By Gregory Curfman
An ongoing patent battle over omega-3 fatty acids, colloquially known as as fish oils, may have broad implications for the marketing of generic drugs.
Icosapent ethyl (Vascepa®) is an omega-3 fatty acid preparation used to treat high triglycerides. It was explicitly designed to be different from most other omega-3 fatty acid preparations — instead of containing a mixture two fatty acids (docosahexaenoic acid and eicosapentaenoic acid), it is a purified preparation of just the latter, and it is a much higher dose than what is typically used.
In 2015, Hikma Pharmaceuticals, a generic drug company, filed an abbreviated new drug application (ANDA) for its generic formulation of icosapent ethyl.
The manufacturer of branded Vascepa, Amarin Corporation, promptly filed a patent infringement lawsuit citing six method of use patents (the ‘728, ‘715, ‘677, ‘652, ‘560, ‘929 patents) on Vascepa that the company believed were infringed by Hikma’s ANDA.
The case, which was heard by the chief judge of the U.S. District Court of the District of Las Vegas, proceeded in two steps.
In the first step, the judge ruled that Amarin’s six patents were infringed by Hikma’s ANDA, and therefore Amarin prevailed in the first step.
But, in a second step, the judge ruled that all six patents were invalid on the basis of her determination that they were obvious when first issued.
On review, the U.S. Court of Appeals for the Federal Circuit affirmed the district court ruling. Thus, the ruling provided a pathway for Hikma to move forward with the ANDA, and in 2020, the FDA issued its approval for the generic formulation.
The approval applied to a single label indication — the treatment of severe hypertriglyceridemia — which was no longer patent-protected following the ruling that the relevant patents were invalid for obviousness.
Following the 2012 FDA approval of innovator Vascepa for the treatment of severe hypertriglyceridemia, Amarin undertook a large randomized clinical trial of Vascepa for the prevention of cardiovascular events in patients with established cardiovascular disease or clinically significant risk factors for cardiovascular disease. The results of the REDUCE-IT trial, published in 2019, in over 8000 patients followed for nearly 5 years, showed that Vascepa reduced the risk of major cardiovascular events by 25%. On the basis of the REDUCE-IT trial, the FDA granted an extension of the original label for Vascepa to include a second clinical indication for the prevention of cardiovascular events in patients with established cardiovascular disease or significant risk factors. Amarin applied for and received patent protection for this new label indication for Vascepa.
For Hikma to proceed with marketing of its generic formulation, the drug label would have to avoid infringement of the newly issued patents for the indication of the prevention of cardiovascular disease.
Hikma would need to create what is referred to as a “skinny label,” i.e., a label that would include only indications not patent-protected, in this case the indication of severe hypertriglyceridemia, and avoid notation of the second indication of cardiovascular disease prevention. Such skinny labels are defined in Section 505(j)(2)(A)(viii) of the Food, Drug, and Cosmetic Act (aka “Section VIII Statement or Carve-Out”).
Amarin disputed whether Hikma’s drug label met the requirements of the Section VIII Statement and filed a patent infringement lawsuit against the generic company naming three allegedly infringed patents (the ‘537, ‘077, and ‘861 patents), which include claims referencing the indication for cardiovascular disease prevention.
Hikma filed a motion to dismiss, which was heard by Magistrate Judge Jennifer L. Hall of the U.S. District Court for the District of Delaware and decided on August 3, 2021.
Amarin’s complaint was that Hikma, through its drug label, website, and advertising, “instructed, promoted, and encouraged” physicians to prescribe its generic formulation for the prevention of cardiovascular disease, an indication that would apply to a much larger number of people than the indication for severe hypertriglyceridemia.
For example, when Hikma submitted its ANDA in 2016, the proposed drug label included only the indication for severe hypertriglyceridemia and also included a limitation-of-use statement for cardiovascular disease prevention. In the final label, which was approved in 2020, the limitation-of-use statement had been removed. Further, Hikma’s website contained advertising for its generic formulation indicating that it had an AB rating, meaning that it is therapeutically equivalent to the brand drug, but without stating explicitly that the AB rating did not apply to the prevention of cardiovascular disease.
For these reasons, among others, Judge Hall concluded:
“(1) that Hikma’s label and public statements could instruct and/or encourage third parties to use its product for the cardiovascular indication, which Plaintiffs allege is covered by the asserted patents; and (2) that Hikma both knew and intended that third parties would use its product for that purpose.”
On this basis, the Magistrate Judge recommended to the Court that the motion to dismiss be denied.
The wider implication of this ruling is that in preparing Section VIII carve-outs, generic companies may have to take special care not to imply that their generic formulations are intended for indications covered by active patents on the innovator formulation. Skinny labels not composed with sufficient attention to detail may not survive close legal scrutiny.
However, it has been observed that even if Amarin prevails in its infringement lawsuit against Hikma, it may still face an invalidity suit based on obviousness just as it did in the previous lawsuit decided in the U.S. District Court for the District of Las Vegas.
Also, authorized prescribers may legally prescribe prescription drugs for uses not listed among the labeled indications. The likelihood of a prescriber prescribing a drug for an off-label indication may depend on the specific drug and its potential adverse effects. For Vascepa, a side effect of concern is a small increase in the risk of atrial fibrillation, but this is not likely to dissuade a physician from prescribing either the brand-name drug or generic counterpart off-label for cardiovascular prevention, especially if the generic formulation is significantly less expensive than the innovator formulation.
Thus, even if the Court ultimately rules in Amarin’s favor, further revisions to Hikma’s label for generic icosapent ethyl may have little impact on prescribing behavior. This case will next move ahead to trial on the merits.