Patent Busting: Move a nitrogen, file a patent
September 26th, 2025 By John Widen
In the patent busting world, Thursdays are patent day for medicinal chemists in the United States. This can be a great day if you or your company is publishing a patent application. Especially, if it is the first within a series! It is a joyous day after waiting 1.5 years to finally feel at ease (at least somewhat) and know that the claims and molecules are now owned by your company. It takes at least a few years for the claims to be awarded, but that typically isn’t a major issue. The time between the filing and publishing of a patent application is a long-held breath and involves searching new patents every Thursday.
On the other hand, it can be a sad day if you run a search and find that you’ve been scooped.
In my short career, I have already had this happen. I cannot disclose the target, but it was, and still,
is a target with very crowded prior art. At that point in time, almost every week resulted in at least
one newly published patent application. And sure enough, one week a patent application was disclosed
that covered chemical matter we had discovered independently. It wasn’t the end of the world because
there were other avenues to pursue and further improvements to be made. The race to FDA approval for
this target is still ongoing five years later.
Patent applications that are not directly covering your claims or chemical matter can be incredibly useful. In that case, another company’s work can speed up your own efforts. Maybe they explored an R-group that your team hadn’t focused on. You might as well stitch it onto your molecule and see what happens. It always amazes me the diversity in thinking and approaches between different medicinal chemistry groups. You might think something is obvious but then others never seem to pursue the same idea, or vice versa. The reverse instance is that you think there is no way somebody else will try the idea and it pops up in the literature.
In terms of obviousness, nothing could be more obvious than moving a nitrogen one position. Remember,
I'm not a lawyer and not providing legal advice. The word obviousness is an important one in legalese, but here I am
simply stating that moving a nitrogen around a ring to escape prior art is a relatively common approach by medicinal chemists. But
as mentioned above, it depends on the person!
There are times where the difference between one atom can have profound effects on a molecule,
but I feel pretty safe stating that a lot of the time it is for the sole purpose of getting out of prior art.
That brings us to the topic of this article, which is a case study of exactly that: Move a nitrogen, file a patent.
Casma Therapeutics recently disclosed a patent application involving TRPML1 agonists. They have been developing small molecule agonists towards TRPML1 at least since 2019 when they filed their first patent application in this space. TRPML1 is a divalent cation channel that is predominantly active on lysosomes and endolysosomes. Calcium flux via TRPML1 from lysosomal compartments into the cytosol activates a transcription factor, TFEB (Transcription Factor EB). Activation of TFEB occurs through a dephosphorylation and translocation into the nucleus to transcribe genes related to lysosomogenesis, autophagy, and exocytosis.
These initial Casma patent applications were part of a patent busting exercise based on chemical matter related to literature compounds such as ML-SA1 and ML-SA5 (Fig. 1A). There has been a lot of work developing TRPML1 agonists towards neurodegenerative diseases and cancer. Most publicly disclosed patent applications describing TRPML1 agonists riff off of scaffolds similar to ML-SA1&5. Libra Therapeutics, Casma Therapeutics, Caraway Therapeutics, and others have patent applications in this space.
Beginning in 2021, Caraway Therapeutics has published several patent applications based on a different scaffold
(Fig. 1B). This scaffold supposedly originated from a high-throughput screen
conducted by the NIH (National Institute of Health) against TRPML1. Data to this screen is
publicly available on PubChem (PubChem AID: 624414) and the data can be downloaded for free.
You can see that the central core and substitution pattern are the same between the NIH hit and
Example 101 from the Caraway application WO2023055920. The Markush structure from Caraway’s patent
applications dealing with this chemical matter covers diaza-indoles and indazoles. The core has two
positions, W1 and W2, that can be either a carbon or nitrogen. The dominating
scaffold by far across patent applications is the diaza-indole.
Casma Therapeutics must have liked what they saw in the Caraway disclosures
and decided to put effort into creating their own novel chemical matter based on
this new class of TRPML1 agonists. Casma’s recent TRPML1 agonist disclosure, WO2025193691,
published on September 18th, 2025. The Markush structure and Example I-1 are in Fig. 1C.
There is a striking similarity between the Markush structures and examples that represent many
exemplified molecules in both patent applications.
Don’t be fooled by the X on the Casma Markush structure. There are only two examples with a nitrogen at
that position within the 70 or so exemplified molecules. Those examples, I-40 and I-67, are inactive (not tested)
and in a lower potency bucket of 0.5-1 µM for their reported TFEB assay. The rest of the examples contain a
pyrrolotriazine core as seen in Example 1. Casma Therapeutics made an observation that Caraway did not go very
broad on their claims surrounding the central core of this scaffold. So, what did they do? Well, they moved a
nitrogen one position over! Not the most creative approach to patent busting but it certainly escapes Caraway’s
prior art and is one point of differentiation. This is a classic example of patent busting that some
shake their head at and see as a waste of time and resources. That is potentially true in this case
but without evaluating the properties of these new molecules, it is hard to say. Move a nitrogen,
file a patent was a successful strategy (at least thus far) in this case for Casma Therapeutics.
To be fair, Casma did make one other point of differentiation and that is at the piperazine substitution.
Caraway was also narrow in these claims and stuck to piperazine specifically at this position. Oddly enough,
Caraway also claims spirocyclic containing heterocycles in their earlier patent applications (Fig. 1B)
but never exemplify any of the compounds. It is a weird choice but I’m sure they had some reason for doing so.
Casma Therapeutics also saw this as an opportunity and point of a second differentiation from the Caraway genus.
For this one, they removed the nitrogen from the piperazine ring as seen in Example I-2 (Fig. 1C).
All to say that Casma seemed to throw creativity out the window and stick to the basics of patent busting on this one.
Move one nitrogen over and take one nitrogen away and BOOM. You have yourself novel chemical matter. Who knows?
Maybe these two changes were needed to improve the properties of these molecules and progress them into the clinic.
They do have some examples in the most potent bucket (EC50<100 nM). But…maybe not. We shall see!
Caraway was
purchased by Merck in 2023.
Merck had been involved in funding Caraway Therapeutics from
their inception and made the acquisition about 4 years after the
start of the company. Since that disclosure there has been a couple smaller published
patent applications expanding the genus around the original diaza-indole scaffold, mostly focusing
on differentiating the substitutions extending from the piperazine ring.
Time will tell if Merck has continued to work on TRPML1 agonists.
I’m confident in saying that it is very likely Casma Therapeutics has several
other patent applications to expand on this work coming down the pike.
For now, let this patent application serve as an example of moving a nitrogen one space over to bust another patent application series. Is this a great use of resources? I do not know. Is it creative? Definitely not. Could it lead to a better drug some day? Maybe. No one has started a phase 1 clinical trial for TRPML1 agonists yet. The field is wide open, and it is anyone’s game. Maybe you can convince your boss to move another nitrogen over a spot and stake your claim. Godspeed to you.
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