"At-Home" Testing for BRCA Gene Mutations

By Kevin E. Noonan --

With great fanfare (if not braggadocio), researchers at the University of Maryland, College Park have published a paper in Genome Biology that purports to provide the means for individuals to assess their risk for breast or ovarian cancer despite patenting of isolated human BRCA1 and BRCA 2 genes by the University of Utah (licensed to Myriad Genetics).

As disclosed here, Professor Steven L. Salzberg and Mihaela Pertea from the Center for Bioinformatics and Computational Biology report "a computational screening method that test[s] an individual's genome for mutations in the BRCA genes, despite the fact that both are currently protected by patents."  The method utilizes "open source" software (found here) for "do-it-yourself home testing . . . for interrogating a genome for the presence of mutations in the BRCA genes."  The methods are set forth broadly as follows

We used the Bowtie short-read alignment program (Langmead et al., 2009, Genome Biol. 10: R25) to screen all sequence reads against the BRCA1 and BRCA2 regions (located on chromosomes 17 and 13, respectively) and against a set of 68 known mutations from the Online Mendelian Inheritance in Man (OMIM) database (see Methods).  The size of the datasets ranged from 2.8 to 4.1 billion reads for each genome, with most reads being 35-36 bp.  The BRCA genomic regions are each about 80-90 kb; with these small target sequences Bowtie is extremely fast.  Using only a single 2.4 GHz processor, Bowtie aligned reads at 127 million reads per hour, and alignment of the largest of our datasets took about 8 hours.  Thus despite the enormous number of reads for each genome, screening was relatively fast.

Using these methods, the researchers interrogated publically available whole genome sequence information from Asian and African males and a Caucasian female.  A single mutation was found at one site in the genomic BRCA2 gene in the female, known to be associated with a 30-40% increased risk of breast cancer, according to the paper.

The researchers tout the benefits of their method:

If free software can be used to diagnose human genetic mutations, then individuals will be able to run their own tests in the privacy of their own homes.  Fundamentally, this seems no different from measuring one's temperature or blood pressure, but because of gene patents, the act of reading one's own genome may require the permission of a private company.  It is hard to envision how the patent holders can enforce their claims in this scenario.  Our contention is that these patents never should have been awarded, and that no private entity should have rights to the naturally occurring gene sequences in every human individual.

While consistent with the uninformed lay opinion that "private companies . . . own" human genes, the adage that "the name of the game is the claim" has not been abrogated for gene patents, and the limits of a patentee's right to exclude conduct by others is limited by the terms of their claims.  For the BRCA patents, it is informative to review the fifteen claims of the seven patents involved in (and invalidated by) the ACLU's lawsuit (AMP v. U.S. PTO).  Specifically, the following U.S. patents were set forth in the complaint:  U.S. Patent Nos. 5,747,282; 5,837,492; 5,693,473; 5,709,999; 5,710,001; 5,753,441; and 6,033,857.  Not all claims of these patents were challenged (see Patent Docs post).  Of these claims, none of the claims challenged by AMP and its co-plaintiffs for the '282, '492, or '473 patents would be infringed by Dr. Salzberg's disclosed method, because inter alia they require isolation of DNA encoding the BRCA1 or BRCA2 proteins that is not required for the practice of his method.

For the remaining patents, the following claims could be implicated:

For the '999 patent:

1.  A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1.

For the '441 patent:

1.  A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject.

(Infringement of these claims would require the sequence to be the germline sequence and that it be obtained from a tissue sample.)

For the '857 patent:

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.

2.  A method for diagnosing a predisposition for breast cancer in a human subject which comprises comparing the germline sequence of the BRCA2 gene or the sequence of its mRNA in a tissue sample from said subject with the germline sequence of the wild-type BRCA2 gene or the sequence of its mRNA, wherein an alteration in the germline sequence of the BRCA2 gene or the sequence of its mRNA of the subject indicates a predisposition to said cancer.

The challenged method claims of the remaining patent, No. 5,720,001 would not be infringed using Dr. Salzberg's method, since it requires that a tumor sample is analyzed, something even the most ambitious at-home diagnostic test is unlikely to perform.

As described by Dr. Salzberg's paper, it is necessary to determine a human's genomic DNA sequence and then use the software to compare the sequence with known mutations in BRCA1 or BRCA2 associated with disease.  (The paper notes that the method could readily be adapted for other genes and other mutations for other diseases.)  This is something that is undoubtedly outside the scope of any at-home test, and presumably would require an outside vendor to make the genomic sequence determination and provide the individual's genomic sequence using conventional (and ever more rapidly-provided) methods.  The individual would then perform the method that the paper asserts would be infringing ("because even a noncommercial use -- such as examining one's own genome -- is considered to be patent infringement," ironically citing the ACLU's website about its "free speech" challenge to gene patents).  While technically correct, there is no movement or groundswell for patentees to sue individual users (in contrast to record companies suing copyright infringers, for example).  Rather, it is more likely that any commercial entity providing whole genome sequences for use with Dr. Salzberg's method might be liable for inducing infringement (although the evidentiary burden for establishing liability may be high).  It is also possible that Dr. Salzberg could be adjudged liable as well, depending on whether this paper is the extent of his involvement or if he is actively involved in promoting commercial exploitation of the method.

Acknowledged in Dr. Salzberg's paper is a consequence that is much more serious than whether his method could be used to circumvent Myriad's patent rights.  This is that "at-home" methods are devoid of the support systems (physicians and genetic counselors) that are provided by commercially available test providers (as well as with testing provided by clinical genetics labs).  The same emotional aspects of human genes that seemingly motivates much of the animus against human gene patents is attendant on any genetic diagnosis, and while the consequences of bearing certain BRCA mutations are a high likelihood of developing breast or ovarian cancer, other mutations are not as predictive.  It is difficult to envision how an at-home test could provide sufficient information for an individual to properly assess the difference.  As a consequence, in addition to providing "free" access to an individual's genetic complement, such at-home tests would provide unnecessary pain, suffering, and anxiety for an individual and her family.  These costs should not be ignored in the overall calculus of the value of thwarting private companies from providing (and profiting from) genetic testing.

Comments

[EG]

Kevin,

Very interesting article. Your point about the danger of "at-home" testing to assess for risks as serious (and as complex) as these is "spot on." In fact, the folks who wrote and published this article are at risk of more than inducing patent infringement. What if someone did this "at-home" testing and through ignorance missed a "warning sign" for either breast or ovarian cancer that Myriad's testing would have found? We're now talking about potential tort liability if that person later develops that cancer. Just some thinking out loud.

[Moocow]

Huh? What does that tell us about the ACLU's assertion that patents on "isolated" or "purified" DNA molecules (like the BRCA sequences in the Myriad case) are impossible to design around?

That aside, I don't think there would ever be a realistic risk that even the broad and generalized method claims would be asserted against Dr. Salzberg or anyone else - because the described method simply doesn't interfere with Myriad's business. No patient, and no provider, would ever decide to perform a mastectomy, oophorectomy, or any other medical procedure on the basis of a computational at-home test alone, without the confirmation of a real CLIA-certified diagnostic test. If anything, Salzberg's method would generate more business for Myriad and other test providers.

[Donna Ferber]

We should keep in mind that taking one's temperature might require the use of a patented thermometer!

[Skeptical]

Inflammatory? "but because of gene patents, the act of reading one's own genome may require the permission of a private company."

Highly dependent on just how that act of reading was undertaken, and like myriads (pun intended) of other patented methods that may be done at home, just as protected.

[Bob Cook-Deegan]

Kevin,

Thanks for this analysis. I'm not so sure about the quick dismissal of the composition of matter claims in the '282 patent on BRCA1, and its equivalent claims on BRCA2. By my reading, those claims would arguably be infringed by any method that would be an input to the Salzberg process. Any way of determining a DNA sequence of which I am aware, including single-molecule methods and most certainly any first- or second-generation method that entails "DNA prep" before sequencing steps, is arguably creating "isolated" DNA. Any sequence would also generate sequences longer than the 15-mers claims for both genes (claims 5 and 6 of '282).

It turns out these claims are probably invalid based on novelty, but that has not been determined. None of us can know how courts will interpret scope of these claims until and unless a court makes such determination. To my knowledge there is zero case law on this, and even the AMP v USPTO case is now about section 101 patent-eligibility, not 103 novelty. Perhaps we will get to questions of novelty and enablement/written description in that case after appellate review, but we're not there now.

Your points about DIY diagnosis and caution are quite interesting and a vexing policy matter. But not about patents.

To my eyes, both the composition of matter claims and the method claims in these BRCA1 and 2 patents (and others like them on other genes) are quite broad and might well be deemed infringed; then we'll have to figure out if the claims infringed are valid. And then we can choose sides about whether granting patents with such claims in them is a good idea or not as a policy matter.

[Kevin E. Noonan]

Dear Bob:

I confess that it has been a long time since I left the lab, but I don't think the kind of whole genome sequencing discussed in the paper would infringe any of the composition of matter claims. But I have been a patent attorney long enough to know it could be raised; I just don't think very successfully. And remember: a broad claim is not necessarily a good thing, since it provides a bigger target for invalidity.

Thanks for the comment.

[Kevin E. Noonan]

Dear Moo:

I wrestled with writing "de minimis non curat lex" in the post, but I agree with you - while probably providing a frisson of "taking it to the Man" in the authors, I don't think such "at-home" tests will supplant CLIA-verified testing labs. But I do think the sentiments expressed by the authors reveal the danger that public opinion has been swayed to the view that there is something "wrong" with permitting companies like Myriad from making such tests available to the public, and that the at-home version is a viable alternative.

Thanks for the comment.

[6]

Funny how exactly the thing I brought up a few months ago has now become a reality.

It's like every other comment I make on your blog foretells the future Kev.

"patented thermometer!"

Do you have thermometer's, unisolated, in your body atm?

[C.L]

does brca cDNA occur naturally? I know they can pinpoint the 1/2's exact position in the genome, but can someone clarify to me the cDNA claim portion? cDNA is present in some viruses and is arguably the same in function.

[Kevin E. Noonan]

Dear CL:

The short answer to your question is "no" for the BRCA genes. But I need to expand the explanation a little.

The claim is to an isolated cDNA encoding the BRCA gene having a specific sequence. It is not to all "cDNAs" so that the existence of viral cDNA (having a different sequence) does not impact the claim. No one is claiming all cDNAs of all sequences.

I could make an argument that the "isolated" part even distinguishes viral cDNA in cells from viral cDNA isolated from the cell, but I don't need to in order to provide an answer to your question. But consider: if I discover and isolate an improved lubricant from crude oil, can I patent it? If I can, why not an isolated DNA?

Thanks for the comment.