NUKED: Patent puzzles, with FB Rice

The rule of thumb in biotech is that it costs around $1 billion to bring a new therapy from lab to market. Protecting that investment is the patent system. But what if part of your product is not made by your contract manufacturer, but by the people who are giving it to patients? Ie, their doctors.

We explore an example in Australia where this push-pull when the years and money required to develop a groundbreaking new therapy goes up against medical professionals' desire to help their patients.

And we also take a look at what the future might hold, based on what people are protecting today.

In episode 5 of NUKED we speak with FB Rice patent attorneys, senior associates Brittany Ashton and David Herman about what they're seeing in the tea leaves of patent application filings.

Transcript

Rachel Williamson: 0:00

Imagine you've got a scary disease and your doctor tells you she can get you the best, most modern therapy on the planet. You can have the patented product for about $A60,000 a dose. And you'll need four. Or an alternative for eight grand a pop. Which would you choose? 

I'm Rachel Williamson, And this is Phase III. 

This episode is about patents. Trends, how biotechs can play the IP game in radiopharmaceuticals, and the challenges they will face. 

But to start, I will tell you a story about a unique situation that has some in the sector reaching for the popcorn. 

This year Novartis registered Pluvicto in Australia. That's it's lutetium PSMA therapy for treatment resistant, metastatic prostate cancer. It owns the patent for this treatment. The company hasn't released its local pricing yet but in the US a dose costs $US42,500, or just over $A60,000. 

Then there is the alternative. A group of specialist doctors say they can do something very, very similar for the cheap and cheerful price of $A8,000 a dose, if Medicare funds the hospital compounded version that is already being used extensively in Australia. 

In an application to the Medicare funding arbiter, MSAC, the group said the alternative is an almost identical peptide to the PSMA product that Novartis owns. 

Over the last three years, during the process to get a recommendation that this product should be funded, these doctors pointed out that no one knew if or even when Novartis might bring it's lifesaving therapy to Australia. They said they could do it much cheaper and heck, they'd even helped build it through local clinical trials anyway. Novartis countered all along the way, saying, "um, remember who owns the patent?" 

This year, the situation started to get very complicated. 

In April the doctors won over MSAC, the independent reviewer of Medicare benefits applications. It recommended the therapy be funded. 

Then three months later in July, Novartis finally registered Pluvicto in Australia. And in August announced plans to have it publicly funded. 

Will Novartis be able to wrench a now very-extensively used therapy from the hands of hospital radio pharmacists across the country? Will those doctors switch to the commercial product given it's here now, and I never thought it would be? 

We reached out to the doctor group for comment, the Australasian Association of Nuclear Medicine Specialists. General manager Lisa Maddock told us their main concern is patient access to treatment and they will continue working for equitable access to the therapy. 

We also asked Novartis for a comment. They said Novartis understood the MSAC application is for a different product to Pluvicto. But also notes the recommendation is conditional on providers having a legal right to use. 

I tell you this story, not just because it's an interesting insight into some of the frictions playing out in real life. Radiopharmaceutical manufacturing is an industry that is powerfully controlled, at least in Australia, by hospitals. Patented products might be in the crosshairs of how this will evolve. 

And this is where we welcome our guests, FB Rice patent attorneys Brittany Ashton and David Hammond. They have done the hard yards for us collecting data about where the interesting patterns are coming from, and where the sector might be going. 

What intellectual property trends are you guys seeing in radiopharmaceuticals in Australia and globally?

Brittany Ashton: 4:27

We are seeing a bit of a boom at the moment. So, uh, the trend is really taking off. We're seeing more and more filings in the area. Um, David and I have actually done some research recently where we've looked at the global patent filings and narrowed it down specifically to the categories that define radiopharmaceutical filings. So we've had a look at what's happening in the area. Um, we can see that filings were relatively stable up until about 2021 and from here, we're seeing a really sharp increase in filings over the next couple of years. And I think that's pretty typical of what's happening in terms of research as well. So it's great to see that the patent filings are sort of following that innovation trend in terms of what companies are doing.

Rachel Williamson: 5:10

In terms of locations, where are the most coming from? And are there any locations that are surprising you?

Brittany Ashton: 5:18

Yeah, so we're seeing that filings in the US, I guess, unsurprisingly, they make up the majority of the filings that we're seeing and that's been pretty consistent for years now. But the change is coming more from the ASEAN region. So China, for example, that's where we're seeing a big push upwards in terms of radiopharmaceutical filings. And they now account for a huge majority, um, of the filings that we're seeing coming from.

David Herman: 5:43

I was just going to say within, within the uptick that Brittany was talking about in terms of the subject matter that we're seeing increase, it's, it's really largely sort of driven by the small molecule therapeutic, the drug that's being administered or to be administered to the patients. But also there has been a small uptick also in intellectual property being pursued for how to make these isotopes and the manufacturing processes.

Rachel Williamson: 6:07

Can you go a bit deeper into what you're seeing about the filings for the biological side of radiopharmaceuticals? And, can you speculate on, on why these ones are, becoming so popular in research?

Brittany Ashton: 6:21

Yeah, okay, so we're seeing more and more obviously the traditional diagnostic purpose being replaced with the more therapeutic applications, so the theranostics, and then the pure therapeutic indications coming through. And I think what we're seeing is, you know, as we've had so many advances in molecular cell biology recently, we're able to really target the radiopharmaceuticals coming through, and this is what we're seeing. We're seeing radiopharmaceuticals conjugated to small molecule inhibitors. We're also seeing them conjugated to antibodies, for example, for specificity. And so a lot -

Rachel Williamson: 6:57

And for our, for our non-biotech listeners, conjugated means linked.

Brittany Ashton: 7:01

That's right, yep, so joined together. So essentially what you have is a small molecule or an antibody delivering the radionuclide to the site of action. So where the small molecule would normally sit or hit as a target, it's bringing that, that nuclide along with it and that's where it's exerting its effect. This is obviously particularly useful around, um, cancer tumours, for example. So now that we're having these further developments in molecular cell biology, we're seeing that really come through in terms of the research that's being undertaken, and we're seeing that come through in terms of the molecules that are entering clinical trials as well. So, um, I think it's a shift towards that more therapeutic application that we're seeing.

David Herman: 7:45

Yeah, and as we are seeing developments into actually new radioisotopes that are being used in therapy, so from lutetium 177 and actinium, uh, through to now the targeted alpha therapies such as, uh, lead and bismuth. We're also seeing developments around the chelator portion of the small molecule. Now the chelator is the specific part of that structure that's going to conjugate or attach to the radioisotope itself. And by tinkering with the chemistry of that, uh, particular part you can change the binding strength. You can also sort of tailor how it's going to be released or when it's going to be released, um, once it gets to the site that it needs to treat. So there's advances in specifically designing that part of the molecule and and changing the chemistry as a result.

Rachel Williamson: 8:32

And what about the isotope. We're seeing a huge number of radiometals in particular coming through that companies are doing research on. What are you seeing in these IP trends around potentially new ones that no one's really talking about yet, but are suddenly starting to pop up in filings. Are you seeing anything there?

Brittany Ashton: 8:54

Yeah, so historically we've seen, um, technetium, that, that's been sort of the mainstay for the last 30 odd years, filings are steady in that area, um, again, more towards the therapeutic side of things now, um, but of course there's so many new radionuclides coming through that are being pushed through into the clinic as well. And I think a big driving force into the investigation of new radionuclides is this complementary with, I guess, what's carrying it into the body. So for example, an antibody might take three days to be cleared from the body. So you need to have a radionuclide that's complementary to that. And I think that's driving a large part of the innovation. I think we're seeing that come through with filings. We're trying to see that pairing up of the appropriate radionuclide to the carrier molecule. I think a lot of it also is spurred based on availability of these isotopes. We saw a shortage in 2008, I think it was with molybdenum. And so we've had to pivot, for example, and we're looking into, um, different radionuclides that perhaps might be easier to source and have a sustainable renewable source coming through to support potentially these really large scale applications.

David Herman: 10:08

Oh, and it's also, the development we're also seeing from the radioisotope side is also somewhat driven by the manufacturer of the radionuclide. Typically, many of the radioisotopes that we have seen previously are generated using sort of neutron bombardment or large cyclotrons, which can be energy intensive and also quite large. We are seeing a shift in manufacturing methods or processes of making radioisotopes that are a smaller footprint, um, less energy intensive, and as a result, it's actually opening the doors to seeing, um, that's where we're seeing the lead 212, for example, coming from, and other generation methods.

Rachel Williamson: 10:46

That's interesting. Can you talk a little bit more about that?

David Herman: 10:49

If we could, moving technology towards the sort of more sort of benchtop approach, so more of a, um, a simpler setup to, to develop radioisotope, something as, for example, a new ceramic material where the decay can just happen naturally and the radioisotope falls out can allow for not only, um, A smaller footprint for that manufacturer so you can have more sites populated around a certain, certain city. You can also, um, tailor that development to have, develop a high purity radioisotope. Sort of a higher, sort of, higher concentration of the, of what you want to actually put into the patient. So it also improves the outcome in that regard as well.

Rachel Williamson: 11:23

That's crazy. A benchtop, basically particle accelerator to make the products that you need.

David Herman: 11:32

Yeah, but not even a particle accelerator, it could be just the fact that the material is perfectly housed in a certain material that allows it to just decay naturally to its daughter progeny and then that, that daughter radioisotope then just can fall out and be collected and then conjugated or attached to the the radio ligand and administered to the patient.

Rachel Williamson: 11:50

Amazing. Are you seeing IP around this starting to come through as well?

David Herman: 11:55

Absolutely. Yes. Yes. Um, not only from our research, but from our active involvement with working with Australian based companies. Yep.

Rachel Williamson: 12:02

Australia's not known as a nuclear power, how are Australian companies stacking up at that end of the radiopharmaceutical supply chain?

Brittany Ashton: 12:14

I'd say we've probably got some distance to go. Um, I, I mean, we have, what is it, one nuclear reactor, is it OPAL, or?

Rachel Williamson: 12:23

Lucas Heights ANSTO nuclear reactor, uh, OPAL, yeah.

Brittany Ashton: 12:26

Right. And that's servicing a huge geographical region. So we're always going to have, if that's what we're relying on, we're always going to have these challenges of getting the nucleotides to the source, to the patient. Obviously, that's a logistic problem, but we do have companies that are coming through. We were at a BioMelbourne conference the other day, where it was talking about addressing some of these problems. So it's at the forefront of suppliers minds that we need to be innovative in this area and come up with new ways to get the nuclides to the patients. Um, and I think that's where a lot of our innovation will come in the next few years. I think it has to, for us to be competitive in this field. Um, so I think that's something we'll be on the lookout for in terms of the logistics and innovation around getting it to the patient.

Rachel Williamson: 13:14

Off the top of my head, I know of Cyclotek. They are the biggest cyclotron provider in Australia. There's CycloWest, which has just started its journey. AdvanCell has its generator in Brisbane. And then you've got the Australian Nuclear Science and Technology Organisation, that's ANSTO, uh, in Sydney with the nuclear reactor. One of the few in the world that can produce lutetium, actually. That's all that I can think of off the top of my head in Australia. Would that be correct?

David Herman: 13:51

Yeah, that's all I can, yeah, that, that, that's what comes to mind.

Rachel Williamson: 13:55

I'd like to move outside Australia a little bit because we talked about China just before. They are set, they want to become self sufficient in isotope production and people I've spoken to for this series say that they think this will happen reasonably soon. But in our previous conversations you guys have also mentioned Malaysia as an interesting location for radiopharmaceuticals and radiopharmaceutical IP. Can you talk a little bit about those two countries, um, the quality of the IP, what the trends are sort of in and out of those countries.

Brittany Ashton: 14:31

Yeah, absolutely. So I think, um, Malaysia comes into the picture more broadly in terms of pharmaceuticals. More generally, it's becoming a new manufacturing hub in many ways for pharmaceuticals. And so, um, obviously that means in terms of patenting, it's becoming a key area where somebody who's looking to manufacture in the area will need to seek patent protection. Um, that's what we're seeing in terms of radiopharmaceuticals as well, it's following that broader trend. Um, the issues I think which will be challenging, I mean, a patent is only so good as you can enforce it. And I think that's where some challenges might lie in Malaysia, for example. It's not as straightforward as enforcing a patent in the U.S Australia or even China. So there are some risks still associated with the region, but I think we will continue to see growth, um, as people look, um, for different regions to, to manufacture.

Rachel Williamson: 15:32

Let's talk about defence. The radiopharmaceuticals industry around the world is almost going up against defence as a major rival for talent and nuclear material. So how, uh, legislation and defence industries around the world affecting IP in the medical space?

David Herman: 15:58

So a number of countries do have sort of exclusions to patentability when it comes to sort of nuclear energy or atomic energy. It is largely related to defense, so defense technologies. So for example the United States is only really concerned about patent applications that talk about making the atomic bomb, so you won't be able to get a patent to that, but in terms of, um, radioisotope for clinical use no such apparent barriers are there in the United States. Some countries do apply sort of a blanket exclusion when it comes to sort of materials obtained generally by nuclear transformation, so nuclear substances. But again, you have to sort of dive into the legislation for those countries to see why, um, you know, what specifically is that going to trigger? So, for example, in India, um, if your patent claims just generally refers to an atomic, a radioactive substance, it's going to be sent to the, uh, the government for them to decide whether it sort of falls foul of their atomic energy, um, provision, so the, which means you might be able to get a patent there, but if your attorney can argue or sort of lobby on the client's behalf, you can get claims through, suitably crafted maybe. Other countries such as China has a similar provision, but again, as Brittany noted, we're seeing numerous filings coming out of China. And indeed, we've had successful, in many, many cases of patents being granted in China to radio ligands. So, so it's just a case about carefully drafting the IP with these jurisdictions in place. Um, so, so the reality is there are these defence related, um, exclusions to nuclear energy in certain countries, but it's, it's unlikely to trigger, um, a barrier to radiopharmaceuticals per se. Um, India's probably the only one that really comes to mind that you'd have to navigate that hurdle.

Rachel Williamson: 17:43

Yeah. India is an interesting one. I've been reading how it has incredible potential to be a radio pharmaceuticals manufacturer, but is nowhere close to getting that sector underway. I'd like to ask you both now about what can actually be patented in radio pharmaceuticals.

David Herman: 18:02

There's probably one more hurdle, um, regulatory hurdle we need to talk about is just the fact that some countries don't permit the penancing of methods of treatment, so the active step of actually applying the therapy to the patient, um, that's because they view, such as Europe and New Zealand, they view that the doctor patient relationship is almost like sacrosanct and you shouldn't, you shouldn't be able to impede on the physician's sort of right to, or, ability to administer a therapy.

Rachel Williamson: 18:28

So what can be patented? Because presumably you can't patent an isotope.

David Herman: 18:33

No. No, unless you generate a new radioisotope, which means you're sort of getting into the realm of sort of Iron Man, um, and Tony Stark but no, you can definitely patent the process for making the radioisotope, such as the, a new source material, or a new generator, or a new um, a new process for, for making the radioisotope or a generator that's configured to develop the radioisotope in a purer form, for example,

Brittany Ashton: 18:54

And then on the therapy side, um, we have the traditional approaches that we would take to patenting pharmaceuticals. So, um, the composition of matter per se. So, the radiotherapy itself, and then, um, what we try and do as good patent attorneys is look to maximise that protection as much as possible to extend the exclusivity period to that compound. So we'd be looking at secondary patent application filings as well, so things like the use of the radiopharmaceutical in a method of treatment, um, as David touched on, in jurisdictions where that's allowed. Um, we'd be looking at compositions comprising the radiopharmaceutical, uh, dosage forms, as well as dosage regimes. Formulations, combination therapies, all of these aspects, provided they're novel and inventive and have that industrial applicability, can form the basis of a new patent filing. And so we would look to thicket, is what we term it in the field, and build up that protection and layers of protection so that the market exclusivity is extended because it's going to be harder for someone else to bring that radiopharmaceutical onto the market because there's all these patents in the way.

Rachel Williamson: 20:09

So in some ways a company like a Telix or an AdvanCell has an advantage because then they can say, alright, we make our isotope in this way and we also make our radiopharmaceutical in this way and we attach it in this way. And they don't only own the whole process they also own the IP all along the way. And so that would be what you'd mean by a thicket, I guess.

David Herman: 20:38

It's important to note that, um, patents can also be a business asset and a business tool to gain Investment and sort of increase your revenue so you can then further develop new products or further optimise your trials and all that so having a robust IP protection around, for example, the chelator side of your molecule, all the way through to how you're making a radioisotope. You can then license that to other companies, let's say if it's the gold standard to making an isotope, or if it's the gold standard to chelate a certain, uh, radio, um, nuclide. You can license that out and generate revenue for them to further grow your revenue stream and therefore keep your company kicking on. And for a lot of our small startup clients who are looking to attract investment, one of the first things they're being asked is what's your IP strategy? And, and if I can communicate that and a clear strategy with patents in place and timelines of showing that exclusivity and when that exclusivity expires, investors can see a clear picture of what the potential monopoly will be for a certain rate of pharmaceutical, for example, and it's sort of almost like they can see it's a no brainer to invest because they can see there's going to be a big market share that can be sort of gained by, by, by the asset or the company.

Brittany Ashton: 21:57

And we shouldn't forget that, um, It's not just about your IP, it's about others' IP as well. So, um, due diligence along the way. It's about knowing what other patents are out there. So knowing your competitors, what they own in terms of IP, whether that's going to be a roadblock for what you're wanting to do in the future, that might affect your ability to bring on a, a patent. a collaborator because, you know, you're going to hit this hurdle at some point and things could all fall over. It might mean that, um, licensing needs to take place down the track. It's also really useful for deciding how to direct the research. If you're in a really crowded space, it might mean that you need to pivot slightly if you want to get exclusivity in terms of patent protection later on.

David Herman: 22:45

Yeah, as Brittany touched on, knowing that patent landscape might identify an opportunity, uh, again, I refer to the key later space that no one has touched on yet. So By knowing what your competitors are filing from an IP perspective, you might see an opportunity to pursue a certain key later, for example, that could end up being the gold standard and that's, that could be your, that's where you, that's what you're staking your claim on

Rachel Williamson: 23:09

Cool. Thanks guys. Uh, is there anything else that's super interesting about what you're seeing in the space right now, which we haven't touched on?

Brittany Ashton: 23:17

I just think it's really cool that Australia is keeping up. We're seeing that, we're seeing such a renewed interest in the radiopharmaceuticals abroad and that's being reflected here. So we're seeing that in terms of BioMelbourne events AusBiotech is featuring radiopharmaceuticals in an upcoming issue. We've got the ARC Research Hub at the University of Queensland, so AMTAR, that's been set up to facilitate all of this. It's nice, it's encouraging to see that we're keeping up and, and we're following what's happening globally. And I think we're poised to be really highly competitive in this space and I can't wait to see what sort of happens over the next five or so years.

David Herman: 23:56

Yeah. And that's, and that's also evident by the, just the big growth that we've seen in our, our flagship companies coming out of Australia and the radio pharmaceutical space. So  Telix, for example, AdvanCell three years ago, going from three people to 60 plus and having offices in the United States, Clarity Pharmaceuticals, their filings are well up there in Australia, sort of representing the growth from an Australian homegrown perspective. So all those lovely case studies of how Australia is keeping up, as Brittany said.

Rachel Williamson: 24:28

That was Brittany Ashton and David Herman from FB Rice. 

The world of intellectual property protection as wide open for radiopharmaceuticals today. Companies are rapidly widening the arena of what can be made and even how, to the giddy excitement of patent attorneys who are just as wide-eyed about the rising field as the scientists and the investors in these companies. 

In our next episode and the last in our series on radiopharmaceuticals, ae are going to take that idea of wide open blue skies even further. We'll explore the tech advances, the chemistry breakthroughs, and the 50 year outlook for this industry.