How will REDUCE-IT impact generic entry for Amarin’s Vascepa?
Zachary Silbersher
We previously blogged about the upcoming litigation trial between Amarin Pharmaceuticals ($AMRN) and Dr. Reddy’s and Hikma, which are two prospective generics for Amarin’s Vascepa®. While that blog post provided a general overview of the issues to be litigated at the upcoming trial, there are numerous other issues and questions around the upcoming trial. This post will focus on how the REDUCE-IT trial may impact Amarin’s fight with the existing generics, if at all.
Can Amarin rely upon REDUCE-IT to show its patents are not invalid?
The first question is whether the results of the REDUCE-IT trial show that Amarin’s patents are not obvious. Amarin has asserted six patents against the generics in the existing litigation. Those patents generally cover dosage regimes of pure EPA under the earlier indication, namely patients with hypertriglyceridemia, which are severely high levels of triglycerides (“TGs”) above 500 mg/dL. The patents grew primarily out of the MARINE trial, which apparently showed that Vascepa safely lowers TG levels in patients with high TG levels without also increasing bad cholesterol, namely, LDL-C.
In response to the lawsuits, the generics have argued that the asserted patents are invalid based upon numerous prior art references. (The primary references relied upon by the generics were discussed in our earlier blog post.) Under patent law, if an accused infringer shows that a patent is prima facie obvious under the prior art, the patent-holder can nonetheless prevent the patents from being invalidated if it can show that, under certain circumstances, the inventions embodied within the patents were nevertheless surprising or unexpected. Thus, Amarin can theoretically prevail if it can show that the inventions embodied within its patents nevertheless showed surprising or unexpected results. (Indeed, that was the principle reason the patents were granted by the Patent Office in the first instance, but for reasons obviously unrelated to the REDUCE-IT trial, the results of which were announced after the patents were granted.)
The results of the REDUCE-IT trial, which were announced in September 2018, apparently showed that Vascepa brought an approximately 25% relative reduction in risk of major adverse cardiovascular events on top of the risk reduction accomplished by statin therapy. Amarin has previously told the court that the results of the REDUCE-IT trial were “stunning” and met with “surprise, speculation, and hope” and “prais[ed] for the unexpected results.” (See Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc., Case No. 2:16-cv-02525-MMD-NJK (D. Nev.) (Dkt. 234) at 3 (citations omitted)).
Thus, the question is whether Amarin can use the results of the REDUCE-IT trial to show that the patents asserted against the current generics should not be invalidated because they were based upon unexpected results. Amarin is apparently planning to do just that at the upcoming litigation trial. In response, the generics recently asked the Court to bar Amarin from presenting any evidence regarding REDUCE-IT at trial. (This request has taken the form of a motion in limine, which is a motion to exclude evidence from a trial. See Case No. 2:16-cv-02525-MMD-NJK (D. Nev.) (Dkt. 310).) Yet, even if the Court does permit Amarin to introduce the REDUCE-IT results at trial, Amarin faces several obstacles for leveraging the results of REDUCE-IT to show the patents currently asserted against the generics are not invalid.
First, the patents currently asserted against the generics technically cover a dosing regime that is different than what was administered during the REDUCE-IT trial. For instance, the asserted patents require administration to a patient who has TG levels in excess of 500 mg/dL. By contrast, the patients in the REDUCE-IT trial had TG levels between 150-499 mg/dL. In addition, the asserted patents require administration for 12 weeks, whereas the observed effects in REDUCE-IT purportedly did not occur for at least a year. There are other distinctions outlined in the generics pending motion in limine.
Put another way, even if everyone agrees that the results of the REDUCE-IT trial were truly surprising, that trial did not necessarily cover the dosing regime claimed in the patents currently asserted against the generics. And therefore, anything purportedly surprising about REDUCE-IT does not necessarily read-through to the validity of the currently asserted patents.
There is another obstacle. The generics also argue that the results of the REDUCE-IT were not actually unexpected or surprising. While those results may have been surprising to numerous doctors and scientists, the generics point to an earlier study in Japan (the JELIS study) that purportedly showed that purified EPA could reduce cardiovascular risks in patients with abnormal lipid levels who were on statin therapy. The JELIS study preceded the priority date for Amarin’s patents. Amarin argues the JELIS study is flawed, but the generics can clearly make hay from the results to argue that the REDUCE-IT was not sufficiently surprising as regards any patents Amarin has for Vascepa®.
Perhaps more importantly, the generics also argue that Amarin relied upon the JELIS study in connection with its application to the FDA for the expanded cardiovascular indication. The generics essentially argue that Amarin essentially took opposing positions—telling the FDA that the JELIS study supported their bid for a cardiovascular indication, while taking the position in this litigation that the JELIS study was flawed. Amarin attempts to back away from any admissions to the FDA regarding the JELIS study. For instance, Amarin argues that its Amarin’s to the FDA regarding JELIS are irrelevant to the question of whether a person of skill would view REDUCE-IT to have been “unexpected.” (Case No. 2:16-cv-02525-MMD-NJK (D. Nev.) (Dkt. 316) at 8). That’s a bit hard to swallow, and is more likely to be construed as an admission by Amarin (whatever it was that Amarin actually said.)
In all likelihood, it would not be surprising if Court allows Amarin to introduce evidence regarding REDUCE-IT at the upcoming litigation trial. Yet, even presuming that happens, it is far from clear that Amarin can successfully use REDUCE-IT to show that the patents currently asserted against the generics—which cover the hypertriglyceridemia indication—were somehow so surprising and unexpected that they should not be invalidated. That does not necessarily mean that Amarin will not successfully defend the validity of its patents. Rather, it would only mean that REDUCE-IT is unlikely to be its saving grace.
Can the generics sell off-label for the cardiovascular indication?
The second question, which is likely more important, addresses to what extent any generic that enters the market in the near-term can sell off-label for the new cardiovascular indication. This question presumes that Amarin either does not prevail in the upcoming trial, or there is not a settlement that permits near-term entry by Dr. Reddy’s or Hikma. If Amarin theoretically prevails at the upcoming litigation trial, and that decision is affirmed by the Federal Circuit, then it is unlikely that either Dr. Reddy’s or Hikma will be able enter—at least not under their existing ANDAs—until expiration of the asserted patents, which is in 2030,
Both Dr. Reddy’s and Hikma filed their ANDAs for generic Vascepa® long before Amarin received FDA approval for the cardiovascular indication. Thus, the generics’ existing ANDAs do not seek a license to distribute a generic version of Vascepa® for the cardiovascular indication. Instead, the existing ANDAs only cover the earlier hypertriglyceridemia indication. Thus, under their existing ANDAs, Dr. Reddy’s and Hikma cannot receive FDA approval to market their generics for the new cardiovascular indication.
Even so, under the Hatch-Waxman statute, generics are free to carve out indications from their label to avoid contending with patents that might otherwise delay their entry. If the generics were to launch within the next year or two, that would not necessarily stop off-label prescriptions of the generic drugs for the cardiovascular indications. Those off-label prescriptions might eat into Amarin’s profits if it is forced to compete with lower-cost generics that have yet to even receive FDA approval for the cardiovascular indication.
There are two sides to this question. The first is whether and to what extent the generics would be liable for off-label sales of their generic formulations for the cardiovascular indication. The second is, regardless of whether the generics bear any liability, will that stop it from happening.
On the first side, the generics will likely take all steps necessary to mitigate their liability. Because this is a patent blog, when we speak about liability, we are primarily speaking about patent liability. The generics’ label will not include the cardiovascular indication, and the FDA may likely require that the label provide a specific warning that the generic formulation has not yet been approved for the cardiovascular indication. That alone may go a long way to mitigating any liability by the generics for decisions by physicians for prescribing the generic formulations for the cardiovascular indication. The generics defense will be that they cannot be encouraging or “inducing” doctors to prescribe for an off-label indication given the carve-outs and warnings set forth in the label against prescription for the cardiovascular indication.
Moreover, there is precedent to support this. In Takeda v. W-Ward Pharm., 785 F.3d 625 (Fed. Cir. 2015), the Federal Circuit held that a generic was not infringing patents for acute gout flare given that the label carved out that indication. The Court further held that mere knowledge by the generic company that doctors may prescribe the drug off-label is not in itself sufficient to rise to the level of intent required to prove induced infringement. In short, there is a very palpable universe where Hikma and Dr. Reddy’s can launch generics with a label covering only the hypertriglyceridemia indiction, and yet nonetheless benefit from off-label prescriptions for the cardiovascular indication without risking significant liability.
On the other hand, likely everything in the law, this is not entirely black and white. Technically, if Dr. Reddy’s or Hikma otherwise engage in conduct that induces or encourages doctors to prescribe their generics off-label, regardless of what their labels actually state, that conduct may form the basis to impose liability on them. While that is typically remote in most scenarios, this scenario may be an exception. It bears emphasis at this point that Vascepa® is relatively unusual circumstance. While brand pharmaceuticals often receive new indications, the patient population for Vascepa®’s new indication is going to significantly eclipse that of its original indication. The sheer potential windfall scenario that the generics face from this unique circumstance may cloud what would otherwise be a straight-forward non-infringement argument for the generics. That remains to be seen, although at this point it is at best speculative.
The other piece of this puzzle will hinge on the patents that Amarin owns that actually cover the cardiovascular indication. The patents currently asserted against the generics cover the hypertriglyceridemia indication, not the cardiovascular indication. The cardiovascular patents do not yet appear to have been added to the Orange Book. Some of these patents appear to have already been granted, such this one and this one. Other patents may still be working their way through the Patent Office. Thus, this question regarding off-label generic sales for cardiovascular indications remains dependent on which patents Amarin adds to the Orange Book for that indication.
A key point here is whether Amarin has patents covering the cardiovascular indication that are not, themselves, method of use patents. If so, proving infringement of those patents would not necessarily rely upon indirect or induced infringement to impose liability on the generics. That may mean carve-outs and warnings on labels are insufficient to avoid infringement. On the one hand, that is relatively unlikely. If Amarin had those types of patents—such as formulation patents or manufacturing patents—they would presumably apply to the earlier indication as well as the cardiovascular indication. In that case, Amarin would most likely already be asserting those patents against Dr. Reddy’s and Hikma. (One of the commenters on our earlier blog post inquired whether Amarin has any patents covering the manufacturing process. Whether Amarin has such patents is irrelevant at this point because they have not been asserted against Dr. Reddy’s or Hikma in the pending litigation.) On the other hand, life-cycle management has with past pharmaceuticals proven the ability to make patents seemingly appear out of nowhere, just when generic entry is most imminent. That also remains to be seen.
Yet, even if generics face no liability for off-label prescriptions for their formulations, it may nevertheless happen. In the Takeda case, the generic label included a warning that the drug had not yet been approved for the patented indication, and even though the FDA itself had previously acknowledged that it may be natural for a doctor to prescribe the generic version for the patented indication, the Court found no induced infringement.
Generics can only do so much to hamstring doctors for how they prescribe their drugs. And the same goes for Amarin itself. There is practically no universe where Amarin will go so far as to sue doctors for patent infringement to prevent them from prescribing generic formulations in a certain way. Off-label prescription of generic drugs for unapproved indications is a practice that that is not technically illegal or proscribed by the FDA. So, at the end of the day, for Amarin, there is only so much it can do with its patents, and that really is what it is.
But for Amarin, that is also not the full story. Now that Amarin has a new indication with a greatly increased patient population, it will likely face a barrage of new ANDA applications. To the extent that Amarin has NCI (new indication) exclusivity, those ANDAs can be filed at any time, but they cannot be granted for another three years. Amarin will also likely add numerous new patents to the Orange Book covering its new cardiovascular indication. Those patents will of course have to be litigated as well, and generics may file IPRs against those patents in an effort to expedite their time to entry. (If Amarin did not receive FDA exclusivity for the cardiovascular indication, those ANDAs will lead to litigation even faster.) All of this will soon create another cloud of patent uncertainty.