Adamis Pharmaceuticals Corp v. Belcher Pharmaceuticals LLC

1. Case Identification

• Case #: IPR2019-01021
• Patent #: 9,283,197
• Filed: April 26, 2019
• Petitioner(s): Adamis Pharmaceuticals Corporation
• Patent Owner(s): Belcher Pharmaceuticals, LLC
• Challenged Claims: 6-7

2. Patent Overview

• Title: Injectable Liquid Pharmaceutical Formulation of L-Epinephrine
• Brief Description: The ’197 patent describes an injectable liquid pharmaceutical formulation of l-epinephrine intended to have improved stability. The invention centers on maintaining a specific pH range (2.8 to 3.3) to limit the degradation of active l-epinephrine into its less active isomer (d-epinephrine) and other impurities like adrenalone, both at the time of release and over a shelf-life of at least 12 months.

3. Grounds for Unpatentability

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

• Prior Art Relied Upon: Stepensky (a 2004 article in the Journal of Pharmaceutical Sciences).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Stepensky, which studied the long-term stability of commercially available l-epinephrine injections, disclosed every element of claim 6. The study analyzed formulations with an l-epinephrine concentration of 1.03 mg/mL, a pH range of 3.25-3.7 (which overlaps the claimed 2.8-3.3 range), and included sodium chloride as a tonicity agent. Stepensky’s data showed a d-epinephrine content of about 2% at 0.2 years and 3% at 1 year, well below the claimed limits of 6% at release and 12% over 12 months. Although Stepensky did not explicitly mention adrenalone, Petitioner contended that because the tested formulations were made "in accordance with the United States Pharmacopeia" (USP), they would inherently contain less than the 0.5% adrenalone limit required by USP standards.

Ground 2: Obviousness over Stepensky and USP - Claims 6-7 are obvious over Stepensky in view of USP under 35 U.S.C. §103.

• Prior Art Relied Upon: Stepensky (a 2004 journal article) and USP (the 2009 United States Pharmacopeia Monograph for Epinephrine).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground supplemented the anticipation argument. If Stepensky were found not to inherently disclose the adrenalone limits, Petitioner argued that USP explicitly taught them. USP requires epinephrine injections to have an adrenalone content of less than 0.5%. Since Stepensky’s formulations were USP-compliant, a person of ordinary skill in the art (POSITA) would have known to meet this standard. USP also taught a 1 mg/mL concentration for l-epinephrine, as required by dependent claim 7.
  • Motivation to Combine: The motivation was explicit, as Stepensky stated its studied injections were prepared in accordance with USP standards. A POSITA reading Stepensky would naturally consult USP for controlling guidelines on identity, purity (including adrenalone limits), and potency, viewing it as a routine reference for formulating any epinephrine injection.
  • Expectation of Success: A POSITA would have a high expectation of success in ensuring a Stepensky-like formulation met the USP adrenalone limit, as it was a well-established regulatory requirement for such products.

Ground 3: Obviousness over Bruss, USP, and Fyllingen - Claims 6-7 are obvious over Bruss in view of USP and Fyllingen under §103.

• Prior Art Relied Upon: Bruss (Application # 2008/0269347), USP (a 2009 monograph), and Fyllingen (a 1990 article in Acta Pharm. Nord.).

• Core Argument for this Ground:

  • Prior Art Mapping: Bruss taught injectable epinephrine formulations with enhanced stability, disclosing an optimal pH between 3.0 and 4.0 and examples with a pH of 3.3 and a concentration of 1 mg/mL. Fyllingen studied degradation in aged epinephrine injections and taught that raising the pH above 2.4 would reduce racemization (conversion to d-epinephrine). This combination taught the claimed pH, concentration, and tonicity agent. USP, as in Ground 2, supplied the explicit requirement for adrenalone levels below 0.5%. Fyllingen's data, showing less than 10% d-epinephrine after 38 months, suggested the claimed racemization limits would be met.
  • Motivation to Combine: A POSITA starting with Bruss’s teaching of a stable formulation would be motivated to consult Fyllingen to further optimize the pH to balance the competing degradation pathways of oxidation and racemization. Because Bruss also described its formulations as USP-compliant, a POSITA would be motivated to incorporate the USP standards, including the adrenalone limit.
  • Expectation of Success: The combination involved applying known principles (pH optimization) to achieve predictable results (improved stability). A POSITA would reasonably expect that formulating an epinephrine injection according to the teachings of Bruss and Fyllingen, while adhering to the mandatory USP standards, would result in a product meeting all limitations of the challenged claims.

• Additional Grounds: Petitioner asserted additional obviousness challenges, including combinations of Stepensky/Gupta; Gupta/Fyllingen/Zeleznick; Szulczewski/Fyllingen; and Szulczewski/Fyllingen/Gupta, all relying on similar principles of combining teachings on pH optimization, stability, and impurity limits.

4. Key Claim Construction Positions

• Petitioner argued for adopting constructions from a related district court case for several terms. The most critical position concerned the timing of the claimed parameters. Petitioner contended, consistent with the Patent Owner’s infringement contentions, that limitations such as "having a pH between 2.8 and 3.3" and the specified impurity levels refer to the final product "after the compounding step has been completed." This construction was central to applying prior art data, which typically measured the properties of final, stored formulations.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that institution was warranted under 35 U.S.C. §325(d) because the petition relied on numerous prior art references and combinations that were not considered by the examiner during the original prosecution. Key references such as Stepensky, USP, Gupta, Bruss, Fyllingen, and Zeleznick were all new to the proceeding, and their disclosure was not cumulative to the art previously considered.

6. Relief Requested

• Petitioner requests institution of an inter partes review and cancellation of claims 6 and 7 of the ’197 patent as unpatentable.