Sanofi v. Glenmark Pharms. Inc.

Based on Defendants’ proposed ANDA labels, the court found Defendants liable for induced infringement; the claims were not invalid as obvious.

October 25, 2016

Robins Kaplan GENERICally Speaking: A Hatch-Waxman Litigation Bulletin

Case Name: Sanofi v. Glenmark Pharms. Inc., Civ. No. 14-264-RGA (Consolidated), 2016 U.S. Dist. LEXIS 116950 (D. Del. August 31, 2016) (Andrews, J.) 

Drug Product and Patent(s)-in-Suit: Multaq® (dronedarone); U.S. Patents Nos. 8,318,800 (“the ’800 patent”), 8,410,167 (“the ’167 patent”) and 8,602,215 (“the ’215 patent”)

Nature of the Case and Issue(s) Presented: Atrial fibrillation (AF) is the most common heart rhythm disorder and is characterized by an irregular, rapid heartbeat from the atrium, the upper chamber of the heart. In AF, the electrical signals that are normally generated regularly by the sinus node, which keep the heart beating in a coordinated fashion, become disorganized, leading to the disordered contraction of the atria followed by the regularly irregular pumping response of the ventricles. There are generally three types of AF. Paroxysmal AF occurs for short periods of time and the heart is generally able to return to normal sinus rhythm without medical intervention. Persistent AF lasts for a longer period of time, usually a week or more, and often requires medical intervention, such as electrical cardioversion or drug therapy, in order to restore normal sinus rhythm. Permanent AF occurs when patients cannot be returned to normal sinus rhythm, even after drug therapy or attempts at electrical cardioversion. One strategy that medical professionals use to treat AF is called “rhythm control” and involves the administration of antiarrhythmic drugs (“AADs”), a class of drugs designed to maintain the heart’s normal sinus rhythm. Multaq is an AAD indicated to reduce the risk of hospitalization for AF in patients in sinus rhythm with a history of paroxysmal or persistent AF. The ’800 patent claims pharmaceutical compositions containing dronedarone. The ’167 patent claims methods of decreasing the risk of cardiovascular hospitalization and hospitalization for AF in a specific class of patients. Both patents are listed in the FDA’s Orange Book.

Plaintiffs sued eight generic defendants alleging infringement of the patents-in-suit. Many of the issues were resolved via stipulations prior to trial. The court held a three-day bench trial on Sanofi’s claims against Watson and Sandoz, related to issues of infringement and invalidity pertaining to the ’167 patent. The court found the asserted claims valid and most of them infringed.

Why Sanofi prevailed: The court first addressed the issue of infringement. Defendants raised three arguments: (i) with regard to inducement, defendants argued that their proposed labels did not instruct only administering dronedarone to patients having one of the claimed risk factors; (ii) defendants argued that their labels did not instruct using dronedarone with diuretics or for at least twelve months; and (iii) defendants argued that Sanofi failed to prove contributory infringement because defendants’ proposed ANDA products were capable of substantial, non-infringing uses.

The court found that defendants’ proposed labels encouraged physicians to prescribe dronedarone to patients with at least one of the cardiovascular risk factors claimed in the ’167 patent. In fact, Sanofi’s identical label for Multaq already encouraged such use, demonstrated by the fact that at least 77% of patients who are prescribed Multaq have at least one of the claimed cardiovascular risk factors. Moreover, the court found that Sanofi  has proven by a preponderance of the evidence that defendants knew that their proposed labels would actually cause physicians to prescribe dronedarone to patients with the cardiovascular risk factors claimed in the ’167 patent, and that defendants knew that such a use would infringe the ’167 patent. Sanofi’s expert testified that the layout of Defendants’ labels, particularly the section describing one particular clinical trial, demonstrates “a clear encouragement of the use of Dronedarone in patients with cardiovascular risk factors in accordance with Claim 1 of the ’167 patent.” He also testified that a POSA would read the labels with the understanding that past studies involving AADs showed either negligible benefits or even adverse consequences from taking dronedarone, such as increased mortality. In their first section, Defendants’ labels stated, “Dronedarone tablets are indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF).” If the reader followed these instructions and looked at the clinical studies section (14), this section described the patient population for the relevant trial as those having the same risk factors described in the claims of the ’167 patent. Although descriptions of multiple clinical trials appear in Section 14, this relevant description is prominently placed first and is by far the lengthiest.

Defendants also separately disputed whether their labels induced infringement of claims where the patient received a specific diuretic-based treatment. Defendants’ proposed label explained that certain of the clinical population were treated with dronedarone “in addition to conventional therapy for cardiovascular diseases that included,” among other treatments, diuretics. Defendants argued that almost half of the clinical population did not take a diuretic, and that there was nothing in the labels that explicitly directed doctors to administer dronedarone to patients taking diuretics. However, diuretics are commonly used to treat various common cardiovascular conditions. Likewise, the fact that over half of the clinical population were taking diuretics, and that the diuretics did not decrease positive outcomes from dronedarone, would encourage at least some physicians to administer dronedarone concomitantly with diuretics. On the other hand, the court found that the labels’ warning about the serious side effects that can result from concomitant administration of potassium-depleting diuretics could not reasonably be viewed as encouraging the use of dronedarone in conjunction with non-potassium sparing diuretics, according to claim 5. Therefore, defendants’ proposed labels induced infringement of claim 4 of the ’167 patent, but did not induce infringement of claim 5.

As to contributory infringement, the issue was whether there were any substantial non-infringing uses of defendants’ generic dronedarone product falling outside the scope of the method claims of the ’167 patent. The court concluded that there were substantial non-infringing uses for defendants’ proposed ANDA product. The court rejected Sanofi’s argument that using dronedarone to reduce the risk of first AF recurrence and to prolong the time to first AF recurrence was off-label as an unconvincing, litigation-inspired explanation of its advertising activities. Accordingly, there was no contributory infringement.

Next, defendants argued that a POSA in 2008 would have been motivated to treat AF patients with dronedarone, having the reasonable expectation that it would reduce the risk of cardiovascular hospitalization and hospitalization for AF. Defendants’ obviousness case focused heavily on two particular pieces of prior art: a January 2008 article in the Journal of Cardiovascular Electrophysiology about the rationale and design of the ATHENA clinical trial (“Hohnloser 2008”) and the actual clinical trial protocol for ATHENA (“”). Defendants’ theory combined either of these two references with an October 2006 Public Assessment Report from the European Medicines Agency (“2006 EMEA Report”), which disclosed taking dronedarone twice a day with a morning and evening meal. Sanofi did not contest that Hohnloser 2008 and both disclosed all but two of the elements of the asserted independent claims (1 and 8) of the ’167 patent. But Sanofi argued that Hohnloser 2008 and did not disclose: (i) the results of ATHENA that actually demonstrated the clinical benefit of reducing cardiovascular hospitalization; and (ii) administering dronedarone twice a day with a morning and an evening meal. However, Sanofi did not dispute that the 2006 EMEA Report disclosed that dronedarone should be administered twice a day with a morning and an evening meal. Therefore, the issue was whether a POSA would have expected dronedarone to reduce the risk of cardiovascular hospitalization and hospitalization due to AF in the ATHENA patient population. The court found that a POSA would not have said expectation. Hohnloser 2008 was a brief article describing the rationale and design of the ATHENA clinical trial before any results were reported, and was principally written by the investigators involved in the trial. The central conclusion of the document was not the likely result of the trial, but simply that “ATHENA will be the largest efficacy and safety trial of dronedarone, a multichannel blocker compound with properties from class I, II, III, and IV antiarrhythmic drugs developed to treat patients with AF.” Hohnloser 2008 was a hypothetical that requires future testing, not a concrete expectation of success.

The court further found that a POSA in 2008 would have critically evaluated statements of “expectation” in documents outlining the rationale and design of a clinical trial, especially in light of the post-hoc nature of the data and the overall history of unexpected results in trials involving dronedarone and other antiarrhythmic drugs. Moreover, the clinical history of dronedarone itself, in particular the fact that its use resulted in increased mortality during the previous clinical trials, would counsel a POSA against giving too much weight to the results of a post-hoc analysis without further experimentation. Next, the court found that the historic uncertainty in the field regarding the efficacy of AAD treatments generally and the lack of consistent clinical trial results were factors that would cause a POSA to take a more exacting look than usual at a post-hoc analysis. Finally, the court credited secondary considerations favoring a finding of non-obviousness. For instance, while there were multiple other AADs on the market, there was a need for an AAD with fewer adverse side effects, that could be safely taken by high-risk patients. The fact that no other AADs, including ones with properties similar to dronedarone, had been proven to reduce cardiovascular and AF hospitalizations, and that no such other compounds were later developed by other pharmaceutical companies, suggested that the reduction in such hospitalizations was not obvious. Also, the 4.8 million prescriptions for Multaq, demonstrating a prescription market share of 11% and a dollar market share of 50%, demonstrated that Multaq has been at least a moderate commercial success to this point, even if its mean sales were lower than other more established AADs. 

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