Dronedarone - USA

On Oct. 23, 2017, Court of Delaware issued a trial opinion in Multaq® case & found asserted patent valid & infringed by ANDA filers.

Plaintiffs Sanofi brought this consolidated patent infringement case against Defendants Watson Laboratories, Inc. and Sandoz Inc. This opinion addressed allegations of infringement and invalidity with respect to U.S. Patent No. 9,107,900. Sanofi-Aventis U.S. LLC is the holder of approved New Drug Application No. 022425 for dronedarone tablets, 400 mg, which are prescribed under the trademark Multaq®. The '900 patent, entitled "Use of Dronedarone for the Preparation of a Medicament for Use in the Prevention of Cardiovascular Hospitalization or Mortality” & is expiring on Apr 16, 2029.

Infringement: Plaintiff asserted claims 1, 6-9, and 14 of the '900 patent against Defendants. Plaintiff argued that Defendants' product labels will induce infringement of the asserted claims under 35 U.S.C. § 271(b). Defendants argued that they do not induce infringement of claims 1, 7, 9, and 14. Those four claims are directed to patients with coronary heart disease and who meet the Age Criteria. With respect to the label generally, Plaintiffs' expert, Dr. Kim, acknowledged that there is no express reference to a patient who has coronary heart disease and is over 70 years of age. The Indications and Usage section of Defendants' labels indicates administering dronedarone tablets for reducing "the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation." This section does not expressly indicate the drug for patients with coronary heart disease. However, the Clinical Studies section (ATHENA study) of Defendants' labels supports the conclusion that the labels teach that dronedarone could be used for some patients with coronary heart disease. But the words "coronary heart disease" do not expressly appear anywhere in said section (14.1).

Section 14.2 discusses the EURIDIS and ADONIS study. This study followed 1,237 patients treated with either dronedarone 400 mg twice daily or placebo. Section 14.2 states, "The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%)." This language suggests that coronary heart disease is a subset of structural heart disease. Overall, in the context of Defendants' labels, a POSA would understand "structural heart disease" to include “coronary heart disease” and that a person with coronary heart disease would be described as having structural heart disease.

Court held that there is encouragement to prescribe dronedarone to some patients within the Age Criteria. Defendants' labels suggest that dronedarone could be used in patients in the Age Criteria. The ATHENA patients ranged from 23-97 years old, where 42% were 75 years old or older. Dr. Zusman (Defendants' expert) conceded that assuming the label discloses use in coronary heart disease patients, a physician "might have inferred" that dronedarone would provide a benefit in terms of reduction in cardiovascular hospitalization and death in patients consistent with the overall ATHENA population." Dr. Zusman estimates that based on his experience, approximately 80% of dronedarone patients do not have both coronary heart disease and meet the Age Criteria.

In sum, while the Indications and Usage section does not expressly instruct the administration of dronedarone to patients with coronary heart disease who meet the Age Criteria, it directs a POSA to review, and a POSA would review, the Clinical Studies section. From the Clinical Studies section, it would be readily apparent to a POSA that the use of dronedarone for patients with coronary heart disease and who meet the Age Criteria would reduce the risk of cardiovascular hospitalization. The labels encourage a POSA to prescribe dronedarone to some patients within the Age Criteria. Therefore Plaintiffs have met their burden of showing that Defendants' labels would induce infringement of claims 1, 7, 9, and 14 of the '900 patent.

Defendants further argued that they do not induce infringement of claims 6 and 8, which is directed to patients with New York Heart Association Class III congestive heart failure. Defendants' labels contain a Black Box warning on the first page that discourages physicians from using dronedarone in patients with "decompensated heart failure." Dr. Zusman believes that the warning applies "very definitely" to Class III patients & label "clearly teaches away" from the use of dronedarone in Class III patients.  Considering all of the evidence as a whole, court held that Plaintiffs have not shown that Defendants' labels instruct a POSA to use dronedarone for patients with stable NYHA Class III CHF. A POSA would not be encouraged by Defendants' labels to prescribe dronedarone to such patients.

Obviousness: Defendants argued that claims 1, 7, 9, and 14 of the '900 patent are invalid as obvious. Dr. Zusman testified that a common cause of hospitalization for AF patients is the recurrence of AF resulting in problems such as fainting, chest pain, heart failure, palpitations, stroke or systemic embolization, and tachycardia (the rapid heart rate associated with AF). Dr. Zusman acknowledged that as of 2008, it was not known whether the maintenance of sinus rhythm actually prevents stroke in patients with AF. Dr. Zusman acknowledges that as of 2008, it would be a significant finding if a company could demonstrate that dronedarone would reduce heart failure.

Comparing the Prior Art and the Claimed Subject Matter the central dispute is whether a POSA would reasonably expect dronedarone to reduce the risk of cardiovascular hospitalization in Atrial Fibrillation (AF) patients with coronary heart disease and within the Age Criteria. Considering all the evidences, Court do not think that Defendants have sufficiently shown that a POSA at the time of the priority date would have a reasonable expectation that dronedarone would reduce hospitalization for the sicker, older patients that make up claims 1, 7, 9, and 14 of the '900 patent. While the EURIDIS/ADONIS post-hoc analysis, Hohnloser, and some internal Sanofi statements form the bulk of evidence weighing in Defendants' favor, I think this evidence is significantly undermined by evidence such as the CAST trials, the rate versus rhythm trials, SWORD, PROMISE, ANDROMEDA, the FDA/EMEA rejections, and also some internal Sanofi statements. There is substantial evidence teaching away from the conclusion that dronedarone would reduce hospitalizations in the claimed patient population. Thus Defendants have failed to meet their burden of showing that US'900 patent is invalid as obvious.