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Isotope Labeling For Fun and Profit

Here’s an article on a company called Molecular Isotope Technologies, and their bid to “revolutionize the drug industry”. From the name, you might expect that this is another deuterium-for-proton idea, and you would say to yourself “But that’s already been done”. But read on.

The company is perhaps better known by the name of one of their divisions, Nature’s Fingerprint. Through the use of painstaking stable-isotope analysis, they’ve been able to assist in drug-counterfeiting and drug-authentication cases – a surprising amount of information about the starting materials and process chemistry involved in a given pharmaceutical can be learned this way. (Here’s a short paper they’ve published on the subject). But the idea they’re talking about here is a bit more aggressive:

Jasper, founder and chief executive of Niantic-based Nature’s Fingerprint, will publish a paper next month in the leading scientific journal Pharmaceutical Technology that opens the possibility of essentially re-patenting existing drugs and extending their lives for up to 20 years through a new process known as molecular isotopic engineering.

“Because MIE designed drug molecules are essentially new chemical entities, MIE has some potentially interesting intellectual property implications,” Jasper and colleagues Peter Farina, Ann Person, Peter S. Mezes and Anthony D. Sabatelli said in the journal article, which he released with approval early to The Day.

Jasper said that by using isotopic engineering, pharmaceutical companies may be able to tinker with existing formulations using his patented method to make subtle changes that could be considered by regulators as distinct chemical entities. The result could be companies being able to patent multiple versions of the drug, allowing pharmaceutical firms to essentially extend the lives of their brands — if, Jasper emphasized, U.S. and other regulators approve the new idea.

Hmm. The paper isn’t online yet, as far as I can see, but this certainly sounds like taking an existing drug, coming in with a new synthesis using stable isotopes (such as carbon-13) and calling the resulting compound a new molecular entity. And it’s one that should work exactly like the old one, because that sort of isotope change should have zero (or very close to zero) effect on metabolism, mode of action, or anything else. (That’s as opposed to the deuterated-drug idea, where you place the D atoms in just the spots where bonds are being made and broken, in order to have a real effect on metabolism and clearance).

So sure, you can make isotopically labeled versions of drugs. But I can see a number of problems with using this idea to “revolutionize the drug industry” (no doubt the paper will address these?) First off, will these compounds be patentable? There will be interesting questions of novelty and utility, and it seems to me as if the doctrine of equivalents would come into the picture (is a difference that makes no difference really a difference?) That’s one hurdle. Next is the fact that if you’re claiming that these compounds are different enough to have their own patent lifetimes and their own regulatory approvals, then they’re different enough to have their own clinical trials run on them. You will, of course, have the huge advantage of knowing that they’re going to work up front, but you won’t be able, I think, to waltz right to market without presenting the usual sort of package to the FDA.

But that takes us to the third problem, which is a big one: will the FDA accept such an application, and will they approve it? From a pure efficacy-and-safety viewpoint they might have little choice, but then again, the agency hasn’t been faced with the request to approve what is, safe for an almost meaningless distinction, the exact same drug as something that’s already available. The sort of people who get worked up over “me-too” drugs will absolutely blow a fuse about these, and for once, I might join them.

There’s an even bigger problem waiting after that one, and to me, it’s the one that sinks this whole idea: who will pay for these isotopic drugs even if they’re approved? If the idea is, as stated in that article from The Day, to extend the patented lifetime of a given drug, that means that the new fresh Isotopically Distinct! version is going to be competing with the generic form of its parent drug. And if sticking in some carbon-13s or what have you confers no benefit at all, what insurance company would possibly go for it? I just don’t see it happening.

Reading the article, it appears that one advantage that the isotopic-labeling method would offer is a way to make the compound so distinct (by mass spec) that it’s expensive to counterfeit. That’s not a negligible benefit, but (if I’m interpreting the press material from Nature’s Fingerprint correctly), existing isotope fingerprint methods already offer this sort of protection, albeit with more work on the analytical chemistry end of things. I’m just not sure that this is enough to drive this whole idea.

And to be honest, I hope it isn’t. This sort of evergreening will advance medical science not one tiny bit, and just the possibility of it being feasible (from a legal, regulatory, and financial standpoint) seems to me to be a moral hazard. We actually don’t need brand new rent-seeking methods and new opportunities to play games with patent lifetimes and product compositions. Discovering drugs is brutally hard work, and I can understand why people are looking for easy and lucrative ways to bypass the whole thing, but we’re better off when the industry has to make new discoveries in order to keep going. Short-circuiting this arrangement, by any means, seems like a really bad idea.

49 comments on “Isotope Labeling For Fun and Profit”

  1. Anonymouse says:

    I fail to see how this would work. Doesn’t every batch of every drug on the market already have some molecules with 13C (and 14C) at every position? So wouldn’t it be impossible to patent the new drug?

    1. Ioannis says:

      Indeed! As any mass spectrometrist will tell you (and be readily able to demonstrate with data), each carbon atom is ~1.1% C-13 and ~98.9 C-12. So these alleged NCEs have already been manufactured. But the law (like the Lord) works in mysterious ways.

    2. will says:

      You’d claim it by specifying a certain degree of isotopic enrichment at a particular carbon, for instance: D-glucose, having at least 75% 13C at the C-1 position. This would presumably be novel, and non-obvious if you could show it was not easily made (an easier argument for some compounds than others), or had some spectrum of unexpected properties. i agree with derek that if it was different enough to be patentable, you’d probably need new trials to bring it to market

      doctrine of equivalents relates to infringement, not patentability. you could make the argument that a picture-claimed drug compound covered all isotopic variations. i’m not sure if there has ever actually been a case on this

      1. Ken says:

        And when that patent expires, D-glucose enriched at C-2, then C-3, … then C-1 and C-2, C-1 and C-3, … That’s 64 combinations for the carbon atoms alone, then you can start ringing the changes on the oxygens.

        1. Someone other than me uses “ring the changes” on the internet! Yay!

      2. Me says:

        Non-obvious to make, but obvious to test for the indication that the non-isotope ‘parent’ drug is indicated for……or am I reading it wrong?

    3. Kaleberg says:

      More seriously, wouldn’t this be a great patent trolling opportunity? Put in a C-13 and patent the drug. Then sue the generics maker for infringement unless they filter out all the identical versions from the generic drug. That’s our patent system at work.

    4. Walther White says:

      Yes, there’s no way they can ever convince the FDA that enriching isotopes is going to improve the drug’s efficacy. Deuteration is sometimes useful for blocking or minimizing CYP-mediated oxidation, which may prolong the lifetime of the drug in the body, but I doubt it will be enough to convince the FDA to give the ghost another chance.

  2. anon says:

    If polymorphs are patentable, then these should be patentable too.

    1. Hap says:

      Except patentable polymorphs have different properties – the difference in crystal structure makes practical differences (stability, solubility, handling, bioavailability). With these isotopically labeled compounds, the difference in isotope labeling would not confer differences in properties. A difference that doesn’t have any effect might not be patentable, and probably won’t make any money.

      1. anon says:

        I know but they might be able to show that they have different properties such as less side effects etc.?

        1. Hap says:

          Deuterium labeling can change properties (because the , but I don’t know if carbon labeling would much (the isotope effects ought to be smaller, and I don’t think as much metabolism involves C-C cleavage, so the rate of metabolism shouldn’t be much affected); since the atom size shouldn’t be much different, the packing and solubility properties probably wouldn’t change much either.

          Of course, if the properties are different, then you need new trials, which is a big cost for what is likely not much benefit. Probably not much of a win.

    2. b says:

      Except polymorphs are an actual variable when it comes to ADME

    3. Derek Lowe says:

      Ah, but polymorphs can have totally different pharmacokinetics, and these won’t.

    4. Mike says:

      If this becomes a thing pharma companies will just build this into their original patents to protect against other companies jumping in on their market share. This won’t change a thing even if it becomes a thing.

  3. Hap says:

    Won’t cost of goods be a problem? Isotopically pure starting materials are rather pricey.

    1. Joe Q. says:

      ^ This, yes. Even if the new “entities” are patentable, they will cost a lot more to make, require a new supply chain, qualification, etc. I can’t see this being a huge money-maker, for this very reason (plus those Derek cites).

      Also the fact that this kind of patent-law chicanery looks horrible to the outside world. (Greedy pharma industry etc.)

  4. fluorogrol says:

    Re: the question about generic competition still existing if you manage to patent one of these, perhaps the idea is to elbow in on someone else’s drug *before* their patents expire?

    I guess if you didn’t have the same kind of development costs and only (“only”) had to run some clinical trials, you could afford to undercut them?

    Your moral hazard still applies, mind.

    1. tangent says:

      To use this for patent-busting? That’s an interesting thought, although it doesn’t sound from “extend the lives of their brands” like it’s what they have in mind themselves. I am not a lawyer but I hope that the original patent, on material unspecified isotopic frequency, would cover a 13C tweak.

      The substantive article for these folks to publish would be one in a law journal. Which is a statement, isn’t it.

      And yeah, the “brand extension” idea of trying to sell your ‘new’ patented drug against a generic makes no business sense at all, even if the courts buy it.

  5. milkshake says:

    one rather lucrative application of isotopic labeling would be to defeat anti-doping tests that are typically LC/MS and GC/MS based. You would want incomplete, random deuterium labeling on a doping drug, a nice broad distribution from 1 to 15 deuteriums, which would shift the mass spec signal to higher mass and turn it into a bell-shaped grass of smaller peaks that can more easily hide in the background.

    There are simple labeling methods that can accomplish this, i.e. cooking the parent molecule with D2O with some suitable Pd or Ir catalyst…

    With regards to patent evergreening by isotopic – there has to be some demonstrable (even if overhyped) benefit like lower dose/extended PK profile/reduced adverse effects, otherwise the regulators will not allow it. Especially not on election year.

    1. b says:

      A little KAuCl4 and some D2O does the trick of randomly labelling aromatics depending on electron density

      1. jwoods says:

        Could you share a citation for that?

        1. b says:

          I first found it here, doi:10.1016/j.tet.2008.11.105

          They don’t really report a procedure, but it doesn’t require much. Dump, stir, heat, filter through silica, and as an added bonus you usually get to collect some elemental Au flakes at the end. I’ve used it on a variety of aromatics for deuterium labeling studies.

          1. matt says:

            Are you, by any chance, living in Russia and working for their anti-doping organization?

    2. MoMo says:

      That would also mean that drugs of abuse modified by isotope would be legal and undetectable. Can some one from the Medellin Cartel contact me? I need some new investors.

      1. Blunderbuss says:

        The Federal Analogue Act, 21 U.S.C. § 813, is not 35 U.S.C. 103 (obviousness). The case law is limited, but essentially an analog of a scheduled drug is anything the DEA says it is.

  6. Mike says:

    This doesn’t make much sense to me. If your original drug, “Drug A”, is about to go off patent and you create an isotope variation called “Drug B” which has the same clinical characteristics and is patent protected, clinicians will just continue to use Drug A as a generic. There would be no incentive to move from Drug A to Drug B.

    Am I missing something?

    You might say “the company will just stop making Drug A” and that’s true, but if it’s generic, than any company can make Drug A.

    1. milkshake says:

      well that was the famous uproar with S-omeprazole introduction, omeprazole being a racemate prodrug that is metabolized into achiral active metabolites. The difference of using the better enantiomer was very small (in comparison with omeprazole – that was about to go generic) but AstraZeneca managed to sell the (modest) superiority of Nexium, and profited from it.

    2. will says:

      There’s a maneuver called “product hopping” that could be applied here

  7. Mark Thorson says:

    You’re thinking the customers are pharmaceutical companies sitting on drugs about to go off patent. I’m thinking the real customers are venture capitalists who don’t know a heckuva lot about chemistry or patents. It’s a good story if you don’t scratch too deep. Might be worth $50 million to get the ball rolling, doncha think?

    1. tangent says:

      I think you might have nailed it there.

      1. Pennpenn says:

        So investor bait rather than patent shenanigans? Makes more sense, I guess.

  8. Anon says:

    So, even more money spent to duplicate what already exists with no added benefit to the end consumer. Something’s gonna break very soon.

  9. db says:

    If such substitutions were deemed to be different enough to be patentable, what would stop a third party from patenting a stable isotope-differentiated version of a well known drug already under patent and competing with the original?

    Wouldn’t this create a race for all manufacturers to look at their current stable of patented compounds and spend large amounts of resources just to protect against such competition by getting there first?

    Seems like a rather double edged sword.

  10. Chemist turned Banker says:

    Worth a look in this context is Kythera and their double chin eradicator, namely injectable deoxycholic acid. FDA was not happy with animal-derived product, so they make it synthetically. That material has different 14C enrichment (being, essentially, oil-based not animal based) and they have a patent as a result on deoxycholic acid of a certain 14C composition. Genius!

    That said, I completely agree that the idea here is a daft one which nobody will pay for and would only increase rage against the pharma industry. Almost worthy of our erstwhile friend from T*ring;)

    1. Isidore says:

      14C enrichment? Surely they are not injecting radiolabeled deoxycholic acid.! I suppose if they did it may eradicate not just the double chin but the single one also.

  11. CMCguy says:

    Does anyone consider PharmTech as “leading scientific journal”? I find it great for development and operational issues but not where I would go for significant original work. This all smells like a Sales pitch/hype which could possibly be directed at industry to convince would have to purchase licenses to the patents to protect themselves from alternate molecule substitutions as would these be approached more like Biosimilar drugs that may not necessarily be structurally identical? This is much academic speculation and confusion which may or may not be elaborated next month after publication.

  12. Anon says:

    The fact that they have already published their strategy makes any compound design that uses it obvious and thus non-patentable.

    Doh!

  13. Li Zhi says:

    Isn’t this a legal question? If there is a patent for CH4 then can a patent be issued which only differs by claiming that the composition is 98.9% C-12 and 1.1% C-13? Isn’t the purpose to get a new patent while the FDA does NOT have to do any additional work? Lumping the patent office and the FDA under “the regulators” umbrella will only work if their responses are identical, nicht wahr? At what threshold does a mixture of C-12 and C-13 become different from C? (in a given chemical composition). Only if you can show (at P=0.05, maybe one of 20 experiments run) that the “new” composition is different from the old? I have no idea what the USPO thinks about the precedents in this area. Time for a “donation”?

    1. milkshake says:

      one gambit I can imagine is to get a patent exclusivity and FDA approval for a very tightly isotopically defined active molecule for which the original composition of matter patent is already expired. It might be hard for generic manufacturers to match that isotopic pattern. But it is a stretch. I know this kind of approach is already being tried with the known impurity profile.

      1. Hap says:

        Isn’t that why Premarin hasn’t gone generic? (The company that makes it in mare’s urine claimed the cometabolites were key to the activity, and so the generic pure compound was not (bio?)equivalent.)

  14. Barry says:

    very very few drug patents ever get litigated, but this one seems a candidate. To get a patent, you have to persuade the USPTO that your innovation is:
    novel
    AND
    utile
    AND
    non-obvious. Nothing I’ve seen suggests that this innovation is utile (the primary isotope game of retarding metabolism by swapping H->D is already prior art and therefore not “novel”). And failing on any one of the three criteria invalidates the patent

  15. Srdjan Tufegdzic says:

    Well I guess that for diagnostic purposes labeling some ordinary molecules with rare isotopes might have valid ground for use but it is not like it is not been around for some time. Labeled urea for breath detection of H.pylori intestinal infection comes to my mind first but there has to be other examples. I also remember there was some time ago a hype for labeling some anti-tumor drugs with fluorine for easier detection, tracking and concentration in organism evaluation. In my book that is on the same page as what is described in above article but I also remember a sentence one famous lecturer gave disgruntled after one major pharma firm rip-off his patent “they have more lawyers then chemist” so I guess they beat us by the shear mass and numbers.

  16. matt says:

    I think they need to rename the carbon-13s to something sexier, maybe something like “Organessence.” Then they can advertise their product as “25x the Organessence of __(name brand product)__!”

  17. Pennpenn says:

    I would have thought by now that anyone claiming that their product/method/service/voodoo will “Revolutionise the [whatever] industry!”, they are almost certainly a scammer or blinded by overly optimistic projections, regardless of whatever they say next.

    Things aren’t considered revolutions until they’ve happened. It’s a retrospective label at best.

  18. DJK says:

    If Jasper’s method is published (as it will be) and if a method for preparing Drug A is published, then it’s fairly likely that a patent claim to new isotopomer Drug A* would be considered obvious in light of Jasper’s method combined with the method of Drug A, UNLESS Drug A* has an unexpected benefit.

    This would be the patent system working as it should – it would reward a meaningful scientific advance.

  19. Anon says:

    I can imagine a couple of arguments for patentability but none, short of a miracle, for getting payers to pay for non-natural abundance Drug rather than generic natural abundance Drug.

    – The original patent might not claim constitution of matter with non-natural abundance at some positions leaving the non-natural abundance (NNA) compounds free for the new guys to claim.

    – Even if the old patent did claim those enriched isomers, it might not TEACH someone skilled in the art how to make the NNA isomers rendering the claim of those isomers purely prophetic.

    – I can see a claim of utility equivalent to the NA drug. That is, if judged alone, enriched-Drug has utility for USPTO purposes, even if it is no better than NA Drug for FDA purposes.

    I’m not too keen on allowing someone to patent isotopic isomers as a new drug but I think it could pass. At some point (are we past that point?), isotopic enrichment becomes obvious and no longer novel.

    But as others have already commented, why would an independent payer pay for an expensive version of Drug rather than cheap generic Drug if there is no therapeutic advantage?

    In the meantime, I want to lay claim to the isotopically DEPLETED forms of all Drugs. Instead of 98.9% C12 / 1.1% C13, I will use 99.9% C12 in my drugs (and 99.8% Cl35 when needed, 99+% N14, etc.). If depleted uranium works for armor plating and if General Electric can make 99.9% C12 diamonds with improved thermal properties over natural abundance. en.wikipedia.org/ wiki/ Isotopically_pure_diamond

    I just want to make sure I own depleted drug space. I hope I didn’t blow it by posting here before filing any patents.

    1. Dionysius Rex says:

      Taking this to its logical extension, I wish to patent “atomically depleted” APIs, that is pharmaceuticals where each atom has been replaced with an isotope of zero amu (e.g. carbon-0, hydrogen-0). I might just call this concept “zeropathy” – I believe it will be especially good at treating miasms, phlegms and extirpation of luminiferous ethers.

      1. Derek Freyberg says:

        I’m sorry, Dionysus, but I believe that concept is already taken, though the zeropathy is usually diluted with water, sometimes a little alcohol, or lactose. You can even buy some of these products at your local pharmacy, from manufacturers like Boiron: they’re called homeopathic remedies (an oxymoron if ever there was one).

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