PTAB

IPR2022-00964

Eyenovia Inc v. Sydnexis Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Low-Concentration Atropine Formulations
  • Brief Description: The ’447 patent discloses ophthalmic compositions for treating myopia. The compositions contain a low concentration of atropine (0.001% to 0.03%) where deuterium oxide (D₂O) is used as a solvent in place of ordinary water (H₂O) to allegedly increase the formulation's stability, particularly at higher pH levels suitable for patient comfort.

3. Grounds for Unpatentability

Ground 1: Claims 1-3, 6-7, and 12-19 are obvious over Chia and Siegel in view of Kondritzer.

  • Prior Art Relied Upon: Chia (a 2012 journal article on low-dose atropine for myopia), Siegel (a 1964 journal article on stabilizing procaine with D₂O), and Kondritzer (a 1957 journal article on atropine stability in aqueous solution).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Chia disclosed all elements of a conventional low-concentration (0.01%) atropine formulation for treating myopia, except for the use of D₂O. Siegel taught that substituting D₂O for H₂O in ophthalmic solutions of procaine—a compound structurally and mechanistically similar to atropine—increased its stability. Kondritzer established that atropine's primary degradation pathway is base-catalyzed ester hydrolysis, the same mechanism affecting procaine, and that its stability is optimal at an acidic pH of 3-5 (pD 3.4-5.4), which overlaps with the claimed pD range of 4.2-7.9.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA), starting with Chia’s clinically effective low-concentration atropine, would have been motivated to improve its long-term stability, particularly at a pH closer to the eye's natural pH of 7.4 to improve patient comfort and compliance. Kondritzer’s teachings on atropine’s pH-dependent instability would have directed a POSA to seek stabilizing solutions. Siegel provided an explicit solution, teaching that D₂O could be valuable for stabilizing ophthalmic solutions subject to hydrolysis, like procaine. Given the known similarities in the degradation mechanism of atropine and procaine, a POSA would combine these teachings to stabilize Chia's atropine formulation.
    • Expectation of Success: A POSA would have had a reasonable expectation of success because the underlying scientific principle—the kinetic solvent isotope effect (SIE)—was well-understood. Siegel demonstrated that D₂O successfully stabilized procaine by slowing its hydrolysis. Since Kondritzer taught that atropine degrades via the same mechanism, a POSA would reasonably expect that substituting D₂O for H₂O in Chia’s formulation would similarly slow atropine’s degradation and increase its stability.

Ground 2: Claims 1-19 are obvious over Chia, Siegel, Kondritzer, and Remington.

  • Prior Art Relied Upon: Chia, Siegel, Kondritzer, and Remington (a 1995 standard pharmaceutical sciences textbook).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground adds Remington to the combination in Ground 1 to render the remaining dependent claims (4-5 and 8-11) obvious. Remington, a seminal text, taught the use of standard, conventional excipients in ophthalmic formulations. Specifically, Petitioner asserted Remington disclosed using osmolarity adjusting agents like sodium chloride (as recited in claims 4 and 5), various buffer agents including phosphates (claims 8 and 9), and pH/pD adjusting agents (claim 10) such as hydrochloric and acetic acids (leading to the deuterated versions in claim 11) in standard atropine solutions.
    • Motivation to Combine: A POSA formulating the low-concentration atropine solution from Chia would have been motivated to include the standard components taught by Remington to ensure the final product was safe, stable, and effective for clinical use. Remington provided well-known, textbook solutions for achieving isotonicity, buffering for stability and comfort, and adjusting pH. This was standard practice in ophthalmic formulation.
    • Expectation of Success: Since the components disclosed in Remington were standard and widely used in aqueous ophthalmic solutions, a POSA would have a high expectation of success in incorporating them into the D₂O-based formulation. The substitution of D₂O for H₂O would not be expected to present any unique formulation challenges or incompatibilities with these common excipients.

4. Key Claim Construction Positions

  • "Extended period of time": Petitioner argued that, based on repeated disclosures in the ’447 patent specification, a POSA would understand this term (recited in claims 2 and 15) to mean "at least about 1 week." This construction is relevant to the obviousness of claims concerning pD stability over time.

5. Key Technical Contentions (Beyond Claim Construction)

  • The Solvent Isotope Effect (SIE) Was Not Unexpected: Petitioner contended that the increased stability of atropine in D₂O, which the Patent Owner presented as an unexpected result during prosecution, was in fact an entirely expected outcome. The petition cited an extensive body of prior art showing that the SIE predictably slows the rate of base-catalyzed hydrolysis for a wide range of carboxylic esters. Therefore, the improved stability observed for atropine was merely a confirmation of a well-known scientific principle, not an inventive discovery.

6. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under §325 would be improper because the asserted prior art is materially different from the art considered by the Examiner during prosecution. The Examiner relied on references like Teva, which taught D₂O for stabilizing benactyzine in injectable nerve agent antidotes, not ophthalmic solutions for myopia. Petitioner asserted its combination, centered on ophthalmic-specific art like Chia and Siegel and fundamental stability art like Kondritzer, was neither cited nor considered by the Examiner and presents a much stronger, more direct case for obviousness.

7. Relief Requested

  • Petitioner requests the institution of an inter partes review and cancellation of claims 1-19 of the ’447 patent as unpatentable under 35 U.S.C. §103.