In a recent post, John Conley analyzed the ACLU’s lawsuit challenging Myriad Genetics’ patents on the BRCA-1 and BRCA-2 “breast and ovarian cancer susceptibility” genes. Several readers responded with the same general inquiry: if an individual undergoes a whole-genome sequence analysis, will the individual (or the company providing the sequence) be required to pay royalties to Myriad because the BRCA-1 and -2 loci will have been sequenced?
Although focused on the BRCA genes, the question is broadly applicable to the entire genome sequencing industry: when sequencing all or a portion (e.g., the exome) of an individual’s genome, are individual gene patents infringed upon by either the company providing the sequence or the individual purchasing or requesting it? The answer is not entirely clear, but, at least in the case of Myriad and the BRCA genes, it appears to be no. Or at least, not yet.
Let’s begin with what is not patented, which includes a majority of genes and the vast majority of the human genome. Genes—those stretches of DNA that encode for proteins—make up approximately 2% of the human genome. The estimate of the exact number of genes ranges from between roughly 20,000 to 30,000 and, of those, a 2005 study in the journal Science found that only 20% of human gene DNA sequences are patented (subscription). Although those numbers are certainly subject to change, the reality is that, today, it is likely that less than 1% of the entire human genome has been patented.
Of course, that very small number belies the fact that the genes which have been patented consist of some of the most important identified genes associated with the prediction or determination of human health and disease. The high-profile BRCA genes are an excellent example and thus make for a good case study.
To understand how whole-genome sequencing interacts with a particular gene patent we should start with the actual claims of the patent itself, which define exactly what is covered. In the case of Myriad’s BRCA patents, the broadest claim is illustrated by Claim 1 of U.S. Patent No. 5,747,282, issued to Skolnick et al. in 1998 and assigned to Myriad:
1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.
Note that the patented breast cancer susceptibility gene is defined by its function: the claim covers any DNA molecule that codes for the protein that has the amino acid sequence listed in the cited attachment. A second claim (called a dependent claim) further defines the patented gene by reference to its DNA sequence:
2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1.
In either case, the patent law is clear: anyone who makes, uses, sells, or offers to sell that gene needs permission from Myriad. The single significant limitation in this case is that Myriad’s patent covers only isolated versions of the BRCA-1 gene. What does isolated mean?
Here we turn to the ancient—if somewhat awkward—patent maxim that “the patentee is his own lexicographer.” Although terms in a patent claim typically receive their ordinary meaning, courts, along with the USPTO, allow patentees, subject to some limitations, to define the terms used in the patent as they choose, even in a manner inconsistent with a term’s ordinary meaning. Here’s what Skolnick et al. said in their BRCA patent:
“Isolated” or “substantially pure”. An “isolated” or “substantially pure” nucleic acid (e.g., an RNA, DNA or a mixed polymer) is one which is substantially separated from other cellular components which naturally accompany a native human sequence or protein, e.g., ribosomes, polymerases, many other human genome sequences and proteins. The term embraces a nucleic acid sequence or protein which has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biologically synthesized by heterologous systems.
The critical point is that, to be covered by the patent, the gene must be “substantially separated from other cellular components which naturally accompany a native human sequence”—including “many other human genome sequences.” Removing the BCRA-1 gene from its natural environment (the genome) to test it or to synthesize it would be a clear case of infringement. But whole-genome sequencing is different. Companies that offer whole-genome sequencing services (e.g., Knome and Illumina) could argue—plausibly—that they do not separate Myriad’s gene (or any other gene) from its natural neighborhood of other genes because of the method in which they sequence the genome.
Whether or not this technical distinction would succeed if challenged by Myriad in court is unclear but it may help explain why Myriad, which has been aggressive in asserting its patent rights to exert exclusive control over testing for the BRCA-1 and -2 genes, particularly in clinical settings, has not publicly asserted its patent rights against any commercial providers of whole-genome sequencing.
Unfortunately for the whole-genome sequencing industry, this type of analysis—an examination of the specific patent claims in light of a company’s sequencing technology—may be required for all or many of the thousands of human gene sequences subject to patent protection. Earlier this spring an article in Nature concluded that, among thousands of gene patents, “some patent claims will be infringed by full-genome sequencing,” and the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) concluded in its draft report on the effects of gene patenting (pdf) that the number of gene patents “could have significant implications for the development of whole-genome sequencing,” including forcing “a developer that wished to offer whole-genome sequencing…to obtain licenses for all unexpired patents…from the human genome.”
As with so many other aspects of the nascent whole-genome sequencing industry, the ultimate impact of gene patents remains to be seen. At present the cost of a whole-genome sequence remains high (Illumina is the current standard-bearer at $48,000, although Knome offers exome sequencing—which likely includes sequencing of most patented genes—for as little as $19,500), and the number of individuals who have had their entire genomes sequenced (whether by commercial or research outfits), although not known with precision, is almost certainly less than 100 worldwide.
With such a low level of current whole-genome sequencing activity there is a good practical reason for companies like Myriad to avoid pressing the infringement issue: their legal costs, not to mention the likely adverse publicity, would dwarf any licensing revenue. But as the era of the $1,000 genome approaches, the number of whole-genome sequences is predicted to rise rapidly and the economics are set to radically shift. Today, Myriad charges roughly $3,000 for its BRCA test. If and when whole-genome sequencing becomes available for a price in the neighborhood of $1,000, it becomes nearly impossible to imagine anyone—insurers or consumers alike—handing over $3,000 for the sequence results of a single gene when they could receive their entire genome for a fraction of that cost.
At least for the moment, whole-genome sequencing and gene patents coexist, despite considerable uncertainty. But while it’s impossible to accurately predict even a few months into the future in such a turbulent field, there is a basic economic truth that cannot be ignored: high-cost licenses for the rights to specific gene patents are fundamentally incompatible with low-cost whole-genome sequencing.
When and where will the next chapter be written? While the ACLU challenges the validity of gene patents (including Myriad’s BRCA patents), and the whole-genome sequencing industry continues to drive costs down, the next scheduled development is the release of the final SACGS report on gene patenting, which is due out in October and will be eagerly awaited by patent holders and licensors, DTC testing and sequencing companies, and policymakers alike.