I recently had a question from an interested reader, who’s outside of medicinal chemistry, wondering about how we find room to work in patent space. From his viewpoint, there seemed to be many areas that were so worked over that he found it had to see how any new project could make headway, or be able to keep track of what had already been claimed. There’s certainly something to that. Some structural classes have been beaten on pretty thoroughly over the years, for sure, but there are ways.
A quick bit of background, keeping in mind that I Am Not A Patent Lawyer. I’m going to focus on “composition of matter” claims, where you claim the actual chemical compound itself, rather than method/use claims, which are a different beast. Composition of matter is actually one of the fundamental pieces of US patent law itself. Title 35 of the US Code, describing what’s eligible for a patent, says that you can get one for “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof”. So for a drug, that’s an exact description of the new molecule you’ve made.
You’ll note that it has to be both new and useful (novelty and utility), but for a drug patent, utility can be a pretty easy bar to clear – this new compound is useful for giving to patients in need of a treatment for medical condition X. (That’s not always the case, but we’ll continue with the ones where it is). And that takes us to “new”, which is where the original question comes in. After there’s been a lot of patent activity in a particular chemical class, just how new can a compound be?
Once in a while, you’ll see a patent that claims one compound and one compound only. But that’s rare; most of the time there’s a structure with a bunch of R and X and Y groups hanging off of it. That’s a “Markush” structure, named after Eugene Markush, who filed a patent in 1924 whose prosecution ended up establishing this as a legitimate way to make claims in chemical space. You can vary things by length of a chain, by position and place of attachment, by listing acceptable substituents, and so on, and as you’d imagine, this can rapidly lead to a huge universe of possible compounds. I’ve seen some truly insane Markush structures over the years, things that if fully enumerated would reach into hundreds of millions of compounds.
If you have a hot new molecule you’re interested in developing, you’ll want to search these things. Markush searching is painful – no other way to describe it. The existing computational methods for doing it invariably pull in far more patent filings than you really have to worry about, because of all the vague claim language out there, and you have to dig through them manually at that point. But you can sort things down a bit. For example, you’d first want to see if any of those patents are going after the same sort of activity/target/disease that you are, because those are clearly the ones that you should be most worried about.
Then you have to get a sense of just how deep into the claims any overlaps seem to go. What you have to keep in mind is that these Markush lists are never fully exemplified – that is, the specific compounds are not all described with their unique physical properties to show that they were really prepared. There’s not enough time or money in the world for it. So you need to see what the patent in question really starts to zoom down on, what it “teaches toward”. A patent is required to state the best “embodiment” of the invention, and its claim are generally written in an order that narrows down on that. If your compound hits the outer penumbra of their Markush structures, but their patent then heads off in another direction when the claims start to get more serious and directed, that’s a good thing. At the other end of the scale, if they specifically exemplify your exact compound, you have a real problem.
It’s that latter situation that comes up in the heavily-worked-over parts of chemical structure space. Not only are there a heap of Markush overlaps, but there are an awful lot of real compounds, too, and once they’ve been disclosed, really disclosed as in “here’s how you make this one and here’s its unique spectral data to prove that we did it”, you absolutely cannot get a composition of matter patent – it is “prior art” and no way around it. For the most part, you just want to stay away from areas like this – surely you have another structural series that’s just as interesting? If you have to pick your way through the cratered landscape, though, it can often be done. Chemical space is large, insanely large, and there are almost always variations that will allow you to prepare a compound that has never been described. Fluorinate it over here, add a heteroatom over there, tie a ring back – there’s usually something, and it all depends on how much you want that part of chemical space and how much time and money you’re prepared to spend to find the right piece of it. It would definitely serve you best if some of these changes also made a difference in the compound’s activity and usefulness, since there’s a “doctrine of equivalents” that basically says that a difference that makes no difference is no difference, but you can generally find enough of a ledge to stand on.
The general feeling among med-chemists is that any patent can be broken by enough of a determined effort, but it’s a bit like putting a lock on a door. Any lock can be defeated by enough of a determined effort, too – you just have to figure out how strong to make it (that is, how much money to spend on it) to protect what’s behind it. Shoring up a patent claim involve exemplifying more compounds in as many plausible variations as you can think of, until someone cries “Halt! Enough!” The hope is that you haven’t left any incredible holy-cow analogs untouched, because those would have the advantage of not being obvious “to one skilled in the art” as the patent lawyers say, and you certainly weren’t teaching toward them in your claims, either. Every drug composition-of-matter patent is, in theory, vulnerable to this sort of thing, but for the most part, given the odds of this happening, it’s a better use of time and money to try to find something that’s more in the clear, unless the patent in question leaves some obvious gaps and the potential benefit is clear.