United States: Combine the Label with Phase III Clinical Results and a Carefully Crafted, Mirroring US Patent Application to Achieve Longer Patent Exclusivity for US Life Science Patents

Federal Circuit Decision:  Sanofi v. Watson, 875 F.3d 636 (Fed. Cir. 2017)

Background The invention at issue in Sanofi v. Watson, was dronedarone, an antiarrhythmic agent directed towards the treatment of heart rhythm problems in patients with atrial fibrillation. The commercial embodiment prescribed in the U.S. is known as Multaq®.

Sanofi filed a patent application on a dronedarone composition in 1998, after which Sanofi conducted clinical trials for approximately a decade. The Phase III clinical trial results eventually led to (1) filing a priority application in France and an international application, which resulted in the U.S. patent at issue, 8,410,167, in 2009, and (2) FDA approval of Multaq®.

Sanofi originally filed a claim broadly reciting a method of treatment comprising administering dronedarone:

  1. A method of decreasing the risk of mortality, cardiac hospitalizations, or the combination thereof in a patient, said method comprising administering to said patient an effective amount of dronedarone or a pharmaceutically acceptable salt thereof, with food.

However, the specification, both in the U.S. and in France, strategically recited clinical study results, including contraindicated symptoms, severe heart failure dangers, and patient cardiovascular risk factors. The Multaq® label similarly included all of those details in the clinical trial data section. 

The issued version of claim 1 of Sanofi's '167 patent recited all those details as claim limitations:

A method of decreasing a risk of cardiovascular hospitalization in a patient, said method comprising administering to said patient an effective amount of dronedarone or a pharmaceutically acceptable salt thereof, twice a day with a morning and an evening meal, wherein said patient does not have severe heart failure, (i) wherein severe heart failure is indicated by: a) NYHA Class IV heart failure or b) hospitalization for heart failure within the last month; and (ii) wherein said patient has a history of, or current, paroxysmal or persistent non-permanent atrial fibrillation or flutter; and (iii) wherein the patient has at least one cardiovascular risk factor selected from the group consisting of:

  1. an age greater than or equal to 75;
  2. hypertension;
  3. diabetes;
  4. a history of cerebral stroke or of systemic embolism;
  5. a left atrial diameter greater than or equal to 50mm; and
  6. a left ventricular ejection fraction less than 40%.

At first blush, one skilled in U.S. patent law might readily conclude that such a lengthy patent claim passes muster under 35 U.S.C. §§ 102 and 103 but might wonder how the claim would succeed under the written description and enablement sections of §112(a).  And how would anyone infringe, either directly or indirectly, such a lengthy patent claim?  The answers follow.

The Multaq® label recited the clinical trial data, cross-referencing the same in the label's Indications and Usage section:

Multaq® is 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) [see Clinical Studies (14)]. (emphasis added)

Sanofi provided in Section 14 of the label results from the pivotal ATHENA trial and other clinical studies. In particular, Sanofi included results from the 2005-2008 large scale, pivotal outcome ATHENA clinical study, and also the EURIDIS, ADONIS, and ANDROMEDA clinical studies.

In later litigation, this ingenious label/patent application combination strategy trapped the generic manufacturers into proposing the same labeling for generic versions of Multaq®, ultimately sealing their fate for infringement purposes. On its way to victory, Sanofi had to clear a hurdle of convincing the court that its label provided a basis for showing a specific intent to induce infringement.

Issue:  This case raises intriguing possibilities, particularly for the strategically-minded U.S. practitioner working closely with a client during Phase III clinical trials and who files a patent application that includes the Phase III results before those results are published.

Outcome: The district court held that Sanofi's patents were valid (i.e., Sanofi experienced no problems under any of 35 U.S.C. §§ 102, 103, and 112) and that the generic label provided a basis for a finding of intentional encouragement of infringement and thus inducement to infringe. Id. at 644. "Watson and Sandoz 'kn[o]w that their proposed labels would actually cause physicians to prescribe dronedarone to patients with the cardiovascular risk factors claimed' and that 'such a use would infringe the '167 patent')." Id. at 644-45.

The Federal Circuit affirmed, finding that the label referred to the clinical studies. As noted above, the clinical studies set forth all the risk factors recited in the claims, and the Sanofi patent claim recited those risk factors. According to the Federal Circuit: "The content of the label in this case permits the inference of specific intent to encourage the infringing use." Id. at 646. "[T]he inference in the present case is based on interpreting the label's express statement of indications of use and the internally referred-to elaboration of those indications." Id.

The Federal Circuit, furthermore, highlighted: "[t]he reference to the Clinical Studies section (14) of the label expressly directs the reader to that section for elaboration of the class of patients for whom the drug is indicated to achieve the stated objective, i.e. reduced hospitalization. Section 14 leads with and features a subsection on the ATHENA study...[a]nd it is only the ATHENA subsection...that identifies a class of patients as having been shown to achieve reduced hospitalization from use of dronedarone...The label thus directs medical providers to information identifying the desired benefit for only patients with the patent-claimed risk factors."" Id. at 645. (emphasis added)

Sanofi won, successfully quelling the generic challenge. Sanofi thus achieved the valuable result of 10 more years of patent exclusivity; the first patents relating to dronedarone expired in the middle of 2018, but the Federal Circuit upheld the '167 patent expiring in 2029!

The Federal Circuit found irrelevant the defendants' evidence of substantial non-infringing uses. In contrast to contributory infringement under 271(c), there is no such restriction on induced infringement under 271(b).

Prosecution Takeaway:

  • The Sanofi v. Watson patent claim might alarm U.S. patent drafters for its narrowness, with a concomitant fear of ease of designing around. This decision undercuts those causes of alarm in the context of (1) clinical trial results, (2) a properly drafted patent application setting forth the pivotal outcome of clinical trial(s), and (3) inclusion in the label of the results of the pivotal outcome clinical trials, as well as (4) reference to the pivotal outcome clinical trials in the Indications and Usage portion of the label. To the extent, as in Sanofi v. Watson, the generic/biosimilar manufacturer has to copy the label to obtain FDA approval, method-of-treatment claims that appear to be very narrow can defeat the generic/biosimilar manufacturers where the claim limitations are based on a U.S. patent specification that closely corresponds with the label language and the Phase III clinical trial results. And, of course, for this strategy to work in the U.S. the initial patent application loaded with all that clinical trial information must be filed BEFORE the clinical trial results become disabling prior art under 35 U.S.C. § 102(a) in the absence of any 102(b) exception(s) (And of course, the innovative pharma company will want to pursue drug substance and drug product claims.).
  • Consider drafting claims based on a specification reporting results of Phase III clinical trials that will be included in the label and that will be referenced in the Indications and Usage portion of the label.
    • What Phase III results can you include in all of the patent specification, the clinical studies portion of the label, and the Indications and Usage portion of the label? Consider making the label a set of instructions to the physician to treat patients who satisfy all of the claimed method of treatment steps.
    • Will an alleged infringer be able to carve out the clinical studies and the Indications and Usage?
  • Early and frequent coordination between the patent arm and the regulatory arm of the NDA holder/reference product sponsor will help facilitate this strategy.
  • Carefully draft use codes to comply with FDA standards and to be of the same scope as the claimed method of treatment, as well as the results of the Phase III clinical studies.
    • Marshal support from the entire labeling—not just the indications and usage section—to support a use code that is not overly broad.
    • Keep in mind induced infringement of method of treatment claims when you draft the use code.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

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