Amarin makes bad bet on weak patents; generic secures FDA approval by carving out strong indication from its label.

On March 30 of this year, a Federal District Court in Nevada ruled that six of Amarin Pharma Inc.’s (“Amarin”) 52 patents for Vascepa® were invalid, thus paving the way for generic competition absent a reversal on appeal.  Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc., Case No. 2:16-cv-02525-MMD-NJK (D. Nev. 3/30/2020). Amarin’s decision to come to market early, rather than waiting until after it had completed its cardiovascular outcomes trial, appears to have backfired, potentially allowing generic competition much earlier than Amarin had anticipated.

For those unfamiliar with the story, Vascepa® contains a highly purified form of EPA, one of the two main omega-3 fatty acids present in fish oil and sold in omega-3 fatty acid dietary supplements.  Omega-3 fatty acids have been widely studied for their cardiovascular benefits for decades and, in 2004, Reliant Pharmaceuticals secured FDA approval to market a purified form of omega-3 fatty acids for reducing triglycerides (“TGs”) in patients with severe hypertriglyceridemia ("hyper TG") (i.e. TG concentrations ≥ 500 mg/dL).  That drug, now known as Lovaza®, contains a mixture of omega-3 fatty acids, principally EPA and the ethyl ester of docosahexaenoic acid (“DHA”).

In the mid-1990’s researchers began to test purified forms of EPA and DHA to determine which was most responsible for modulating lipid activity, and whether the two ingredients had different lipid effects.  Two of those studies,  Hayashi (1995) and Mori (2000), determined that EPA and DHA both reduced TG concentrations, but that only EPA reduced concentrations of low density lipoprotein cholesterol (“LDL-C”), the so-called “bad cholesterol.”  According to this research, DHA actually increased LDL-C concentrations.  A similar result was observed in clinical testing of Lovaza®, with one study reporting that Lovaza® increased LDL-C by as much as 44.5%.

Amarin first secured FDA approval for Vascepa® on July 26, 2012, for the same indication as Lovaza®, i.e., for lowering TGs in patients with severe hypertriglyceridemia.  The indication read:

VASCEPA is an ethyl ester of eicosapentaenoic acid (EPA) indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

Amarin secured FDA’s approval for this limited indication on the basis of a relatively straightforward 12 week study demonstrating that Vascepa® lowered TGs in this patient group when administered once daily.  Amarin had secured several patents that covered the use of purified EPA in this indication, and must have felt comfortable launching the product on the strength of these patents. 

Long term, however, Amarin had its eye on a much more lucrative indication, for preventing adverse cardiovascular events in patients who were already on statins but continued to have moderately elevated concentrations of TGs (i.e., TG concentrations ≥ 150 mg/dL).  For ease of reference, we will refer to this indication as the “CV risk indication.”  Amarin secured FDA approval for the CV risk indication on December 13, 2019, after a seven-year study that enrolled 8,179 patients at 410 different study sites.  It’s new FDA approved indication reads:

as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization, and unstable angina requiring hospitalization in adult patients with elevated triglyceride (TG) levels (≥ 150 mg/dL) and • established cardiovascular disease or • diabetes mellitus and 2 or more additional risk factors for cardiovascular disease.

As of this writing, Amarin has 52 patents listed in the Orange Book for Vascepa, covering (1) methods of using purified EPA to lower TGs in patients with severe hyperTG (the “hyperTG patents”), and (2) methods of using purified EPA to prevent adverse cardiovascular events in patients with elevated TGs (the “CV event patents”).

The following claims are representative claims from these two categories of patents:

U.S. Patent No. 8,293,728      1. A method of reducing triglycerides in a subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl who does not receive concurrent lipid altering therapy comprising: administering orally to the subject about 4 g per day of a pharmaceutical composition comprising at least about 96% by weight of all fatty acids present, ethyl eicosapentaenoate, and substantially no docosahexaenoic acid or its esters for a period of 12 weeks to effect a reduction in triglycerides without substantially increasing LDL-C compared to a second subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl who has not received the pharmaceutical composition and a concurrent lipid altering therapy. 

U.S. Patent No. 10,576,054         1. A method of delaying or preventing a major adverse cardiovascular event in a subject, the method comprising administering about 4 g per day of icosapent ethyl to the subject for a period effective to delay or prevent the major adverse cardiovascular event, wherein the subject is 50 years of age or older, has diabetes and at least one additional risk factor for cardiovascular disease.

I would venture to say that the CV event patents are much stronger than the hyperTG patents.  When Amarin filed its application for the CV event patents, no clinical study had ever proven that an omega-3 fatty acid could prevent adverse CV events, particularly when added to a statin in patients with only moderately increased TG concentrations (i.e. ≥ 150 mg/dL).  This is in contrast to the hyperTG patents, where substantial prior art demonstrated the ability of omega-3 fatty acids to lower TGs, and several publications had even investigated the differential effects of EPA and DHA.

By securing approval for two indications, Amarin created a problem for itself.  Generics did not need to secure marketing approval for Amarin’s strong and most lucrative indication – preventing adverse CV events. Because Amarin had secured approval for lowering TGs in severe hyperTG patients, generics could avoid Amarin’s CV event patents by securing FDA approval only for reducing TGs in severe hyperTG patients (≥ 500 mg/dL).

In 2016, that is precisely what happened.  While Amarin was in the midst of its CV risk reduction  study, it received a notice from a corporate predecessor to Hikma Pharmaceuticals (“Hikma”) under the Hatch Waxman Act that the predecessor had filed an ANDA seeking approval to market a generic version of Vascepa for the hyperTG indication, and that the predecessor had filed a paragraph IV patent certification with the FDA, challenging the validity of Amarin’s hyperTG patents.

When the case was finally decided in March of this year, the Court held the asserted patent claims invalid.  Amarin argued  that its purified EPA produced unexpected results in this population because, unlike DHA or mixtures of DHA and EPA, purified EPA did not increase LDL-C, but the studies by Hayashi (1995) and Mori (2000) were fatal to this argument. The Court rejected this argument because:

Mori, Hayashi, and Kurabayashi [already] disclosed that EPA did not increase LDL-C …

One issue that puzzled me was why Amarin’s CV prevention study did not save its hyperTG patents.  We all know that unexpected results in support of a patent can be generated after the filing date of a patent application, and the fact that EPA prodices a CV benefit in hyperTG patients seems unexpected to me.

Amarin argued this point but the Court rejected it.  The problem, the Court found, was that the claims of the hyperTG patents were not commensurate in scope with Amarin's CV outcomes study.  In particular, Amarin’s clinical trial was limited to patients on statins, but the claims of the asserted hyperTG patents did not require the patient to be on statins.  Ironically, some of Amarin's asserted claims might have survived if they had been limited to patients who were also on statins.

This decision is probably not the last chapter to be written in this story.  Amarin has appealed the Court’s decision, and FDA recently approved Hikma’s generic version of Vascepa®, but Amarin has proven very resilient protecting its Vascepa® business, and will undoubtedly continue its efforts to protect Vascepa® from generic competition.