Can Novartis’ new chicken-pox patent protect Gilenya from generic competition?
Zachary Silbersher
We recently blogged about the pending appeal of an IPR that upheld the patentability of the ‘405 patent covering Gilenya®. If Novartis ($NVS) prevails in that appeal, then that could potentially secure another seven years of exclusivity for Gilenya® without generic competition. Novartis, however, has a back-up plan. The Patent Office recently granted Novartis an additional patent (U.S. Patent No. 10,543,179) covering Gilenya®, which will also not expire until December 2027. Novartis has already commenced Hatch-Waxman suits against numerous generics to enforce the ‘179 patent. How strong is this patent?
The ‘179 patent is directed to a method of treating a patient with RRMS who may be at risk of contracting an infection, such as chicken pox, from the varicella zoster virus. The patent only has four claims and one independent claim. The independent claim is essentially a method performed in three steps: first, identify if the patient may be susceptible to contracting an infection caused by the varicella zoster virus, such as chicken pox, presumably because the patient either never had it or was not previously vaccinated. If the patient is susceptible, then in the second step, the patent requires vaccinating the patient before the third step, which is administering 0.5 mg of fingolimod.
At its heart, the patent is fairly straightforward: for patients with RRMS who will be administered fingolimod, if they have not yet had the chicken pox, then vaccinate them first. This is the alleged “invention” that if successfully enforced against generics, could pocket Novartis billions of dollars in Gilenya® revenue over the next eight years.
At the outset, the patent will be most likely infringed by the generics. The current label for Gilenya®, which will presumably be copied by the generics, states, “Test patients for antibodies to varicella zoster virus (VZV) before initiating GILENYA; VZV vaccination of antibody negative patients is recommended prior to commencing treatment with GILENYA.” Thus, to circumvent the ‘179 patent, the generics will most likely require need to show that the patent is invalid.
The back-and-forth between Novartis and the Patent Office (known as the prosecution history) is particularly interesting for the ‘179 patent. A brief review of that history will shed some light on how likely it is that generics will be able to prove that the ‘179 patent is obvious.
During prosecution, the Examiner identified a prior art reference (Garber, Nature Biotechnology, 2008; 26(8):844-45). The Garber reference disclosed that a patient taking fingolimod died from the chicken pox. The Garber reference thus suggested that doctors should be especially careful about administering fingolimod to patients who remain susceptible to contracting the chicken pox. Based on this, the Examiner rejected Novartis’ patent application. According to the Examiner, since a patient taking fingolimod died from the chicken pox, a doctor would be motivated to vaccinate patients against chicken pox before administering fingolimod. (App. 15/986,992, Office Action, Nov. 16, 2018 at 10-12).
Novartis disagreed. In response to the Examiner’s rejection, Novartis argued that Garber did not teach proactive infection prevention. Rather, Novartis alleged that Garber only taught increased vigilance in monitoring patients taking fingolimod who may be susceptible to the chicken pox. Indeed, Novartis went so far as to suggest that the Garber reference would discourage doctors from proactively vaccinating patients against the chicken pox before administering fingolimod. Why? Because, according to Novartis, vaccinating a patient taking an immunomodulating drug with a VZV vaccine may actually cause the infection. (App. 15/986,992, Amendment, Jan. 15, 2019 at 9).
The Examiner was not persuaded. Indeed, the Examiner wrote a very lengthy response to Novartis’ arguments that stated, on no uncertain terms, that the Examiner did not believe that vaccinating patients against the chicken pox before administering fingolimod was a patentable invention. For instance, the Examiner stated that from the Garber teachings, it “would be without question readily obvious to any doctor or nurse or anyone else with basic common knowledge of the medical and pharmaceutical arts [] that the adverse effect of death from varicella zoster virus infection can be readily eliminated simply by making sure the patient, before starting fingolimod treatment, has either already had chicken pox, or has been properly vaccinated against the varicella zoster virus.” (App. 15/986,992, Office Action, May 9, 2019 at 9).
To point a finer point on it, the Examiner also stated that Novartis’ alleged invention “is not a patentable advance in the art by any stretch of the imagination, but is simply the sort of routine and basic common sense practices that take place in hospitals and clinics every day all over the world.” (Id. at 10). The Examiner further stated that because it was known that chicken pox can kill patients taking fingolimod, then vaccinating patients before beginning administration of the drug is “plain common sense to anyone in the medical and pharmaceutical arts.” (Id. at 11). The Examiner outright rejected Novartis’ suggestion that “the skilled artisan, out of an abundance of caution, would not readily take on the risks associated with the proactive approach” of vaccinating patients for chicken pox before administering fingolimod. The Examiner characterized this reasoning as “baseless, not supported by a shred of hard evidence, [] entirely unconvincing, and is not even representative of the typical mindset of those in the medical arts with treating a disease like multiple sclerosis.” (Id. at 13).
Undeterred, Novartis continued to press for allowance of the patent. Among other reasons, Novartis argued that the Garber reference did not conclude that the patient death resulted from fingolimod. Rather, Novartis argued that the Garber article indicates that the patient was also taking steroids, and there was a prior understanding that steroid use can substantially increase the risk of fatal varicella. Based on this, Novartis argued that Garber purportedly taught away from proactively vaccinating RRMS patients before administering fingolimod, and rather only suggested increased vigilance, namely, watchfulness for signs and/or symptoms of infection. Furthermore, Novartis argued that vaccinating a patient before administering fingolimod would delay treatment for RRMS, which could increase the risk of relapse. (App. 15/986,992, Amendment, Jul. 9, 2019). Because of this, Novartis suggested that vaccinating before administering fingolimod should be patentable.
The Examiner continued to disagree with Novartis. The Examiner pointed out that while increased “vigilance” may have been prescribed in the art for patients that had already commenced fingolimod therapy, Garber did not teach away from vaccinating patients against varicella zoster infection who had yet to commence fingolimod therapy. (App. 15/986,992, Office Action, Aug. 22, 2019 at 8-9). The Examiner also disagreed that Garber did not suggest that fingolimod was responsible for the death of the chicken pox patient given that the article states that the “announcement has cast a pall on FTY720.” (Id. at 8).
Then something peculiar happened. Novartis conducted an interview with the Examiner. This, in itself, is a common practice during the patent application process whereby the applicant, or the applicant’s patent agent, meets with the Examiner either in person or by phone to discuss the pending application. Yet, what was peculiar was that the interview was not with the Primary Examiner who had been issuing all the prior Office Actions rejecting Novartis’ patent application. Rather, the interview was conducted with that Examiner’s supervisor. And during that interview, the Supervisory Examiner agreed to allow the claims as long as they required vaccination before administration of fingolimod.
On the one hand, it is not necessarily peculiar that a Supervisory Examiner would conduct an interview in lieu of the Primary Examiner overseeing the application. On the other hand, the Supervisory Examiner appears to have allowed the patent claims despite the prior rather fervent rejections by the Primary Examiner. Indeed, the Primary Examiner repeatedly asserted that vaccinating for chicken pox before administering fingolimod would have been obvious in light of Garber. So what changed?
Looking at the Notice of Allowance does not necessarily shed much further light. In this case, the Notice of Allowance, which is the document issued by the Patent Office explaining why a patent application was allowed, offers reasons why this patent was allowed. Those reasons state that the prior art does not “expressly disclose[] verbatim that vaccinating a patient determined to be at risk of contracting infection caused by varicella zoster virus thus limits the risk of infection caused by varicella zoster virus.” (App. 15/986,992, Notice of Allowance, Dec. 11, 2019 at 3).
Huh? It may be necessary to read that sentence a few more times to understand what it says. Because, after you read it a few more times, you realize that it really says what you think it says. Namely, the Examiner appears to have determined that Novartis’ patent application was allowable because the prior art purportedly does not teach that vaccinating a patient, who has not had chicken pox, with a chicken pox vaccine, may reduce the risk of contracting chicken pox.
Hmm . . . The actual text from the Notice of Allowance is copied below.
(App. 15/986,992, Notice of Allowance, Dec. 11, 2019 at 3)
Novartis’ principle argument in favor of this patent is that it was not obvious to administer a chicken pox vaccine to patients still susceptible to the chicken pox, before administering fingolimod. As further proof of that, Novartis argued that other DMTs have not followed this paradigm of recommending vaccination before drug administration. Novartis specifically argued, “[o]ther DMTs not following this paradigm, so how is it obvious?” (App. 15/986,992, Agenda for Examiner Interview, Oct. 2, 2019).
For patients prescribed fingolimod, who are still susceptible to the chicken pox, there is essentially two options: either you vaccinate or you don’t vaccinate. Both options were indisputably known to doctors before Novartis’ patent application. The fact that there may purportedly be disagreement between those two very finite options does not necessarily make either option not obvious. By that logic, both options would be patentable. Just because there may be disagreement among doctors shouldn’t mean that everybody gets a patent on their opinion.
Ok, but what does Novartis’ patent say actually about this? Does the patent specification elucidate information on Novartis’ purported “invention” for why vaccinating before administration was inventive or surprising? Unfortunately, the patent itself discloses no data, no clinical trials, no tests and no evidence regarding this invention. Apart from the patent claims themselves, the meat of the specification only mentions the phrase, “varicella zoster virus” three times. And the sum total of the disclosure on the claimed invention is this sentence: “Prior to starting administering the S1P receptor modulator or agonist, the patient may be tested for history of infections, e.g. viral infection, in particular chickenpox. In case the searched serology is negative, the patient may be vaccinated, e.g. against varicella zoster virus or influenza virus.”
So what does all of this mean? It means that Novartis scrapped together another patent at the last hour in an attempt to stave off generic competition for Gilenya® for another eight years. That patent is directed to vaccinating patients against chicken pox before administering fingolimod. Novartis claims that before its invention, reasonable doctors would not have done that. Indeed, Novartis claims that it was the one that came up with the idea of vaccinating patients against chicken pox before administering fingolimod.
Because Novartis was awarded a patent, the burden is now on the generics to prove that patent is invalid. And they must do so by a high standard of “clear-and-convincing evidence.” And if they fail, then consumers will have to wait another eight years for lower-cost generic fingolimod for Gilenya®. And the time required for the generics to litigate the validity of the ‘179 patent could itself take years. And then who wins?