The U.S. Court of Appeals for the Federal Circuit reversed-in-part and affirmed-in-part a district court finding of non-obviousness in a Hatch-Waxman litigation involving an improved brimonidine formulation for reducing intraocular pressure associated with glaucoma.   Allergan Inc. v. Exela PharmSci Inc. and Apotex Inc., Case Nos. 10-1102, -1103 (Fed. Cir., May 19, 2011) (Bryson, J.) (Dyk, J., concurring-in-part, dissenting-in-part).

In 2001, Allergan introduced Alphagan® P brimonidine solution intended to address an allergic response in some patients to Allergan’s Alphagan® brimonidine solution.  Alphagan® P solution contains a lower concentration of brimonidine, higher pH and a solubility-enhancing component.  Despite concern of possible oxidation of brimonidine, the Alphagan® P solution also contained stabilized chlorine dioxide (SCD) instead of benzalkonium chloride, a known eye irritant.  After Exela and Apotex each submitted an Abbreviated New Drug Application (ANDA) for to the U.S. Food and Drug Administration (FDA) for marketing approval of a generic version of Alphagan® P brimonidine solution, Allergan alleged infringement of its patent directed to a buffered, aqueous ophthalmic solution and four related patents each directed to brimonidine-containing products.   Following a bench trial, the district court found all of the asserted patents to be non-obvious.  Apotex then stipulated to infringement and the district court entered an injunction.  The defendants appealed.

On appeal, Apotex challenged the district court findings of non-obviousness.   Apotex’s invalidity argument relied on to prior art patents, Stockel and Ratcliff.  Apotex argued that Stockel explicitly discloses the modifications that Allergan argues impart patentability (i.e., use of SCD as a preservative in an ophthalmic solution and that the desirability of an isotonic solution).  Allergan argued that Stockel teaches away from the use of SCD as the only preservative because it would irritate the eye and recommends a combination of preservative agents.  The Federal Circuit concluded that Stockel’s teaching regarding the quantity of SCD does not undercut the strength of the teaching that physiologic pH and osmolality by use of buffer and tonicity components would have been simple and well-known modifications.

Apotex also argued that Ratcliff discloses an SCD solution and that the modifications that led to the claimed invention would have been obvious to a person of ordinary skill in the art.   Allergan argued that Ratcliff requires activation of the disclosed SCD.  The Federal Circuit disagreed with Allergan, noting that the claims in issue are directed to an SCD solution irrespective of its activation. The Court also stated that it would have been obvious to a person of ordinary skill in the art to create an ophthalmic solution that was adjusted to ocular pH and tonicity and that relied upon SCD as to sole preservative.

As to the four other related patents, Apotex argued that every asserted claim reads on a combination Refresh Tears® product and Alphagan® brimonidine solution, both owned by Allergan, and that such a combination would have been obvious to a person of ordinary skill in the art and faulted the district court for considering each asserted reference in isolation.  The Federal Circuit, giving deference to the district court’s weighing of testimony, concluded that the district court did not err in its factual determinations because the combination of Allergan’s products would not have been an “anticipated success” and that a person of ordinary skill in the art would not have been expected to disregard the solvability and oxidation roadblocks caused by the prior art.

The Federal Circuit also reversed the district court’s holding that Exela’s product would infringe an Allergan patent. The Court distinguished the facts here from its holding as to when it is appropriate for a court to consider material outside the four corners of the ANDA to determine if an ANDA describes an infringing product.  Here, neither Allergan nor Exela dispute that if Exela complies with its ANDA, Exela will never manufacture or sell a product at a pH falling within the asserted claims.  Thus, the Court stated that it cannot assume that Exela will not act in full in compliance with its representations to the FDA.

Judge Dyk, in dissent, cited KSR and concluded that for the four related patents the “obvious to try” standard was met because a person of ordinary skill in the art would have been motivated to try a combination of Allergan’s products to arrive at the claimed formulation.  Judge Dyk engaged in a deep factual review of the record and concluded that the district court made erroneous fact findings that led it to determine that solubility and oxidation concerns would have deterred a person of ordinary skill from trying the combination of Allergan’s products.