The US Supreme Court finds ‘isolated DNA’ unpatentable

The U.S. Supreme Court finds “isolated DNA” unpatentable

Canary in the mine shaft for personalized medicine patents?

Personalized medicine holds the promise of more individually focused diagnostics, strategies for preventing disease and tailored therapeutic regimens that are more effective and/or have fewer drug side effects – basically smarter medicine.

However, as the drama around the legal battle over gene patents culminating in the recent U.S. Supreme Court decision in Association for Molecular Pathology et al. v. Myriad Genetics, Inc. et al. (“AMP v. Myriad”)1 unfolded, it showed that personalized medicine is fraught with contentious moral/ethical and legal, including intellectual property, issues.

AMP v. Myriad addressed the debate on gene patents that has been raging in the U.S. for some time. As is well known in the personalized medicine industry, the Supreme Court tried to lay down a bright line test, invalidating claims to naturally occurring “isolated” DNA and affirming the patentability of laboratory made synthetic DNA that is not naturally occurring. But as can sometimes be the case, the bright line distinction, in this instance the distinction between naturally occurring and synthetic DNA, is actually blurry and nuanced.

The AMP v. Myriad drama took over four years to wind its way through the courts. The suit was launched in 2009 by the ACLU and the Public Patent Foundation who represented a group of plaintiffs including the Association for Molecular Pathology (AMP) and other medical associations, medical professionals, universities and breast cancer patients. The suit took aim at invalidating patents to human genes generally and invalidating Myriad’s patents on two breast cancer susceptibility genes (BRCA1 and BRCA2) more specifically. The plaintiffs claimed that patents on BRCA1 and BRCA2 were unconstitutional and invalid because “human genes are products of nature, laws of nature and/or natural phenomena, and abstract ideas or basic human knowledge or thought.” The challenged claims included claims to isolated

DNA, methods of detecting germ-line mutations and drug screening. Interestingly claims to vectors comprising BRCA DNA, cells comprising such vectors, DNA primer pair sequences for detecting BRCA mutations and isolated DNA comprising BRCA1 regulatory sequences were not challenged.

By way of background, Myriad Genetics was founded in 1991 as a spin-off company from the University of Utah. In August 1994, researchers at Myriad, the University of Utah, the NIH and McGill University published the sequence of the BRCA1 gene and later that year, Myriad and its collaborators filed its first BRCA1 U.S. patent application. Subsequently, Myriad and University of Utah researchers isolated and sequenced the BRCA2 gene and the first U.S. BRCA2 patent application was filed in 1995. In 1996, five years after the company’s inception, Myriad began offering its BRACAnalysis® testing service for hereditary breast and ovarian cancer testing and aggressively guarded its patent position, launching lawsuits against for profit institutions that tried to offer services that infringed of one or more of its patents.2 As a result of its patent position, Myriad became effectively the only commercial provider of BRCA diagnostic testing in the United States.3 Interestingly, Myriad reportedly saw its first profit only in 2012, 17 years and $500 million in development costs later, costs which could presumably be born because of its patent position.4

In a decision that sent shock waves through the personalized medicine industry, the federal district court in New York invalidated all of Myriad’s challenged patent claims. The Federal Circuit then reversed the district court’s rulings on isolated DNA patent claims, holding unanimously that synthetic DNA such as “cDNA”, which is a form of DNA artificially synthesized, is patentable subject matter and holding 2 to 1 that isolated genomic DNA is patentable as well.

The plaintiffs claimed that patents on BRCA1 and BRCA2 were unconstitutional and invalid because “human genes are products of nature, laws of nature and/or natural phenomena, and abstract ideas or basic human knowledge or thought.”

The Federal Circuit affirmed the district court’s ruling that Myriad’s method of interpreting mutations by analyzing sequences was not patentable as the “analyzing” step did not meet all the requirements for patentability, but reinstated Myriad’s claims to methods of testing drug efficacy.

The plaintiffs petitioned the Supreme Court asking it to review the case. The Supreme Court granted the petition and on March 26, 2012, sent the case back to the Federal Circuit to be reheard in light of its recent decision in Mayo Collaborative Services v. Prometheus Laboratories, Inc. In what was interpreted by some as a snub to the Supreme Court, the Federal Circuit in a 2-to-1 decision in favor of Myriad held its ground and issued a new court opinion that was nearly identical to the original.

The plaintiffs again petitioned the Supreme Court. The petition was allowed for the single question “Are human genes patentable?”

On June 13, 2013, Justice Clarence Thomas delivered the opinion of the Supreme Court in a decision that seemed to allow both sides to claim victory.5 The Supreme Court held that claims to “isolated” DNA were not patentable as “isolated” was insufficient to confer patentability - genes and the information that they encode “are not patent eligible…simply because they have been isolated from the surrounding genetic material”. The Supreme Court also stated that “uncovering of the precise location and genetic sequence” of the BRCA1 and BRCA2 genes (identified as the principle contribution of Myriad) did not “create or alter the genetic structure of DNA”. This finding overturned long standing law with regards to patentability of isolated DNA that is isolated from its surrounding genomic context.

The Supreme Court took a more favourable view on claims related to synthetic DNA such as cDNA. The Court held that since cDNA is devoid of certain regions found in genomic DNA called “introns” and since it can only be made in the laboratory, it therefore cannot be a product of nature. Simply stated, naturally occurring DNA, even when isolated from adjoining DNA, is not patentable whereas synthetic DNA that is not found in nature would appear to be patent eligible.

When discussing fragments of synthetic DNAs, the Supreme Court noted that a short cDNA may be indistinguishable from natural DNA and hence not patentable. This results in the strange situation where a cDNA corresponding to a full gene may be patentable but a shorter sequence of that same cDNA that may useful, for example for synthesizing or sequencing DNA (e.g. primers) or for detecting specific mutations (e.g. probes) may not be patent eligible unless it spans an intron-exon junction or includes non-gene sequence or a non-naturally occurring element such as a label. Shorter fragments however are typically not found in nature and generally could only reproducibly be made in a laboratory the same criteria used to find cDNA patentable. This is doubly ironic since claims too short DNA sequences including primers and probes were not challenged by the plaintiffs.

What level of modification would be sufficient to render a naturally occurring DNA patentable remains to be defined. Based on the patentability of cDNA, the required level of modification may be minimal. Also the Supreme Court noted that “Myriad’s claims are simply not expressed in terms of chemical compositions” (p. 14). Hence compositions of naturally occurring DNA and specific diluents not found in nature may also render a DNA in composition form patent eligible.

It also remains to be seen whether the Court’s reasoning regarding “isolated” DNA will be extended to other types of “isolated” biomolecules such as proteins, cells, organisms and other natural products. The Supreme Court does caution at page 11 of its decision that “[t] he rule against patents on naturally occurring things is not without limits”. It is conceivable that the decision’s “limit” may be to “isolated genes” as indicated in the Court’s conclusion: “[W]e merely hold that genes and the information they encode are not patent eligible under §101 simply because they have been isolated from the surrounding genetic material” (p. 18).

The Supreme Court was also clear to emphasize what is not implicated by the decision - “[t]his case, it is important to note, does not involve method claims, patents on new applications of knowledge about the BRCA1 and BRCA2 genes, or the patentability of DNA in which the order of the naturally occurring nucleotides has been altered” (p. 17-18). As the Supreme Court acknowledged many of Myriad’s unchallenged claims are limited to applications using knowledge of BRCA1 and BRCA2. These would presumably be at least in principle patent eligible.

Is the AMP v. Myriad decision likely to prevent patenting of new personalized medicine tests? Given the high development costs involved with bringing a diagnostic to market, this could dramatically deter new test development. Unlikely – at least going forward.

As full genome sequencing has led to the disclosure of most human DNA sequences, the effects of the decision may be circumscribed if the reasoning is limited to isolated naturally occurring DNA. Identifying disease mutations however is an important and active area of biotech research and investment. One effect of the decision is that it could encourage patentees to pursue greater secrecy over early stage discoveries.

Also, the Supreme Court decision seems to have left the door open to a variety of claim types. Although the decision allowed both sides to claim victory as noted in Myriad’s press release - “the Court ruled that five of Myriad’s claims covering isolated DNA were not patent eligible. Following today’s decision, Myriad has more than 500 valid and enforceable claims in 24 different patents conferring strong patent protection for its BRACAnalysis® test.” Myriad and likely the personalized medicine industry in general would seem to still be in a pretty healthy patent position.

One potential land mine, however, may be in regards to the many existing issued patents. Many issued patents include claims to “isolated DNA”. In light of the above, where the “isolated DNA” can include both non-naturally occurring and genomic DNA, such claims it is expected will be invalidated if challenged. In the futute, a review of existing patents would seem warranted and the assessment of options where “isolated DNA” claims are present would be prudent.

References

1. No. 12-398 (569 U.S. June 13, 2013) 2. Although Myriad began offering BRACAnalysis in 1996, Myriad underwent 3 years of clinical trials to obtain the endorsement from medical societies key for obtaining insurance reimbursement and encourage adoption by doctors. 3. Although Myriad also benefi ts from owning or being a licensee of

CA patents related to BRCA susceptibility testing and cease and desist letters were sent out to the Ontario and British Columbia governments, no lawsuits were launched in Canada. See CMAJ

February 19, 2002 vol. 166 no. 4 f available at http://www.cmaj. ca/content/166/4/494.1.full. 4. JJ Colao “How A Breast Cancer Pioneer Finally Turned A Profi t”,

November 5, 2012 issue of Forbes. 5. The ACLU reported on its website “ACLU VICTORY! Supreme Court sides with ACLU: genes cannot be patented!” Myriad also issued a press release with the heading “Supreme Court Upholds Myriad’s cDNA Patent Claims; Court Also Highlights Patent Eligibility of Method Claims”.

When discussing fragments of synthetic DNAs, the Supreme Court noted that a short cDNA may be indistinguishable from natural DNA and hence not patentable.

Carmela DeLuca is an associate and registered patent agent at Bereskin & Parr LLP. Carmela’s practice focuses on patent matters, including advising on the management of patent portfolios in Canada and abroad, the preparation and prosecution of patent applications in the life sciences and the analysis of patent issues such as validity, infringement and freedom to operate.

To see this story online visit http://biotechnologyfocus.ca/?p=9064

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