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About this site
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Here we'll review recent developments in drug discovery and medicine and the IP issues and financial implications they have, along with general thoughts about research. Also likely to make an appearance: occasional digressions into useful topics like which lab reagents smell the worst.
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About this author
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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.
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Osmium Tetroxide, Of All Things
This morning brings the news, via ABC, that the recently discovered bomb plot in London involved a quantity of osmium tetroxide. That's a surprise.
I know the reagent well, but it's not what anyone would call a common chemical, despite the news story above that calls it "easily obtained." It's quite odd that someone could accumulate a significant amount of it, and it's significant that anyone would have thought of it in the first place. It's found in small amounts in histology labs, particularly for staining in electron microscopy, but that's generally in very dilute solution. If these people had the pure stuff, well, someone's had some chemical education, and probably in my specialty, damn it all.
The reagent is used in organic synthesis for a specific (and not particularly common) reaction, the oxidation of carbon-carbon double bonds to diols. I've done that one myself once or twice. OsO4 comes in and turns the alkene into a matched pair of alcohols, one on each carbon, and it stops there. Other strong oxidizing reagents can't help themselves - they find the diol easier to attack than the double bond was, and go on to tear it up further. There was a recent paper in the literature on the mechanistic details, actually, going into just why the osmium reagent stops where it does.
Unfortunately, the alkenes it could attack are unsaturated fatty acids and such, as found in lipoproteins and cell membranes. Exposed tissue is vulnerable. Breathing a large amount of the vapor can kill a person through irritation of the lungs, but it's not as bad that way as the better-known agents like phosgene. A bigger problem is the cornea of the eyes, and the reagent is mostly feared for its ability to bring on temporary (and in some cases, permanent) blindness.
There's no doubt in my mind that any terrorist with the stuff was going for that effect. Could it have worked? Well, it's a solid at room temperature, but a hot day will melt it. The stuff sublimes easily; it has a high vapor pressure. Just being around the solid crystals is enough to get you overexposed to the vapors. I don't know how much of the reagent these people had, but I tend to think (again, contrary to the ABC story) that an explosion would have dispersed it to the point that it was just down to irritant levels. I wouldn't want to find out, though.
If they were planning to use it in a non-explosive gas attack, that's another matter. But the vapors are said to be very irritating, with a distinctive chlorine-like smell - which I cannot verify, thank God. It's not like no one would have noticed that there was some nasty chemical in the air. I think that they could have done some damage, certainly. But what disturbs me more than the reagent itself is the thinking behind it. . . |
Oblivious to One Skilled in the Art
I've noticed that discussions of patent law really wilt my traffic something fierce, so I thought I'd go ahead and get another one out of my system now. Perhaps the effect isn't additive. (It'll serve me right if turns out to be nonlinear the other way).
One of the things that hits you when you start worrying about patenting chemical compounds is that there sure have been a lot of them patented. The number of compounds exemplified is pretty large all by itself, but it's just a roundoff error compared to the number that have been claimed. I've seen patent specifications that I swear would run well into the millions if every claimed variation were rung.
They aren't, of course. There's no way that they could be. The extra space is just breathing room, to try to keep the competition from coming too close to the good stuff. It's also to protect some of it for you if you happen to come across something else that's good after you file, but that's a two-edged sword - if you find it too much later, you've got a patent with years of its lifetime already expired, for one thing.
It's important to remember that these drug patents aren't just randomly distributed around the world of chemical structures, either. There are plenty of things that no one is going to be interested in patenting, because they're too reactive or toxic. And there are other structures that just lend themselves to drug discovery: piperidines, piperazines, biphenyls, imidazoles, and tricyclics are just a few that come immediately to mind. The patent space around those things has been trampled, plowed, clear-cut and strip-mined.
These things are all prior art for new patent applications to worry about. Exemplified, reduced-to-practice compounds are bulletproof prior art: if it's been described in the literature, you can't own it. You can claim a new way to make it, or a new use for it, but you can't claim the chemical matter. Section 103 of the patent code says that an invention has to be nonobvious, and you don't get much more obvious than something that's already there. But what about all those claims, those huge, inflated claim structures that reach well into the Kuiper Belt? Are all those off limits?
We'd be in big trouble if that were the case. After all, the problem gets worse each year, nonlinearly worse as the pace of research (and the pace of patenting) picks up. But there's a way to sneak into those putatively fenced-off reserves. If you turn to the MPEP, the patent examiner's manual, you find that "the fact that a claimed species or subgenus is encompassed by a prior art claim is not sufficient by itself to establish a prima facie case of obviousness." Good news, indeed.
For a patent examiner to reject a claim on the grounds of obviousness, the manual says that "it is essential that Office personnel find some motivation or suggestion to make the claimed invention in light of the prior art teachings. . .regardless of the type of disclosure, the prior art must provide some motivation to one of ordinary skill in the art to make the claimed invention. . ." And that's the key. Those massive edifices of claim language eventually have to get down to earth. As the claims roll on, page after page, they start narrowing down. A preferred embodiment of the invention is. . .a still more preferred embodiment. . .a particularly preferred embodiment. . .eventually you get down to what they really, really want to protect.
And legally, what they're doing is teaching you the invention. The claims teach toward the true invention, and the rest of the patent is supposed to teach you how to carry it out (including the "best mode" requirement I mentioned yesterday.) If you're claiming something that's way out in the fringes of the first forest of claims, then the rest of the patent is clearly going to teach away from it. And that means that you can get it for yourself.
There are complications. This is patent law; of course there are complications. It'll hurt your case if you're going for the same use as the original compounds. Your best chance there is to show that your compounds perform in some unexpected way, which the original patent claims clearly didn't anticipate. A less common way to break out of this situation is to show that the original patent's methods wouldn't even be able to produce some of the distant structures - if they don't teach how to make the structures, they can't have 'em.
So that's how it's done. That's not to say that patenting isn't getting harder all the time, because it is (after all, there are all those truly exemplified compounds piling up.) But at least it isn't getting impossible. Nothing a lot of time, effort, money, and legal resources can't attack, anyway. |
Obvious to One Skilled in the Art
Not much time to post tonight. Things have been fairly busy in the research world, with the added burden of some patent filings and some evaluations of other filings from the competition. These only confirm to me that there is no way that I could possibly keep bread on my table as a patent lawyer.
Some of my co-workers might find that a bit odd, since I have the reputation at work of knowing a bit more than usual about the subject, for a medicinal chemist. But that just means that I know enough about it to be an irritant to the attorneys. I can't shake, while thinking about the legal issues, a feeling that all that mental effort could surely be put to some better use.
As no doubt it could, but only with some other species. As with any other field, there is no way to write the rules in such a manner that no one can get around them. Writing a patent is a deadly mixture of drudgery and, well, trickery. You're required to disclose the best mode for realizing your invention, and you'd better do it, too. But you're not required to mount a flashing neon sign pointing to it. And you have to exemplify the things that are at the heart of your claims, to reduce them to practice, as the lingo has it. But there's nothing that says that you can't exemplify lots of other things, too, during which you feel like a cuttlefish spewing ink.
Nope, it's not something I can do for long stretches. I enjoy brief visits into Lawyer Country, but I make sure that I have my return ticket in my pocket at all times. No doubt they'd find it easier if they didn't have to deal with us lab types so much, too. I won't ask; they'd tell me. |
Differences Between Academia and Industry, Pt. 2
One of the main things I noticed when I joined the pharmaceutical industry (other than the way my black robe itched and the way the rooster blood stained my shoes, of course) was how quickly one moved from project to project. That's in contrast to most chemistry grad-school experiences, where you end up on your Big PhD Project, and you stay on that sucker until you finish it (or until it finishes you.)
My B.PhDP. was a natural product synthesis, and I had plenty of time to become sick of it. My project seemed to be rather tired of me, too, judging by the way it bucked like a mad horse at crucial stages. Month after month it ground on, and the time stretched into years. And I was still making starting material, grinding it out just the way I had two years before, the same reactions to make the same intermediates, which maybe I could get to fly in the right direction this time. Or maybe not. . .time to make another bucket of starting material, back to the well we go. . .
Contrast drug discovery: reaction not working? Do another one. There's always another product you can be making - maybe this one will be good. Project not going well? Toxicity, formulation problems? Everyone will give it the hearty try, but after a while, everyone will join in to give it the hearty heave-ho, because something else will come along that's a better use of the time. Time's money.
It keeps you on your toes. You have to learn the behavior of completely new classes of molecules each time - no telling what they'll be like. You dig through the literature, try some reactions, and get your bearings quickly, because you don't have weeks or months to become familiar with things. The important thing is to get some chemistry going. If it doesn't make the product you expected, then maybe it'll make something else interesting. Send that in, too. You never know. |
Copyright 2003-2004 Derek Lowe. All rights reserved. Terms of use
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