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.