Epinephrine – USA

On Nov. 23, 2020, Federal Circuit affirmed district court & held that Hospira’s ANDA infringes composition limitations.

Background of the case:

The plaintiffs (Par) own US 9,119,876 and US 9,295,657, which claim particular compositions containing epinephrine. These patents cover Par’s marketed product, Adrenalin®. Hospira filed ANDA seeking permission to manufacture and market a generic version of Par’s Adrenalin®, 1 mg/mL, product. Par sued Hospira for patent infringement based on ’876 and ’657 patents. District court found in favor of Par & held Hospira’s ANDA infringing certain limitations of asserted claims.

The ’876 and ’657 patents share same specification. Claim 1 of the ’876 patent is representative:

1. A composition comprising:

in the range of about 0.5 to 1.5 mg/mL of epinephrine and/or salts thereof, in the range of about 6 to 8 mg/mL of a tonicity regulating agent, in the range of about 2.8 to 3.8 mg/mL of a pH raising agent, in the range of about 0.1 to 1.1 mg/mL of an antioxidant, in the range of about 0.001 to 0.010 mL/mL of a pH lowering agent, and in the range of about 0.01 to 0.4 mg/mL of a transition metal complexing agent, wherein the antioxidant comprises sodium bisulfite and/or sodium metabisulfite.

Relevant here, the issues related to limitations of tonicity agent, pH lowering agent & transition metal complexing agent.

Federal Circuit analysis:

With respect to “about 6 to 8 mg/mL of a tonicity regulating agent” limitation, Hospira argued that its ANDA contains concentration of 9 mg/mL of sodium chloride & thus not falling into the claim limitation. However, during claim construction parties agreed in the district court that the term “about” had its “plain and ordinary meaning; i.e., approximately.” Hospira did not propose any further narrowing construction.  Federal Circuit said that the evidence supported a finding that “about 8” encompasses 9, considering the purpose of the upper limit. The court credited Dr. Elder’s testimony on this point, which focused on the technological facts, the importance of the purpose of the limitation, and the limitation’s noncriticality. Dr. Elder explained the purpose of both ends of the claim range—to avoid hypertonicity of the solution (which would lead to cell shrinkage) and to avoid hypotonicity of the solution (which would lead to cell swelling) and thereby achieve isotonicity, which is the stated goal of Hospira’s inclusion of sodium chloride. And he explained why it was clear that a “physiologically acceptable” concentration would include concentrations as high as 9 mg/mL, there being nothing critical to the exact numbers in the claimed range given the purposes of the upper and lower limits. Thus, Federal Circuit find no clear error with the district court’s finding on this matter.

With respect to “about 0.01 to 0.4 mg/mL of a transition metal complexing agent” limitation, Hospira argued that district court’s analysis should have focused entirely on the characteristics of the composition that Hospira was likely to sell, not on what compositions the ANDA, if approved, would allow Hospira to market. Federal Circuit disagreed & said that the district court did not commit clear error in finding that citric acid acts as a transition metal complexing agent in Hospira’s ANDA product. Hospira represented to the FDA that its citric acid buffer has a “chelating effect” allowing it to complex with transition metals. Moreover, Hospira’s experts acknowledged at trial that citric acid has “chelating properties” and therefore could bind with elemental impurities in its product.  As it is a Hatch-Waxman suit, statements made in the ANDA to gain approval can be used to find infringement. And if ANDA is silent on those statements then it is the product that the generic company is likely to sell that guides the infringement analysis. But, here, Hospira made these statements & thus it is the ANDA that governs infringement analysis & not the product which would likely to sell.  

With respect to “about 0.001 to 0.010 mL/mL of a pH lowering agent” limitation, Hospira argued that the trial court improperly accepted Par’s counting not just hydrochloric acid but also citric acid as a pH lowering agent. Hospira contends that citric acid—specifically, the citric acid that remains after subtracting the amount that serves as a transition metal complexing agent—cannot be a pH lowering agent because it is already included in the buffer system that counts toward meeting the claim limitation requiring a certain amount of pH raising agent. Federal Circuit however said that Hospira has not made and preserved a claim-construction argument that, an acid, i.e., a pH lowering agent, cannot also be part of an agent that overall serves to raise pH. Indeed, the passages of the specification of the ’876 and ’657 patents that discuss a “buffer system” made up of an acid and a base, at least strongly suggest the opposite. Federal circuit thus rejected Hospira’s argument that citric acid molecules must be allocated between the pH raising agent limitation and the pH lower agent limitation.