Orange Book Insights No. 26: Interesting New Patents From FDA''s Orange Book: Vol. 41, Supplement 3

Is a method of preventing certain patients from receiving a drug a “method of using” the drug?

Patents directed to computerized methods of preventing a patient from receiving a drug have previously been listed in the Orange Book. Most notable are patents listed by Celgene for their thalidomide product, THALOMID®. Thalidomide can cause significant birth defects if a woman takes the drug while pregnant. The Celgene patents were directed to a computer system meant to prevent a pharmacy from selling THALOMID to a woman who has not had a recent negative pregnancy test.

So when I saw that the “What’s New” for Supplement 3 of my Orange Book Companion® showed that Zogenix had listed a patent with computer system claims for their FINTEPLA® (fenfluramine) product, I thought of one of Yogi Berra’s famous witticisms: “it’s déjà vu all over again”!

Why might FINTEPLA have a computer system patent? Fenfluramine was part of an infamous diet drug combo called “fen-phen” in the 1990’s. Fen-phen was blamed for serious and sometimes fatal cases of pulmonary hypertension and heart valve problems. The computer system claimed in the newly listed Patent No. 10,950,331 is meant to prevent patients from receiving FINTEPLA unless they have had their regularly scheduled echocardiograms to detect any sign of heart valve damage. And, no, fenfluramine is not for weight loss anymore! The current indication for FINTEPLA is the “treatment of seizures associated with Dravet syndrome in patients 2 years of age and older.”

The preamble of independent claim 1 of the ‘331 patent describes the claim as a “method of treating one or more refractory epilepsy patients with fenfluramine.” [emphasis added]. However, the eleven paragraphs of the claim are mostly directed to what could best be described as a computerized record keeping system for the REMS that the FDA required the NDA holder to create. To give you a sense of what this patent is all about, here are the first two paragraphs of claim 1 that follow the preamble:

providing a data storage facility comprising a database of patient records, each patient record having a medication authorization field for entering a first prescription for fenfluramine to treat the patient;

a central controller having one or more processors coupled to a communication network, which central controller is coupled to the data storage facility to read and write data to the data storage facility via the network; and . . . [Col. 20, lines 35-43].

Why create this system? That question is answered in two short phrases buried within the eleven paragraphs of claim 1:

the patient receives or continues to receive medication only on entry of satisfactory echocardiography assessment results, [Col. 20, line 67 to Col. 21, line 3 (emphasis added)]

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whereby overuse or misuse of fenfluramine is inhibited [Col. 21, lines 11-12].

Preventing overuse or misuse of fenfluramine is, of course, a laudable goal. But does the patent actually claim “a method of using” fenfluramine that would make the patent eligible for listing in the Orange Book under FDCA Sec. 505(b)(1)? I am sure that there are commentators out there who will argue that the claim should at least contain a step that is directed to treating seizures associated with Dravet syndrome with fenfluramine. Maybe someday a court will address this eligibility question.

While we are waiting for that court opinion, what better quote can I drag out from the past than Senator Charles Schumer’s criticism in 2002 of Celgene’s computer system patent listings for THALOMID. Senator Schumer considered Hatch-Waxman to apply to patents on drugs, not computer systems. At a hearing on Hatch-Waxman issues, he discussed a piece of proposed legislation (which was never enacted, BTW) called the Greater Access to Affordable Pharmaceuticals (“GAAP”) Act. In his statement, Senator Schumer criticized several “so-called innovations” whose patents he did not feel should be listed, including the THALOMID computer patents:

Our bill would require a name-brand drug company to first prove to a judge that the case has merit before the [30-month] delay is triggered. Now, let's look at some of the innovations, so-called innovations, that the brand companies are listing in the FDA's Orange Book. It's these kinds of patents which can automatically delay competition.

* * *

On Thalomid, a cancer drug, the company has come up with not one but two computer programs that pharmacists can use when doling out prescriptions. Same drug, new computer program. That is what we are talking about here to get a new patent. Not a new drug, a new computer program.

Give me a break. (emphasis added).

[United States Senate. Committee On Health, Education, Labor, And Pensions. Closing The Gaps In Hatch-Waxman: Assuring Greater Access To Affordable Pharmaceuticals, (S. Hrg. 107-450; Date: May 8, 2002). Text in: govinfo.gov; Accessed: April 30, 2021.]

(OK, I do not know for sure that Senator Chuck actually raised his voice to emphasize that last sentence, but the transcript shows that he said it, and the words speak for themselves as a sign of his frustration).

The Cocaine Saga Continues

A new patent for GOPRELTO (cocaine hydrochloride) was listed in the Orange Book in Supplement 3. Patent No. 10,933,060 claims a method of inducing local anesthesia in the nasal cavity of a patient so that a medical procedure may be carried out. In a previous blog posting I had remarked about the irony that the nose numbing effect of cocaine, which was a complaint from partyers during the Disco Era, is now an FDA-approved indication.

The sole independent claim of the ‘060 patent (claim 1) recites that the method is carried out using an aqueous solution of three ingredients: cocaine hydrochloride, citric acid and sodium benzoate. Each of the three ingredients is restricted to a specific concentration range in a way that is similar, if not identical, to four earlier GOPRELTO patents.

Like those four earlier patents, there is at least one additional element of claim 1 that distinguishes the method of the ‘060 patent from those claimed in the previous patents. In the ‘060 patent, that element is a measurement called the “absorptivity factor” (Cmax/AUCinf). Both Cmax and AUCinf can only be determined through blood tests on the patient who needs their nasal passages numbed. The AUCinf requires multiple blood samples to be taken over time. Can you imagine the doctor who is planning to carry out the medical procedure interrupting their work to take multiple blood samples from a patient in order to assure that they are not infringing the patent?

I think it would be interesting to know if the “absorptivity factor” element could ever be avoided when the citric acid and sodium benzoate concentrations are within their respective claimed ranges. Such a result would show that a GOPRELTO competitor could avoid inducing infringement of the ‘060 patent by discovering a citric acid/sodium benzoate combination that, while each is within their respective claimed range, does not result in an absorptivity factor that is within its claimed range. However, if such a result is not possible, there is a plausible argument that the absorptivity factor element of the claim is simply an inherent result of administering the recited cocaine, citric acid, and sodium benzoate formulation. In such a case, absorptivity factor would not further limit the scope of the claim.

The lack of the absorptivity factor as a claim limitation could leave the claims of the ‘060 patent open to 35 USC Sec. 102 “on sale” and/or “public use” attacks if earlier topical cocaine products were formulated with citric acid and sodium benzoate within the ‘060 patent’s claimed ranges. According to an article in the Hyman, Phelps & McNamara FDA Law Blog, a company called Lannett had been marketing an unapproved cocaine topical solution since December 1, 2008 (they eventually obtained approval using the 505(b)(2) pathway in 2020 through their Cody Labs subsidiary). So Lannett’s December 2008 launch was long before the February 7, 2017 earliest priority date of the ‘060 patent. Further, a package insert dated March 2008 for Lannett’s product disclosed citric acid and sodium benzoate as excipients.

Interesting, huh? But there is more. GOPRELTO’s manufacturer, Genus Lifesciences filed a patent infringement suit against Lannett on June, 8, 2020 in which they asserted three Orange Book listed patents. Then, on March 23, 2021, Genus filed a First Amended Complaint in which they asserted three additional Orange Book listed patents, one of which is the ‘060 patent.

So what happens to the ‘060 patent if the “absorptivity factor” is not really a limitation, and Lannett can demonstrate that their formulation of cocaine, citric acid and sodium benzoate has remained unchanged since 2008? By accusing Lannett of infringement Genus is alleging that all of the remaining limitations of their independent claim 1 are met by Lannett’s products. This raises the possibility that the old adage: “that which infringes if later anticipates if earlier” might be heard from in this case. Lannett has not yet answered the First Amended Complaint, so we need to stay tuned.


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