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Analytical Chemistry

A Horrible, Expensive, and Completely Avoidable Drug Development Mixup

TIC10C&E News has a story today that is every medicinal chemist’s nightmare. We are paid to find and characterize chemical matter, and to develop it (by modifying structures and synthesizing analogs) into something that can be a drug. Key to that whole process is knowing what structure you have in the first place, and now my fellow chemists will see where this is going and begin to cringe.
Shown at left are two rather similar isomeric structures. The top one was characterized at Penn State a few years ago by Wafik El-Deiry‘s lab as a stimulator of the TRAIL pathway, which could be a useful property against some tumor types (especially glioblastoma). (Article from Nature News here). Their patent, US8673923, was licensed to Oncoceutics, a company formed by El-Deiry, and the compound (now called ONC201) was prepared for clinical trials.
Meanwhile, Kim Janda at Scripps was also interested in TRAIL compounds, and his group resynthesized TIC10. But their freshly prepared material was totally inactive – and let me tell you, this sort of thing happens all too often. The usual story is that the original “hit” wasn’t clean, and that its activity was due to metal contamination or colorful gunk, but that wasn’t the case here. Janda requested a sample of TIC10 from the National Cancer Institute, and found that (1) it worked in the assays, and (2) it was clean. That discrepancy was resolved when careful characterization, including X-ray crystallography, showed that (3) the original structure had been misassigned.
It’s certainly an honest mistake. Organic chemists will look at those two structures and realize that they’re both equally plausible, and that you could end up with either one depending on the synthetic route (it’s a question of which of two nitrogens gets alkylated first, and with what). It’s also clear that telling one from the other is not trivial. They will, of course, have the same molecular weight, and any mass spec differences will be subtle. The same goes for the NMR spectra – they’re going to look very similar indeed, and a priori it could be very hard to have any confidence that you’d assigned the right spectrum to the right structure. Janda’s lab saw some worrisome correlation patterns in the HMBC spectra, but X-ray was the way to go, clearly – these two molecules have quite different shapes, and the electron density map would nail things down unambiguously.
To confuse everyone even more, the Ang. Chem. paper reports that a commercial supplier (MedKoo Biosciences) has begun offering what they claim is TIC10, but their compound is yet a third isomer, which has no TRAIL activity, either. (It’s the “linear” isomer from the patent, but with the 2-methylbenzyl on the nitrogen in the five-membered ring instead).
So Janda’s group had found that the published structure was completely dead, and that the newly assigned structure was the real active compound. They then licensed that structure to Sorrento Therapeutics, who are. . .interested in taking it towards clinical trials. Oh boy. This is the clearest example of a blown med-chem structural assignment that I think I’ve ever seen, and it will be grimly entertaining to see what happens next.
When you go back and look at the El-Deiry/Oncoceutics patent, you find that its claim structure is pretty unambiguous. TIC10 was a known compound, in the NCI collection, so the patent doesn’t claim it as chemical matter. Claim 1, accordingly, is written as a method-of-treatment:

“A method of treatment of a subject having brain cancer, comprising: administering to the subject a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and a pharma­ceutically accepted carrier.”

And it’s illustrated by that top structure shown above – the incorrect one. That is the only chemical structure that appears in the patent, and it does so again and again. All the other claims are written dependent on Claim 1, for treatment of different varieties of tumors, etc. So I don’t see any way around it: the El-Deiry patent unambiguously claims the use of one particular compound, and it’s the wrong compound. In fact, if you wanted to go to the trouble, you could probably invalidate the whole thing, because it can be shown (and has been) that the chemical structure in Claim 1 does not produce any of the data used to back up the claims. It isn’t active at all.
And that makes this statement from the C&E News article a bit hard to comprehend: “Lee Schalop, Oncoceutics’ chief business officer, tells C&EN that the chemical structure is not relevant to Oncoceutics’ underlying invention. Plans for the clinical trials of TIC10 are moving forward.” I don’t see how. A quick look through the patent databases does not show me anything else that Oncoceutics could have that would mitigate this problem, although I’d be glad to be corrected on this point. Their key patent, or what looks like it to me, has been blown up. What do they own? Anything? But that said, it’s not clear what Sorrento owns, either. The C&E News article quotes two disinterested patent attorneys as saying that Sorrento’s position isn’t very clear, although the company says that its claims have been written with these problems in mind. Could, for example, identifying the active form have been within the abilities of someone skilled in the art? That application doesn’t seem to have published yet, so we’ll see what they have at that point.
But let’s wind up by emphasizing that “skilled in the art” point. As a chemist, you’d expect me to say this, but this whole problem was caused by a lack of input from a skilled medicinal chemist. El-Deiry’s lab has plenty of expertise in cancer biology, but when it comes to chemistry, it looks like they just took what was on the label and ran with it. You never do that, though. You never, ever, advance a compound as a serious candidate without at least resynthesizing it, and you never patent a compound without making sure that you’re patenting the right thing. What’s more, the Oncoceutics patent estate in this area, unless I’m missing some applications that haven’t published yet, looks very, very thin.
One compound? You find one compound that works and you figure that it’s time to form a company and take it into clinical trials, because one compound equals one drug? I was very surprised, when I saw the patent, that there was no Markush structure and no mention of any analogs whatsoever. No medicinal chemist would look at a single hit out of the NCI collection and say “Well, we’re done – let’s patent that one single compound and go cure glioblastoma”. And no competent medicinal chemist would look at that one hit and say “Yep, LC/MS matches what’s on the label – time to declare it our development candidate”. There was (to my eyes) a painfully inadequate chemistry follow-through on TCI10, and the price for that is now being paid. Big time.

31 comments on “A Horrible, Expensive, and Completely Avoidable Drug Development Mixup”

  1. Pete says:

    It’d be interesting to know if any of the ‘wrong’ compound was present in crude reaction product when the compound was first synthesized. Computed C13 NMR spectra might have been useful in this situation. Scripps IP position is potentially weakened by need to demonstrate novelty. The lawyers will have a field day.

  2. Martin says:

    Ok I don’t know in what quantities you can get these things from the NCI these days but how exactly were they proposing to progress to trials _without_ having made it at some scale?

  3. These are great points for biotech investors to consider when looking at a company’s IP portfolio and pipeline.
    Sadly, I’d bet Oncoceutics raised some outside financing from investors who let their greed and enthusiasm for speculative biotechs get in the way of proper due diligence.

  4. Bender says:

    When the dust settles from all of this, the only people who will have benefited are the lawyers. Everyone else loses, from scientists to patients.

  5. Hap says:

    1) A previous comment ( noted that their company had patented a misassigned natural product; with the caveat of Pete above, it seems like that would be a bad prior sign for Oncoceutics.
    2) In the original structure, you shouldn’t get any nOes off the imidazole protons but you could get one from the benzyl protons to the neighboring tetrahydropyridine ring (although the shifts might fall on one another and make it not possible to see the nOe); in the correct structure, the imidazole protons should have nOes to the tetrahydropyridine ring, and since they should be separated in shift, they probably should be visible, while the benzyl protons should only have nOes to the methyl protons and to the phenyl proton. Does that make sense?
    3) I assume the IP people where the original professor patented the compound were not competent either. “You have one compound that you want to patent? No problem!”

  6. Anonymous says:

    Who were the investors? They must be in hiding right now.

  7. Harrison says:

    There is a long history of academic groups discovering a compound, forming a company around it, and eventually blowing millions of VC dollars because they don’t know anything about pharma discovery/development. This is just a particularly egregious example.

  8. Cellbio says:

    From the company website:
    “Oncoceutics, Inc. announced the closing of an investment by Calvert Cure Male Impotence – How to Cure Erectile Dysfunction Research, LLC into the company that will be used to advance ONC201 to an IND filing.”
    Yeah, probably not the experts in biotech IP diligence.
    And this:
    “Clearly Calvert’s decision to invest in this development corroborates our views, that ONC201 has a unique profile in terms of mechanism of action, efficacy and safety. ” “We have started to broaden the external validation effort for our in-house findings on ONC201, specifically for verifying and expanding its efficacy, safety, and mechanism of action profile,” added Josh Allen, PhD, Director for Development at Oncoceutics. “I am delighted to see so much interest from premier institutions and investigators that have led to several collaborations.”
    So, is it about collaborations and validation or drug development? I have personally lived through a ‘company’ that was nothing more than an academic’s attempt to find another source of money for research, where ‘success’ sounded a lot like the the above quote.
    And then this gem:
    “There are also claims for ONC201 to be used in combination with other anticancer drugs and to be given orally to generic cialis cheap treat brain cancers.”
    Not a confidence builder….

  9. PPedroso says:

    Nice story, although I have to admit that if everyone just patented the one compound that they studied and have data for, the Intelectual Property world would be a much simpler place…

  10. Chemjobber says:

    @8: I suspect that Oncoceutics’ website has been infected by malware that randomly inserts SEO search terms into the text.

  11. Biff says:

    #3 BuyersStrike – Due diligence? What is this thing of which you speak?

  12. Anonymous says:

    Ah yes, that makes much more sense.

  13. Anonymous says:

    Not really a nightmare for Med. Chemists. I guess oncology labs will realize they need to hire good Med. Chemists!

  14. Anonymous says:

    Where I was a post-doc, students would get X-ray on their compounds (sometimes) before an NMR. Unfortunate this technology isn’t more widespread.

  15. watcher says:

    Typically, independent synthesis should be used to confirm such a structure to compare all related characterizations, eg NMR, IR, LC/MS/MS.
    Derek: seems to me you’ve just presented evidence for denying any overriding patent coverage on an ongoing legal determination. While this is your personal judgement, seems your open, published statement could bias any decision by the patent office or later legal fight.

  16. Chrispy says:

    Clearly, Janda’s group could not have found this compound without the help of El-Deiry; even if they had the structure wrong they had the compound right. And Janda had nothing until they were shipped the right compound. Had they been sent a compound with unknown structure would they be entitled to determine the structure and patent it? It will be interesting to see how this plays out…

  17. nitrosonium says:

    i see this very frequently in academia (where i work as a med chemist): one compound and off to spin out a company and carve out all the IP space as soon as possible. though this seems to be the modus operandi around here, i have yet to see where it has paid off.

  18. CMCguy says:

    I think the real medchemist nightmare would be if had followed up on the initial structure and was assigned to establish baseline SAR and then generated a series of 4-12 analogs before finding out they were all dead and then asking the question. I do not know if that is what Janda was attempting to do here but have seen a number of cases where programs where launched on somewhat flimsy evidence, although more commonly it the bioassay at issue not the chemical structure.
    In terms of what is in patents I have occasionally wondered if “misleading compounds or chemical procedures” have been intentionally including to inhibit potential progress by competitors. This would IMO violate the first principle behind patenting however ethics can take a backseat or be totally left behind at times it seems.

  19. cispt2 says:

    The DTP library is only as good as the chemistry that went in to it (and of course there is the function of time the compounds have been in their library). Structures come from the group submitting the compound for testing. There are plenty of other examples of the structure in the database and the true structure of the compound being different – for example NSC73306 was thought to have two chloro groups, but the mass spec told otherwise (

  20. CMCguy says:

    BTW if the compound was already in NCI database/collection then Oncoceutic could not be after a composition of matter so would be a use Patent? Therefore their claim the error does not matter may be rational and although Janda may be able to now argue of for a new structure coverage could not likely get the ability to use for same treatments covered? Does seem it the lawyers again who will win as get paid either way.

  21. Hap says:

    But for a use patent don’t I have to claim a particular compound or set of compounds for a particular use? I can’t just claim anything used by a prior method, otherwise I could claim the method without any actual invention (anything that does what I’m saying I can do).
    If the compound was wrongly identified, but the wrong structure was the only compound claimed for that use, then it seems like the original patenters can’t claim that they have rights over the correct compound if it’s not what they claimed or within the scope of what they claimed. They could have claimed a set of compounds but didn’t, and the method ought to have been prior art, so without a compound (that acts according to their claims) or a method, don’t they lack anything to patent?

  22. Potstirrer says:

    To complicate matters further, the “third” compound offered by MedKoo appears to be depicted incorrectly in the Janda paper. One of the nitrogens is tetravalent but no positive charge is indicated. I guess a double bond should be moved.

  23. NodrugsNoJobs says:

    Assuming this is an open case meaning they can file continuations, they do have support for claiming the compound according to its NSC number which is NSC350625. Assuming this is the compound Janda pulled and found worked, then the situation can be analogized to those of protein deposits where the deposited material or cell line or whatever serves as the enablement for the later claimed method or composition. By analogy, it seems entirely plausible to me that in a continuation application, the inventors file new claims that go to the NSC number. Assuming that one of ordinary skill in the art can produce the NSC material without undue experimentation, they can argue that it is enabled and that the structure mix up is not fatal. If Janda attempts to patent and enforce a claim to the proper structure, they are likely anticipated by the previous patent disclosure/filing as the inventors already did what he will attempt to claim. In other words, his subsequent work is inherently (if not explicitly anticipated) by the prior art disclosure. One might argue that Janda simply repeated the prior art method using the disclosed NSC number. When he requested that compound disclosed by the NSC number, he got the same result as previously described.
    This is not legal advice nor a thorough analysis but I seem to recall similar cases where claimed structures were wrong but the procedures in the patent were sufficient to produce the active structure. In this case, one would/could argue that the patent describes the wrong structure but the disclosure references the way to get the correct compound (from the NSC number) and that one of skill in the art could determine the correct structure and make it without undue experimentation. Enablement can get pretty tricky as the legal definition is not as rigid as you might presume. Once a patent is issued, its presumed valid. The patentee could argue that what Janda did was what one of skill in the art would do and by his own actions showed that the disclosure was in fact enabled. How hard is it to order the reference compound, verify its activity and confirm its structure? Skill in the art is an objective inquiry and is not based on the patentee’s own failure necessarily (in principle anyway!)

  24. Rock says:

    @23 is correct. This is an example of the doctrine of inherency:
    It can get mighty complicated and I would expect the legal battle could go on for many years.

  25. Nick K says:

    Perhaps now after this debacle/lawyers’ field day, the people at the top of Pharma will finally get it into their thick heads that medicinal/organic chemists are actually vitally important, and not merely expendable cogs in a machine.

  26. sepisp says:

    Overreliance on spectral characterization seems to be the culprit. If you do any wet chemistry on these, they’ll be obviously different. For instance, a dearylation (e.g. with hydrogen) or amide hydrolysis give two very different products.

  27. Goodhumor says:

    Melting points anyone?

  28. JSR says:

    I assume everyone wins here. Kim looks like a chemical genius/trickster, which he is. Lawyers get paid lots of money. And now 2 companies race to make this stuff into a drug, which helps patients.
    I imagine the med chemists here are looking too much at the chemistry. I imagine Oncoceutics doesn’t even need to have molecular structure ID to have a patent covering use of material purified by a particular procedure from a specified source for treating a particular condition. Janda/Sorrento can make the ‘actual’ compound, and analogues, and have at it.

  29. anonandon says:

    @23 is right. This doesn’t necessarily sink their patent, particularly since the compound is available. The Onconeutics guy has a good argument that the structure recited is irrelevant to their invention. The structure is just one way of identifying the compound used.
    There are several precedents. It may be straightforward to fix if they have a continuation pending. Structural misassignments happen all the time and good patent attorneys prepare for the eventuality.

  30. newnickname says:

    @11 “Due diligence?” One of my responsibilities at a former job was to diligently investigate competitors as well as potential academic collaborations. I trashed some real dogs and encouraged the pursuit of some projects that I thought had excellent potential. Management (not a scientist among them) ignored everything I said and licensed projects based on fame and the personality cult of the PI and wouldn’t touch anything from a junior academic regardless of how good I thought it was.
    Every licensed project crashed and burned. Some of the “lost” technology had success elsewhere but some of my favorites are still languishing, unfunded and untouched, in obscure literature.

  31. Anonymous says:

    Many seem to support Onconeutics or think it has valid patent. But I think it should be invalid.
    1. Synthesis part: incomplete work. “mixed somethings and got something”.
    2. Use part: Can we patent the finding “I tested something and it seems to cure cancer”? (and amend someday what that something is! Like using a dummy to hold a spot just for priority). I would think that should not be supported or promoted, but may be it is approved?
    It seems to me as wrongful claim or vague claim and not complete enough for anything, not even for publishing.
    If somebody has a right for reaction mixture, others must have the right for fully characterized purified product. Even crystalline polymorphs can be individually patented.
    Is poor science patentable? MAY BE!!!

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