Regadenoson – USA

Regadenoson – USA

On May 19, 2022, Delaware Court found non-infringement in favor of Hospira in a Hatch-Waxman litigation.

 

Plaintiffs (Astellas/Gilead) brought infringement action against Defendant (Hospira) who sought approval to market ANDA for Lexiscan® drug product. Lexiscan® is a pharmacological agent used in myocardial perfusion imaging (MPI), a type of nuclear stress test. Plaintiffs asserted infringement of three patents: US 8,106,183; US RE47,301 and US 8,524,883. The asserted patents, in essentially, claim a “monohydrate” or “crystalline monohydrate” form of regadenoson-i.e., “Form A regadenoson. XRPD analysis of Form A regadenoson shows peaks near, among
other points, 5.6, 9.1, 1 I.I, 13.1, 14.4, and 16.8° 2-theta with most intense peak at 5.6. Regadenoson also exist in other various crystalline forms such as Form B, Form C, Form D, Form G, and two different forms that have each been designated by different artisans as Form E.  Form A is the only known monohydrate crystalline form of regadenoson and is the most stable of the known regadenoson crystalline forms. Other forms such as crude, Form F, and Form G which are anhydrous tend to get converted into Form A in the presence of moisture/water.

 

Hospira used Form G in their product which was taken from API supplier, Curia. Form G is manufactured by converting crude form to Form F and then to Form G. Plaintiffs alleged that Curia disclosed in its original DMF “that Curia considered Form A as an impurity/intermediate in its process”. Defendant argued that Curia considered Form A to be a reference standard as opposed to an impurity or intermediate. Hospira and Curia nonetheless had reason to be concerned at the time Hospira filed its ANDA that Form A could result from the exposure of crude and Forms F and G regadenoson to water in Curia’s manufacturing process. As a result of these concerns, Curia amended its DMF in 2021 to “optimize” its manufacturing process to limit the presence of water in the process and to “tighten” its specifications for the identification of Form G by XRPD. Specifically, Curia amended the “specifications” and “stability” sections of its DMF to explicitly require the identification of the final Form G product by an XRPD analysis in which the “[s]ample pattern conforms to the Regadenoson anhydrous Form G reference pattern, designated prominent peaks are present, and no peaks are observed for other solid forms. As a result of these amendments, Curia’s extant DMF specifications “rule out the observation of any other solid forms,” including Form A regadenoson, in Curia’s final product. Curia also amended its batch records in 2021 to require Form F to be stored in an MSC weighing isolator before the Form G stage of the process. The MSC isolator is purged with nitrogen and, as a result, “free of water.” This addition of the MSC isolator provides an added layer of certainty that the Form F regadenoson will be protected from water and airborne humidity, thereby decreasing the likelihood that it will convert to Form A. The 2021 batch records also require more than 20 additional in-process checks throughout the crude, Form F, and Form G stages to ensure that the water specification for the 200-proof ethanol reagent is below the specified level (1000 ppm) at all stages of the process and each time it is used. Curia also tightened the water specification for its solvent methylamine (33% in ethanol), narrowing the upper limit from 1.0% water to 0.2%, but Curia represented that it had “historically met this [lower] limit.”

 

Court found that the addition of the MSC isolator provided an “additional layer of certainty that [the Form F regadenoson] will be protected from water [and] from moisture.” Court said that Plaintiffs never offered at trial documents or testimony to support, confirm, or clarify Dr. Myerson’s “rough calculation” and “quick estimate” of the relative amounts of water and regadenoson in Curia’s manufacturing process. Court, however, found testimony of Dr. Steed more credible that “the trace” and “residual amounts of water” in Curia’s process are “far, far less than [the required] concentration” to convert the crude and anhydrous crystalline forms of regadenoson into Form A and “can’t be enough to induce the crystallization of Form A”. Moreover, Plaintiffs offered no evidence to suggest that Curia’s testing of the May 2021 samples was deficient in any respect, other than to suggest that Form A, even if undetected, might still be present below the limit of detection of the XRPD testing. Therefore, Plaintiffs failed to prove by a preponderance of the evidence that Hospira infringes the asserted claims.

 

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