PTAB

IPR2025-00874

Aquestive Therapeutics Inc v. IOno Pharma LLC

Log In
Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Pharmaceutical Formulation For Sublingual Or Buccal Delivery Of Epinephrine Or A Pro-Drug Thereof
  • Brief Description: The ’437 patent relates to diester epinephrine prodrugs formulated into a rapidly dissolving film for sublingual or buccal administration. The key limitations require the compounds to have a Log P value between 0.5-6.0 and a half-life for conversion to epinephrine of 1-6 minutes.

3. Grounds for Unpatentability

Ground 1: Claims 1-3 are obvious over Truelove 1, Ashraf, and Almoazen Paper.

  • Prior Art Relied Upon: Truelove 1 (Patent 3,809,714), Ashraf (a 2014 journal article), and Almoazen Paper (a 2016 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Truelove 1 disclosed diester epinephrine prodrugs that, after correcting for obvious nomenclature errors, meet the claimed structural and half-life limitations. Specifically, Truelove 1’s Table 3 disclosed three diester epinephrine compounds with half-lives of 3, 4, and 6 minutes, all falling within the claimed 1-6 minute range. Almoazen Paper, authored by the inventor of the ’437 patent, taught the formulation of epinephrine into a fast-dissolving film for buccal administration. Ashraf taught that a Log P value range of 1-5 is satisfactory for mucosal absorption, which encompassed the claimed range of 0.5-6.0.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) seeking to develop a rapid, non-injectable treatment for anaphylaxis would combine these references. A POSA would have looked to Truelove 1 for suitable epinephrine prodrugs with rapid cleavage rates and to the Almoazen Paper for a known, effective buccal film delivery system. Ashraf provided established principles confirming that the Log P values of the Truelove 1 compounds were suitable for the mucosal delivery taught by the Almoazen Paper.
    • Expectation of Success: A POSA would have had a reasonable expectation of success because combining the known prodrugs from Truelove 1 with the known film technology from the Almoazen Paper involved applying known technologies for their intended purposes, with predictable results.

Ground 2: Claims 1-3 are obvious over Truelove 3, Ashraf, and Almoazen Paper.

  • Prior Art Relied Upon: Truelove 3 (Patent 3,868,461), Ashraf (a 2014 journal article), and Almoazen Paper (a 2016 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner asserted that Truelove 3 disclosed diester prodrugs of isoproterenol, a compound structurally very similar to epinephrine. Table 3 of Truelove 3 reported half-life values of 3, 4, and 6 minutes for these isoproterenol prodrugs. Petitioner argued that due to the close structural similarity, a POSA would have expected that creating epinephrine prodrugs with the same ester promoieties taught in Truelove 3 would result in compounds having the same half-life values. The teachings of Ashraf and Almoazen Paper were applied for the same purposes as in Ground 1: establishing the suitability of the Log P range and providing the fast-dissolving film formulation.
    • Motivation to Combine: A POSA would have been motivated to apply the successful prodrug strategy from Truelove 3 to the structurally similar epinephrine molecule to achieve the same goal of rapid hydrolysis. The general motivation to create a non-injectable epinephrine product would drive a POSA to combine this prodrug knowledge with the film delivery system of the Almoazen Paper.
    • Expectation of Success: The expectation of success was based on the well-established principle that structurally similar compounds often exhibit similar properties. A POSA would reasonably expect that attaching the same ester promoieties to the same positions on the epinephrine backbone would yield half-life values nearly identical to those reported for isoproterenol in Truelove 3.

Ground 3: Claims 1-3 are obvious over Truelove 1, Truelove 3, Ashraf, Almoazen Paper, Fuchs, Schobel, and Florence.

  • Prior Art Relied Upon: Truelove 1 (Patent 3,809,714), Truelove 3 (Patent 3,868,461), Ashraf (a 2014 journal article), Almoazen Paper (a 2016 journal article), Fuchs (Patent 4,136,145), Schobel (Patent 11,191,737), and Florence (a 2011 textbook).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground combined the arguments from Grounds 1 and 2 and added further references to reinforce the obviousness of the claimed formulation. Fuchs and Schobel were cited as further evidence of the common knowledge of using rapidly dissolving films for mucosal drug delivery, with Schobel specifically teaching films for epinephrine prodrugs. Florence was cited to provide additional support for the optimal Log P values for buccal absorption, corroborating the teachings of Ashraf.
    • Motivation to Combine: A POSA would have been motivated to survey the entire field of art to develop an improved epinephrine delivery system. This would include investigating known epinephrine prodrugs (Truelove 1), analogous prodrugs (Truelove 3), established formulation technologies (Almoazen, Fuchs, Schobel), and guiding physicochemical principles (Ashraf, Florence). The combination represented the logical synthesis of well-known elements to solve the known problem of needing a fast, non-injectable epinephrine product.
    • Expectation of Success: The addition of Fuchs, Schobel, and Florence strengthened the expectation of success by demonstrating that every element of the claimed invention was not only known but was common in the art, making their combination straightforward and predictable.

4. Key Claim Construction Positions

  • "half-life t1/2": Petitioner argued this term should be construed as "the time for one-half of the epinephrine to be formed from its prodrug in human plasma." This construction was based on the methodology described in the Truelove prior art, which measured the rate of hydrolysis in in vitro human plasma. Petitioner asserted this construction was necessary to align the claims with the data in the primary prior art references and the ’437 patent’s own limited disclosure.

5. Key Technical Contentions (Beyond Claim Construction)

  • Correction of Obvious Errors in Prior Art: A central contention was that a POSA would have immediately recognized and corrected significant nomenclature errors in Truelove 1. Petitioner argued that Truelove 1 incorrectly named its ester compounds as ketone derivatives (e.g., "dibutyryl" instead of "dibutyroxy"). However, based on the patent's title ("Novel Ester..."), its description of synthesis via esterification, and its stated purpose, a POSA would have understood these to be diester compounds, making the reference directly applicable. This correction was foundational to Petitioner’s arguments in Ground 1.