Genetic Future

One of the major potential stumbling blocks for the field of genome-based diagnostics – particularly as we begin to move into the whole-genome sequencing era – is the unresolved issue of gene patents.

Currently somewhere in the order of 20% of the protein-coding genes in the human genome are covered by some kind of patent protection. However, the legal status of gene patents remains contentious.

Yesterday’s astonishing defeat of Myriad Genetics in an ACLU-led case before a United States District Court is unexpected, and potentially a positive outcome for companies seeking to offer large-scale genome-based diagnostics. The decision invalidates patents held by Myriad on the BRCA1 and BRCA2 genes, mutations in which are associated with increased risk of breast and ovarian cancers, and casts doubt on the validity of thousands of gene patents.

As you might expect, the place to go for expert coverage and analysis of the decision is Genomics Law Report. GLR has already posted some initial thoughts on the case from Dan Vorhaus, followed by a superb and thorough analysis by Dan and colleague John Conley.

The take-home message: this is a truly astonishing victory for critics of gene patents, but the full implications are yet to become clear. Myriad still has room for appeal, and the legal scope of the case is limited. Vorhaus and Conley argue that the decision should be viewed as just one part of a much larger battle:

In the broader policy debate surrounding gene and biotechnology patents, however, this decision is the latest, unmistakable shot across the bow of gene patent holders, particularly those such as Myriad Genetics that have developed businesses around patent-protected genetic tests supported by exclusive rights in underlying gene patents. As we wrote last summer, and as the SACGHS report pointed out in detail, there is a coming crisis at the intersection of multiplex genetic testing and whole-genome sequencing and biotechnology patents, particularly gene patents. This decision is sure to intensify the public policy discussion surrounding the appropriateness of gene patents, and ratchet up the media and public attention paid to the issue.

If the decision is upheld it seems likely to be a strong positive for companies like 23andMe and Counsyl, who offer multi-gene scans for genetic variants associated with diseases and other traits, as well as for academic diagnostic labs. It’s also good news (at least in the short term) for those of us interested in affordable personal genomics. [Update: I've transiently deleted a confusing sentence here until I have enough time to actually write something coherent.]

For updates on the decision, keep an eye on Genomics Law Report and follow Dan Vorhaus on Twitter.

Added 30/03/10: See the comments below for more useful discussion, including comments by Dan Vorhaus, Keith Grimaldi and 23andMe co-founder Linda Avey.

Comments

#1 Neuro-conservative
March 30, 2010

So, by your logic, someone writing a comprehensive book on genetic testing should be able to freely plagiarize, in its entirety, your writing on this blog, Dan Vorhaus’ blog, and any other blog that has written on the topic.

If authors offering such a book were forced to acknowledge each and every one of the bloggers (or worse, are prevented from stealing their material and forced to write for themselves), there’s little question that the publication of the book will be held back.
#2 Daniel MacArthur
March 30, 2010

A poorly worded sentence on my part, now deleted.
#3 Neuro-conservative
March 30, 2010

You can delete the sentence, but I think that is still the underlying sentiment of your post.

Of course, now that you have deleted the sentence to which my previous comment referred, my comment will not make much sense to future readers.

I think it would be fair to acknowledge that my second paragraph @ comment #1 was a satiric paraphrase of the sentence you deleted. A poorly worded sentence, indeed.
#4 Daniel MacArthur
March 30, 2010

I acknowledge that the second paragraph of comment 1 was a satiric paraphrase of the sentence I deleted.

To explain my original intent: my major focus in this blog is to explore the implications of news for the field of personal genomics, and my original sentence was focused solely on the likely net positive of the Myriad decision for companies operating this field and their customers. However, I should have taken pains to emphasise that a broad loss of patent protection could also have a negative effect on innovation. I’ve attempted to do so in a revised final paragraph, but it still needs work.

Anyway, fair and useful criticism – thanks.
#5 Anon
March 30, 2010

It’s expensive to research and develop new genetic tests.

Why would any company bother to try and develop new genetic
tests if they can’t be patent protected?

This decision “feels good”, but it’s terrible for the industry in the medium and long term.
#6 keith grimaldi
March 30, 2010

One possible negative is delaying publication of results in order to develop a genetic test that would have to rely on confidential information rather than patent protection to give it a market jump. In reality though I wonder how much this is likely. Most discoveries emerge from academic labs and for most academics the sought after reward is publication not patents or profit. The risk of holding back on publishing is of course that someone else will publish before you and you lose everything. That’s a lot to lose in return for some possibility (remote) of some future royalties. I think that useful discoveries will make their way into commercial tests whether patent protected or not, in fact if this ruling is the start of some clarity, I think that some barriers to innovation will be removed.
#7 Thomas Robey
March 30, 2010

The ACLU was a part of the lawsuit, but their claims to first amendment violations were thrown out by the judge, so it’s a little misleading when you can call it an “ACLU-led” case.
#8 Dan Vorhaus
March 30, 2010

A few quick comments:

1) Neuro-conservative: I don’t know what the now-deleted sentence said but, actually, you are free to reuse all of the GLR’s content provided that you provide attribution. Among many, many other differences between patent and copyright, that type of permissive access to copyrighted work – which is enabled by a Creative Commons license – is not generally seen when it comes to patented material. So, although I lack full context, I’m not certain I agree with your analogy.

2) On the issue, raised by several commentators, of incentive to innovate, let’s all try to remember that the scope of the Myriad decision, even if it is upheld in its full, sweeping authority, which is unlikely, is still rather limited. It covers certain types of fundamental gene patents (isolated DNA sequences) and other very broad process or method patents. It is very doubtful that this decision, without more, would undermine many of the existing patents that protect, for example, many other diagnostic tests, as well as therapeutic treatments such as pharmaceuticals.

For that reason, as well as the reasons Keith gave about additional incentives to innovate, and others on top of those, the jury is definitely still out when it comes to what sort of impact, if any, this type of decision would have on scientific or commercial innovation.
#9 Dan Vorhaus
March 30, 2010

Oh, and one last thing – I don’t think it is in error to describe this as an “ACLU led” case. They have been – and will continue to be – instrumental in organizing the plaintiffs, including the legal strategy used to procure this first and significant victory.

The fact that, as Thomas Robey points out, the constitutional claims were dismissed (without prejudice, I might add) is both irrelevant to who is driving the activity in the case and a red herring substantively. The claims were thrown out using the doctrine of constitutional avoidance. In essence, because the plaintiffs had fully prevailed on their patent invalidation claims, there was no need to tackle the constitutional challenges (although they are preserved for later rounds, should they be needed by the plaintiffs). That wasn’t a loss for the plaintiffs or the ACLU, it was just an acknowledgment by the Court of a complete victory at a prior stage of argument.
#10 Linda Avey
March 30, 2010

Adding to Keith’s and Dan’s comments about patents and innovation, I agree that Sweet’s ruling probably won’t have a negative impact on future developments in the use of genetic data/associations for follow-on inventions, whether diagnostic or therapeutic in nature. My hope is that this ruling stands and companies will need to actually innovate and create new advances BASED on genetic findings, not dependent on sole access to them. Rather than relying on obscure patent language and legal strategies, companies will need to develop products that are competitively positioned, something that will be good for consumers i.e. patients. With all due respect to the legal profession, we need to have more scientists and innovators in the lab, not lawyers.
#11 Dan Vorhaus
March 30, 2010

It’s sad to see Linda kicking me out of her future labs, but I share her sentiment: law, and patent law in particular, are meant to promote innovation. The current biotechnology patent landscape appears to be failing in that task, and this opinion is largely an acknowledgement of that fact. It’s not going to be the ultimate resolution to the problem – that chapter has yet to be written – but it does advance the ball.
#12 Larry Parnell
March 30, 2010

Discovery and innovation continue. We have no plans to alter our research and analysis agenda with respect to identification of genetic variants involved in metabolic syndrome and the response of those variants to lifestyle choices of diet, physical activity, alcohol and tobacco use, etc. Nor do we intend to adjust our plans as to the analysis of the data. Furthermore, we will publish as much as we can, as soon as we can – just as we have always done. In other words, as Keith noted, we will continue to supply data and interpretation of a small number of variants to those who extract those from our publications.
#13 p-ter
March 30, 2010

this can only be a good thing; the arguments about “innovation” are specious, especially in this case–Myriad’s test of BRCA1/2 does not assay a number of potentially causal mutations; a law that encouraged “innovation” would protect people inventing clever methods to assay these mutations, not prevent anyone from even trying.
#14 Jesse
March 30, 2010

I don’t see what the problem is.

Look, genes aren’t made by companies. There’s no reasonable way I can see to patent any of them unless you create them. I can’t patent a new species of woodpecker if I run across it in the wild. I can’t patent oxygen, even if I discover a new way to use it, and prevent people from studying it without paying me a royalty.

To me, the whole practice of patenting genes was based on specious reasoning, having too few staffers at the patent offices who understood the science, and underfunding the office to begin with while rewarding them for issuing new patents. It’s no better than patenting “business methods” which was simply stupid and led to all kids of idiocy w/r/t internet businesses.

Have you got a new method of testing? Great, patent it. Have you got a new process for using proteins? Go nuts. But the idea of patenting an underlying gene or naturally-occurring substance of any kind seems a real stretch to me.

If you have to patent the individual genes to protect your method, then it seems to me your method wasn’t all that innovative to start with.
#15 Jordanna Joaquina
March 30, 2010

I have been reading and enjoying the thoughtful discussion here and at GLR (amazing job Dan and John!). I am surprised, however, that there is little mention of the potential impact of this decision on patients and individuals at risk for life-threatening diseases. For these individuals, this case was personal and primarily about making a genetic test that can impact their disease management, screening, and even prevention options more accessible and affordable.
#16 A Robertson
March 30, 2010

Regarding incentive for innovation, it seems pretty important to remember that other incentive mechanisms exist – gov’t grants, prizes, first-mover advantage, reimbursement, etc… Patents aren’t the only way to push innovation in this field.

On this note, though, does anyone have an actual dollar figure on the price of developing a gene-based molecular diagnostic? I’ve seen comments saying that it’s expensive, I’m just wondering how expensive.
#17 keith grimaldi
March 30, 2010

@Jordanna

You’re right of course, although when referring to removing barriers, avoiding negative effects on innovation etc, the unstated goal is to bring discovery to the individual as quickly, responsibly, and as widely as possible. But it needs spelling out clearly as well, as you do – and who funds most of the original work that leads to these sorts of patents? Those very same patients and individuals. Hopefully one big barrier will now be removed regarding this test in particular, how much is the Myriad test? Something like $3,500? Now that really is “jaw dropping”!
#18 Daniel MacArthur
March 30, 2010

Thanks to everyone for their comments in this thread, which I’ve found extremely useful.

I’ve done a spectacularly bad job of conveying my own views on the Myriad patents in this post and comment #4, partly because my opinions are still somewhat confused, but also as a result of some over-hasty typing and editing.

By “a broad loss of patent protection could also have a negative effect on innovation” I wasn’t originally intending to refer to the Myriad decision per se, but rather to make a rather mundane statement about the possible negative consequences of eroding patent protection. The comments from Dan, Linda, p-ter and others in this thread make a pretty convincing argument that the loss of these specific Myriad patents (or gene-based patents in general) are unlikely to have negative consequences for innovation in the field.

Anyway, hopefully I’ll have a bit of time to compose something more coherent later tonight.
#19 Jonathan Eisen
March 30, 2010

Do you know how this might apply to products from non-humans?
#20 Linda Avey
March 30, 2010

Now the money behind these patents is starting to sound off, http://goo.gl/JjFs, although BIO seems to hedge their bet a bit. Already hearing IP attorney predicting decision will be overturned. How much does common sense/public opinion matter in cases like these?
#21 Neuro-conservative
March 30, 2010

Linda — Your link is broken — can you repost?

Dan V — I tried to post some related comments at GLR, but they have never appeared — did you receive them?
#22 Neuro-conservative
March 30, 2010

So far, no one has really discussed the distinction between: a) patenting a gene sequence (or an “isolation” of a gene sequence); and
b) patenting a method for detecting disease susceptibility.

While most of the Myriad claims are phrased like “a”, I think the real intellectual property is “b”.

Judge Sweet’s opinion deals with the latter issue only very briefly (p. 146-147), in the context of a discussion of “analyzing” and “comparing” claims, which I think misses the point.
#23 Dan Vorhaus
March 30, 2010

First, apologies for the fact that comments over at the GLR are broken. We are working on the problem.

In no particular order:

1) Jonathan Eisen, re: non-human products. The same reasoning could be extended to non-human products and other biological products, although the same caveats (district court opinion and thus not binding, limited to reading the Myriad patents, etc.) still apply. If it makes it up to the SC, if they take on the products of nature issue that would almost certainly have implications beyond just human gene patents.

2) Neuro-conservative, re: process/method patents. As John and I wrote at the Genomics Law Report, that part of the opinion’s discussion was surprisingly short. That may have everything to do with Judge Sweet’s obvious awareness that the SC will be handing down its ruling in Bilski shortly – we are looking at a few months, if not a few weeks – and, thus, that part of the opinion is on particularly transitory legal footing.

As many have pointed out, that’s where the real technical / clinical innovation is taking place, and those types of patents are far more likely to be narrowed rather than completely wiped out.

3) Linda, re: public opinion. I think public opinion matters, but not necessarily significantly. Federal courts (thankfully, unlike some state courts) are not really in a position to be influenced by public opinion. It can certainly impact other policy / legislative activity, such as the SACGHS report, but the effects are going to be somewhat attenuated and difficult to predict.

4) A Robertson, re: cost of diagnostics. Somebody else might be able to weigh in more intelligently, but my experience is that it depends hugely on the nature of the test. This is particularly true when you are dealing with the IP and legal costs associated with creating and commercializing a test, which includes everything from Freedom To Operate (FTO) assessments to, where necessary, patent licensing costs.

5) Jordanna, re: patient access. This is one of the outstanding questions: will this actually improve patient access in the near term? I’m not sure that it will. I think it would be a mistake for a commercial provider to simply infringe Myriad’s patents on the basis of this ruling. In addition, often overlooked is the fact that this ruling covers a minority of Myriad’s patents and claims, so it is not clear to me (and, in fact, seems unlikely) that this ruling, even if upheld, would necessarily pave the way for a direct competitor to Myriad’s BRCA testing. That doesn’t mean this won’t help to open up access – which I agree is one of the primary goals – but I’m not certain that’s inevitable.

- Dan
#24 Neuro-conservative
March 30, 2010

Thanks, Dan. Did you find it odd that Judge Sweet relied so heavily on Justice Breyer’s dissent in the Lab Corp v Metabolite case, which 5 justices did not even want to hear? Don’t you think the 5 conservative Justices will tend to be supportive of Myriad’s patent claims, which are vaguely similar to those upheld in Lab Corp?
#25 Glenn
March 30, 2010

The Federal Circuit (where this will go on appeal) is well-known as not really giving a shit what the district courts have to say on patent issues. Don’t know what the ultimate outcome will be, but Judge Sweet’s opinion is hardly the last word.
#26 keith grimaldi
March 30, 2010

Regarding costs of developing a genetic test, for an established lab such as DNA Direct the “wet work” I don’t think would be much, the costs of the reagents and extensive validation work. More expensive would be developing the packaging and the marketing, but as Dan V mentions, the licensing costs can be a, if not the, major factor.

Regarding stifling innovation, in this particular case, and in the case of genes in general, if there had been no IP on the BRCA genes:

a) would a breast cancer test have been developed?
b) if so would it have appeared sooner or later than it did?
c) would it have cost less?
d) would it have been more widely available?
e) would it have helped a greater or lesser number of individuals?

Finally, right now it would not be a good idea to infringe Myriads patents, that is very good legal advice from Dan!
#27 Neuro-conservative
March 30, 2010

If there had been no IP for Myriad, there would have been no investors. Similarly with Decode, etc (obviously it didn’t work out that well for Decode’s investors, but they were investing strictly on the implied promise of IP).

It might feel good to break Myriad and give away free breast cancer tests for everybody, but would you be willing to go back in time and erase Decode from existence? Would you be willing to sacrifice every finding from that dataset?

Presumably, Francis Collins or MCK would have nailed down BRCA1 soon enough, even if Myriad had never attracted investors. But this case has the potential to deprive us of investment in future efforts that we can only imagine.
#28 Dan Vorhaus
March 30, 2010

Comments over at the GLR are now fixed, or so it appears. If anybody is still having trouble posting, please let me know.

Also:

1) Neuro-conservative, re: Lab Corp. I didn’t find it odd to see the Lab Corp dissent show up, if for no other reason than the Supreme Court has continued to duck that issue. Citing the dissent is just another in a long line of invitations for the Supreme Court to take up the products of nature issue again. That says absolutely nothing about what result they would reach if they did hear the issue. I don’t really know if this is a conservative vs. liberal thing. Patent law often doesn’t really break along political party lines in the same way other areas of law appear to.

2) Keith, re: stifling innovation. Those are the right questions to ask, conceptually. They are just so difficult to answer in practice. Wouldn’t it be great to be able to design a prospective study that asked that question under two radically different patent regimes?
#29 A Robertson
March 30, 2010

Dan, Keith – many thanks.

Personally, I would think that the BRCA 1/2 scenario isn’t a good gauge for whether gene patents are required for innovation in today’s world, mostly since BRCA research was conducted pre-genome.

If I remember, the Myriad venture money was in the tens of millions. Costs today should be much, much lower (although the only estimate I found was from 2007, with a $1 million price tag for a 2,000 person, 500,000 SNP GWAS, coming in at $0.001/SNP).

If research costs are less prohibitive, then presumably more people would be willing to undertake the early stage research needed for gene-test development for a lower reward-incentive. Just a hunch, though.
#30 Matthew Markus
March 30, 2010

Almost all research in genetics is taxpayer funded. Yes, the commercialization of a test may require investors. Myriad’s BRCA patents cover more than a test, though, they cover the ability to even access the genes in question! When only one company can look in one area of the human genome for years, the pace of innovation comes to a crawl and costs soar. The decision to invalidate Myriad’s composition of matter claims is clearly a win for innovation.
#31 Karl E
March 30, 2010

I haven’t read all the comments but noone seems to have mentioned that the case for gene patents have weakened during the last decade. The more we expand our knowledge about how genes work, the more we understand that genes usually function as small parts of incredibly complex networks. Scientifically, patenting individual genes makes less and less sense, and the possibility of doing so might inhabit any real understanding of how genes actually work.
#32 Douglas Watts
March 30, 2010

It might feel good to break Myriad and give away free breast cancer tests for everybody, but would you be willing to go back in time and erase Decode from existence? Would you be willing to sacrifice every finding from that dataset?

Free breast cancer tests for everybody !!!

With breasts.

Sounds like a good deal.
#33 Steven Murphy MD
March 30, 2010

Gosh,
what a great comment string. We need to acknowledge that the costs of running a publicly traded company are extremely high. That being said, 3120 USD is a hell of a lot to examine 2 genes.

Research labs have also made quite a profit on genetic tests, I think about the transition of the familion SCD tests. These costs are prohibitive to personalized medicine. Even insurers who now bear the burden of paying with someone else’s money are complaining about costs.

This is why MedCo bought DNADirect and Caremark is playing with Generation Health. They need to save money from these genetic tests.

The dissolution of these types of patents will likely stand, but it will take a SCOTUS case.

The results will not be a major barrier to biotechnology innovation, it will mean a change in strategy from walling off a gene to inventing some technology around them.

This is a good thing and MYGN will do ok. Why? Because they deliver a great service and have allied with a distribution channel known as healthcare.

-Steve
#34 Linda Avey
March 30, 2010

Daniel, sorry for the broken link–couldn’t find the statement from BIO (maybe I’m just missing it). They may have pulled it.
#35 George White
March 30, 2010

The notion that the loss of patent protection to human genes would stifle research and innovation, limit testing options and “would have a pretty significant impact on the future of medicine” as the NY Times quoted Kenneth Chahine, is completely without merit. Yes, few companies will lose their cash cows, but by and large it will have the opposite effect.

Just look at the IT industry. Do you think that the Internet and the web was at the state it is today if a company like Myriad held the IP for the underlying technology? Or, do you want to go back to the days that a handful of companies held the IP to telephone technology?

Companies like Google and Cisco succeeded without owning the rights to TCP/IP or VoIP. The biotech industry will do just fine without patent protection to genes.
#36 Dan Vorhaus
March 30, 2010

I generally agree with both Steve’s and George’s comments re: the impact of a scaling back of biotechnology patents along certain lines (e.g., to isolated DNA sequences) would not cripple the industry. Indeed, it wouldn’t cripple a market leader such as Myriad who, as Steve rightly points out, has other important advantages in addition to patent exclusivity. (That does not mean, of course, that Myriad isn’t facing other serious challenges, most notably from multiplex testing.)

I think Andy Pollack’s follow-up piece in The New York Times does a nice job balancing the competing industry perspectives. Even among those that would make their business lives by selling genetic tests, there’s far from a consensus as to whether the status quo is desirable.
#37 Grant
March 30, 2010

I’ve no problem seeing Linda’s link, here’s the full URL:

http://www.bio.org/news/pressreleases/newsitem.asp?id=2010_0330_02

Good to see this discussion. My understanding of the (US) legal rights (etc.) is tiny, but the idea of patenting what amounts to observations of a pre-existing thing always has bothered me. To me it doesn’t matter how sophisticated the means needed to make the observation, it’s still just an observation.

I’m interested in the ruling on tests and would like to learn more about that. I work in computational biology (bioinformatics) and it could have implications there. I’m thinking of computational methods (which I believe aren’t usually patented), but these are also “tests”; somewhere along the way Myriad will be using a computational methods to score their diagnostics, etc.
#38 Neuro-conservative
March 31, 2010

Dan V — I think both the NY Times article and the comments here are skewed towards a “retrospective” analysis — i.e., what happens to gene patents and tests that already exist. How about those that would not exist or will not exist as quickly because there is less incentive to develop them?

As I asked before, would Decode have existed if sort of regime were in place a decade ago?
#39 Matthew Markus
March 31, 2010

As I asked before, would Decode have existed if sort of regime were in place a decade ago?

The real question is: “Would deCODE have existed without the support of the Icelandic government?” The answer is, “No.” Gene patents, in their current form, are just a way to privatize discoveries made with public resources. Gene patents promote rent-seeking behavior, the antithesis of innovation.
#40 keith grimaldi
March 31, 2010

A sentence from the Pollack article cited by Dan above caught my eye: “When hundreds or thousands of genes are being tested at once, patents on each individual gene can become a hindrance to innovation rather than a spur”.

It’s true even when putting a panel of just a few genes together, and often there is more than one patent holder to deal with even for a single gene:

1. Owner of gene/SNP patent
2. Owner of gene-disease association patent
3. Owner of gene-environment interaction patent

This is an example from real life (can’t give details though) that required long drawn out discussions with often inept university tech “transfer” offices demanding exorbitant upfront fees and ongoing percentages. The result after over a year of back and forth was no deal, gene was not used, the scientists who actually did the discovery work were upset (they just wanted to see their efforts put to use) and everybody lost.

How Navi, 23andme, decode, etc manage – I would really like to know

And then there is still the GTG “junk” DNA patent portfolio to contend with – now that IS broad and is still actively being enforced
#41 true religion jeans
March 31, 2010

oh cool, this information is really useful and definately is comment worthy! hehe. I’ll see if I can try to use some of this information for my own blog. Thanks!
#42 Geneticist from the East
March 31, 2010

What about deCODE’s TCF7L2 Type 2 Diabetes patent? Are they in the process of suing 23andme and Navigenics on that?
#43 Mary
March 31, 2010

On a political blog that I frequent I have already had the discussion I expected about this: a guy with a PCR machine in his garage intends to offer BRCA testing to his neighbors.

I have tried to tell him that there are issues of quality control and counselling around this. He dismissed it as the same thing as buying counterfeit Viagra. He said:

I suppose one can’t really have it both ways
i.e., these type of tests can be patented and kept under strict quality control (after all, a company has a vested interest in having a reliable product).
Or, you can let me (or anybody) do it for pennies on the dollar. Results may vary.
They say the same principles apply to viagra. Not that I know anything about that.

So whether or not you have an erection is equivalent to a decision about having your breasts and ovaries removed. ‘Mkay. Results may vary. Nice.
#44 JDP
March 31, 2010

Re: Mary

The Myriad test currently on the market has been criticized extensively for having a false negative rate as high as 12%.

There is no, literally, no competition and no way to get a second opinion, and the tests cost upwards of $3k to a consumer, whereas they probably cost several orders of magnitude less in terms of materials and labor.

Killing the patent is good for women.
#45 keith grimaldi
March 31, 2010

Neuro-conservative asks “How about those [tests] that would not exist or will not exist as quickly because there is less incentive to develop them?”

How many genetic tests are there that are carried out by fully certified labs that have never had any patent protection? According to EuroGentest, there are 1,500 centres in Europe that conduct genetic tests for about 1,000 different genetic conditions. The majority of these will be far less utilised than BRCA – so the incentives do exist beyond IP for even comparatively low volume tests to be developed.

Traditionally the race to find disease genes was always driven by research curiosity, desire to do something beneficial, and of course ego…
#46 Dan Vorhaus
March 31, 2010

I agree with Keith, Matthew and others that patents are neither sufficient nor necessary to incentivize innovation, including the development of genetic tests. It depends on many other variables. Asking just one question – “Can I receive patent protection that will keep others from offering this test?” – is not enough.

Ultimately, however, I think it’s more important to ask whether a test is useful, not whether it is offered (or how many labs/providers offer the test). (Keith points to EuroGentest, and the same point can be made by looking at Genetests.) The motivation behind the Myriad challenge, as well as other attempts to clean up the biotechnology patent landscape (e.g., SACGHS), is to improve clinical care access and quality, including w/r/t diagnostic testing.

Certainly, this district court opinion is unlikely to have a meaningful short-term impact in that regard. The comment Mary forwarded is disturbing, but I hope just noise. Ignoring the legal problems with a garage-based DIY BRCA testing lab (forget patents, what about CLIA?), there are numerous other technical and commercial barriers to entry for would-be Myriad competitors.

For instance, even if we ignore, for the sake of argument, the fact that Myriad still has very strong patent protection, there is still the matter of whether a competing lab could match Myriad’s quality. This is and should be of paramount important to clinicians, patients and payors alike. Myriad has been at this a long time, and has accumulated knowledge – e.g., in interpreting variants of uncertain significance – that might not be easily matched by a competitor. On the other hand, plenty of concerns (here and elsewhere) have been raised about the quality of Myriad’s tests.

The question from a policy perspective should be whether patent protection, and the resulting commercialization, serves to improve the quality, affordability and accessibility of genetic tests. I think the evidence to date is equivocal, although I think the movement to multiplex testing may be tilting the argument in the direction of patents as a hindrance, rather than a help.

In today’s NY Times piece, Andy Pollack wrote the following:

But the industry is already moving to a period of somewhat less dependence on DNA patents for its sustenance. Diagnostic laboratories, for instance, are shifting from testing individual genes to testing multiple genes or even a person’s entire genome. When hundreds or thousands of genes are being tested at once, patents on each individual gene can become a hindrance to innovation rather than a spur.

I think that’s right, but we’re not going to know for sure unless the law actually changes. And let’s all keep in mind that has not actually happened yet.
#47 Mary
March 31, 2010

@JDP: I understand that testing isn’t perfect–ever. But at least if it is done in a medical setting these things can be explained to you. Your hacker neighbor may not provide any awareness of that.

I support this ruling. I just don’t support people doing this in their basements.
#48 J.J.E.
March 31, 2010

“How about those [tests] that would not exist or will not exist as quickly because there is less incentive to develop them?”

People test their mtDNA to see what their maternal racial origins are. Did the lack of a patent hinder that field, which is less useful and in less demand? Can you actually list any tests that would not exist or were slowed? And what about future tests that will be delayed or prevented because of existing patents? With the routine full-genome sequencing on the horizon, do we really want to incentivize the well-being of a comparative handful of patients from the mid-90s until maybe 2015 at the cost of everyone that comes afterwards until the patents expire?
#49 Neuro-conservative
March 31, 2010

I believe that Keith and Dan are both committing a logical fallacy in reference to currently available tests.

Just because labs are offering tests that are not protected by patent, it does not follow that patent protection was unnecessary for the development of those tests.

By analogy, manufacturers of generic medications do not receive patent protection for their products, but many of their products would not exist if they had not been developed under patent protection by other Pharma companies.

We do not know how many genetic tests rely on data that were acquired under the expectation of profit under the existing patent regime.
#50 keith grimaldi
March 31, 2010

Dan – thanks for your continued input, and everyone, it’s obviously an emotive topic.

I hear that Myriad do a good job, I think that if the BRCA suddenly became open-access there would quickly be a handful of reputable competitors (Lab Corp, Quest, and others in Europe & Asia), the quality would be at least equally high, the price would drop and the availability increase. To still be at >$3,000 per test is the result of the stranglehold. The problem with this type of patent is that there is NO alternative way, there is no possibility of improvement or of competition. Apple make an iPhone packed with Apple IP, at least others can come up with alternatives to do something similar thing. Is gene patenting unique in that it gives the owner total control? Should a patent be able to create a monoply? Even with a novel pharmaceutical competing companies can still develop alternatives (and improvements) so we don’t have one statin or one antibiotic ruling the market. Thank goodness Myriad do a good job!
#51 Neuro-conservative
March 31, 2010

Dan @46 states:
The question from a policy perspective should be whether patent protection, and the resulting commercialization, serves to improve the quality, affordability and accessibility of genetic tests.

I respectfully disagree with this statement, which seems to be entirely consumer-focused. What about protecting the rights of the scientists developing the knowledge?
#52 Andro Hsu
March 31, 2010

Dan V., I was wondering if you could talk a bit about the Grams decision mentioned on p.145 and how it interacts with Bilski. It looks like simple “analysis” of multiple data inputs was considered to be a mathematical algorithm and thus unpatentable. Is this because the particular claim in Grams is very broad and didn’t specify what the inputs were or what abnormality was being identified (i.e. were not “particular”)? Because what is being claimed in Grams certainly sounds a lot like what Genomic Health and other companies do.
#53 Neuro-conservative
March 31, 2010

JJE @48 — You make the point of whole genome testing, as do Dan & Keith elsewhere. But this raises 2 questions in my mind:

1) Should Illumina, etc. not be entitled to patent protection for their sequencers, since they are merely reading out data that exists in nature?

2) As has been frequently described on this blog and others: it is one thing to have sequence data, and another to have clinically meaningful tests using that data. The latter require considerable scientific effort to develop, and should not be brushed aside in the race to provide whole genome sequence data to the consumer.
#54 keith grimaldi
March 31, 2010

@Neuro-conservative – the majority of genetic tests available today are for rare gene disorders. The scientific literature over the last 30+ years demonstrate clearly that almost all, if not all, of the discoveries which enabled the tests were made in the absence of expectation of IP.

The analogy with pharma does not quite fit – in a few years time there will be “generic” BRCA tests when the patents expire but with cystic fibrosis etc, as soon as the mutations were discovered royalty free tests were immediately available by myriad public and private labs (excuse the pun…)
#55 Neuro-conservative
March 31, 2010

Keith — I think you must be overstating the case. I know of too many geneticists who formed companies in the 90′s (and even more recently) in the hopes of big $$$. Perhaps these efforts did not result in financially successful IP, but they definitely contributed to the knowledge base of the field. Otherwise, what was the whole Celera race all about?
#56 J.J.E.
March 31, 2010

@ Neuro-conservative

You seem to be making a fair case for patents in a general sense, but it seems to fall apart whenever the specifics of the Myriad case intrude. The specific case of patenting naturally occurring nucleotides is what gets peoples’ hackles up. BRCAs were KNOWN to exist and discovering their positions and sequences was simply a matter of time. Mapping and sequencing them was obvious and indeed they were active targets of study for anyone who had 3 neurons to rub together and a genetics degree. What Myriad did used no new techniques, generated no new techniques, and their profit model is based on forbidding any competing diagnostic tests if and only if those tests target a particular stretch of information that Myriad just happened to get mere months (or at most a few years) before everyone and their siblings would have gotten them anyway.

Of course Solexa/Illumina, ABI, Celera, et al. should be able to patent clever applications of molecular biology. Those applications, while not exactly “bolt out of the blue” novel if you know about molbio, were nonetheless sufficiently non-obvious enough to patent in the same way that a clever pair of safety scissors might be worth patenting. Those companies all patented processes and technologies that are broadly applicable and arguably would have been substantially delayed without incentives. If Affy used its SNP chips to patent all SNPs it found that’d be terrible. But if they patented their arrays (as they have presumably done) and a process for finding SNPs, that’s entirely different.

And it is a damned good thing that Celera didn’t patent the rest of the genome. The negative repercussions boggle the mind. Imagine Celera sending cease and desist orders to anyone that dares use the knowledge of a gene sequence to run a diagnostic test on it (excepting BRCA genes, of course. Those belong to Myriad!) That’s simply absurd. And focusing your effort on a few genetic variants that are statistically associated with disease is hardly any better.

Again, if Myriad patented a sufficiently novel diagnostic procedure for which abundant prior art couldn’t be found, more power to ‘em. Plenty of genomics companies have done that. But no, they patented the right to diagnose a stretch of sequence.
#57 keith grimaldi
March 31, 2010

Neuro-conservative – I don’t think I am overstating it as most of the discoveries were pre the 90′s gold-rush. Also as the majority of tests are for the rare diseases they would not have been the choice targets in the $$$ race. But you are correct, there has been a growing expectation of IP and earnings over the last couple of decades. Dan V will know the history better, being a lawyer, but I suppose the whole thing began with the Stanford Cohen-Boyer DNA splicing patents in the ’70′s. Taq PCR in the ’80s. Notable exception was monoclonal antibodies – Cambridge and MRC lost millions but the rest of the world was better off. Then the ’90s, I think, saw the Craig Venter ESTs and resulting controversy. I don’t think many commentators here are against patenting per se, it’s more that the breadth of the patents may take protection too far. As Dan says, this case was brought by the ACLU to widen accessibility to the testing.

There hasn’t really been the returns that were hoped for, the Myriad case seems to be more of an exception, although GTG has also made a nice pile (see #40). Maybe it will all become moot when sequencing becomes commonplace – surely a patent cannot stop me getting my genome sequenced. Do the current batch of gene patents reuqire actual testing to be done or would Myriad expect a fee just for an interpretation of the sequence results (question for Dan)?
#58 keith grimaldi
March 31, 2010

J.J.E. makes a good point about what is obvious should not be considered inventive, even if it required effort to arrive at the actual variants involved. No invention, no patent. Maybe things are different now, I’m sure they are. I blogged recently about the less glamorous world of Celiac disease testing. I mentioned a set of tagging SNPs that could radically reduce the price and availability of screening for genetic susceptibility – but the researchers had applied for a patent. One of the comments (total of 4 comments, 2 from me, i’m not in Daniels league yet, but at least he hasn’t got IP on science blogging so we can always try, or hope…) noted that the documents on the WIPO site suggest that the patent would not be granted. All of the claims were considered NOT to be inventive – to search for tagging SNPs for HLA alleles was considered obvious
#59 Scinotes
March 31, 2010

Great conversation.

I think Keith is right – the pharma analogy doesn’t quite fit. First and foremost, genetic tests don’t have to go through the rigorous (and expensive) FDA approval process as do drugs. Likewise, the risks associated with a false hit are markedly lower than drug discovery, making any investment much less of an all-or-nothing risk.

A new drug costs around $1.2 billion in today’s money to develop. I don’t see this even being close to the figure required for the development of a genetic test, especially in the post-genome era. Of course SOME costs are incurred in developing a genetic test, but if these are low enough to be satisfied through first-mover and market sharing, then patents are not needed.

The generic drug model in my mind is quickly becoming the proper analogy, with the “innovative” step being taken by publicly funded research labs.
#60 JDP
March 31, 2010

re: Mary

If you’re spending $3k on genetic testing for a deadly disease, then the error rate shouldn’t be 12% for type 2 error.

I agree about garage testing, although I wouldn’t be adverse to seeing more research/medical geneticists offer cheaper alternatives.
#61 p-ter
March 31, 2010

1) Should Illumina, etc. not be entitled to patent protection for their sequencers, since they are merely reading out data that exists in nature?

the answer here is obviously no (or yes, of course they are entitled to protection). but let’s say they sequence a human and discover a piece of sequence carried by that individual but absent from the reference genome; can they then patent that sequence, and prohibit anyone from assaying that piece of DNA by any technology? I think that’s the more relevant question for the Myriad case.
#62 Neuro-conservative
March 31, 2010

p-ter — Your comment is specifically concerned about patenting the sequence per se. I recognize that Myriad’s patents are phrased that way, which was the norm in the pre-genome era of the 1990′s, but the practical import of the Myriad patents are for testing. I think this whole concern about patenting of sequences is understandable, given the patents’ phrasing, but is ultimately a red herring. I also think this is a significant problem with Judge Sweet’s analysis.
#63 p-ter
March 31, 2010

I think this whole concern about patenting of sequences is understandable, given the patents’ phrasing, but is ultimately a red herring

I’m not sure this is a red herring. Myriad has exclusive rights to testing on the entire gene, not just those mutations they identified (as others have pointed out, there are a number of mutations in the gene that Myriad did not discover and which they do not assay, which leads to the test being uninformative for a number of people). Maybe I’m misunderstanding (disclaimer: not a lawyer), but my understanding was that this is because they have a patent on the entire gene sequence, in which case this is the entire crux of the matter.
#64 Matthew Markus
March 31, 2010

@Neuro-conservative,

One could easily posit that gene patents hindered the development of genetics. You mentioned deCODE and all the 90s genomics companies that collapsed. The main reason that they collapsed was that they spent a large fraction of their time looking for and patenting genes instead of developing novel diagnostics and therapeutics. Thus, they had nothing of commercial value once bubble-era financing disappeared. This behavior was caused by the patent system.

Dr. Keith Robison has a great blog post on this instanity:

http://omicsomics.blogspot.com/2009/01/ah-them-gold-rush-days.html
#65 Brian
March 31, 2010

I think this whole concern about patenting of sequences is understandable, given the patents’ phrasing, but is ultimately a red herring

Wow. No, it is in fact the entire reason that everyone is so interested in this case, following the debate, and making comments. The Myriad case is interesting to everyone because it is the test case for the patenting of a genetic sequence. It can’t be a red herring, it’s the actual subject under discussion!
#66 p-ter
March 31, 2010

to briefly follow up, my understanding is that if I were to sequence a family with hereditary breast cancer and identify a previously never-observed mutation in BRCA1, I would not be allowed to design a test for that mutation, because Myriad has the right, not to their particular assay, but to all possible assays involving the gene, including to assay mutations that have not yet been discovered. it’s difficult to imagine an argument that would convince me that this state of affairs is not absurd.
#67 DM
April 1, 2010

I wanted to comment on the idea of someone offering BRCA testing out of his garage. At present, Myriad does just the testing. Genetic counseling and the decision to go forward, isn’t done by Myriad.

Also, not everyone recognizes the Myriad patent. Testing done in Canada does not go through Myriad and I believe the same is true for Europe.
#68 qetzal
April 1, 2010

Great discussion here! I wish I’d seen it sooner.

I looked at the claims and patents referenced in Judge Sweet’s opinion, and I think p-ter is correct. For example, here is the full text of Claim 1 from < href="http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=6033857.PN.&OS=PN/6033857&RS=PN/6033857">US #6,033,857:

1. A method for identifying a mutant BRCA2 nucleotide sequence in a suspected mutant BRCA2 allele which comprises comparing the nucleotide sequence of the suspected mutant BRCA2 allele with the wild-type BRCA2 nucleotide sequence, wherein a difference between the suspected mutant and the wild-type sequences identifies a mutant BRCA2 nucleotide sequence.

IMO, that’s about as bad as the Ariad patents that tried to claim anything that had any effect on NF-kB levels – including drugs that were approved with no prior knowledge that they did affect NF-kB!
#69 David R Bachinsky
April 2, 2010

Thomas Kepler and colleagues at Duke have an interesting, recent analysis of BRCA1 claims in genomics.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WG1-4YK2F2W-1&_user=10&_coverDate=03%2F10%2F2010&_alid=1278817083&_rdoc=1&_fmt=high&_orig=search&_cdi=6809&_sort=r&_docanchor=&view=c&_ct=1&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=168bdc49d93947be822620d8f5b414a8
#70 Henry Furneaux
April 2, 2010

Just a simple question. How were the boundaries of the BRCA genes defined in the patent application ? The sequence that encompasses the open reading frame? The sequences that comprise the mRNA sequence(ie just the exons ?). The whole genomic DNA sequence ( exons and introns ) from transcription start site to poly A addition site. Enhancer/ promoter sequences upstream of the transcription start site ? My recollection was that it was only the open reading frame sequence that was patented ? Anyone know ?
#71 Brian
April 2, 2010

Henry, the patent covers thousands of 15mers, encoding just about every conceivable sequence related to BRCA1 & 2. The patent is ridiculously broad, and many think it should never have been granted on completely separate grounds. I think that complicates the discussion of the Sweet opinion quite a bit…
#72 daedalus2u
April 2, 2010

This is the right decision, naturally occurring gene sequences should not be patentable.

I am an inventor, so writing and using patents are an essential part of what I do. The premise of patents is that they foster innovation by providing an incentive to an inventor for disclosing his/her invention. The quid-pro-quo is that in return for disclosing the invention in sufficient detail so that “one skilled in the art” can duplicate it, the inventor is given the right to bar others from making, using or selling the patented invention for a limited time.

It is the disclosure of the invention that allows others to modify and build on it. A gene sequence is not new, unless it has been generated de novo by the inventor. There is no invention to build on or modify that has been disclosed by sequencing a naturally existing gene.

The incentive that the patent provides is in return for the disclosure, not in return for doing the research. That is why something obvious can’t be patented, there is no disclosure that has any use to anyone else.

If one was able to patent an existing gene, one could bar individuals from using it. Presumably that would include using it in their own physiology. That is nonsense because such use of the naturally occurring gene was ongoing before the patent was applied for, the patent cannot make illegal something that was in common use before the patent was applied for.

A gene sequence is information. The patent system is ill suited to protect information. There are other IP systems that are better suited to that, copyright for example. Could a gene sequence be copyrighted? Only by the author. Who is the author of natural gene sequences? Not the person or company or machine that first sequences them. I see a gene sequencer as not that different than a camera. It records data of a naturally occurring thing as a photograph. Can you patent a photograph of a person’s face? No, but you can copyright it. But that copyright doesn’t bar other individuals from photographing the same face too. It can bar derivative works, such as making a painting from a picture (which I think is screwy).
#73 Simon Easteal
April 3, 2010

This morning, as I took my twin grandsons for a walk through the suburb of Fizroy in Melbourne (its their second birthday and Fitzroy is an interesting place), we passed the laboratories of GTG, the company that holds, but does not enforce, an exclusive licence to the Myriad patents in this part of the world.

The boys’ parents have decided not to enrol them in the Australian Twin Registry because of their sense of unease about engagement in genetic research. I frequently encounter this feeling that genetic research, more than other areas of medical research, is something one needs to be wary of. This is a barrier to research that depends on public participation and which has the potential to greatly benefit a large number of people. I wondered if the owners of gene patents, such as GTG and Myriad, might be partly to blame, but I think the real culprits are those clamouring to legally prohibit gene patents.

The key issue about gene patents is inventiveness. Does the isolation of a gene involve an inventive step? Is a gene, isolated in a vector or by amlification using the polymerase chain reaction, different from the gene as it occurs in nature? Here in Australia eminent scientists and reputable organisations such as the Cancer Council and the Royal College of Pathologists have very publicly declared that the idea of patenting genes is absurd. As one of them put it in a television interview last year “It is absolute nonsense to consider that the gene could be patented. It’s a naturally occurring substance. It would make as much sense to patent a gene as it does to patent the moon.”

But as every biologist (as distinct from clinical geneticist) knows, context and interaction are fundamentally important in biological systems. There is no question that in principle it is possible to configure naturally occurring nucleotide sequences in a way that is novel, useful, inventive and non-obvious, just as it is possible to configure naturally occurring wood and metal in the same way to develop a better mouse trap. Inventiveness is about changing relationships and context more than about changing stuff. A segment of DNA is just stuff – it is not what is being invented when it is recombined and then used as a therapeutic or diagnostic, just as bits of wood and the metal are not what is being invented to produce a better mouse trap.

A recombinant gene may have the same function as its naturally occurring counterpart in the sense that it can be induced to produce the same protein, but by existing in a novel context it can be used for things (like saving peoples lives) that are not possible when it is in its natural state. It is fundamentally changed. Whether that change constitutes an invention depends on the particular circumstances of gene’s isolation. There may be reasons why specific gene patent applications should be denied, but there is no reason why applications involving nucleotide sequences should be denied in principle.

So, do I think that all isolated genes constitute legitimate inventions: Absolutely not. In most cases the isolation of specific genes is neither inventive nor non-obvious.
Do I think that patent offices should grant patents on isolated genes? That is a matter for the examiners and depends on the details of specific applications.
Do I think that gene patents should be prohibited by law? Absolutely not. There is no reason why nucleotide sequences should be treated any differently under patent law than any other configuration of naturally occurring molecules such as wood or, for that matter, the polymerase enzyme extracted from Thermus aquaticus, that makes the isolation of specific segments of DNA possible.

I am not interested in patenting genes but I am very interested in genetic research. And I am deeply concerned about the indirect effects of advocating that genes should be treated differently under patent law than other components of biological systems. It creates in people’s minds the false notion that there is something about investigating someone’s genes that is fundamentally different than studying some other aspect of their biology. This message, amplified and distorted by the media, raises concerns in people’s minds about participation in studies and programs and impedes progress in an important area of predictive and preventive health.
#74 Serhan Alkan, MD
April 4, 2010

Biocompanies are indicating that the discovery will be affected with this decision may be true but similarly if one company holds a patent on a particular gene, it also prevent further research on that gene. For example, there was a study showed that Myriad detection method mutation on BRCA missed some of the mutations in some individuals since it did not covered some rare mutations. If your the patient being investigated for presence of mutation, you may be reported falsely as negative. I am a director of a molecular laboratory and daily encounter that the patent given to Myriad or several other companies on other genes are effecting what I could set-up for clinical testing. Many individuals will be overcharged by a company if it owns a such a patent. I rather wait for a delayed discovery by an academic institution since this will be better for humanity than helping out someone’s pocket and also have the eventual freedom to develop my own novel cheaper alternative testing for the patients.
If a biocompany is here to make profit, there is a legitimate way of making it possible: make a drug for that gene that will help the patients and patent the drug not the gene. Then, no one will question your legitimacy. By simply sequencing what already exist is not the way to be in biotechnology business.
#75 J. Wong
April 5, 2010

I think the Myriad decision is correct. A similar case is the company that discovered a natural gene-variant encoding a non-allergenic version of a protein in cats. They have patented the gene in the interest of preventing others developing a test for that gene so that they can sell cats with it at a premium. Otherwise, people could just test cats at a shelter until they found one with the variant.

Instead of patenting the process, i.e., the test, they’ve attempted to patent the end result. A pharmaceutical company can patent a drug, but not the cure, leaving others free to develop competing drugs that are perhaps a better cure.
#76 Dan Ullfig
April 6, 2010

I think there is a general sentiment that without patent protection, you can’t make money at genetics, and therefore no one will invest in it. I think this is a fallacy. There have been numerous examples of very profitable businesses in the past that have made money without patent protection. Take the aircraft industry for example. During the golden age of aviation, there where many companies competing with each other, and it was still profitable. I’m not sure I’m buying this argument that without patents there will be no genetic research.
#77 Ron Ranauro
April 6, 2010

I would think that the discoverer of the genetic biomarker, in this case for early diagnosis of breast cancer, has the right to patent protection. Is this different than the way drugs are discovered and marketed? Just like pharma’s that have to navigate competition from generics that come off patent, so too will diagnostic tests that face patent expiry.

I’m not a lawyer, but it seems to me the core issue is the breadth of what is claimed. The patent was granted at a time when low-cost, whole genome scans were unfathomable. Now, we know diseases involve many genes and soon we can screen all the genes of a patient for a few thousand dollars. Having to remove the BRCA from the diagnosis in order to avoid infringement makes little sense, especially when the diagnosis might lead to something that has little to do with breast cancer.

Despite the Myriad patents, there is still alot of patentable research available on the BRCA genes. I grabbed the BRCA genes from GenBank and launched a search in our system. A report of all the patents that use or claim BRCA is here: http://bit.ly/9HHUCb
#78 Neil
April 13, 2010

@44

In trying to explain the quoted false negative rate of 12% for the Myriad BRCA1/2 test to a maths teacher (H/T Lottie!), I realised I didn’t know what it meant.

It comes from this paper, which is well worth a look:

http://jama.ama-assn.org/cgi/content/full/295/12/1379

Walsh, T et al (2006). Spectrum of Mutations in BRCA1, BRCA2, CHEK2, and TP53 in Families at High Risk of Breast Cancer.

JAMA. 2006;295:1379-1388.

ABSTRACT

Context Genetic testing for inherited mutations in BRCA1 and BRCA2 has become integral to the care of women with a severe family history of breast or ovarian cancer, but an unknown number of patients receive negative (ie, wild-type) results when they actually carry a pathogenic BRCA1 or BRCA2 mutation. Furthermore, other breast cancer genes generally are not evaluated.

Objective To determine the frequency and types of undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN among patients with breast cancer from high-risk families with negative (wild-type) genetic test results for BRCA1 and BRCA2.

Design, Setting, and Participants Between 2002-2005, probands from 300 US families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic test results for BRCA1 and BRCA2 were screened by multiple DNA-based and RNA-based methods to detect genomic rearrangements in BRCA1 and BRCA2 and germline mutations of all classes in CHEK2, TP53, and PTEN.

Main Outcome Measures Previously undetected germline mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN that predispose to breast cancer; frequencies of these mutations among families with negative genetic test results.

Results Of the 300 probands, 52 (17%) carried previously undetected mutations, including 35 (12%) with genomic rearrangements of BRCA1 or BRCA2, 14 (5%) with CHEK2 mutations, and 3 (1%) with TP53 mutations. At BRCA1 and BRCA2, 22 different genomic rearrangements were found, of sizes less than 1 kb to greater than 170 kb; of these, 14 were not previously described and all were individually rare. At CHEK2, a novel 5.6-kb genomic deletion was discovered in 2 families of Czechoslovakian ancestry. This deletion was found in 8 of 631 (1.3%) patients with breast cancer and in none of 367 healthy controls in the Czech and Slovak Republics. For all rearrangements, exact genomic breakpoints were determined and diagnostic primers validated. The 3 families with TP53 mutations included cases of childhood sarcoma or brain tumors in addition to multiple cases of breast cancer.

Conclusions The mutational spectra of BRCA1 and BRCA2 include many high-penetrance, individually rare genomic rearrangements. Among patients with breast cancer and severe family histories of cancer who test negative (wild type) for BRCA1 and BRCA2, approximately 12% can be expected to carry a large genomic deletion or duplication in one of these genes, and approximately 5% can be expected to carry a mutation in CHEK2 or TP53. Effective methods for identifying these mutations should be made available to women at high risk.

Basically, while Myriad don’t claim too much for a negative result, the lay interpretation uses the wrong null hypothesis – failure to detect a known mutation is not positive evidence for lack of all mutations.
#79 brca gene patent
January 4, 2011

This topic is dear to my heart as it affects my family and descendents. I posted about it recently at http://drpullen.com/brcagenepatent/
#80 RR
January 6, 2011

BOTTOM LINE!!!! PEOPLE ARE DYING AND THEY SHOULD’T BE ABLE TO HAVE A CORNER ON THE MARKET!!!!! SURE THEY SPENT A LOT OF MONEY, BUT AGAIN PEOPLE ARE DYING AND THIS TEST SHOULD BE MORE AFFORDABLE AND READILY AVAILABLE TO PEOPLE!!!!!!!!!!
#81 RR
January 6, 2011

DID I MENTION PEOPLE ARE DYING???? MOTHERS, DAUGHTERS, SISTERS….PEOPLE….REAL PEOPLE!! FORGET ABOUT A PATENT, HOW ABOUT WE START HELPING PEOPLE. AND NOT AT $3,000+ a shot!!