Headlines appeared last night about Moderna losing a patent case that affects its coronavirus vaccine work. I know from long experience on this blog that any discussion of patent and IP issues has an effect on my readership traffic numbers that looks like I’m paying folks not to click on my links that day, but I’m going to brave this one. What’s going on?
For starters, it’s worth realizing that this dispute has been going on for quite a while. To an excellent approximation, all patent disputes have been going on for quite a while. The smattering of new ones are more than averaged out by the ones that have been Jarndycing their way through hearing after hearing. Here’s an article from 2016 and a followup in 2017 that go into some of the details in Moderna’s case. The issue is not about their coronavirus vaccine per se, nor is it quite about their own mRNA technology. It’s about what one has to do to get things like mRNA constructs to survive in the bloodstream so they can even be contemplated as drugs in the first place.
That takes you into modified RNA bases (for one thing) and very much into formulations, for another. Formulation science is one of those things that people outside drug development tend to not think much about (if they even know that it exists), but it’s really important. Getting an orally dosed drug out of the gut (or even just past the stomach) and into the bloodstream, and getting an injected one to circulate around in said bloodstream instead of being destroyed on contact – those can be big deals. It’s definitely a big deal for something like a small bundle of RNA.
Oral delivery is right out for those things – I don’t know what kind of wizardry you’d need to give someone an “mRNA pill” and have it be usefully absorbed into the circulation, but we sure don’t have anything like it yet. Nope, this is an injection from the very start, and even there you have serious problems. Here’s a paper that notes that if you add plain RNA to plasma samples, none of it is intact enough to be amplified after a wait of fifteen seconds. There are “cell-free” RNA species floating around in the blood, but your mRNA therapy is unlikely to share their characteristics, because there are a lot of different forms of RNA. Even those degrade easily enough.
And once into the bloodstream, whatever oligonucleotide species you’ve injected (be they mRNA, antisense DNA oligos, RNA interference species, etc.) that survive are highly likely to end up in the liver anyway, so you’d better be OK with that. Wherever they go, they are probably going to have to be taken up into cells and find their way to the right compartments once inside, and those can be rather high hurdles as well. It’s no accident that all of the neat ideas for dosing RNA and DNA-based therapeutics have taken so many years (and so many dollars) to be realized in practice – a huge amount of thought and experimentation has gone into getting us this far, and we’re still finding out new things.
Moderna, for its part, decided years ago that lipid nanoparticles (LNPs) looked like the way to go. This technique places the RNA constructs inside small lipid bubbles of lipid to protect them, and there’s an ever-growing list of variations on the idea and how to realize such species in practice. Moderna did a deal with a small company called Acuitas for access to this sort of thing, but Acuitas in turn had licensed it from another company, Arbutus. Whereupon Arbutus terminated their agreement with Acuitas, saying that they had no legal right to sublicense the technology to Moderna. They sued Acuitas in Canada in 2016, and ended up with a settlement in 2018 that allowed the Acuitas/Moderna sublicenses to stand (but no others). But. . .at just around the same time, Moderna launched an offensive at the USPTO to try to invalidate two Arbutus patents entirely. Earlier this year they asked for another review on a third Arbutus patent.
Moderna had been spending a lot of time talking about how well, you know, that Arbutus stuff was just OK, not really all that good, and how they’s moved so far past it that it really wasn’t a concern any more, etc. But the move to asking for inter partes review at the PTO is an example of what we call revealed preference, rather than stated preference. A general rule: always watch what people and companies actually do, rather than paying so much attention to what they say they’re doing. Speculation is that the 2018 settlement would have only covered uses in Canada, and that the far-more-lucrative US situation was therefore unresolved, so Moderna opened fire.
Inter partes review has been around since 2012, and it’s fair to say that overall it’s not a popular provision of US intellectual property law if you ask biopharma companies. Many of them consider the process as leaving too low a bar to initiate patent validity challenges – or at least they consider it so until it’s time for them to challenge someone else’s patent, and then it’s any weapon to hand. A big factor is that the IPR process doesn’t take place in the good ol’ Court of Appeals for the Federal Circuit, like such things used to, but rather goes before a Patent Trial and Appeal Board, the PTAB. This speeds things up and makes such challenges much less expensive, which as you’d imagine are only appealing features if you’re playing offense. Inter partes review last reared its shaggy head here during the 2017 Allergan/Mohawk fiasco – the entire purpose of that ridiculous strategy was, in fact, to make some of Allergan’s patents completely impossible to be touched by IPR at all because now (ta-daa) they were owned by a sovereign Indian tribe.
You can ask for such a review only on the patentability criteria of novelty and/or non-obviousness, sections 102 and 103, which come down in many cases to showing that some prior art exists that makes the patent under dispute either not novel or “obvious to one skilled in the art”. Relevant prior art can found in all sorts of stuff – other patents and patent applications, journal articles, public disclosures at scientific meetings, and so on. Moderna actually won their first patent challenge before the PTAB, getting all the Arbutus claims in it invalidated via such arguments. They had a partial win on the next one – some claims were tossed, but some stood. But yesterday they completely whiffed on their third challenge: all 22 claims in that Arbutus patent were upheld.
So what does this tell us? It seems clear that Moderna was worried about Arbutus waiting until such time as the coronavirus mRNA vaccine looked ready to take off, and then getting hit with a filing for infringement. The IPR challenges were an attempt at pre-empting that – can’t claim infringement of invalid claims, can you now? The situation now is unclear. I don’t know which of the upheld claims is the biggest threat to Moderna, and it would take me about a month of study to even have an informed opinion. Patent litigation is excruciating stuff. Neither do I know how much money Arbutus would come after them for, but clearly it was enough of a concern for Moderna to launch their own first strike (remember, Arbutus has never taken Modern to court directly at all).
This latest decision is expected by many to be appealed. That would take it to the Court of Appeals for the Federal Circuit, and that’s a much lengthier process. Moderna certainly seems to have standing for such an appeal (as that link will show, that issue has been the subject of much combat in the last few years), but the question is whether they want to do that now or wait until Arbutus comes after them.Or do they want to approach Arbutus directly and see if they can come to an agreement, rather than continuing to tango in the current fashion? Rather highly-paid lawyers are no doubt considering these questions right now.
You’d have to pay me an awful lot to to work it out, I can tell you right now. What seems certain is that Moderna will be pushing ahead with their vaccine, and that this issue will be hanging over them while they do. I don’t see this slowing down the vaccine development itself, since none of the lawyers are working in the labs. But it is a distraction for the higher-ups and perhaps a weight on the company’s stock price. But hey, Moderna’s executives seem to have unloaded plenty of their positions already, right?