A New Patent Listing Champion!
First, if you haven’t seen it yet, the USPTO has replaced their old patent search interface of “Quick Search”, “Advanced Search” and “Patent Number Search” with a new system called Patent Public Search (“PPS)”. The former “Quick Search” is no longer available where you could use a dropdown to select sections of patents to search (such as the ever popular “Claims”). For patent number searching in PPS, just type the patent numbers (each separated by a space) in the search field and click the “PN” button. Other searches are similar to the old Advanced Search, except that you may have a whole new set of codes to learn. One problem for Mac users is that PPS does not work with Apple’s Safari browser. So Mac users will need to install Google Chrome or Mozilla Firefox.
This change at the USPTO broke the patent number links in my Orange Book Companion® (“OBC”). I had barely gotten off my flight to Phoenix to visit family on October 1 when I discovered that none of the patent number links in the OBC worked anymore. So I had to go right to work revising the programming that creates the OBC’s patent tables so I could get Supplement 9 posted for my subscribers on time.
A New Patent Listing Champion!
Supp. 9 added 132 new patents to the FDA’s Orange Book. That is a lot more than the usual 30-70 patents! It turned out that 93 of those new patents were listed for one product! Yes, 93 patents for a single product. It’s not like this is a product that contains a New Chemical Entity. In fact, it is just a combination of two old active ingredients whose patents expired years ago!
The product in question is AUVELITY (dextromethorphan HBr and bupropion HCl) from Axsome Therapeutics. Feel free to check out the very long list of patents in the free “What’s New” for Supp. 9 that is available from the public Orange Book Companion home page. Be sure to read my warning about the changes that PPS brought to the ability to view the text of a patent before you click on one of the OBC patent number links.
AUVELITY was approved on August 18, 2022 for the treatment of major depressive disorder (“MDD”), and is an interesting combination. Dextromethorphan is well known as a cough suppressant. It is the “DM” component of Robitussin® DM. Bupropion is a well known antianxiety agent, previously marketed by Bristol Myers-Squibb under the trademark BUSPAR®. However, its inclusion in AUVELITY is not so much for its antianxiety effect, but for its ability to inhibit cytochrome P450 2D6 (CYP2D6) which inhibition slows the rate at which a patient metabolizes dextromethorphan. In fact, forty-three of the ninety-three patents listed for AUVELITY claim methods of using bupropion to reduce the rate of dextromethorphan metabolism. Here are a few examples of claim 1 preambles from several of those forty-three patents that illustrate the variety of ways that the enhanced bioavailability of dextromethorphan is claimed. None of these patents have claims that mention depression in any way:
• 9168234: 1. A method of increasing dextromethorphan plasma levels in a human being, comprising• 9198905: 1. A method of increasing the metabolic lifetime of dextromethorphan, comprising• 9700553: 1. A method of correcting extensive metabolism of dextromethorphan in a human subject in need thereof, comprising• 9707191: 1. A method of reducing a trough effect of a dextromethorphan in a human subject, wherein the human subject is an extensive metabolizer of the dextromethorphan in need of treatment with the dextromethorphan, comprising
Since the approved indication for AVELITY is:
the treatment of major depressive disorder (MDD) in adults,
there can certainly be a question about the above-illustrated patents (and the thirty-nine others with analogous claims) being eligible for listing in the Orange Book. The argument would likely be that these patents, which are directed to methods of increasing dextromethorphan exposure in a patient, do not claim AUVELITY’s sole approved use of treating major depressive disorder.
One More Time: Watch Out For The Breadth Of Your Use Codes
I also noticed another interesting thing about the AUVELITY Orange Book listings. All of the listed patents contain method claims, and every single one of those patents has the same use code, U-3419, that has the following description:
dextromethorphan and bupropion in combination to treat major depressive disorder.
For simplicity, I shall refer to the use code description as the “use code,” as the FDA did in the Federal Register notice for the Medicare Modernization Act Final Rule (see 81 Fed. Reg. 69580 (October 6, 2016) at 69580, column 3).
Since the above use code is a nearly verbatim recitation of the approved indication for AUVELITY, was Axsome Therapeutics saying via the same use code that all ninety-three patents claim the same thing? Wouldn’t that have created a §101 statutory double patenting issue?
Well, it turns out that the ninety-three patents listed for AUVELITY do not all claim the same thing. First, there is a viable argument that the forty-three patents directed to methods of increasing dextromethorphan exposure in a patient do not claim the treatment of “major depressive disorder”, and so are not eligible for listing in the Orange Book in the first place.
Second, all of remaining fifty patents claim subject matter that is narrower than the indication recited in the U-3419 use code recited above. That, of course, creates a different problem. Instead of having the same use code, each listed patent should have a different use code since they all claim somewhat different subject matter!
FDA regulations require that use codes should not be broader than the broadest claim in a patent that is being listed as a method of use patent. As discussed by the FDA in their response to comments concerning the agency’s regulations to implement the Medicare Modernization Act (“MMA):
Although we decline to provide hypothetical examples, the following general principles illustrate the clarifying revisions to the regulations regarding the content of use codes.
* * *
Patented method of use is narrower than an indication or other approved condition of use: If the method of use claimed by the patent does not cover an indication or other approved condition of use in its entirety, then the NDA holder must describe only the specific approved method of use claimed by the patent—not the broader indication or other approved condition of use that may include, but is broader than, the use claimed by the patent.
81 Fed. Reg. 69580 (October 6, 2016) at 69598-99 (italics in the original; underlining for emphasis).
In the case of AUVELITY, there are fifty patents that all claim methods of treating depression in some way. Small differences in the independent claims are the rule! For example, the claims of seven patents require the patient to be an “extensive metabolizer of dextromethorphan” (e.g., 10,548,857, 10,596,167) or at least an “intermediate metabolizer of dextromethorphan” (e.g., 11,213,521, 11,311,534). However, in other patents the ability of the patient to metabolize dextromethorphan is not a claim limitation (e.g., 10,772,850, 10,780,064).
It turns out that the claims of a number of the listed patents are directed to specific treatment regimens, and so are easily seen as being narrower than the very broad U-3419 use code
For example, in some patents, the claims are limited to twice a day administration (10,548,857), while in others once or twice a day administration is claimed (e.g., 10,596,167, 10,786,469). The length of administration also is varied from patent to patent. A couple of patents contain claims that require at least eight consecutive days of treatment (10,548,857, 10,596,167), while a couple more require at least 14 days of treatment (10,772,850, 10,881,657).
There is one patent whose claims require a regimen of once a day for the first three days followed by twice a day for at least eleven days (10,780,064). There is one patent whose claims require a longer period of treatment: once or twice a day for at least 23 days or at least 30 days (10,799,497).
One patent in particular stood out because the independent claim is limited to treatment of major depressive disorder in patients of Asian descent (10,780,064). Also included in that patent are dependent claims that are limited to patients of Chinese, Japanese or Korean descent.
So, shouldn’t the very broad U-3419 “dextromethorphan and bupropion in combination to treat major depressive disorder” shown for all of the patents listed for AUVELITY be replaced with use codes that are limited to the breadth of the broadest claim of each individual patent? The FDA’s response to comments concerning their implementation of the MMA certainly sound like they should be.
It’s All In The Family
One might suspect that the fifty AUVELITY patents that claim a method of treating major depressive disorder might have been the result of a small number of patent families that were created through multiple continuations. Such a conclusion might be why a bipartisan mix of US senators sent a letter to USPTO director Kathi Vidal in June expressing concern over so-called “patent thickets.” The senators were particularly concerned about overuse of continuation filings to create patent thickets as a potential means of delaying generic entry. But why were the senators concerned about thickets? One point was made in a July 21, 2022 "FDA Law Blog" posting discussing patent thickets and continuations where author Sara Koblitz said “while the term of the patent is not extended, multiple patents increase litigation burden.” In other words, while patent thickets cannot extend exclusivity for a drug, they might result in a longer period of litigation during which the ANDA filer might be unable (due to the 30-month stay) or be reluctant to launch due to the threat of treble damages for willful infringement.
So what do the patent families for AUVELITY look like? Not what you might think! By coincidence, the OBC free sample for “Patents Grouped by Family” happens to show all products whose trademark begins with “A”. So you do not need an OBC subscription to see the ninety-three patents listed for AUVELITY organized by patent family! Just go to the public OBC Home Page and click on the “Tradename–A Families” link. Then scroll all the way down to AUVELITY.
The first thing you will see at the top of the patents column is that, while AUVELITY has ninety-three patents listed, there are also a large number of families -- seventy-four to be exact. That results in an average of less than two patents per family! The two largest AUVELITY patent families contain only seven and five patents, each. That is quite different from VASCEPA, about which I have previously blogged. VASCEPA has larger families (the two largest have fifteen and thirteen listed patents, respectively), and has an average of over eight patents per family among its total of sixty-nine listed patents.
What I noticed about the AUVELITY patents is that many seem to have a number of continuations-in-part rather than just a whole line of continuations. It also seems that in many cases such patents are the sole member of their family. In fact, the final fifty-six patents for AUVELITY in the Tradename-A Families list show only one patent per family. So could it be that filing lots of CIPs will be less likely to show up on someone’s radar screen as a patent thicket? Your thoughts are welcome.
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