A Do-It-Yourself Genomic Challenge to Myriad, the FDA and the Future of Genetic Tests

Over the weekend, Steven L. Salzberg and Mihaela Pertea published a short but significant article in the journal Genome Biology. In “Do-it-yourself genetic testing,” Salzberg and Pertea describe the creation of “a computational screen that tests an individual’s genome for mutations in the BRCA genes, despite the fact that both are currently protected by patents.”

The software-based test can be downloaded from the website of the University of Maryland’s Center for Bioinformatics & Computational Biology, where Salzberg is the director and Pertea is on the faculty. The test purports to test genomic sequence data against a set of known mutations in the BRCA genes. In addition to representing a conceptual alternative for those seeking to evaluate their risk of hereditary breast cancer, the so-called “Salzberg Screen” is also a direct challenge to Myriad Genetics, the FDA and the existing legal, regulatory and policy regimes that continue to struggle to keep pace with the science and technology of genomics and personalized medicine.

Below, we examine how the Salzberg Screen fits—or does not—within the current legal and regulatory landscape, as well as what it signals for the future of do-it-yourself genomics, whole-genome sequencing and the law.

BRCA Background. First, a quick primer on the clinical and legal significance of the Salzberg Screen’s target: the BRCA genes. BRCA-1 and BRCA-2 are perhaps the two most well-known human genes. This stems in part from the role which mutations in those genes play in dramatically increasing the risk of breast and/or ovarian cancer for certain individuals.

The notoriety of the BRCA genes has also been significantly enhanced in the past year thanks to high-profile litigation in both the United States and Australia challenging the validity of the BRCA gene patents held by Myriad Genetics. Myriad’s patents covering the isolated BRCA-1 and BRCA-2 genes, as well as certain methods of diagnosing breast cancer susceptibility, were ruled invalid by Judge Robert Sweet of the Southern District of New York earlier this year. Judge Sweet’s opinion is currently being appealed to the Court of Appeals for the Federal Circuit, where hearings are expected to get underway later this fall. Despite the litigation, Myriad’s BRCA patent portfolio has enabled it to serve as the sole (lawful) provider of BRCA screening in the United States and numerous other countries worldwide.

The Salzberg Screen. Myriad’s role as exclusive provider of BRCA screening is a fact that has clearly irked both Salzberg and Pertea:

We believe that any individual should be allowed to interrogate his or her genome for all mutations of interest, regardless of whether a private company claims to ‘own’ the rights to particular gene mutations. To challenge the restrictive gene patenting system, we have developed a computational assay that, as a proof-of-concept, tests for 68 known variants of the BRCA1 and BRCA2 genes. In other words, we empower any individual using our software (whether this is a private individual, a clinician or a clinical or basic researcher) to test for these mutations and circumvent the gene patents.

The Salzberg Screen compares whole-genome sequence data (or, presumably, data from targeted sequencing of the BRCA genes) against a list of “68 known mutations in the [BRCA] genes” drawn from the Online Mendelian Inheritance in Man (OMIM) database. Salzberg and Pertea readily admit that their DIY screening tool is far from perfect, noting that “…the 68 mutations used in this proof-of-concept assay do not represent a comprehensive list of BRCA mutations,” but pointing out that “additional mutations could easily be added to our test…”

In addition to only testing for a fraction of the publicly identified BRCA mutations, a number that does not include additional proprietary information about BRCA mutations possessed by Myriad Genetics, the Salzberg Screen also possesses another significant current limitation: cost. Myriad’s BRACAnalysis test costs several thousand dollars, but it includes targeted sequencing of the individual’s BRCA genes. While the Salzberg Screen is free to use, it requires the user to come up with her own whole-genome sequence data.

At the moment, whole-genome sequencing is still more expensive than Myriad’s BRACAnalysis, a test which is covered by many insurers where clinically indicated. The price of a whole-genome sequence is a moving target and depends upon the quality of the sequence (including accuracy and depth of coverage), whether it is generated in a clinical (i.e., CLIA-certified) or research facility, the level of associate interpretation or analysis that is provided and a host of other factors. Current best estimates put the cost at anywhere from $1,000 to $10,000 per genome, although Salzberg and Pertea, like so many others, note that we are “rapidly approaching the day when it will be cheaper to fully sequence a genome before testing the sequence for all known genetic mutations associated with a given disease than to conduct multiple separate tests for each disease.”

While that day is not quite at hand, Salzberg and Pertea’s goal is not to create a computational screen that is a replacement, right now, for Myriad’s test. Instead, they have developed a “…template that can easily be modified to test for almost any known genetic mutation,” and thereby one day circumvent not only Myriad’s testing monopoly, but also all human gene patents.

What This Means, Part I: Myriad and its Patents. More than a year ago we wrote about the impending collision between single gene sequencing, such as that provided by Myriad, and inexpensive whole-genome sequencing (see: Whole-Genome Sequencing and Gene Patents Coexist (For Now)). As the cost of gene sequencing continues to fall, we expect that more and more software-only tools like the Salzberg Screen will spring up. But can such tools be used, as Salzberg and Pertea hope, to “empower any individual…to test for [BRCA] mutations and circumvent the gene patents”? More pointedly, can such tools circumvent gene patents legally?

Infringement, Direct and Indirect. A patent can be infringed in two ways: directly or indirectly (see Section 271 of the Patent Act). Direct infringement consists of someone making, using, offering to sell, or selling the patented product or process. Usually, the infringer must be duplicating the patented invention exactly as described in one of the patent claims; in patent jargon, the infringed patent claim must “read on” the infringer’s activity, element-by-element. Indirect infringement comes in two forms: inducement and contributory infringement. Inducement, sketchily codified in Section 271(b), requires knowledge of the patent and an affirmative act to cause or direct a third party to carry out an act of infringement. In other words, you can’t escape liability by contracting with someone else to make a patented product or carry out a patented process. Contributory infringement, codified in considerable detail in Section 271(c), usually consists of selling a component of a patented invention, knowing that the component has no use except in that invention. The theory here is to prevent a conspiracy of infringers from escaping liability by individually selling pieces of the protected invention. Significantly, you can’t be guilty of indirect infringement unless someone is engaging in direct infringement.

So the first and most important question here is whether use of the Salzberg Screen would result in someone infringing one or more of Myriad’s patents. That is, would either the individual or someone else (for example, a clinician or genetic counselor helping the individual use or understand the Salzberg Screen or a similar service) be making, using, or selling a product or process covered by a Myriad patent? (This whole analysis assumes, of course, that the relevant Myriad patents are not ultimately found invalid at the conclusion of the ongoing Myriad litigation.)

It’s worth remembering that Myriad’s patents include both product and process claims. On the product side are claims like Claim 1 of U.S. Patent 5,747,282 (pdf):

An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having [a listed] amino acid sequence.

Would anyone in the chain of use of the Salzberg Screen be making or using this gene in isolation? That is a factual, scientific question that turns on whether the particular sequencing technique involves using “the gene.” Our science sources tell us that the answer depends on the sequencing method, but, at least for whole-genome sequencing, it is probably “no.” (Sequencing just the BRCA genes, as opposed to whole-genome sequencing, would likely be a different story.)

There are also claims like Claim 5 of the same patent: “An isolated DNA having at least 15 nucleotides of the DNA of claim 1”—i.e., any 15-mer oligonucleotide that can be found in the patented gene. While almost no one expects a claim like this to survive in the Federal Circuit, if it did, then almost any sequencing process might infringe solely as a matter of statistical probability (pdf).

A Method of Inducement? On the process side, Claim 1 of U.S. Patent 5,709,999 (pdf) is one of the broadest. Here is how the claim reads:

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

And here is how Judge Sweet, in his Myriad opinion (pdf), translated that claim, shortly before finding it to be invalid:

Claim 1 of the ‘999 patent is directed to the process of ‘analyzing’ a BRCA1 sequence and noting whether or not the specified naturally-occurring mutations exist. The claimed process is not limited to any particular method of analysis and does not specify any further action beyond the act of ‘analyzing.’”

Under that reading, would Claim 1 of the ‘999 patent cover the activities of an individual who downloaded and ran the Salzberg Screen in order to “analyze” their BRCA-1 sequence? Would it cover the activities of a clinician or genetic counselor assisting a user in interpreting the Salzberg Screen’s results? That would be a matter for a court to decide, although it is certainly possible that, depending on the specific court and specific set of facts, the answer could be “yes.” If so, there would be an act of direct infringement.

If a court were to find an act of direct infringement, then Salzberg and Pertea could well be liable for indirect infringement, most likely in the form of inducement of infringement.

A Calculated Gamble? Salzberg and Pertea are clearly aware of the Myriad patents (a requirement of inducement) and explicitly invite individuals to “test for [BRCA] mutations and circumvent the gene patents.” They also readily acknowledge that they are asking Salzberg Screen users to commit patent infringement.

In creating this software, we are not violating the BRCA patents directly but any user would be, because even a noncommercial use (such as examining one’s own genome) is considered to be patent infringement.

The fact that Salzberg and Pertea claim not to be violating the BRCA patents “directly” suggests that they are aware of the risk of indirect infringement. They do not, however, appear to be overly concerned that Myriad will pursue such a claim.

For Myriad to make out a claim of indirect infringement against Salzberg and Pertea, it would likely first have to show that individual users are directly infringing Myriad’s patents. Suing a direct infringer could involve challenging in court the activities of an individual using a freely available software program to examine her own genes from the privacy of her own home.

But Myriad wouldn’t have to actually sue the direct infringer—it could decide to sue only Salzberg and Pertea for indirect infringement. In fact, the whole premise of indirect infringement is that it provides a patent holder an avenue of redress when it isn’t feasible to pursue the direct infringer. Still, given the substantial negative publicity that continues to swirl around Myriad’s BRCA patents, and the fact that suing for infringement would also mean subjecting its patents to a new set of invalidity challenges (a near-certain argument in defense from any alleged infringer), Salzberg and Pertea may be taking a calculated gamble that Myriad simply does not have the stomach to initiate any BRCA patent infringement litigation, whether direct or indirect.

Myriad’s Next Move. Myriad derives 90% of its revenues from its BRACAnalysis product, so neither the company nor its investors are likely to take any challenge to its BRCA business lightly. At present, however, the Salzberg Screen does not pose a credible commercial threat to Myriad. It does not test for the full range of deleterious mutations covered by Myriad’s BRACAnalysis, and it also requires something few people have: access to a high-quality copy of their genome. For those reasons, and in light of the negative publicity that would flock to any attempt Myriad might make to quash the Salzberg Screen, the strong likelihood is that Myriad will simply ignore this development, at least for the moment. What’s more, as Myriad is no doubt aware, pending the appeal of Judge Sweet’s decision invalidating certain of Myriad’s patents, an alleged infringer could use that decision to defend itself under an arcane legal doctrine called “issue preclusion.”

Conceptually, however, whole-genome sequencing has always been a threat for single-gene diagnostic companies such as Myriad. The Salzberg Screen brings that tension into particularly sharp relief. Once individuals routinely have access to high-quality whole-genome sequences, they are likely to ask why they need to pay the Myriads of the world several thousand dollars to analyze a handful of genes when they could pay far less—or perhaps nothing at all—to have the same analysis automatically performed by a software program.

As the technical limitations fade in the face of ubiquitous whole-genome sequencing, the Salzberg Screen, or perhaps one of its descendants (Salzberg and Pertea have created a fully open source piece of software), will come to present a viable alternative to Myriad’s test, at least in certain circumstances (e.g., for second opinion or confirmatory testing). How quickly this will occur remains unknown, but there is a strong likelihood that it will be before 2015, which is when the first group of Myriad’s BRCA patents are set to expire.

In many ways, the Salzberg Screen is every bit the frontal attack on Myriad’s patents that the ACLU-initiated litigation represents.  Like the ACLU litigation, it publicly, deliberately and unapologetically challenges Myriad’s right to control access to BRCA information. Allowed to evolve unchecked, it could one day threaten Myriad’s core business. So even if Myriad takes no action right away, you can safely bet that the company will be watching the development of the Salzberg Screen with considerable interest.

What This Means, Part II: Regulatory Acronym Soup or: WGS means more LDTs go DTC and DIY, creating a problem for FDA. While Salzberg and Pertea focus a majority of their attention on circumventing Myriad’s gene patents, their conclusion recognizes at least one other potential obstacle to widespread adoption of their BRCA screening test:

Finally, we recognize that there may be some controversy about giving ordinary individuals the ability to test their own DNA, without also providing expert genetic counseling.

The “controversy” is a nod to the FDA’s recent and widely discussed proposal to more aggressively regulate not only direct-to-consumer (DTC) and do-it-yourself (DIY) genetic tests, but all laboratory developed tests (LDTs). As we wrote earlier this fall, “recent developments suggest that innovation in personal genomics is an increasingly difficult undertaking.” From Pathway Genomics’ short-lived attempt to offer its product on Walgreens’ shelves, to U.C. Berkeley’s unsuccessful attempt to innovate genomics education by offering non-clinical genetic testing to its incoming freshmen, the recent regulatory climate has been none-too-kind to those intent on thinking outside the box in the personal genomics space.

Salzberg and Pertea are aware, no doubt, of these recent events, but remain resolute in their desire to liberate individuals from the strictures—patent, regulatory or otherwise—that would inhibit personal genomic access:

Nonetheless, the door to this new technology is already open and it cannot be closed. Rather than trying to keep patients in the dark, we need to embrace the technology and work harder to educate both physicians and patients about the power and the limitations of genetic tests.

With the FDA in the middle of developing a formal proposal to regulate all LDTs, including those offered DTC, there’s simply no knowing whether or how the FDA will respond to this development. While we think any immediate and public FDA reaction unlikely, the Salzberg Screen should be setting off alarm bells at the agency.

Regulating Tomorrow’s LDTs Today. At the recent public meeting convened by the FDA to solicit feedback on the agency’s plan to regulate all LDTs, there were two areas of discussion in particular that were defined less by disagreement over how or whether to implement FDA regulatory oversight and more by the creeping suspicion that neither the FDA nor any other regulatory agency is  currently prepared to address the issue: (1) testing based on multiplex or whole-genome sequencing data and (2) software-only bioinformatics or genetic testing services.

After Day 1 of the FDA’s public meeting, we wrote:

What about tomorrow? Another area of considerable confusion, if not necessarily disagreement, was what to do with the coming wave of multiplex diagnostic tests including, ultimately, a proliferation of whole-genome sequence data and corresponding interpretive tools. This was not an issue that the FDA tackled directly, but it was clear in the afternoon question and answer session that many of the panelists, at least, were unsure how the next generation of diagnostic tests would fit into the current (or contemplated) regulatory model. The challenges posed by the next generation of sequencing and bioinformatics tools are hardly new, but designing a regulatory framework equipped to survive the next decade will be one of the FDA’s greatest challenges.

While there is no greater clarity today than there was back in July, the unveiling of the Salzberg Screen crystallizes the importance of addressing these issues today, before the coming proliferation of whole-genome sequence data and associated bioinformatics tools.

The arrival of inexpensive and widespread genomic data will be followed, nearly simultaneously, with an explosion of new genomic-based tools and services prepared to analyze that data. These will not be LDTs in the traditional sense, and many will be unlikely to have any need for a laboratory at any stage. Targeting individuals with data in hand, they may well look like more sophisticated versions of the Salzberg Screen, bringing together data and returning personalized genomic analyses.

The Salzberg Screen is not the first computational test that relies on the individual to supply raw data. A familiar example is the Reynolds Risk Score, which takes as inputs user-supplied risk factors such as blood pressure, cholesterol and family history and then “predict[s] your risk of having a heart attack, stroke, or other major heart disease in the next 10 years.”

The Salzberg Screen adopts a similar DIY model for genomic data. In addition to a number of similar open-source and/or academic tools and projects already in progress (the Personal Genome Project, Genomes Unzipped and DIYgenomics all offer good examples), commercial variants of this model are also in the works. A new California-based start-up, Existence Genetics, recently described its plans to leverage the coming decline in whole-genome sequence data. According to CEO Brandon Colby, although the company today supplies both genetic tests and analysis to patients, “eventually … we see ourselves disengaging from utilizing gene chips completely, disengaging from all lab work, and instead solely being an analysis company.”

Colby, to his credit, recognizes that such a model will undoubtedly attract the attention of the FDA:

Colby said that he expects the agency to provide clear guidelines and regulations for LDTs soon, and when they do, ‘we really do look forward to working with them. The big question is how they’re going to regulate and what the timeline is … but once both of those are worked out by the FDA, we’re going to be front and center and willing to work with them and make sure we comply.’

With the FDA still “trying to decide what [its] options are,” Colby may be more optimistic than most in viewing  “clear guidelines and regulations for LDTs” as likely to arrive “soon.” Regardless of when those LDT guidelines actually do arrive, the more important question remains whether they will provide a meaningful degree of insight into the agency’s plans for reviewing multiplex and whole-genome sequencing products and the software-only bioinformatics services that will be developed to leverage low-cost whole-genome sequencing.

Drawing the Right Lines. The examples presented by the Reynolds Risk Score calculator, Salzberg Screen and Existence Genetics products, among others, challenge us, and particularly the FDA, to carefully establish what constitutes an appropriate regulatory target. As genomic tests and services move out of the laboratory and into the genomics data cloud, where and how will the FDA direct its regulatory energies?

If the FDA focuses on the risk level of the condition analyzed, how will it respond to multiplex or whole-genome interpretations that analyze both high- and low-risk conditions simultaneously? If the FDA seeks to install clinician gatekeepers between data and interpretations, even when those interpretations are not coupled with a laboratory test or other traditional medical device, will the agency also attempt to forbid individuals from accessing or attempting to analyze their medical records or raw genomic data on their own?

Drawing the right lines will be exceptionally difficult, and will require considerable foresight if the regulatory framework now being developed is to be sufficiently flexible to accommodate what are likely to be substantial changes in the way health information is collected, interpreted and delivered. The recently disbanded Secretary’s Advisory Committee on Genetics, Health, & Society (SACGHS), which had been slated to take up the implications of whole-genome sequencing, might well have helped the FDA in this process. Instead, the onus now falls more heavily on the FDA, as well as other public and private regulatory and advisory bodies, to think prospectively and creatively about these issues before the Salzberg Screen and its kin become the norm in personal genomics.

A Final Thought: Keeping Up With the Salzbergs. Even more fundamentally than its challenge to Myriad’s gene patents or to the FDA’s preparedness for a future in which whole-genome sequencing exists alongside do-it-yourself personalized medicine, the Salzberg Screen is a reminder of the Herculean task lawmakers, policymakers and regulators face in attempting to keep up with the pace of scientific and technological innovation in the fields of genomics and personalized medicine.

Whatever we think of Salzberg’s Screen and his aggressive challenge to the status quo of gene patents and federally regulated access to genetic testing, we must applaud the work that Salzberg and others do to continually push forward both the science and the application of genomics and personalized medicine. It’s doubtful that the Salzberg Screen will effectively undermine Myriad’s patents or cause the FDA to wholeheartedly embrace DIY genomics, at least in the short term. But by forcing all of us to think more concretely about such possibilities, Salzberg is spurring valuable discourse and forcing lawmakers, policymakers, regulators and businessmen to respond. We hope that the response, when it comes, will include a recognition that even if we cannot keep up with the Salzbergs—those bent on innovation, no matter how much it strains our current structures—we can do much more, now, to anticipate where they are leading us.

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Note: The image that appears is used and modified with the permission of DIYgenomics.

Filed under: Bioinformatics/IT, Direct-to-Consumer Services, FDA LDT Regulation, General Interest, Genetic Testing/Screening, Genomic Policymaking, Genomic Sequencing, Genomics & Society, Industry News, Legal & Regulatory, Myriad Gene Patent Litigation, Patents & IP, Pending Litigation, Pending Regulation
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