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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 10, 2013

Deuterated Drugs: An Obvious Idea?

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Posted by Derek

Nature Medicine has an update on the deuterated drug landscape. There are several compounds in the clinic, and the time to the first marketed deuterium-containing drug is surely counting down.

But, as mentioned at the end of that piece, another countdown that also must be ticking away is the one to the first lawsuit. There are several places where one could be fought out. The deuterated-drug landscape was the subject of a vigorous early land rush, and there are surely overlapping claims out there which will have to be sorted out if (when) the money starts to flow from the idea. And there's the whole problem of obviousness, a key patent-killer. The tricky thing is, standards of what is obvious to one skilled in the art change over time. They have to change; the art changes. (I'll risk some more gritted teeth among the readership by breaking into Latin again: Tempora mutantur, nos et mutamur in illis.

We've already seen this with respect to single enantiomers - it's now considered obvious to resolve a racemic mixture, an to expect that the two isomers will have different activities as pharmaceuticals. At what point will it be considered obvious that deuteration can improve the pharmacokinetics? If that does ever happen, it'll take longer, because deuteration is not as simple a process as resolution of a racemate. Itt can be difficlut (and, well, non-obvious) to figure out where to put the deuteriums for maximum effect, and how many need to be added. Adding them is not always so easy, either, which brings up questions of enablement and reduction to practice. You need to teach toward the compounds you want to claim, and for deuteration, that's going to mean getting pretty specific.

There's another consideration that I hadn't been aware of until this weekend. I had the chance to talk with a patent attorney at a social gathering (not everyone's idea of a big Saturday night, admittedly, but I enjoyed the whole affair). He was explaining to me a consequence of the Supreme Court's recent ruling on obviousness, the 2007 KSR v. Teleflex decision. Apparently, one of the major effects of that ruling was the idea that if there are a limited number of known options for an inventor to choose from, that can take the whole thing into the realm of the obvious. The actual language is that when ". . .there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. . .the fact that a combination was obvious to try might show that it was obvious under § 103". You can see the PTO itself trying to come to grips with KSR here, and it seems to be very heavily cited indeed by examiners (and in subsequent court cases).

Naturally, as with legal matters, the big question becomes exactly what a limited number of options might mean. How many, exactly, is that? In the case of a racemate, you have two (only two, always two), and it's certainly reasonable to expect them to be different in vivo. So that would come under the KSR principle, I'd say, and it's not just me. But what if there are a limited number of places that a deuterium can be added to a molecule? At what point does deuterating them become, well, just one of those things that a person skilled in the art would know to try?

Expect a court case on this eventually, when some serious money starts to be made in the area. This is going to be fought out case by case, and it's going to take quite a while.

Comments (30) + TrackBacks (0) | Category: Patents and IP | Pharmacokinetics


COMMENTS

1. processchemist on June 10, 2013 8:46 AM writes...

A more classical construction would be:
"Mutantur tempora, simul et nos mutamur"

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2. Gaspode on June 10, 2013 9:17 AM writes...

The only time I encountered deuterated drugs so far was one last desperate attempt to improve Bioavailability. Are there any other applications (other than patent reasons) for example better off-target profile? The size of deuterium shouldn't make any difference, apart from metabolism due to the different bond behavior.

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3. watcher on June 10, 2013 9:27 AM writes...

Seems to me for the question of obviousness in terms of deuteration, the question could well be case by case. People knowledgeable in enzyme mechanisms, mechanism based inhibitors, metabolic ADME mechanism, or example, would likely say that placement of "D" in specific positions would be obvious places to try in making impacct. Placement in other places may not be so obvious...it could well depend who is consulted as being skilled in the art. Today, design & optimization of drugs when conducting SAR extends beyond the ability to stick together carbon molecules and running the most favored reduction or oxidation reactions (pardon me, no disrespect intended), but typically involves some knowledge of mechanism(s) of action(s), primary means of elimination from the body, etc. So, cocnsultation form areas other than the traditional chemist who often writes the patent extensions, for example, really would be needed to make judgement in such cases. As has been said, the times: they are a-changing.

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4. weirdo on June 10, 2013 9:51 AM writes...

I think this is going to come down to "surprising result". That is, it may be obvious that a D for H swap at a primary site of metabolism can improve PK. But what about a D for H swap at a secondary site of metabolism having an effect? What if it affects the CYP profile in a way meaningful enough (define THAT!) to differentiate?

What if the original patent claims "isotopes"?

Good times to be an attorney.

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5. NoDrugsNoJobs on June 10, 2013 10:00 AM writes...

The key thing to appreciate is that as long you are talking about obviousness and not questions of lack of novelty, the obviousness is considered only a presumption that can be rebutted by a showing of unexpected properties - So to your point about enantiomers, even in this very simple case, there are many examples where the court of appeals of the federal circuit (one below the supreme court and essentially the final word for 99% + of cases before it)where the commercial enantiomer patent was upheld as nonobvious. It is an old maxim of patent law jurisprudence that a drug and its properties are inseparable. This means that for a compound to be finally obvious, not only must the structure have been an obvious one to make, but its properties must have been predictable and expected. What is expected for an enantiomer? Generally, we might expect that one enantiomer is inactive or very weak and the other one might have all the potency. However, if one of the enantiomers has much of the toxicity and little of the activity, we more than likely will not have expected this - Generally, how could we predict the relative toxicity in advance? In reality this is a good concept because it encourages companies to take forward the compounds with the very best properties, not just the ones with the least challengeable structures. If I am a patient taking a drug, what do I care for if the structure was really nonobvious but more toxic - I don't care if it is a close cousin to another compound in the prior art provided its a better compound! Patent laws don't exist as abstract rules of nature that cannot be contravened but rather are tools that work to serve the real needs of the population rather than the theoretical reasoning of patent theorists.

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6. Rock on June 10, 2013 10:30 AM writes...

On the issue of obviousness, the concept may well be, based on the deuterium isotope effect, but the results are hardly predictable. This raises another issue in the deutero-drug field: Did the isotope actually improve anything? Recent literature, and my own experience with deuterium-labeled compounds, is that you can sometimes see an in vitro difference in microsomal turnover without an in vivo benefit. (Is the former enough to obtain a patent?) The preferred method for showing an advantage is to have the labelled and unlabelled compounds co-dosed in the same animals (and ultimately, humans). Without clear guidance of what constitutes "significant improvement" over the parent drug, this H to D switch could simply be used as a gimmick for extending the patent life of a blockbuster drug.

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7. Anonymous on June 10, 2013 11:30 AM writes...

Deuterium has a natural abundance of about 0.0155%. It is present in nature. Drugs made by normal synthetic means (no isotopic enrichment), will contain trace amounts of the deuterated analog.

Would the natural presence of the deuterated analog in a previously patented drug be enough to stop someone from applying for a new patent of the deuterated analog? The deuterated analog technically has already been made, although in small amounts. Also, the naturally occurring deuterated analog may confer chirality to the carbon to which it's attached, which is another issue to consider.

On the issue of chirality, the drugs with deuteration on a chiral center would need to have both resolved enantiomers tested. I doubt resolving these would be easy.

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8. imaging guy on June 10, 2013 12:22 PM writes...

I was once told that tritium labeling of small molecule drugs (to be used in ADME) did not change the biochemical properties of the original molecules as it was just isotopic substitution (cf. fluorophore labeling). Is that wrong?

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9. Hap on June 10, 2013 1:06 PM writes...

I assume that it would depend where - if it's at a site that isn't involved in any bond-breaking (isn't a site of metabolism or a site acted upon by the enzyme), then the isotopic substitution would probably not matter.

If, though, substitution is at a site where metabolism happens (in which case the tritium-labeled compound might not be a great probe anyway), then the isotopic substitution might affect the rate of metabolism (if C-H bond breaking is involved in the rate-detemining step of its reaction in the presence of an enzyme, then isotopic substitution would decrease the rate of that step). If the compound is partially tritiated at metabolized sites, then it might still be processed with a similar rate (because the isotope effect of tritium on the cleavage of the neighboring proton would likely be small and wouldn't affect the rate of metabolism much). The biological effect would depend on what happens to the compound. Is a more active metabolite formed, or a less-active or inactive one? Are the metabolites easier to get rid of or harder? There might be other issues, as well.

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10. Steven on June 10, 2013 1:10 PM writes...

Not exactly. It just depends on where the hydrogen is. If it's in a part of the molecule that won't be chemically modified, then no, it shouldn't have any effect. But if the C-D bond is breaking or going from sp3 to sp2 (or back), then it will have an effect and change things.

For more, http://en.wikipedia.org/wiki/Kinetic_isotope_effect

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11. anon2 on June 10, 2013 1:18 PM writes...

These days, 14C is the preferred approach for ADME studies.

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12. isodope on June 10, 2013 1:40 PM writes...

Merriam Webster had a nice translation of Derick's Latin phrase. Processchemist's Latin alternative, while perhaps meaning something to the Roman, didn't make the cut.

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13. isodope on June 10, 2013 2:14 PM writes...

Ah, isotope chemistry! It pays the bills for some of us. I'd like to touch on a couple of points made above. Tritium would not be placed in a molecule near the site of metabolism because it would complicate the metabolism study if it were metabolized away. That is why C-14 is generally preferred - much more difficult to lop off and get lost. Deuterated drugs would generally have several D per molecule - not a natural situation and that natural abundance would be multiplied by each D added. Now, suppose there are three D's are all on one methyl (on top of the natural abundance!); what are the odds of that isotopomer being in the natural mix? And finally, it should be understood that it is an assumtion (for scientific purposes) that the least perturbation of a compound for the sake of measuring it in an assay is to make an isotopic substitution (as opposed to a fluorescent tag or a different element).

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14. NoDrugsNoJobs on June 10, 2013 3:26 PM writes...

The novelty issue with regard to the natural presence of D can be easily overcome by claiming an enhanced ratio, something like>50% D; >90% D. >98% D, etc. The battle will be about obviousness in that case. However you are correct that if the drafter were careless and simply tried to claim the deuterated compound without further limitation, the "inventor" could be out of luck as a novelty rejection cannot be overcome by arguing properties, etc.

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15. BG on June 10, 2013 4:55 PM writes...

Does anyone have an idea of how much more the deuterated version would cost the consumer versus the non-enriched version?

What made me think about this is the huge price difference of something relatively simple, like deutero-dichloromethane versus protio-dichloromethane. I'm looking at Aldrich now: 10g of CD2Cl2 costs as much as a liter of CH2Cl2.

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16. anon2 on June 10, 2013 8:43 PM writes...

15: Typically, cost of goods is a minor contribution to the actual price that is charged for a prescribed drug. This should have little impact.

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17. sepisp on June 11, 2013 1:59 AM writes...

This just underlines how fundamentally arbitrary the patent system is. Trying to science a solution to these problems like "what is obvious" is like a trying to answer the question "what is the color of Thursday". We're still kneeling down to the king for a letter of patents for a royally sanctioned monopoly.

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18. Cymantrene on June 11, 2013 2:13 AM writes...

@sepisp: Thursday (csütörtök) for me is a dull and somewhat menacing grey with a hue of red-orange. Just like the setting sun glowing through the edge of a stormcloud.
;-)

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19. overthetop on June 11, 2013 12:56 PM writes...

@17 sepisp: You have a common misunderstanding of what rights a patent actually confers. It does not necessarily give you a monopoly, it merely gives you the right to exclude others from making your invention. It doesn't necessarily give you the right to actually make your product...you might owe others for using elements of their technology.

@5 nodrugsnojobs: a very nice explanation of obviousness in the pharma context.

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20. will on June 11, 2013 1:47 PM writes...

@19 - what do you think is the difference between a monopoly and the right to exclude others from making or selling your invention?

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21. metaphysician on June 11, 2013 2:19 PM writes...

And on top of that, IIRC, a patent does not actually exclude others from making your invention/discovery in all circumstances. I believe a lab can create their own batch of whatever patented compound they want for research purposes; they just can't go out and provide it as an article of commerce.

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22. Deeg on June 11, 2013 2:56 PM writes...

@21 metaphysician - not necessarily. You have to be careful on that one--go ask Duke University. Basically, if you are engaged in research activity for the purposes of preparing an NDA/sNDA/ANDA, you are protected by Hatch-Waxman before the patent expires. If, on the other hand, you are engaged in anything other than amusement, idle curiosity, or strictly philosophical inquiry (and Duke's research activities were deemed directed towards a business purpose), you may be liable. http://cyber.law.harvard.edu/people/tfisher/2002Madeyedit.html.

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23. Loweeel on June 11, 2013 5:21 PM writes...

@20 -- A monopoly is an affirmative right to practice, a right to exclude is not.

So if you invent A+B+C, the person who has a patent on A+B can prevent you from practicing your invention, because he has the right to exclude others. Similarly, you can exclude somebody from practicing A+B+C+D, even if neither you nor he can practice it yourself.

Even there, it's still not a monopoly, in any but the most trivial sense (after all, eachh of us technically has a monopoly on our own labor, Coke has a monopoly on Coke, Chrysler-Fiat on Jeeps, Bounty paper towels has a monopoly on Bounty paper towels), etc. because the world is chock full of definitional monopolies. Rather, the issue is about market power in a relevant market, and to say that something is a "monopoly" tells us nothing about the actual economic effect, but only about their (usually trivially narrow) market definition.

Some pioneering patents may be so broad as to effectively have a lot of market power, but even there, you cannot necessary say that there's a monopoly without analyzing market substitutes.

The concept of monopoly and patent thickets (e.g., smartphone wars, the sewing machine wars) cannot be simultaneously true in a given field.

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24. srp on June 11, 2013 8:13 PM writes...

Let's say there are N plausible spots to deuterate something. Use C(M,k) = M!/k!(M-k)! to mean the number of ways to choose k items from a set of M items, Then there would be C(N,1)+C(N,2)+...+C(N,N) possible deuteration patterns to test. For N=5 this would give 5+10+10+5+1=31 choices. Would that be obvious?

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25. James Cajal on June 12, 2013 11:03 AM writes...

Deuterium can effect microtubules. Think Alzheimer's,think cancer,etc. Deuterium bonds may be worth more than treasuries.

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26. James Cajal on June 12, 2013 11:04 AM writes...

Deuterium can effect microtubules. Think Alzheimer's,think cancer,etc. Deuterium bonds may be worth more than treasuries.

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27. patently on June 13, 2013 6:58 AM writes...

Speaking as a patent attorney...

Yes, times change and the criterion for obviousness changes as a result. What was inventive yesterday becomes obvious tomorrow. But do not forget, the obviousness test for a particular patent (or application) is judged as of its filing date, so by the time it comes to be litigated, that may be more than a decade earlier.

It must be so, of course - if not, then the most successful, influential and groundbreaking inventions would be deemed obvious with hindsight due to their own influential effect. But it does result in Courts deeming something to be "non-obvious" to the utter bemusement of those working in the field for whom it is (now...) a routine process.

As and when deuteration becomes something that is widely seen to be effective, and the process of choosing the sites to deuterate becomes better characterised, so will the threshold for obviousness rise. But there will still be scope for patenting, but perhaps just in the moments when you look at your colleagues notebook and think "You put the D there?? And it worked??".

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28. randomattorney on June 13, 2013 2:03 PM writes...

@7, that's just an exercise in claim drafting: "X, containing more than 0.2% D..."

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29. Christopher R lee on June 14, 2013 8:47 AM writes...

There seem to be a lot of misconceptions about what was common knowledge 40-odd years ago when 2-deutero-3-fluoroalanine was being developed (I think it was that one).

Deuterium at the right position can indeed have a major effect on metabolim. Writing from memory, a study in humans was stopped when deuteration made the metabolism of a steroid switch to a different pathway.

Even carbon-13 shows isotope effects; the chains of branched chain amino acids are significantly depleted.

Deuterated compounds are not good internal standards for determinations by chromatography-mass spectrometry, as they are always less retained than the unlabelled analogues. Receptor binding involves greater free energy changes than that.

We can conclude that deuterium should be considered to be another element as far as drug discovery is concerned, though in many positions it will be similar to hydrogen.

The patents stuff just goes to show that those ancient laws to protect profit-making have always been a severe hindrance to scientific and technical development. There are plenty of examples in the field of analytical instrumentation. As with antibiotic research, we need a completely new model for R&D financing.

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30. petros on August 4, 2014 2:02 AM writes...

Interesting new review that addresses how the USPTO is ruling on the obviousness of many of these filings.

http://informahealthcare.com/doi/abs/10.1517/13543776.2014.943184

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