are weak bases, specifically atropine sulfate. The United States Pharmacopeia had
`
`long required atropine sulfate ophthalmic solution to be packaged for storage at a
`
`solution pH no greater than 6.0 and no less than 3.5. EX1018, 179. As I explain in
`
`detail below, it would have been highly counterintuitive in 2015 to employ a buffer
`
`or a buffering agent for an ophthalmic aqueous solution of atropine or atropine
`
`sulfate, especially for low-concentration atropine, because it was believed that
`
`buffering the solution at the pH of 3.5-6.0 would needlessly impair patient comfort
`
`as well as compromise atropine efficacy. Avoidance of such a buffer was
`
`understood to permit the pH of the solution to rise rapidly from the acidic pH of
`
`storage (where atropine was considered to be stable) towards physiological pH of
`
`tears (where atropine was more comfortable for the patient and more effectively
`
`absorbed) immediately upon instillation to the eye. In view of the state of the art,
`
`POSAs thus avoided using any buffer or buffering agent for ophthalmic aqueous
`
`atropine sulfate solution.
`
`13.
`
`This state of the art is reflected in EX1019, which contains excerpts
`
`from Volume II of Remington: The Science and Practice of Pharmacy, Nineteenth
`
`Edition (Remington). Remington, which pharmaceutical scientists colloquially call
`
`-6-
`
`
`
`the formulator’s “bible,” reflects conventional wisdom regarding the formulation
`
`of ophthalmic aqueous solutions of active ingredients that are weak bases (such as
`
`atropine sulfate), as discussed below.
`
`14. Remington states (at EX1019, 52), and I agree, that:
`
`A number of requirements must be considered in the preparation
`of ophthalmic solutions, suspensions or ointments. These include
`sterility, clarity, buffer, buffer capacity and pH, tonicity, viscosity,
`stability, comfort, additives, particle size, packaging and preservatives.
`Many of these requirements are interrelated and must be considered
`collectively in the preparation of an ophthalmic product.
`15.
`In other words, formulating an ophthalmic product is a complicated
`
`question that involves a large number of interacting and often competing variables.
`
`It may be unpredictable how these variables will interact with one another.
`
`Accordingly, when a working formulation for a given active has been used
`
`successfully for many years, a POSA would be reluctant to adopt contrary
`
`formulation practices without a very good reason.
`
`16. Remington identifies an aqueous ophthalmic vehicle that it says is
`
`suitable for salts of atropine (listed among three others). EX1019, 52 (left column).
`
`Among other ingredients, this conventional vehicle includes ophthalmic
`
`preservatives (Disodium Edetate and Benzalkonium Chloride) that serve as
`
`antimicrobial agents. These preservatives are used in the aqueous ophthalmic
`
`-7-
`
`
`
`solution in small quantities. In this solution, they are not buffering agents and
`
`provide no buffer, but are solely antimicrobial preservatives.
`
`17. Remington’s conventional aqueous ophthalmic vehicle for atropine
`
`also includes specific amounts of NaH2PO4 and Na2HPO4. Remington calls them
`
`Sodium Acid Phosphate anhydrous and Disodium Phosphate anhydrous, but these
`
`phosphate salts also are synonymously called dibasic sodium phosphate and
`
`monobasic sodium phosphate, or disodium hydrogen phosphate and sodium
`
`dihydrogen phosphate. In every case, the cation used with the phosphate could be
`
`sodium or potassium. These conventional phosphate salts were, and continue to be,
`
`used regularly for a solution pH very near to physiological pH, based on the middle
`
`pKa value for phosphoric acid. EX1040, 135 & Table 8. A conventional buffer
`
`system made using these salts is called phosphate buffered saline, which is
`
`commonly used for physiological applications. But it is not a buffer or a buffering
`
`agent for an ophthalmic solution having a pH of 3.5-6.0.
`
`18.
`
`These conventional phosphate salts may be used in aqueous
`
`ophthalmic solutions and other applications where attaining physiological pH is
`
`desirable. A pharmaceutical scientist could formulate these components to make a
`
`buffer for a solution having a solution pH close to the relevant pKa, 7.2. As a
`
`general description, a buffer or buffering agent may be formulated using a weak
`
`acid or a weak base together with the conjugate salt of the weak acid or weak base,
`
`-8-
`
`
`
`respectively. EX1038, 2-3, 6. In contrast, a strong acid or base such as
`
`hydrochloric acid or sodium hydroxide is used to adjust solution pH but is not a
`
`buffering agent. EX1039, 39-41, 43-44. A weak acid or base may be used as a pH
`
`adjustor when the solution pH is not close to its pKa. For example, Remington uses
`
`boric acid (pKa 9.15) as a pH adjustor. Like the conventional phosphate salts used
`
`in Remington, boric acid’s pKa is too high for it to be a buffer or buffering agent at
`
`a solution pH of 3.5-6.0. EX1018, 179 (USP solution pH limits for atropine sulfate
`
`ophthalmic solution). Adjusting solution pH by adding acid or alkali is distinct
`
`from using a buffer or buffering agent to provide a target pH.
`
`19.
`
`In the context of topical administration, a buffered ophthalmic
`
`solution, by definition, resists reestablishment of native tear pH for an appreciable
`
`period of time upon instillation to the eye. A primary rule of formulating a buffer is
`
`to select a weak acid whose pKa is as close to the target pH of the buffered
`
`solution as possible. Thus, a formulator would use approximately equal molar
`
`amounts of the weak acid and the conjugate base to maintain the solution pH near
`
`the pKa of the buffering agents. See, e.g., EX1038 (Pfannkoch), 3. As Pfannkoch
`
`states, “Simply having a weak acid and the salt of its conjugate base present in a
`
`solution doesn’t ensure that the buffer will act as a buffer.” Id. Pfannkoch asks the
`
`question, “When Is a Buffer Not a Buffer?” It answers the question: “Buffers are
`
`most effective within ± 1 pH unit of their pKa. Outside of that range the
`
`-9-
`
`
`
`concentration of either the acid or its salt is so low as to provide little or no
`
`capacity for pH control.” Id. Adding phosphate salts (such as those in Remington,
`
`discussed above) to a solution thus does not make a buffer (or make the salts
`
`buffering agents) when the solution pH is outside the buffering range for the salts.
`
`In other words, the conventional phosphate salts employed in Remington are not a
`
`buffer or a buffering agent in the ophthalmic aqueous solution of atropine or
`
`atropine sulfate having a pH of 3.5-6.0 because this solution pH is outside of the
`
`buffering range for these salts.
`
`20.
`
`Even within the buffering range, bare disclosure of the salts at issue
`
`together with a solution pH does not mean that the salts buffer at that solution pH.
`
`Pfannkoch explains that “a properly chosen buffer will have a 50:50 ratio of acid to
`
`base at the target pH[.]” EX1038, at 4. Pfannkoch explains that even large changes
`
`(e.g., 20%) in the ratio of acid to conjugate base result in only small changes (e.g.,
`
`0.1 pH unit) in the solution pH. Id. In Remington, for example, the atropine
`
`ophthalmic vehicle uses somewhat more than twice as much monobasic phosphate
`
`as dibasic phosphate on a molar basis, but this alters the pH only by about 0.3 pH
`
`units. Accordingly, extremely large and counterintuitive variations from standard
`
`buffer protocols are required to make a given salt buffer near the limits of its
`
`buffering range.
`
`-10-
`
`
`
`21. A standard practice for ophthalmic solutions was to use conventional
`
`phosphate salts because they did not provide a buffer or buffering agent at a
`
`solution pH of 3.5-6.0. This was true where the active ingredient of the ophthalmic
`
`solution was atropine, as reflected in Remington. Using such a formulation was
`
`understood to be important to patient comfort. Remington explains that the
`
`“Solution pH must be selected for optimum drug stability,” but that the solution pH
`
`of optimum stability of weak bases such as atropine was “generally lower” than the
`
`pH of tear fluid (about 7.4) where patient comfort is optimal. EX1019, 52.
`
`Remington thus teaches that the solution pH for weak bases such as atropine is a
`
`different concept from whether the solution should be buffered at that pH. Id.
`
`(distinguishing “Solution pH,” which must be selected for optimum drug stability,
`
`from “buffer, buffer capacity and pH”).
`
`22. While Remington reports that most active ingredients that are weak
`
`bases have an optimum stability “as low as 4.0-5.0,” atropine’s pH of maximum
`
`stability was reported to be even lower. Kondritzer & Zvirblis, for example,
`
`reported that “[t]he pH of minimum hydrolysis [of atropine] has been calculated
`
`and found to vary with temperature from pH 4.11 at 0° to pH 3.24 at 100°C.”
`
`EX1005, 531 & Abstract. Lund (EX1007) performed another study of atropine
`
`stability ten years later and extended the solution pH of greatest stability
`
`downward to a lower pH of 2. Lund evaluated atropine stability “in the pH range
`
`-11-
`
`
`
`of 1-6” because this pH range was where “the alkaloids would be in their
`
`protonated form.” EX1007, 3087. Lund calculated half-life values in Table 6 at pH
`
`2.0, 3.0, and 4.0. Lund reports that the pH range in Table 6 (i.e., 2.0-4.0) is “where
`
`atropine has its maximum stability.” Id., 3096. Lund thus expanded the solution pH
`
`of maximum stability of atropine from the range of 3-4 reported by Kondritzer &
`
`Zvirblis to include a solution pH of 2-4.
`
`23. Remington did not leave the skilled artisan without guidance for how
`
`to store atropine with “optimum stability” consistent with its teaching to ensure
`
`patient comfort immediately upon instillation. The conventional solution provided
`
`by Remington in view of the state of the art for atropine (stored at solution pH of
`
`3.5-6.0 per USP monograph for Atropine Sulfate Ophthalmic Solution) was to use
`
`a solution with phosphate salts as excipients instead of any buffer or buffering
`
`agent. Remington distinguishes solution pH from the pH provided by the buffering
`
`agent, stating: “The proper pH [i.e., solution pH], buffer, and buffer capacity often
`
`represent a compromise between stability of the drug and comfort in the eye[.]”
`
`EX1019, 52. Remington counsels the skilled artisan to “minimize” buffer capacity
`
`at the solution pH of storage “to the point where tear fluid can overcome capacity
`
`and readjust to pH [of] 7.4 immediately after instillation in the eye.” EX1019, 52;
`
`see also id., 54; EX1045, 16.
`
`-12-
`
`
`
`24. Remington expressly cautions (at EX1019, 54) against using any
`
`buffer or buffering agent to resist adjustment of the eye drops from the acidic
`
`solution pH of storage toward the tear fluid pH of 7.4 immediately upon instillation
`
`to the eye:
`
`It generally is accepted that a low (acid) pH per se necessarily
`will not cause stinging or discomfort on instillation. If the overall pH
`of the tears, after instillation, reverts rapidly to pH 7.4, discomfort is
`minimal. On the other hand, if the buffer capacity is sufficient to resist
`adjustment by tear fluid and the overall eye pH remains acid for an
`appreciable period of time, then stinging and discomfort may result.
`
`Using a buffer or buffering agent for a solution pH of 3.5-6.0 would not only be
`
`undesirable because it would be uncomfortable for the patient, but also because
`
`excessive tearing resulting from use of a buffer would accelerate clearance of the
`
`drug from the ocular surface, thereby diminishing the drug’s therapeutic effect.
`
`EX1045, 8 (“excess tearing may occur that may influence bioavailability in affected
`
`individuals”); EX1035, 2 (“[T]ears are mainly responsible for the short residence
`
`time and low absorption of drugs applied topically to the eye.”); EX1047, 2 (“Poor
`
`bioavailability of drugs from ocular dosage forms is mainly due to the precorneal
`
`loss factors which include solution drainage, lacrimation, tear dynamics, tear
`
`dilution, tear turnover….”), 3 & Fig. 3.
`
`-13-
`
`
`
`25. Under Remington’s instruction “to allow the overall pH of the tear
`
`fluid to be disrupted only momentarily” (EX1019, 54), a buffer or buffering agent
`
`would be used for an acidic ophthalmic solution formulation only if strictly
`
`necessary to maintain the solution pH for stability purposes during storage.
`
`Remington’s ophthalmic formulation for atropine (as well as other actives) does
`
`not use any buffer or buffering agent for a solution pH between 3.5 and 6.0.
`
`Instead, Remington relies on the existing stability profile of atropine at acidic
`
`solution pH without employing a buffer or buffering agent for that acidic solution.
`
`As atropine’s primary degradant was known to be tropic acid (EX1007, 3085),
`
`which has a pKa of 3.53, atropine was not expected to require any buffering agent
`
`at the solution pH of storage (no higher than 6.0 and no lower than 3.5, per
`
`Atropine Sulfate Ophthalmic Solution USP monograph (USP monograph)
`
`requirements). In my opinion, it would have been highly counterintuitive in 2015
`
`to employ a buffer or a buffering agent at a pH of 3.5-6.0 in an atropine aqueous
`
`ophthalmic solution in view of Remington’s teachings and what was known in the
`
`state of the art regarding atropine stability and the necessity of rapid pH adjustment
`
`toward physiological pH immediately upon instillation into the eye. To the
`
`contrary, POSAs avoided using any buffer or buffering agent for ophthalmic
`
`atropine aqueous solutions satisfying the parameters required by the USP
`
`monograph (pH 3.5-6.0).
`
`-14-
`
`
`
`26.
`
`In addition to teaching avoidance of any buffer or buffering agent for
`
`atropine ophthalmic aqueous solution as a prerequisite for patient comfort,
`
`Remington also taught that this practice was important for efficacy for another
`
`reason. The efficacy of any ophthalmic solution was understood to be dependent
`
`on the ability of the active ingredient to enter the targeted tissue (e.g., ocular
`
`tissue). Remington thus identified absorption of the active pharmaceutical
`
`ingredient into the ocular tissue as a critical factor in ophthalmic solution
`
`formulation. For example, Remington teaches (at EX1019, 48):
`
`Drugs administered by instillation must penetrate the eye and do so
`primarily through the cornea. Corneal absorption is much more
`effective than scleral or conjunctival absorption where removal by
`blood vessels into the general circulation occurs.
`
`Many ophthalmic drugs are weak bases and are applied to the eye as
`aqueous solutions of their salts. The free base and the salt will be in an
`equilibrium which will depend on the pH and on the individual
`characteristics of the drug molecule. To aid in maintaining storage
`stability and solubility, the medication may be acidic at the moment of
`instillation but, usually, the neutralizing action of the lacrimal fluid will
`convert it rapidly to the physiological pH range (approximately pH 7.4)
`at which there will be enough free base present to begin penetration of
`the corneal epithelium.
`27. Consistent with Remington’s teachings, avoiding a buffer or buffering
`
`agent in the acidic solution pH of storage so that the eye drops would rapidly adjust
`
`-15-
`
`
`
`towards physiological pH immediately upon instillation into the eye also was
`
`understood to be important so that atropine could be absorbed into the ocular
`
`tissue. See, e.g., EX1045, 8 (“Once neutralized by the tears, the fraction of free
`
`base may increase, and this may be the form of the drug most readily absorbed by
`
`the corneal epithelium.”); EX1034, 167 (rapid adjustment to tear fluid pH
`
`“increase[s] absorption and improve[s] the therapeutic effect of the ophthalmic
`
`solution”). Efficacy based on absorption into the ocular tissue thus provided an
`
`additional reason that it would have been highly counterintuitive in 2015 to employ
`
`a buffer or buffering agent for a solution pH of 3.5-6.0.
`
`28.
`
`I have reviewed EX1004, a document discussing Atropine Sulfate
`
`Ophthalmic Solution, USP 1%, to determine whether its disclosure is consistent
`
`with the direction provided in Remington and the state of the art in 2015 regarding
`
`atropine aqueous ophthalmic solutions. Everything I have read in EX1004 is
`
`consistent with the state of the art before 2015, which was to avoid using a buffer
`
`or buffering agent in the acidic solution of storage within the boundaries (pH 3.5-
`
`6.0) set by the USP monograph. EX1004 lists only one active ingredient: Atropine
`
`sulfate 1%. EX1004, 3. In addition to water, EX1004 lists seven other inactive
`
`ingredients. A POSA would understand that these inactive ingredients are not
`
`buffers or buffering agents in this solution. As discussed above, benzalkonium
`
`chloride and edetate disodium are antimicrobial preservatives. EX1004 also lists
`
`-16-
`
`
`
`dibasic sodium phosphate, hypromellose, and monobasic sodium phosphate as
`
`inactive ingredients. Neither hypromellose nor the phosphate salt inactive
`
`ingredients listed in EX1004 are buffers or buffering agents in this solution, which
`
`was mandated to have a pH between 3.5 and 6.0. Consistent with Remington’s
`
`teaching, EX1004 does not disclose any buffer or buffering agent for this solution.
`
`Instead, EX1004 discloses that “hydrochloric acid and/or sodium hydroxide may
`
`be added to adjust pH (3.5 to 6.0).” In other words, EX1004 discloses using
`
`hydrochloric acid and sodium hydroxide, which are not buffering agents (whether
`
`understood generally or in this particular context), to adjust solution pH in a
`
`manner that does not violate the USP monograph restrictions against having a
`
`solution pH greater than 6.0 or lower than 3.5.
`
`29.
`
`EX1004 does not disclose to a POSA that the solution comprises a
`
`buffer or buffering agent for the disclosed ophthalmic solution. EX1004 certainly
`
`does not disclose a buffer or buffering agent to provide a pH of 3.5-6.0, or
`
`anything similar. EX1004 does not even disclose exactly what the solution pH is,
`
`but merely the limits above and below which the USP monograph prohibits the
`
`solution pH from breaching. Indeed, it would be highly unlikely for any formulator
`
`to select a solution pH close to the boundaries (e.g., pH 6.0) imposed by the USP
`
`monograph. Accordingly, a POSA would not understand EX1004 to disclose that
`
`the pH of the atropine solution was as high as 6.0 or even close to 6.0.
`
`-17-
`
`
`
`30.
`
`I reserve the right to supplement my opinions as expressed in this
`
`Declaration to address any new information obtained in the course of this
`
`proceeding, or based on any new positions taken by Petitioner.
`
`III. CONCLUSIONS
`31.
`In signing this declaration, I recognize that the declaration will be
`
`filed as evidence in a contested case before the Patent Trial and Appeal Board of
`
`the United States Patent and Trademark Office.
`
`32.
`
`I declare that all statements made herein of my own knowledge are
`
`true and that all statements made on information and belief are believed to be true,
`
`and further 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 or Title 18 of the United States Code.
`
`Executed April 15, 2022 at Napa, California.
`
`/ Paul A. Laskar /
`Paul A. Laskar, Ph.D.
`
`-18-
`
`
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