PTAB

IPR2019-01021

Adamis Pharmaceuticals Corporation v. Belcher Pharmaceuticals, LLC

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1. Case Identification

2. Patent Overview

  • Title: Injectable Liquid Pharmaceutical Formulation of l-epinephrine
  • Brief Description: The ’197 patent is directed to a stable, injectable liquid pharmaceutical formulation of l-epinephrine. The claims recite specific parameters including a pH between 2.8 and 3.3, an l-epinephrine concentration of 1.0 to 1.06 mg/mL, and maximum impurity levels for d-epinephrine and adrenalone at release and over a 12-month shelf-life.

3. Grounds for Unpatentability

Ground 1: Anticipation of Claim 6 - Claim 6 is anticipated by Stepensky under 35 U.S.C. §102.

  • Prior Art Relied Upon: Stepensky (D. Stepensky, Long-Term Stability Study of L-Adrenaline Injections, Journal of Pharmaceutical Sciences, Vol. 93 No. 4 (Apr. 2004)).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Stepensky, which studied commercially available epinephrine injections, discloses every element of claim 6. Stepensky disclosed formulations with a measured pH of 3.25–3.7 (overlapping the claimed 2.8-3.3 range), an l-epinephrine concentration of 1.03 mg/mL (within the claimed 1.0-1.06 mg/mL), and a tonicity agent (sodium chloride). Stepensky reported d-epinephrine levels of ~2% at 0.2 years and ~3% at 1 year, satisfying the claimed limits of "no more than about 6%" at release and "no more than about 12%" over 12 months.
    • Key Aspects: Although Stepensky did not explicitly quantify adrenalone, Petitioner contended the limitation was inherently met. Because the studied formulations were made "in accordance with the United States Pharmacopeia," they would necessarily contain less than the 0.5% adrenalone limit required by the United States Pharmacopeia (USP) monograph. Petitioner argued a characteristic is inherent if it is necessarily present in the thing described in the reference, making express disclosure unnecessary for anticipation.

Ground 2: Obviousness over Stepensky and USP - Claims 6 and 7 are obvious over Stepensky in view of USP.

  • Prior Art Relied Upon: Stepensky (Journal of Pharmaceutical Sciences, Vol. 93 No. 4 (Apr. 2004)) and USP (2009 United States Pharmacopeia Monograph for Epinephrine).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground supplements the anticipation argument by using USP to explicitly supply the adrenalone limitation if Stepensky is found not to disclose it inherently. Stepensky teaches all other limitations, while USP explicitly discloses that epinephrine injections must have a pH between 2.2 and 5.0 and an adrenalone limit of 0.5%. USP also teaches a 1 mg/mL epinephrine concentration, relevant to dependent claim 7.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would be strongly motivated to combine the references because Stepensky expressly stated its test samples were formulated "in accordance with" USP standards. This serves as a directive for a formulator to consult the USP monograph to ensure all mandatory parameters, including purity, are met. Thus, a POSITA analyzing the Stepensky formulation would naturally and necessarily consult USP to confirm required properties like the specific adrenalone limit.
    • Expectation of Success: A POSITA would have a high expectation of success, as the combination merely involves applying a known, mandatory standard (the USP adrenalone limit) to a USP-compliant formulation described in Stepensky to arrive at the claimed invention.

Ground 3: Obviousness over Bruss, USP, and Fyllingen - Claims 6 and 7 are obvious over Bruss in view of USP and Fyllingen.

  • Prior Art Relied Upon: Bruss (Application # 2008/0269347), USP (2009 Monograph), and Fyllingen (G. Fyllingen, Racemisation and oxidation in adrenaline injections, Acta Pharm. Nord. 2(5) (1990)).

  • Core Argument for this Ground:

    • Prior Art Mapping: Bruss disclosed a stable injectable epinephrine formulation with a 1 mg/mL concentration and identified an optimal pH of 3.0 to 4.0 to ensure stability, overlapping the claimed range. USP provided the required adrenalone limit of less than 0.5%. Fyllingen studied long-term degradation, confirmed that racemization to d-epinephrine was a key stability issue, and taught that raising the pH would reduce this racemization, providing data showing less than 10% d-epinephrine after 38 months.
    • Motivation to Combine: Petitioner argued a POSITA would combine these complementary references to achieve an optimally stable formulation. Bruss provided a base formulation and identified pH as the "primary determinant of...stability." Fyllingen provided specific, detailed guidance on how to adjust pH to balance the competing degradation pathways of racemization and oxidation. Since Bruss's stated goal was an "enhanced stability" formulation compliant with USP, a POSITA would logically look to both USP for mandatory impurity standards and a specialized study like Fyllingen for detailed degradation kinetics to achieve that goal.
    • Expectation of Success: A POSITA would expect that applying the teachings of Fyllingen (raising pH to reduce racemization) and USP (adhering to impurity limits) to the Bruss formulation would predictably result in a stable product meeting all limitations of the challenged claims.

  • Additional Grounds: Petitioner asserted additional obviousness challenges, including combinations of Stepensky in view of Gupta (WO 2014/127015); Gupta in view of Fyllingen and Zeleznick (Patent 5,002,973); and Szulczewski (a 1978 analytical profile) in view of Fyllingen and Gupta. These grounds relied on similar rationales of combining teachings on pH optimization, impurity control, and stability to render the claims obvious.

4. Key Claim Construction Positions

  • Petitioner noted that certain claim terms were construed in a related district court litigation and adopted those constructions. The key construction, for "compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine," was "having 1.0 to 1.06 mg/mL l-epinephrine in an aqueous solution after the compounding step has been completed." Petitioner contended this construction is critical because it confirms the claimed parameters apply to the final product, allowing for direct comparison with prior art references that report the characteristics of final, finished drug products.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under §325(d) would be inappropriate because the petition relied on prior art and combinations that were not considered during the original prosecution. It explicitly listed Stepensky, USP, Gupta, Bruss, Fyllingen, Zeleznick, and Szulczewski as references that the Examiner did not have the benefit of reviewing, asserting that their disclosure is not cumulative to the art of record.

6. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 6 and 7 of Patent 9,283,197 as unpatentable.