Smothering Competition or Protecting Progress?

The ethics of natural compounds and Markush patents

During my recent reading for a potential project, I looked at patents on psychedelic substances and plant medicines for the first time in many years. What I found was unedifying, but it definitely was educational.

The use of things like LSD and psilocybin for depression etc. can’t be patented as those wouldn’t be new or novel inventions. This is why existing uses of these molecules for legal commercial purposes have some interesting features. They will have a novel method of using them (paired with a particular therapy), delivering them (e.g. a special encapsulation) or use a compound that is just different enough from the original natural or unpatentable molecule for it to be considered a new thing. That last one is how we got Spravato, even though bog-standard ketamine is just as good or better for treating depression.

Let’s be clear: I’m not neutral on drug patents. They’re supposed to protect innovation. In practice, they exist to protect profit by legally enforcing monopolies and stifling competition.

Some of the worst offenders use what's known as a Markush claim, a legal structure that allows a patent to cover a whole family of compounds by describing a range of possible variations on a molecular scaffold. Some psychedelic patents on analogues of psilocybin, LSD, and others cover millions, billions or even trillions of hypothetical compounds in this way. (For more on this see Navigating the Psychedelic Patent Landscape.)

This is where things get ethically worse than your standard patent. Companies that file these claims might run in silico tests (computer simulations) to identify promising leads, but they’re not going to screen all the molecules they’ve claimed. They’re almost certainly not going to synthesize and test more than a tiny fraction. Yet for the 20-year lifespan of the patent, anything that falls within its scope is essentially off-limits: no manufacturing, no sale, no medical use by others.

Take mesembrine, for instance, an active compound in Kanna (Sceletium tortuosum). It's possible to use software to generate analogues of mesembrine without ever setting foot in a lab. Here’s one such analogue and a few things that RDKit says about it:

SMILES: CN1CC[C@@]2([C@H]1CC(=O)CC2)C3=CC(=C(C=C3)OC)C(=O)O

MW: 303.36 | LogP: 2.09 | TPSA: 66.84 | HBA: 4 | HBD: 1 | QED: 0.93

Rendered by https://cdb.ics.uci.edu/cgibin/Smi2DepictWeb.py

As far as I can tell, (and remember I'm neither a patent lawyer nor a chemist, so I could be wrong) this molecule doesn’t show up in databases like COCONUT or PubChem. Probably not ZINC either, though I couldn’t get the search to work, so maybe it is there. On paper, it might be slightly more active than mesembrine, or it might do nothing. I’m not qualified to say either way. What I can say is that if it falls under a Markush claim, no one else can touch it for the 20-year duration of that patent.

And even after the patent expires? It still might go nowhere. There’s less commercial incentive to develop or test compounds that can’t be re-patented or somehow exclusively monetised. No trials, no generics, no affordable alternatives. Just a long list of molecules that might have done some good, but no one will spend the money to test them.

It’s not easy for non-experts to figure out what’s covered and what isn’t. If it does fall under anything, I suspect it would be: ‘Alkyl-substituted derivatives of mesembrine and mesembrenone and therapeutic uses thereof’, patent number: US20240400508A1, which is currently ‘pending.’ Or maybe it fell within ‘Pharmaceutical compositions containing mesembrine and related compounds’, which expired in 2017.

But here’s the fun part. If this analogue isn’t already patented, the fact that I’m publishing it here may count as prior art. That means someone else can’t come along later and claim it as their invention. (This web page might not be forever, but there are ways of making sure something like this is searchable, regardless.)

I should make it clear that like so many things, there are better or worse uses for Markush claims. Using them so that someone doesn’t take your new drug that you spent millions inventing and getting to market, and change it by one atom to get around your exclusive control of it? Highly problematic in terms of what drug companies already do with their monopoly control of life-saving medications, but not the worst. Taking naturally occurring medicinal or psychedelic compounds and putting a billion-analogue fence around them? Worse. Much worse, actually.

Psychotria viridis. Image by Carlo Brescia via iNaturalist

Consider something like DMT. Sure, someone could try to patent every possible analogue of it, for a range of reasons. But they didn’t invent DMT, evolution did. They didn’t discover its psychedelic properties, Indigenous people like the Shipibo-Conibo did that. Later, drug-smoking hippies figured out you could vaporise it for quick trip to other dimensions. The person filing the patent wasn’t even the first to isolate and describe it in the scientific literature. And they definitely weren’t the first person to see its potential for enabling experiences of healing and wonder (that would be Indigenous people and yurt-inhabiting hippies, again.)

Markush Claims as Necessary Evils?

So, what, exactly, gives someone the moral & ethical right to take that unearned knowledge and monopolise anything derived from it, for the next 20 years?

The best I can come up with is that without very robust intellectual property protections, no pharmaceutical company would invest the millions of dollars needed to get a new medicine onto the market. So, the argument goes, Markush claims are a necessary evil if we’re to have commercial drug development. But this entire argument relies on the assumption, as unchallengeable truth, that our civilisation can only develop new medicines within a particular version of corporate capitalism.

That’s the thing about necessary evils, they’re only ‘necessary’ in particular contexts.

I think we’re going to get some very hard lessons in just how socially and environmentally unsustainable our current economic practices are, almost certainly within the lifetime of some patents I’ve read today. So, let’s hope we figure out how to do new drug development outside of the current corporate model.

If we dismiss this utilitarian idea of having to break some ethical eggs to make patentable drug omelettes, what we’re left with is a much weaker position: that, at best, these patents are necessary in the very short term. I’m not convinced this holds water though. While most new drugs have patent protection, new formulations of off-patent compounds can have shorter protections, e.g. New Chemical Entity (NCE) exclusivity of 5 years. More importantly, as far as I can tell (still not a lawyer,) there is nothing legally stopping a drug developer from bringing something to market without patent protections. It’s just going to be much less profitable. It’s almost like a government who, unlike a publicly listed corporation, doesn’t need maximise return on investment for shareholders, could do this. Just sayin’.

Until then, you want to develop your DMT or Mesmebrine analogue for depression? Fine. You want to put a small fence around this, so that trivial changes to the molecule don’t ruin your ability to attract investment? We’re squarely in the territory of creating a monopoly here. But if that’s what it takes to get a life-saving drug to a place where it can help patients, I can see why people might pragmatically accept this.

You want to make it so that you control every chemically conceivable variation of a molecule that is either naturally occurring, or only trivially different from something that is, for the next 20 years? I think not.

And I’m not the only person who thinks this way. The nonprofit, Porta Sophia, keeps a searchable database of psychedelic prior art, and has submitted over 100 interventions on psychedelic patent applications they felt were particularly damaging, with the aim of narrowing their scope of having them rejected altogether.

And there might be other flow-on effects of broad patents. For example, when someone publishes a Markush claim, they give any chemist sufficiently “skilled in the art” a shortcut to a stack of new analogues they may not have thought of, and maybe even a head-start on how to synthesise them. Sure, legitimate commercial operations will be stopped by this. But illicit and grey-market manufacturers are not. This isn’t hypothetical. There’s at a plausible line from the patenting of synthetic cannabinoids like AB-FUBINACA and ADB-FUBINACA (which was not explicitly described in the patent but fell within the Markush space) to their emergence as recreational cannabis alternatives.

Patenting medications and their uses is part of our current model for-profit medicine. Patenting every molecule that’s remotely similar is a strategy related to this and is increasingly common for psychedelics and naturally occurring compounds. At best, these Markush claims are temporarily necessary in an unsustainable system. At worst, they actively prop it up, while stifling research and exploiting Indigenous and underground knowledge. Let’s hope that plenty of prior art is published for patent examiners to find, so, if nothing else, future claims aren’t quite as extensive.