On Feb. 10, 2023 Delaware Court found enalapril formulation patents infringed but invalid in a Hatch-Waxman litigation.

 

Plaintiff (Azurity Pharmaceuticals) sued defendant (Alkem Laboratories) for infringement of US 10,786,482 and 10,918,621 patents as defendant filed ANDA to market generic version. Azurity asserted claims 16, 18, 22, 23, and 28 of the ’482 patent and claims 4, 7, 17, and 18 of the ’621 patent. Alkem denied infringement and alleges
that the patents in suit are invalid due to obviousness and insufficient written description.

 

Infringement:

Alkem conceded that its ANDA infringes most asserted claim limitations, disputing only two. First, Alkem contended that its ANDA contain “pH adjuster” which is not recited in claims. And second, the “concentration of the buffer” in
Alkem’s ANDA is not within the claimed range. Claim 4 of the ’621 patent is illustrative and it recites about enalapril (0.6 to about 1.2 mg/mL) with other excipients such as buffer (about 5 mM to about 20 mM), preservative (Paraben) and water, wherein the formulation is stable at about 5 ± 3° C. for at least 12 months. The asserted claims of the ’621 patent recite an ingredient list preceded by the phrase “consisting essentially of”. By using this phrase, a patentee signals that the invention necessarily includes the listed ingredients but is open to unlisted ingredients that do not materially affect the basic and novel properties of the invention. Alkem argued that this limitation is not met because its ANDA contains pH adjusters sodium hydroxide and hydrochloric acid that materially affect its pH, which, in turn, impacts stability.

Court said that Azurity’s assertion that the pH adjusters will not be added to every batch misreads the ANDA. The designation q.s. means that Alkem will add as much sodium hydroxide or hydrochloric acid as needed to achieve the target pH. Whether that amount could be zero is a factual question the ANDA does not answer. Because the ANDA does not answer the question of whether the pH adjusters will be added to every batch, Azurity must rely on evidence to show what product would be sold if the ANDA were approved. Azurity offers only speculation that some batches might vary in pH such that no pH adjustment would be necessary. Therefore, Azurity has failed to prove that Alkem would likely market some batches of its product without pH adjusters. Azurity next argued that pH adjusters do not matter for infringement because they do not materially affect the basic and novel properties of Azurity’s claimed invention. Azurity presented no evidence that Alkem’s ANDA would be stable if its pH were not adjusted. But, Court agreed with Azurity’s final alternative argument that adding pH adjusters to the mixture does not avoid the consisting essentially of limitation. This is because the pH adjusters are consumed and are no longer present once the solution is mixed. Alkem’s expert Dr. Rabinow essentially conceded that the reaction occurs and that it results in the pH adjusters being eliminated. Therefore, the fact that sodium hydroxide is an unlisted ingredient does not preclude infringement provided that the mixture ultimately contains only listed ingredients.

With respect to buffer concentration limitation, Court credited Azurity’s expert testimony that the buffer concentration in Alkem’s ANDA can be determined by calculating the amounts of citric acid and sodium citrate and adding those two quantities together. When this calculation is performed for Alkem’s ANDA, the result is within the limitation recited in the claim. Therefore, the asserted buffer concentration limitations are met.

 

Invalidity:

Obviousness –

The parties agreed that all ingredients in the asserted claims, including enalapril itself, were individually known prior to Azurity’s invention, and that it was known that enalapril could be mixed with water to make a liquid dosage form. It was also undisputed that the prior art did not disclose any liquid formulation of enalapril known to be stable for a year or more at refrigerated temperature. The parties disagree as to whether a POSA would have expected, before Azurity’s invention, that enalapril in water could be as stable as the asserted claims require.

Court held that Alkem has proven by clear and convincing evidence that the asserted claims would have been obvious. Court said that POSA would have reasonably expected that enalapril in water could be as stable as the claims require that is, at least 95% stable at refrigerated temperature after 12, 18, or 24 months. Prior art publications disclosed some stability studies but not exactly for 12 to 24 months. Court said that these studies would have given a POSA confidence that long-term stability was possible. There was a motivation to formulate the long-term stable enalapril formulation. It was necessary to make an enalapril liquid with long-term stability due to the requirements of distribution time and the FDA’s requirements regarding shelf-life. Also, the claimed stability would have been obvious because a POSA would have known how to achieve it through “routine application of a well-known problem-solving strategy”. Therefore, Alkem has proven by clear and convincing evidence that a POSA would have been able to make a liquid formulation that was long-term stable.

With respect to pH, Court said that a POSA seeking to develop a liquid formulation of enalapril would review published literature and conclude that the pH at which enalapril was most stable in water was about 3. Moreover, formulator would have “optimized” the formulation to find the right pH that is, tried different values until stability
was achieved. For the reasons stated previously, a POSA would have expected success in optimizing stability through pH adjustment and would have been able to achieve the claimed stability through “ordinary skill and common sense” rather than innovation. Therefore, the claims are invalid for obviousness.

 

Written description –

Court said that the the claims at issue in this case use “functional language” to mark the boundaries of the claimed invention. That is, Azurity does not claim ownership of all enalapril liquids made from water, buffers, sweeteners, and parabens, it only claims the subset of those liquids that are stable. The shared specification of the ’482 and ’621 patents describes enalapril liquid formulations based on their ingredients, pH, stability, and other characteristics. But, although every asserted claim requires that the liquid contain a preservative that is a paraben or mixture of parabens, the patents’ shared specification does not contain a complete example of a liquid that uses only parabens as a preservative. Instead, liquids made using paraben preservatives can only be be constructed by combining ingredients from separate places in the specification. Therefore, while a formulation meeting all claim limitations could theoretically be constructed by picking and choosing different parts of the specification, a POSA is deprived of any meaningful guidance into what [formulations] beyond the examples and formulas, if any, would provide the claimed stability [Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 1164 (Fed. Cir. 2019)]. The specification here does not provide the required guidance regarding which paraben-containing enalapril formulations are stable. Therefore, the asserted claims are invalid for lack of written description.