Vascepa® – USA

On March 30, 2020, Nevada district court found method of use patents related to omega-3 fatty acid product (Vascepa) infringed but invalid.

This is a Hatch-Waxman litigation, where Plaintiffs (Amarin) sued Defendants (Hikma & Dr Reddy’s Ltd) for filing ANDA with USFDA. Vascepa® is a highly purified preparation of EPA (eicosapentaenoic acid), also known as icosapent ethyl. Plaintiffs specifically asserted infringement of some of the claims of US 8,293,728; US 8,318,715; US 8,357,677; US 8,367,652; US 8,431,560 and US 8,518,929, which are expiring in Feb. 2030. These patents are related to method of treating hypertriglyceridemia.  The asserted claims are essentially directed to methods of treating severe hypertriglyceridemia having TG levels of 500 mg/dL or above with 4gm per day administration of composition containing 96% of ethyl eicosapentaenoate (EPA) for a period of 12 weeks.

Infringement:

Plaintiffs asserted that Defendants have infringed under inducement theory. Court said that appropriate inquiry should be related to specific intent & whether ANDA label encourages, recommends, or promotes infringement. Defendants mainly disputed on 3 parts of claims; (1) the limitation present in all asserted claims that the drug must be administered for at least 12 weeks; (2) the limitations present in most asserted claims that the drug either reduce TG levels by certain percentages, not increase LDL-C levels, or reduce Apo B levels (the “Other Health Benefits” claims); and (3) the limitations that exclude co-administration of the drug with a with another lipid altering drug such as a statin (the “Excluding a Statin” claims).

a) 12 Week Limitation -

With respect to this limitation, court said that number of factors weigh in favor of this finding. Court said that though “Dosage and Usage” section of label does not explicitly mention administration for 12 weeks but both Plaintiffs’ and Defendants’ experts testified that the indication and usage section of the proposed labels is directed to reducing TG levels below 500 mg/dL and then maintaining that reduction—suggesting that the applicable drugs will be prescribed long term. Trial testimony further established that severe hypertriglyceridemia generally has a genetic component, meaning that it is usually a chronic condition requiring long-term. Moreover, the “Clinical Studies” section of Defendants’ labels, like Vascepa’s label, reports the results of the MARINE study which expressly states that patients were administered icosapent ethyl 4gm per day “for 12 weeks.”

b) Other Health Benefits Claims –

Court said that a doctor would read and understand the Clinical Studies section of the labelling before prescribing Defendants’ ANDA Products because it is vital to understanding the effects of the applicable drug. The Clinical Studies section of the labelling describes how the average patient enrolled in the MARINE study received the benefits described in the Other Health Benefits claims. Specifically, ANDA label suggests to doctors that their ANDA Products will decrease TG levels without raising LDL-C levels. Indeed, Vascepa’s ability to reduce TGs without raising LDL-C, as depicted in the Clinical Studies section, is a primary reason clinicians choose to prescribe Vascepa over other available medications. Defendants’ proposed ANDA labels also suggest to treating clinicians that they can expect a decrease in Apo-B levels when they prescribe Defendants’ ANDA Product. Here, too, the Clinical Studies section of the labeling reports the statistically significant decrease in Apo-B resulting from administration of Vascepa in Table 2. Defendants’ proposed ANDA labels also suggest to doctors that they can expect certain reductions in TG levels by prescribing those ANDA Products, as required by certain other Asserted Claims.

c) Excluding a Statin Claims –

Court with respect to statin limitation said that there is text in several places on Defendants’ proposed labelling that would suggest to doctors Defendants’ proposed ANDA Products could be administered without a concurrent lipid altering therapy. First, the Indications and Usage section does not contain any instructions that Defendants’ ANDA Products must be administered with a lipid-altering drug, though FDA regulations would have required instructions to that effect were that the case. Second, and similarly, the Dosage and Administration section of the labelling would have had to mention it, but did not. Third, the Clinical Studies section of the labelling indicates that only 25% of the MARINE study participants were on a concomitant lipid-altering therapy while remaining 75% of patients in the study were not on concurrent lipid altering therapy.

The Court therefore found that the labels of Defendants’ proposed ANDA Products encourage, recommend, promote, or suggest that clinicians prescribe those products in a way that infringes all of the Asserted Claims.

Obviousness:

a) Prima facie obviousness -

The Court first discussed Defendants’ prima facie obviousness case. Most relevant prior art, Lovaza PDR, disclosed many of the limitations of the asserted claims. Only difference was that Lovanza product contains mixture of EPA & DHA, while asserted claims required purified EPA. One of the finding of Lovaza was that it causes increase in LDL-C level (bad cholesterol).  For this reason many patients who took Lovaza were also given a statin to address the LDL-C increases. Therefore, a skilled artisan would have been motivated to develop a single pill that treats severe hypertriglyceridemia without LDL-C increases.

Further, a skilled artisan would have wanted to know which active ingredient in Lovaza—EPA or DHA—was responsible for the LDL-C increase. And this issue was specifically addressed by second prior art, Mori. It disclosed that the increase of LDL-C with DHA was statistically significant and the increase with EPA was not. Thus, there was direct motivation to combine these references.

With respect to other claim limitations such as minimum reduction in triglycerides (e.g., at least about 20%); no increase in LDL-C; or a reduction in Apo-B, other prior arts such as Hayashi & Kurabayashi disclosed that EPA reduced triglycerides by at least about 20%; that EPA did not increase LDL-C; and that EPA reduced Apo-B. Court said that critically, in view of the claim language, obviousness is proven as long as there was a reasonable expectation that 4 g/day of 96% purified EPA would achieve the claimed effects (i.e., not cause an LDL-C increase) in patients with triglycerides of exactly 500 mg/dL. The Court therefore, found that Defendants established by clear and convincing evidence at Trial that all asserted claims are prima facie obvious. Plaintiffs arguments to the contrary were found unavailing because those were not supported by the evidence.

b) Secondary Considerations -

Court found Long-Felt Need & Commercial Success in favor of finding the asserted claims nonobvious whereas other factors such as Unexpected Benefits, Skepticism, Praise are not. With respect to Long-Felt Need, court held that there was a long-felt need for a drug like Vascepa that could reduce TG levels without raising LDL-C levels, primarily because both sides’ experts testified that patients are more likely to comply with a prescribed treatment regime when  they only have to take one pill, rather than two. With respect to Commercial Success, court held that the substantial and sustained increases in Vascepa prescriptions, net sales, and market share, as well as Vascepa’s positive net present value (“NPV”), demonstrate that Vascepa is a commercial success.  Court said that the Defendants’ contention that Vascepa is not a commercial success is largely based on the theory that Vascepa did not make a profit in its first six years on the market. But, Defendants ignored the reality that drugs have long lifecycles, the beginning of which involves spending vast amounts of money on R&D. Moreover, marketing spending tends to be higher at the beginning of a pharmaceutical product’s life-cycle, given the need to educate physicians about the clinical profile of the new drug in question. Therefore, the pharmaceutical industry considers the entire life-cycle of a drug in analyzing commercial success rather than just the first six years after the drug’s launch.