The FDA has approved an old recreational drug where an unwelcome side-effect is now the indication!

Orange Book Insights #1

Welcome to the inaugural posting of Orange Book Insights. This will hopefully be the first of many.

Not long ago I saw a headline in my local newspaper about the first approval of a cannabis-derived drug. No, this posting is not about that approval. My point is that the cannabis-related approval was considered significant enough to warrant an FDA press release and a newspaper headline.

No, this posting is about an equally well known recreational drug whose approval in December 2017 garnered, as far as I can tell, very little (if any) publicity. There was no press release from the FDA and no separate statement from the Commissioner, as there was for the cannabis-derived drug. No, this posting is about the FDA’s approval, on December 14, 2017, of (drum roll, please . . .) COCAINE!

Yes, cocaine is now an FDA approved drug (GOPRELTO (cocaine hydrochloride, 4% solution) from Genus Life Sciences Inc.). My discovery of GOPRELTO was completely fortuitous. I was looking at the “Full Expirations” index of my Orange Book Companion^®(“OBC”) online service just out of curiosity. I wanted  to find the drug whose next patent expiration date is the furthest out into the future. That drug turned out to be GOPRELTO whose only patent in the Orange Book does not expire until February 7, 2037 (OMG, how old am I going to be when that patent finally expires?). It was only after I went to the full GOPRELTO listing in the OBC that I discovered that the active ingredient in GOPRELTO was cocaine.

So cocaine is now an FDA-approved drug. This should be its first approval (at least in the modern era of the Food, Drug and Cosmetics Act) since GOPRELTO was granted five years of New Chemical Entity exclusivity under the Hatch-Waxman Act. This means that this was the first approval of the active moiety of GOPRELTO, cocaine, without regard to the hydrochloride entity of the drug. So my next question was “for what indication”?

The Indication

Let’s go back the so-called Disco Era of the seventies in which cocaine has been described as “the drug of choice.” This was a powdered crystalline cocaine salt that was inhaled (snorted) into the user’s nose so that the drug could be absorbed through the nasal mucosa. Allegedly, high rollers used to relish the idea of snorting coke using a rolled up $100 bill! This was all before the introduction of smokable, free-base “crack cocaine.” 

One complaint that was heard during that time (strictly second hand!) from users of this so-called “nose candy” was that of intranasal numbness. So, for what indication has cocaine hydrochloride now been approved so many decades after its heyday? Here it is directly from the GOPRELTO label:

GOPRELTO (cocaine hydrochloride) nasal solution is indicated for the induction of local anesthesia of the mucous membranes when performing diagnostic procedures and surgeries on or through the nasal cavities in adults. 

So there you have it. The side effect has become the indication! Or, in the parlance of computer geeks, “it’s not a bug, it’s a feature”!

The Patent

What kind of patent is listed in the Orange Book for an aqueous cocaine HCl drug product? It cannot be directed to the active ingredient. That is old. It cannot be directed to the nasal numbing effect, in general. That is old, too. So, what is claimed?

The GOPRELTO patent listed in the Orange Book is 9,867,815. The preamble of each of the granted independent claims (1, 10 and 26) recites that they involve a method of administering a local anesthetic to a patient who is a member of  one or more specific subpopulations: those with hepatic impairment (claim 1), those with hepatic or renal impairment (claim 10), and those who are >65 years of age (claim 26).

So, in other words, inducing numbness along mucous membranes in patients with liver and/or kidney function issues, or who are >65.

The claimed method steps, themselves, simply call for soaking pledgets, such as those made from a “cottonoid” material, in about 4 ml of a solution comprising cocaine HCl (3.6-4.4%), sodium benzoate (0.07-0.20%), citric acid (0.125%), and an optional coloring additive, and then contacting the pledgets with a mucous membrane, such as nasal mucosa, for a period of time, and then removing them.

The '815 patent was filed without a provisional application, and was allowed twice without rejection with an intervening continuation. The patent was granted in less than a year from its first filing date under expedited examination without publication (so no need to look for foreign filings).

The Examiner found the closest prior art to be a package insert from the Lannett Company of Philadelphia, PA ("Lannett") for a cocaine-based topical anesthetic “of accessible mucous membranes of the oral, laryngeal and nasal cavities.” According to its disclosure, the drug was first marketed without FDA approval in December 2008. One method disclosed in Lannett used a 4% cocaine HCl aqueous solution (smack-dab in the center of the range recited in the ‘815 patent’s claims). The drug used in the Lannett method was formulated with exactly the same excipients as GOPRELTO: sodium benzoate, citric acid, and coloring, except that the concentrations of those excipients were not mentioned. The Lannett disclosure taught that the method could be carried out using cotton applicators or packs.

The Examiner concluded that Lannett could not inherently anticipate the ‘815 claims because it did not disclose the amounts of sodium benzoate or citric acid in the formulation. The Examiner further did not find any teaching or suggestion in the extensive prior art search that he carried out to use the ‘815 patent’s claimed amounts of those excipients.

Moreover, the Examiner also found that the prior art did not teach or suggest administering the Lannett formulation to patients having renal or hepatic impairment. And so he finally concluded that the claims were novel and nonobvious. The Examiner came to all of these conclusions while apparently suspecting that the inventors used the actual Lannett Company’s prior art drug in the testing described in the ‘815 patent’s examples.

So what might an ANDA applicant argue in asserting invalidity of the ‘815 patent in a Paragraph IV litigation? Or should they just try to reformulate to avoid the claimed excipient concentrations? Comments are welcome.

Broad Indication but Narrow Claims

Does there even need to be a Paragraph IV challenge in order for an ANDA to be approved? The indication, as apparent above, is very broad. The claims, as described above, are limited to small patient subpopulations, and so are quite narrow. To paraphrase a former children’s educational TV show host who is currently the subject of a critically acclaimed documentary, “can you say ‘Section viii carve-out'"?

Not so fast! Would the FDA allow the Indication and Usage section of the label to be amended to end with “except in patients with renal impairment, hepatic impairment, or who are >65 years of age”? If the FDA did allow such an exception, would not the continued inclusion of label sections “8.5 Geriatric Use”, “8.6 Renal Impairment” and “8.7 Hepatic Impairment,” make the exception a moot point in the eyes of physicians? Those three sections basically say that the claimed method can carried out on patients in the claimed subpopulations without safety or efficacy concerns. Since doctors are not prohibited from using a drug off-label it would likely be full steam ahead!

So what would be the effect of adding the exception and also deleting those three sections? Those sections generally supply essential information, and are commonly found in drug labels. Would adding the exception to the indication plus deleting the three sections confuse physicians about the purpose of the exception?

Physician: “they say not to use the drug in these patient subpopulations, but there is nothing in the label that tells me why. If there is a danger to the patient wouldn’t they say so”?

Greater regulatory minds than mine will hopefully expound on these issues in the comments. However, we shall have to wait until the NCE-1 date to see if a generic company wants to get into the cocaine business by seeking a carve-out or filing a Paragraph IV challenge. Alternatively, potential ANDA filers could wait until the patent expires in 2037! Since I am already in the geriatric subpopulation of independent claim 26, who knows where I will be by then!

Final Thoughts

A second patent that might be listed, 10,016,407, was granted on July 10. The ‘407 patent was terminally disclaimed over the ‘815 patent. We will have to wait and see if that gets listed in the Orange Book. Stay tuned!

I chose the approval of GOPRELTO for my first blog posting because I found it interesting that the first approval of cocaine slipped in virtually unnoticed while a cannabis-based drug got headlines. But then again, the treatment of a serious seizure disease will beat numbing your nose anytime!