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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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« Crichton, Patents, and Genes | Main | Comments on Comments »

February 14, 2007

Gene Patents, Part One: Genes As Chemicals

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Posted by Derek

A lot of rather heating commentary is coming on on the subject of Michael Crichton's gene-patent article, and on gene patents in general. The subject is large enough that it'll need to be broken down to discuss. For today, here's my take on one aspect, what a patent lawyer would call "composition of matter".

The patenting of isolated genes as chemical entities is tricky. Yes, they are chemicals, and when they're isolated and purified like that they really are in a different state than found in nature. But their size is so far removed from many of the other things patented as substances that I can't help but wonder if a principle is being pushed too far. (The obvious other example here is the patenting of isolated proteins, which of course is also well established, for better or worse).

An analogy occurs to me, and working through it will show some of the complications of this area: suppose I isolated and purified a single molecular weight form (one particular isomer) of some long industrial polymer that's usually made and used as a mixture. Can I patent that? Can I then go after people who sell the mixture, because it includes my proprietary substance?

Now, there are some differences here compared to patenting a gene, because the original polymers I'm thinking of are man-made, and there's a lot of prior art around them. And no doubt some of it includes language that covers polymers of a range of molecular weights and the like, and the older ones have long since entered the public domain anyway. The biggest problem with using this as a path to riches is that I don't think I can turn around and go after people whose polymers have my patented isomer in them, because I believe I'd have to show that it's an essential part of their system (and it probably won't be). So I likely won't be able sneak in on some of that big polyethylene money this way.

How about polymers that aren't man-made, like cotton or silk? We have no good way (at present) to produce or isolate individual single isomers of such things, the way we can with stretches of RNA or DNA. If I invent one, I'll most certainly apply for a patent on the method of doing that, just like someone who invents a new way to separate or purify DNA would. I don't think anyone should have a problem with that, because that would be an inventive step by anyone's definition. But can I then turn around and get composition-of-matter patents on some of the things I can isolate with my new technique? Judging from the genomics examples, I'd say that I could, if I could pass a further test.

That's a big one, though: having to show some utility for them. As I mentioned yesterday, that issue that came up with a lot of the early gene patent applications - back in the far-off days of the 1990s, people just immediately shotgunned the PTO with applications for every gene they came across, often with only the haziest uses in mind. Eventually the rules were tightened up - you can't just march in with your gene now and say "could be useful for a diagnostic test for a disease in which this gene is involved" and get a good reception. (There's also the problem that most of the genetic landscape is already the subject of one application or another by now)! I could have some difficulty showing a particular utility for a particular isomer of (say) a silk protein, but it could probably be done. Perhaps the presence of a particular one would prove to be important for imparting some property to the finished silk, for example.

There would be other patenting difficulties, even if I got mine issued. A big one would be the "doctrine of equivalents", which is the patent law way of saying that a difference that makes no difference is no difference. If I claim a newly isolated pure polysaccharide of X hundred or thousand monomer units, is there anything different about it compared to the X+1 isomer? There had better be a difference at some point if I want to have a patent that will do me any good, and to be on the safe side I'd better try to patent everything out to that point.

DNA, RNA, and proteins are perfectly suited to pass that test, though, since very small changes can be demonstrated to lead to totally different properties and functions. The doctrine of equivalents comes in when you start looking at silent mutations - a base change that doesn't change the amino acid that gets coded for, or (in a protein) a conservative amino acid switch in a part of the structure that doesn't affect anything. Court cases have been fought over just these sorts of issues.

As you can see, the thing that makes DNA, RNA, and proteins different is that they're structurally simple enough to make, handle, and isolate, and structurally complex enough so that there are huge numbers of potential variations. There are also highly evolved systems than can be exploited for their production and alteration, which gives everyone a big head start. Biologically, they're leveraged tremendously, so that seemingly trivial changes can sometimes have huge consequences - and, of course, these consequences bear on human health, which makes them of great social and financial importance. A better recipe for intellectual property wrangling I could hardly imagine. Next time, we talk utility, where even more fun is to be found.

Comments (10) + TrackBacks (0) | Category:


COMMENTS

1. qetzal on February 14, 2007 12:07 PM writes...

[S]uppose I isolated and purified a single molecular weight form (one particular isomer) of some long industrial polymer that's usually made and used as a mixture. Can I patent that?

I believe the answer should be (and very likely is) "yes, if you can show utility of the purified form that goes beyond the mixture."

Can I then go after people who sell the mixture, because it includes my proprietary substance?

Here, I think the answer should be "no" because the mixture and its uses are prior art. You should only be able to prevent others from using the purified form without your permission.

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2. david on February 14, 2007 12:19 PM writes...

Perhaps I'm being difficult, but if someone has the particular DNA sequence as part of their genome, isn't that prior art by definition?

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3. qetzal on February 14, 2007 12:34 PM writes...

Maybe it would help if patent law was changed so that you can't get composition of matter patents if the matter in question is just a purified form of what exists naturally.

In that case, you couldn't patent an isolated gene, but you could patent a particular use of it. If you isolated a gene and used it to develop a test for genetic disease, the use patent would let you prevent others from infringing on your test. But, you wouldn't be able to block others from finding (and patenting) other novel uses for the gene that you didn't think of.

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4. christianhauck on February 14, 2007 12:39 PM writes...

There is no gene that is as long as the whole chromosome. So in order to make the part of the chromosome a molecule (in the small molecule sense) you have to add a hydrogen at one end and a hydroxy group at the other end. O.K., so you patent that molecule (after adding water). But this one is not the one that is in the chromosome (as part of the whole, without the water).
If I had a patent on ethylen, and you have the rights for CH2, who would then have more rights on polyethylene?

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5. hibob on February 14, 2007 1:47 PM writes...

1. One specific issue mentioned by Crichton: patenting the testing of genetic mutations as diagnostics. Does Craig Venter, who had his own genome sequenced almost in its entirety for the human genome project, owe licensing fees to ALL of the stakeholders who had patents for diagnostic mutations? It doesn't seem like he should. But if the fee is only triggered when he specifically looks at, say, his own BRCA genes w/r/t the patented mutations, how do you restrict enforcement to just this step? It's only relevant to a few individuals right now, but it will be increasingly possible to sequence large amounts of DNA cheaply. And it will be trivial for the data to be analyzed privately instead of by the company doing the sequencing.
Will sequencing companies have to delete patented regions from the data they give out? So much for gnothi seauton: Know thyself.

2. What happened to the end run on recombinant protein expression patents where a company, instead of expressing a protein recombinantly in another organism, just upregulated the expression of the protein in the original organism?

3. On the purification of a natural substance issue - aren't many of the gene patents on cDNAs instead of the naturally occuring sequence?

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6. Steve Cooper on February 14, 2007 2:24 PM writes...

An analogy occurs to me, and working through it will show some of the complications of this area: suppose I isolated and purified a single molecular weight form (one particular isomer) of some long industrial polymer that's usually made and used as a mixture. Can I patent that?

Yes, given some unexpected benefit to doing so.

Can I then go after people who sell the mixture, because it includes my proprietary substance?

No.

Your claim would be drawn to "an isolated and purified component with specified properties, to distinguish from the same material as part of a mixture, which was in the prior art. You would have added value by isolating a specific component with especially valuable properties, and that's what you would get rights to - the specific, isolated component - and no more. So you could only go after people selling the specific, isolated component, not the mixture containing it.

Compare the situation of isolating a natural product from its source. In each case, the compound per se occurs naturally, and hence is not patentable without the limitation of "isolated" and/or "purified."

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7. qetzal on February 14, 2007 2:31 PM writes...

"3. On the purification of a natural substance issue - aren't many of the gene patents on cDNAs instead of the naturally occuring sequence?"

D'oh! Good point. Not something I should have forgotten, given my training is mol biol!

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8. Anonymous BMS Researcher on February 15, 2007 7:53 AM writes...

This whole discussion has been intensely interesting for me as one who is listed as an inventor on a patent around claimed utility for certain genetic sequences!

Typically the composition-of-matter claim in a patent says something like "any of the sequences listed below, or any other sequence having X percent identity by algorithm Foo." I regularly get asked by our patents people to perform prior art searches for sequences published before such and such a date with X percent identity to some sequence named in a patent using a particular algorithm. We've had to keep certain now-obsolete algorithms available for such searches primarily for replicating the exact searches specified in patent claims.

I also look forward to what Derek has to say on the issue of "utility," which can be especially important when there are, say, eight different patents claiming the same stretch of DNA with differing amounts of evidence for its utility.

I think my favorite line on this subject, for which I do not recall the source, went something like "however, this does not include claiming a particular strain of mutant rodents can be used as snake food (unless, of course, the applicant presents evidence these mutant rats might in fact make superior snake food)." But an awful lot of the early gene patents came close to being this weak on utility with their generic claims of possible use in diagnostic tests. During the genome gold rush period of racing to patent possibly-interesting sequences, I recall hearing much sardonic talk about companies turning genomic annotation pipelines into "lawyers in a box." Some of these patent filings consisted almost entirely of output from such analyses mixed with generic legal boilerplate. I ain't no lawyer but wonder how patents with so little human intelligence behind them will stand up when tested in court -- all some of these folks did was buy thousands of CPUs with which to feed sequences through well-known algorithms.

I have felt for a long time biotech companies basically fall into one of two categories: those who really want to help discover new ways to help patients, and those who mostly want to discover new ways of extracting royalties from Big Pharma (whose pockets they assume bottomless). Those in the first category deserve rewards commensurate with their contributions; those in the second category deserve zilch. I would be the last to claim the bosses at Big Pharma are entirely pure (guess my opinion of Peter Dolan), but for all our many faults we ARE trying to discover and develop products to fill unmet medical needs and deserve rewards commensurate to our contributions.

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9. john simon on February 16, 2007 7:06 PM writes...

"Perhaps I'm being difficult, but if someone has the particular DNA sequence as part of their genome, isn't that prior art by definition?"

Prior art in the USA is defined as what it covered under 35 USC 102, nothing more. Outside the USA definitions may differ. The pre-existance of a device or compound (under the right conditions) does not necessarily serve as a bar to a US patent being granted.

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