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SCOTUS Justices Struggle to Draw Line between Isolated DNA, cDNA in Gene Patent Hearing

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Originally published April 16.

WASHINGTON ─ US Supreme Court justices this week wrestled with trying to draw a legal distinction between patenting DNA isolated from the body and complementary DNA synthesized by scientists to use as probes in diagnostic testing.

Even though it is difficult to predict how the Supreme Court might decide any given case, experts closely watching the proceeding in Association for Molecular Pathology v. Myriad Genetics this week were increasingly swayed that the justices were attempting to understand the differences between isolated DNA and cDNA, so they could strike a middle ground in deciding whether isolated DNA sequences are patent-eligible.

"My sense is that cDNA will be patent-eligible; genomic DNA won't be," Robert Cook-Deegan, director for Duke University's Center for Genome Ethics, Law & Policy, told PGx Reporter. "And they'll make it as narrow as they think they can, because they're all worried about secondary and unintended consequences and impact on biotech."

In AMP v. Myriad, healthcare providers, researchers, and cancer patients are challenging patents on isolated BRCA1 and BRCA2 gene sequences held by the molecular diagnostics firm Myriad. The patented gene sequences are associated with a heightened risk of hereditary breast and ovarian cancer, which underlie Myriad's BRACAnalysis, a $4,000 test that gauges whether women with a family history of these illnesses harbor the disease-linked mutations. The plaintiffs, represented by the American Civil Liberties Union and the Public Patent Foundation, allege that Myriad's patents on isolated gene sequences are invalid since they are identical to DNA fragments inside the body. Products of nature, such as a person's DNA, cannot be patented under 35 USC section 101.

The plaintiffs are challenging nine of Myriad's patent claims on BRCA 1 and BRCA 2 genes, which include claims on stretches of isolated DNA, as well as claims on cDNA. ACLU lawyer Chris Hansen argued before the court that Myriad's patent claims on isolated DNA and cDNA should be invalidated, since both types of molecules are not substantially different, in the information they contain and their function, from native DNA to warrant IP protection.

In counterarguments, Gregory Castanias from the law firm Jones Day representing Myriad held off on speculating how a decision upholding cDNA but not isolated DNA would impact industry. He asserted, however, that if the court were to decide in this manner, it would place lower courts in the position of having to define how much human manipulation is necessary before an invention that is derived from nature can be patentable.

In attempting to draw the line that patentees must cross in order to transform a product of nature into a patentable invention, lawyers in AMP v. Myriad have repeatedly referred to two cases: Diamond v. Chakrabarty and Funk Brothers Seed Co. v. Kalo Inoculant Co. In Chakrabarty, the Supreme Court found in 1980 that a genetically modified bacterium was patentable because, unlike naturally occurring bacteria, it could break down crude oil. In Funk Brothers, the Supreme Court struck down Kalo Inoculant's patent claims on mixing strains of bacteria that scientists found didn't have a mutually inhibitive effect and could be used together in a mixture to inoculate plants. The court in that case found that the patentee had discovered a phenomenon of nature that certain strains of bacteria had mutually non-inhibiting properties, but held that this discovery did not deserve a patent.

In AMP v. Myriad the Department of Justice has taken the stance that patenting isolated DNA would be similar to the Funk Brothers case, while patents on cDNA would be more akin to Chakrabarty. "Enforcing the distinction between human invention and a product of nature preserves a necessary balance in the patent system between encouraging individual inventors and keeping the basic building blocks of innovation free for all to use," DoJ Solicitor General Donald Verrilli told justices. "Isolated DNA falls on the ineligible side of that divide because it is simply native DNA extracted from the body." In contrast, Verrilli held that cDNA is patent-eligible because "unlike the isolated DNA which is just taken from your body, cDNA is an artificial creation in the laboratory that doesn't correspond to anything in your body."

"I think the court will adopt the solicitor general's position that sequences that do not occur in nature (such as full-length cDNA, recombinant DNA, et cetera) can be patented, but sequences that can be found in nature (such as genes and fragments of genes) cannot," said Courtenay Brinckerhoff, a partner at Foley & Lardner's IP practice group, over e-mail.

Lawyers for the ACLU, however, have maintained that since the plaintiffs are only asking whether isolated DNA is patentable, the Supreme Court doesn't need to make a decision on the validity of cDNA. "We think all of the challenged claims cover isolated genomic DNA (along with cDNA and other things, as defined in the patents)," Sandra Park, staff attorney with the ACLU Women's Rights Project, told PGx Reporter over e-mail. "So, if the court finds that isolated genomic DNA is not patentable, then the claim is invalid, and the court need not decide whether cDNA is patentable."

Regardless, during a significant portion of the hearing, the justices concerned themselves with the question of whether cDNA is patentable. They even discussed whether Myriad's cDNA claims should be reviewed under the Section 101 limit against patenting products of nature, or whether they should be considered in light of Section 103 of US patent law, which restricts patents on claimed inventions that are "obvious" to prior art. The DoJ has put forth the possibility that claims on cDNA may not hold up against the obviousness test.

The justices "truly struggled with the concepts of patentability (e.g., Sections 101, 102, and 103) and how to define 'patent eligibility' with regard to this case," Marylee Jenkins, a partner at the law firm Arent Fox, told PGx Reporter in an email.

Impact on Industry

It is unclear how a Supreme Court decision that would invalidate patents on isolated DNA but not on cDNA would impact industry. Some experts believe that the diagnostics field has little need for cDNA, particularly since technologies are moving toward next-generation sequencing. In a call with Credit Suisse investors, Robert Nussbaum, chief of medical genetics at the University of California, San Francisco Medical Center, conceded that cDNA is a "test tube phenomenon" that is more important to the biotech industry than the diagnostics field.

"I personally don't see cDNA as being a big player in the testing arena," Nussbaum said, adding that if the Supreme Court upholds the patentability of cDNA then that would restrict drug companies from using such molecules to derive proteins that can be of use to them in research or product development.

Experts in the field have said that cDNA is critical to recombinant DNA, which are created by researchers by combining genetic material from different sources. Recombinant DNA, industry observers believe, will be critical to the development of future drugs. However, without being able to patent cDNA, and even isolated DNA, there is concern among industry players that investment in the life sciences field will dry up.

Vamil Divan, analyst for the financial services firm Credit Suisse, advised investors in a note to not place too much weight on justices' comments during the Supreme Court hearing since an outcome in the case is impossible to predict. However, Divan wrote that the discussions during the hearing suggested that the justices "are looking for some controls to be placed around the patenting of genetic material, although the patents that Myriad has around cDNA appear to have stronger support."

If the court upheld only Myriad's cDNA patents then it may delay competition in the BRCA testing market, Divan added. Myriad currently holds a monopoly on BRCA testing for gauging patients' risk of hereditary breast and ovarian cancer. The patents at issue in this case underlie Myriad's BRACAnalysis test, which accounts for more than 80 percent of the company's $472 million in molecular diagnostics revenues last fiscal year.

The Supreme Court's decision in AMP v. Myriad stands to impact not just Myriad's business but the life sciences industry at large, and the justices acknowledged this. Justices Elena Kagan and Antonin Scalia at one point asked ACLU's Hansen why a company would want to put in the immense effort to pinpoint the gene sequence associated with disease and launch a test without the incentive of patent protection. "What does Myriad get out of this deal? Why shouldn't we worry that Myriad or companies like it will just say, well, you know, we're not going to do this work anymore?" Kagan queried.

To this, Hansen responded that in the case of BRCA variants associated with breast and ovarian cancer, there are other labs that are hoping to do this type of testing. In particular, diagnostics companies such as GeneDx and Ambry Genetics, which are focused on launching tests based on next-generation sequencing technologies, have said that if IP barriers were no longer an issue they would perform BRCA testing (see related story, in this issue).

Hansen further told justices that researchers would continue to discover associations between gene variations and diseases spurred by the recognition they would get for this work. On the whole, however, Kagan and Scalia weren't satisfied with Hansen's response in this matter. "Well, that's lovely," Scalia quipped. "I just don't think we can decide the case on the ground, 'oh, don't worry about investment, it'll come.' I just don't think we can do that."

In the end, Hansen did state that while the mere act of isolating a piece of DNA may not make a discovery worthy of a patent, if a company finds a new use for that discovery, that very well may be worthy of a patent. "That's the whole point, isn't it?" Justice Sonia Sotomayor said. "The isolation itself is not valuable … it's just nature sitting there."

Of course, isolated gene sequences are valuable in spurring research and diagnostic innovations. An invalidation of isolated DNA patents would essentially enable patients to seek BRCA testing from other labs who offer tests at prices that are likely lower than what Myriad charges, or garner independent confirmation of an initial test. Patients who are plaintiffs in the case have charged that Myriad, as the sole provider of BRCA testing, has limited their ability to get the most accurate testing that science will allow.

The impact that Myriad's IP-enabled monopoly over BRCA testing has had on patients didn't get much attention during the hearing. However, patient advocacy organizations and friends and families of breast cancer patients picketed outside of the Supreme Court building holding up signs that read, "Outlaw human gene patents," and "Myriad Genetics – Your corporate greed is killing my friends."

Ultimately, the DoJ advised that the Supreme Court should not allow concerns about the impact on industry to sway its decision on AMP v. Myriad. In Mayo Collaborative Services v. Prometheus Laboratories, the Supreme Court last year ruled that in order to transform an application of a law of nature into a patentable invention, the inventor must "do more" than just apply that principle (PGx Reporter 3/21/2012).

In that decision, Justice Stephen Breyer described "patent protection [as] … a two-edged sword" that tries to balance incentivizing invention while not tying up the flow of information that might inspire future innovation. While the Supreme Court's ruling in Mayo v. Prometheus might broadly impact the diagnostics industry, the court left it up to Congress to craft regulations that might address the policy challenges for a particular industry. At the hearing on AMP v. Myriad, Breyer harkened back to the court's decision in Mayo by noting that patent law often requires "uneasy compromises."

In its amicus brief in AMP v. Myriad, the DoJ suggested that the Supreme Court's decision in Mayo might offer guidance as to when an invention is substantially transformed from the natural principle it applies and is patentable. "Mayo … suggests that, in determining whether a modified natural product is 'markedly different' from the underlying natural substance and therefore patent-eligible, one relevant question is whether a patent on the modified product would have the practical effect of preempting the public’s ability to use the underlying natural substance," the DoJ wrote in its brief. "If so, then the differences between the claimed invention and the underlying natural substance are not sufficient to render the composition patent-eligible."

Leaves, Cookies, Kidneys, and Bats

In their attempt to understand how the principles under patent law might be used to differentiate isolated gene sequences from native DNA, the justices during the hearing applied a slew of analogies.

They relied most heavily during the hearing on the "Amazonian leaf" example, put forth by Justice Samuel Alito. He presented a situation in which someone has discovered a leaf in the Amazon that contains a chemical with properties than can treat breast cancer, and he wondered if that chemical isolated from the leaf is worthy of patent protection. To this, ACLU's Hansen noted that while merely extracting the chemical from the plant might not make it worthy of a patent, if the patentee transforms the chemical to make it distinct from what already exists in nature, such as develop a more concentrated form of the chemical and give it a new function, then that might be worthy of a patent.

"Well, when you concede that, then I'm not sure how you distinguish the isolated DNA here, because it has a different function," Alito said. "Isolated DNA has a very different function from the DNA as it exists in nature. And although the chemical composition may not be different … it certainly is in a different form."

To this Hansen responded that Myriad has patented broad swaths of isolated BRCA1 and BRCA2 sequences that have the same function as native DNA in its relationship to cancer. And although Myriad claims that isolated DNA can be used as probes and primers in diagnostic testing, "full-length DNA, which all of these patent claims include, cannot be used as probes and primers."

Another metaphor that Justice Sotomayor used to engage Myriad's lawyer Castanias in discussing the patent eligibility of isolated DNA involved baking chocolate chip cookies. "I can bake a chocolate chip cookie using natural ingredients: salt, flour, eggs, butter … And if I combust those in some new way, I can get a patent on that," she said. "But I can't imagine getting a patent simply on the basic items of salt, flour, and eggs, simply because I've created a new use or a new product from those ingredients."

Castanias felt Sotomayor's example was too simplistic to characterize the complexity of how isolated DNA is a different chemical composition than native DNA. Throughout the case, Myriad has largely relied on the baseball bat analogy to make its case about isolated DNA. A baseball bat is a patented invention, and Myriad has maintained that, just as inventors figured out how to derive the baseball bat from cutting away excess wood that was once part of a tree, Myriad has invented the isolated BRCA1 and BRCA2 molecules by separating the sequences from the body.

The baseball bat analogy didn't curry much favor with Chief Justice John Roberts, however. "The baseball bat is quite different. You don't look at a tree and say, well, I've cut the branch here and cut it here and all of a sudden I've got a baseball bat," he said. "You have to invent it, if you will. You don't have to invent the particular segment of the … [gene] strand; you just have to cut it off."

Myriad's lawyers have argued that isolated DNA sequences are substantially different from native DNA since the segments are snipped from other biological structures inside the body. This led the justices to question whether, by Myriad's reasoning, livers, kidneys, and other organs that have been similarly removed from the body are patentable.

Ultimately, all of these analogies fall short of sufficiently capturing the nature of DNA and its importance to future innovation in the life sciences field. As James Watson, the co-discoverer of the double helix structure of DNA, wrote in his amicus brief to the Supreme Court, "a human gene is fundamentally unique — unlike any ordinary 'composition of matter.'"

In their attempt to liken DNA to things that are easier to conceive of or talk about in terms of patent law, the lawyers and judges involved in AMP v. Myriad have compared isolated DNA to things like bats and cookies, but they haven't considered the possibility that DNA might defy such analogies.

"Indeed, the nature of the gene — and the double-helical structure of DNA on which genes are encoded — mandate that a human gene does not fall within the ordinary meaning of 'composition,' as Congress set forth in the 1952 Patent Act," Watson said in his brief.

After Watson first presented on the structure of DNA in 1958, Leó Szilárd, a physicist who conceived the nuclear chain reaction, asked whether he would patent the double helix structure. "That, of course, was out of the question," Watson wrote.

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