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Drawing Lessons from US Gene Patent Cases, Canadian Hospital Focuses on Enabling NGS Testing

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NEW YORK (GenomeWeb) – A recently launched lawsuit in Canada challenging the practice of patenting genomic DNA is also asking the Federal Court to determine that advanced diagnostics utilizing next-generation sequencing platforms do not infringe patents on older testing methods involving the amplification and isolation of specific mutations.

The lawsuit filed this week by the Children's Hospital of Eastern Ontario challenges the validity of claims in five Canadian patents underlying testing for Long QT syndrome held by the University of Utah Research Foundation, Genzyme Genetics, and Yale University. Long QT syndrome, a rare and at times fatal cardiac disorder, is caused by a number of inherited genetic mutations, five of which are at issue in CHEO v. University of Utah Research Foundation et al..

In the lawsuit, CHEO claims that University of Utah's patents on Long QT syndrome genes — KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A – have hindered its ability to offer a more expanded NGS-based panel test featuring 13 genes linked to the syndrome. CHEO's lawyers, who are working pro bono, will argue that the patent holders' claims on specific gene sequences don't satisfy the definition of an invention in the Canadian Patent Act. Not unlike the language in the US patent law, Section 2 of the Canadian Patent Act sets forth that patents can be awarded to "inventions," defined as "any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement" thereof.

The hospital is also challenging the validity of a number of method claims held by University of Utah and others, including mutation-specific and non-mutation-specific claims, those involving hybridization probes, and some that have no relation to genetic testing. With regard to many of the method claims, CHEO asserts that its NGS-based Long QT test analyzes DNA sequences directly from human exon fragments, doesn't rely on older assays or probes, and therefore doesn't infringe University of Utah's testing methods for Long QT genes.

This particular controversy began in late 2009, when Ontario's Ministry of Health asked regional healthcare providers to submit proposals for genetic tests for a range of conditions that they could develop and perform accurately. CHEO submitted proposals for tests covering various genetic disorders, and the ministry awarded the hospital all the applications except the one describing a multi-gene panel Long QT syndrome test. Legal experts say the ministry's restriction was spurred by a US lab called PGxHealth, now a part of Transgenomic, which in early 2010 sent a letter informing the ministry that it held patents to Long QT testing.

"It was at that point that Ontario decide not to award anybody in Ontario the right to offer this test," Richard Gold, a law professor at McGill University and an advisor to the plaintiffs, told PGx Reporter. As such, healthcare providers in Canada currently order Long QT tests from US labs that charge more than $4,000.

Operating in a public healthcare system, CHEO wouldn't profit from the Long QT test it seeks to offer. As such, the lawsuit brings to focus how gene patents and monopolistic licensing practices can hinder a government-funded healthcare system from delivering care in an efficient and cost-effective manner, according to Gold.

In the US healthcare system, healthcare products are developed by the private sector, and the public's concern around gene patents had more to do with whether such practices were hindering access to second opinion genetic testing, he noted.

"The situation in Canada is different," Gold said. "The public healthcare system is based more around how do we … deliver healthcare well so each individual can get the right test at the right time but keep the cost down. And at the same time, how do we create incentives within Canada or internationally to develop the best test?"

University of Utah didn't respond to requests for an interview or a statement.

Lessons learned

The case in Canada comes a year after the US Supreme Court's decision in Association for Molecular Pathology et al. v Myriad Genetics, in which the justices ruled that Myriad's claims on isolated sequences of BRCA1 and BRCA2 genes were patent ineligible. However, at the same time, the court held that complementary DNA – synthesized probes used to assess whether a genetic marker of interest is present in a person's biological sample – were patent eligible since they don't naturally occur in the body, are created in a lab, and usually don't have the same sequences as those in the body.

After this ruling, the field for Long QT opened up, according to Gold, and multiple labs are performing testing in this space. How the patent holders licensed the Canadian patents for Long QT testing is unclear, as are the details behind why PGxHealth sent the Ministry of Health the cease-and-desist letter, but this is something that will come out as the case progresses.

"Even if that letter had never happened, [under Canadian law] a party like CHEO would still be able to bring an action to impeach the patents in federal court," Sana Halwani, a partner at Gilbert's LLP and a member of CHEO's legal team, told PGx Reporter. Transgenomic, which PGxHealth is now part of, declined to provide comments for this article.

Meanwhile, the two-part Supreme Court ruling in the US created uncertainty in the life sciences industry as to how the decision would impact labs that sell NGS-based diagnostics. Following this decision, Myriad sued competing labs that launched tests for determining BRCA gene alterations, many of them involving NGS platforms. In one case against Ambry Genetics, Myriad is asserting that the lab was infringing its still-valid method claims on BRCA testing by using primers to amplify a given sample.

Myriad's lawyers have asserted that this technique would not have been known to the life science community before Myriad and other collaborators sequenced and identified the location of the BRCA1/2 genes in the mid-1990s. For the time being, this argument has failed to convince a Utah federal district court judge to grant a preliminary injunction against Ambry. However, it could be some time before all of Myriad's lawsuits against its competitors are resolved, and the validity of Myriad's asserted primer method claims are decided.

Having learned from the lawsuits in the US, CHEO's legal team at Gilbert's LLP has taken a more forward-looking approach. The lawyers are not just stopping at trying to invalidate patents on isolated gene sequences, but are also asking the court to determine whether patents covering older diagnostic methods, such as primers and probes, can restrict market introduction of advanced NGS-based technologies poised to become standard diagnostic tools in the coming years.

"The main aim is to get room to operate," Gold said. "How do we ensure that CHEO can deliver its test to patients? They're looking at not only today's tests, but they're looking around the corner at delivering clinical exome and whole genome testing."

These tests gauge large gene sets, and if different institutions hold patents on the critical markers on a panel, "then at that point these patents become more of a concern," Gold said. This is precisely why, unlike in AMP v Myriad, CHEO is not seeking to invalidate claims to cDNA or RNA. Instead, CHEO is claiming that the NGS test it seeks to perform is not infringing University of Utah's method claims at all, plaintiff's lawyer Nathaniel Lipkus explained.

CHEO describes in the lawsuit that its Long QT test would simultaneously sequence different patients' exon fragments for 13 genes. The results would be electronically compared to reference sequences for the disease-linked markers, and a healthcare provider would determine whether a particular result indicates that a patient is at risk of Long QT syndrome.

"The proposed tests will not infringe the isolated nucleic acid claims, because extraction of genetic material from human patients under the proposed tests will not be carried out in a manner that isolates or amplifies the particular nucleic or amino acid sequences claimed" by the patent holders, CHEO states in its complaint. The hospital further argues that its NGS methods wouldn't infringe University of Utah's patents since its test doesn't involve the isolation of cDNA or RNA fragments; doesn't use an RNAse assay; and doesn't rely on hybridization probes to detect specific gene mutations.

"Although this case is structured around Long QT … the goal is to get clarity in terms of freedom to operate generally," Gold said. "That could either arise in the court's decision that some or all of these claims are not patentable. Or it could be through non-infringement or a combination of both." In addition to non-infringement arguments, CHEO's legal team will also make arguments that some of the contested patent claims are invalid on grounds of being "overbroad" or on "obviousness" – the argument that the claimed invention was already known to someone skilled in the art.

All these legal strategies "do wrap around the same core argument that you shouldn't be able to patent genes," Lipkus said. "But we wanted the court to be mindful of the state of the art at the time" Long QT tests were initially launched in the US, "what we have contributed, and take … a broader view than what we've seen in Myriad and elsewhere."

In a single payor system...

Canada is in a curious place with regard to patents on genomic DNA. In 2001 and 2002, when Myriad sought to launch its BRCA tests on the Canadian market, provincial government authorities decided not to allow the company to enforce its patents. But that decision had no impact on the Canadian Patent Office, which since then has continued to grant patents on isolated DNA sequences.

"When Myriad entered the Canadian market, it rose to the highest political levels," Gold recalled. "At that time, the government determined with legal counsel that those patents were likely invalid in Canada and … Myriad never sued." In the case of BRCA testing, because the health authorities made a determination about the enforceability of Myriad's patents, Canadian labs have been freed up to perform testing in this space.

The situation is not so for most other genetic tests, such as those for Long QT, which didn't inspire the political pushback that BRCA did. And so, health care providers in Canada have erred on the side of caution, sending test orders to the US in situations where labs there hold Canadian patents on gene markers.

"When I talk to Americans, they often say, 'Why don't you just do the test and be sued?'" Gold reflected. "You can make that determination if you're a company but you can't do that if you're a government … In the court of public opinion and in the investment community you don't want to be seen as engaging in a process where you're asking people to violate a patent."

Moreover, since the payor in Canada's single-payor system is the government, this places the lawsuit in a different light than in the US. "When an entity like CHEO provides a test, the payor is the Government of Ontario. [CHEO is] not in the business of selling tests in the open market," Gold said. "The dynamics are different. We have a public institution whose mandate is to serve patients, and it is finding [that] these patents do not allow it to do that and it's seeking the freedom to operate."

While there are similarities between Canadian and US patent laws in how they define an invention, the courts in these countries have come to divergent decisions in cases involving the patentability of inventions derived from naturally occurring substances. For example, the Canadian high court has found oncogenic mice to be unpatentable, departing from the US, where such patents remain unchallenged following the 1980 Supreme Court decision in Diamond v. Chakrabarty that genetically modified organisms can be patented.

While it's not clear how the Canadian Federal Court will rule with regard to Long QT patents, it is clear that the uncertainty with regard to gene patents cannot continue in Canada, and the regional governments don't have the resources to decide the enforceability of patents on a case-by-case basis. Nor can they ignore molecular science advances that have resulted in more powerful, faster, and cheaper diagnostics.

"Having to ship tests to the US, particularly if there are different providers, isn't only highly inefficient, but it doesn't fit in with the logic of a public healthcare system," Gold said.

In its complaint, CHEO explains that its long-term aim is to develop a larger NGS panel that tests for many more gene markers associated with inherited conditions. Eventually, the hospital hopes to introduce tests that assess patients' exomes and entire genomes. "It will be impractical and unethical for Children's Hospital to selectively omit the Long QT genes from the … tests," CHEO writes in the lawsuit.

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