The Supreme Court earlier this week heard oral arguments in a landmark case involving two cancer-related genes.
The case, Association of Molecular Pathology vs. Myriad Genetics Inc., holds huge implications for all parties involved:
Myriad, the biotech company that has exclusive rights to the genes, would lose protection—and millions of dollars—if the court nullifies its patents. Moreover, other companies would be deterred from genetic research, some industry observers warn.
If the court upholds the patents, cancer and genomics researchers nationwide will continue to be barred from using the genes until the Myriad patents expire—for the next two years. And other genes will continue to be patented.
In the hearing April 15, the justices drilled down into Myriad’s patent rights to BRCA1 and BRCA2, the isolated genes which are associated with breast and ovarian cancer.
“If you cut off a piece of the whole in the kidney or liver, you’re saying that’s not patentable, but you take a gene and snip off a piece, that is?” Justice Sonia Sotomayor asked Myriad’s attorney, Gregory Castanias, during the oral arguments.
“So what’s the difference?”
The debate over patentability of the BRCA genes drew public attention when the Public Patent Foundation and American Civil Liberties Union—on behalf of several medical researchers, associations and patients— challenged Myriad’s patent claims in 2009.
The plaintiffs prevailed at the Federal District Court in Manhattan.
However, the United States Court of Appeals for the Federal Circuit reversed the decision, leading the plaintiffs to petition the Supreme Court to reconsider several aspects of the ruling.
Nearly 60 “friend of the court” briefs were filed to the Supreme Court—research advocates and medical organizations largely sided with the petitioners. The American Medical Association, AARP and the National Women’s Health Network are among the groups that filed briefs.
“Nobody ‘invents’ genes, so no one should be able to claim ownership of them,” said Daniel Ravicher, executive director of the Public Patent Foundation. “We are not talking about a new drug or a new tool to fight cancer.
“We are talking about a genetic marker that occurs naturally in the human body,” Ravicher said. “That cannot, and should not, be patented.”
PhRMA and BIO, as well as individual drug and biotech companies filed briefs in support of Myriad. Prominent pro-Myriad parties include the Federal Circuit Bar Association, University of Baltimore/Johns Hopkins University Center for Medicine & Law, and the American Bar Association.
Arguably the highest-profile amicus brief was submitted by the Department of Justice, on behalf of the federal government’s interests in support of neither party.
“The justices seem likely to rule in a way that tracks closely to the arguments of the U.S. government’s top lawyer, the Solicitor General [Donald Verrilli], who had ten minutes to make his argument,” said Robert Cook-Deegan, director of the Center for Genome Ethics, Law and Policy at the Duke University Institute for Genome Sciences and Policy.
Cook-Deegan’s commentary on the oral arguments appears at the end of this story.
Present at the hearing were NIH Director Francis Collins and NCI Director Harold Varmus, who helped with the formulation of the DOJ amicus brief.
Earlier, Varmus said the case is of “immense concern to NCI.”
“Francis and I and some others here at the NIH have been called upon by the Department of Justice and the ACLU to help with formulation of briefs,” Varmus said at the National Cancer Advisory Board meeting Feb. 7.
BRCA Science and Money Matters
The BRCA genes were discovered by Myriad, which said it invested more than $500 million into researching the genes and commercializing testing products.
Myriad’s sales of BRACAnalysis, a product that detects mutations in the BRCA genes to determine increased risks for breast and ovarian cancer, added up to $405.5 million in 2012.
The test was granted March 6 preventative care designation under the Affordable Care Act, which allows for BRCA testing to be completed at no patient cost for all new health plans (post-March 23, 2010) when an asymptomatic woman has a qualifying family history.
The tests, which cost $4,000 each, made up more than 80 percent of revenue for Myriad last year. However, the value of BRACAnalysis is measured not only in sales, but in the databases on BRCA genes and mutations that Myriad’s monopoly has enabled the company to collect.
Scientists want access to these data.
A grassroots project called Sharing Clinical Reports is attempting to recreate Myriad’s database from the millions of gene test reports that the company sends out. Launched by Robert Nussbaum, chief of the Division of Genomic Medicine at the University of California, San Francisco, the project has only collected about 1.5 percent of Myriad’s data, sources said.
“The incentives created by such patents are essential to encourage medical innovation that saves patients’ lives,” said the Association of American Physicians and Surgeons in a statement, arguing that patents are necessary to encourage private investment in research.
“Valuable cures are being developed based on patents in many medical fields, including adult stem cells—cures that would not be possible without the incentives established by patents.”
The justices appeared cognizant of these incentives, discussing at length the importance of industry investments:
“Why would a company incur massive investment if it—if it cannot patent?” asked Justice Antonin Scalia of Christopher Hansen, lawyer for the plaintiff American Civil Liberties Union.
Hansen said that “enormous” public recognition for discoveries is sufficient payback for investors and companies.
“Well, I’m not sure the Court can decide the case on that basis,” said Justice Anthony Kennedy. “I’m sure that there are substantial arguments in the amicus brief that this investment is necessary and that makes sense.
“To say, oh, well, the taxpayers will do it, don’t worry, is, I think, an insufficient answer.”
In a March 31, 2010 report on the impact of gene patents on patient access to genetic tests, the Health and Human Services Secretary’s Advisory Committee on Genetics, Health and Society said “patents on genetic discoveries do not appear to be necessary for either basic genetic research or the development of available genetic tests.”
The committee found that patents have been “used to narrow or clear the market of existing tests, thereby limiting, rather than promoting availability of testing. “The substantial number of existing patents on genes and methods of diagnosis also pose a threat to the development of multiplex testing, parallel sequencing, and whole-genome sequencing, the areas of genetic testing with the greatest potential future benefits,” the report said.
Other Myriad BRCA patents are in play in this case as well.
The company also owns patents to the other elements that produce the genes, namely, artificial complementary DNA molecules and other isolated DNA molecules that encode the BRCA genes.
Myriad created the cDNAs, which mirror coding sections of the BRCA genes and “primers” used in diagnostics—these synthetic products, some of the justices appear to agree, are patentable.
cDNAs: Human Manipulation, or Product of Nature?
The petitioners, attempting to loosen Myriad’s hold on cDNAs and the BRCA genes, argued that neither should be patented on grounds that they are products of nature.
“The sequence of the nucleotides is dictated by nature,” plaintiffs’ attorney Hansen said, addressing the natural properties of cDNAs at the April 15 hearing. “The order that they go in is dictated by nature.
“And the question is whether when the body removes the introns, had the body made something markedly different than what is in nature…”
Justice Kennedy appeared unconvinced, arguing that the functions of cDNAs differ markedly from native, unaltered DNA.
“When I looked at this case, I thought that maybe the cDNA was kind of an economy class gene. It wasn’t,” Kennedy said. “My understanding is that it may have a functionality that the DNA isolate does not—easier to tag, etc.”
Justice Ruth Bader Ginsburg proceeded to question Hansen on the extent of human manipulation to cDNA.
“Everything starts with a natural product, but these others the examples that I gave, you said they involve manipulation,” Ginsburg said. “The cDNA can’t be characterized as involving manipulation?”
Hansen responded, admitting there is some manipulation, but that nature, not the scientist, is to be credited for the manipulation.
“You’ve really lost me when you say that it’s nature that does the alteration rather than the scientist,” Scalia said. “I mean, whenever a scientist does an alteration, he does it, you know, by some force of nature.”
The DOJ amicus brief states that artificial DNA molecules, including cDNAs, are human-made interventions eligible for patent protection.
“The resulting cDNA molecule has a different nucleotide sequence than DNA created naturally within the cell, and (because it lacks introns) its ‘preferable’ to isolated DNA for many laboratory uses,” the brief said. “Extending patent protection to cDNAs therefore poses no risk of ‘tying up’ other uses of the natural raw materials involved in the creation of cDNA.”
Myriad’s attorney Castanias said that cDNA was created from hundreds of different patient samples to create a consensus sequence.
“Okay,” Chief Justice John Roberts said. “You’ve got the cDNA.”
DOJ: Isolated BRCA Genes are Not Patentable
According to the Department of Justice’s analysis, Myriad’s claims to the isolated BRCA genes are invalid, under Section 101 of the Patent Act.
The act provides that an inventor may obtain a patent on “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof.”
“Isolated DNA is simply naturally occurring DNA that has been extracted from its cellular environment and separated from extraneous material,” the department’s brief states. “The differences between isolated DNA and native DNA within a cell are merely the inherent and necessary results of removing the DNA from its natural environment.
“Because the removal process is a prerequisite to any exploitation of native DNA, respondents’ isolated DNA claims are the practical equivalent of patents on the underlying naturally occurring BRCA genes themselves.
“The fact that isolated DNA has additional applications likewise does not render it markedly different from native DNA.
“The ‘additional utility’…is simply the ability of researchers to study and exploit in a laboratory the inherent natural properties that isolated DNA shares with native DNA.
“For two of the composition claims at issue here, the relevant compositions of matter are defined by the natural biological function they perform in the human body: the capacity to express BRCA1 and BRCA2 proteins.”
Snipped Like a Baseball Bat
Several justices appeared to side with the DOJ on the issue of isolated BRCA genes, using the analogous examples—leaves, plants, and trees—to determine whether the genes should be patentable.
“Suppose there is a substance, a chemical, a molecule in the leaves of a plant that grows in the Amazon, and it’s discovered that this has tremendous medicinal purposes,” said Justice Samuel Alito to Hansen. “Let’s say it treats breast cancer.
“A new discovery, a new way is found, previously unknown, to extract that,” Alito said. “You make a drug out of that.
“Your answer is that cannot be patented; it’s not eligible for patenting, because the chemical composition of the drug is the same as the chemical that exists in the leaves of the plant.”
If picking the leaf off the tree and swallowing it would enable the consumer to reap the benefits, it is not patentable, Hansen argued.
“We agree that you could get a patent on a use of the leaf that is pulled out of the Amazon or a plant that is pulled out of the Amazon,” Hansen said. “We don’t think you [can] get a patent on the plant itself just because you pulled it out of the ground and took it to the United States.”
At this point, Myriad attorney Castanias turned to the time-honored American approach: when the discourse gets complicated, talk baseball.
“I’ll use my own simplistic analogy which we offered in our brief and which we offered to the lower court,” Castanias said. “A baseball bat doesn’t exist until it’s isolated from a tree.”
“But that’s still the product of human intervention to decide where to begin the bat and where to end the bat.”
The baseball analogy caught on.
“Here, what’s involved is snipping,” Justice Roberts said of the isolated BRCA genes. “You’ve got the thing there and you snip—snip off the top and you snip off the bottom and there you’ve got it.
“The baseball bat is quite different.
“You don’t look at a tree and say, well, I’ve cut the branch and cut it here and all of a sudden I’ve got a baseball bat,” Roberts said. “You have to invent it, if you will.
“You don’t have to invent the particular segment of the strand; you just have to cut it off.”
But scientists wouldn’t even know where to snip until the Myriad invention, Castanias said.
“Okay, so that’s a particular—where you snip,” Robert said. “We’re talking about, though, the patentability of what’s left after you’ve snipped it.”
This could be like baking cookies, offered Justice Sotomayor.
“I can bake a chocolate chip cookie using natural ingredients—salt, flour, eggs, butter—and I create my chocolate chip cookie,” Sotomayor said. “And if I combust those in some new way, I can get a patent on that.
“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.”
Justice Elena Kagan chimed in:
“Mr. Castanias, go back to Justice Alito’s plant in the Amazon, right, because it takes a lot of ingenuity and a lot of effort to actually find that plant, just as it takes a lot of effort and a lot of ingenuity to figure out where to snip on—on the genetic material.
“But are you saying that you could patent that plant because it takes a lot of effort and a lot of ingenuity to find it?”
Castanias replied: “The plant itself, I think not, Justice Kagan, but I think the question that was posed was whether I could take an extract from that plant.”
“Well, but can you patent the thing itself?” asked Kagan.
“The thing itself I would—in that hypothetical, I would say the answer is no,” said Castanias.
The justices are expected to rule on the case before the term ends in June.
Ruling Likely to Concur with Justice Department Arguments
By Robert Cook-Deegan
The author is the director of the Center for Genome Ethics, Law and Policy at the Duke University Institute for Genome Sciences and Policy. His guest editorial on an earlier appellate court ruling in the case appears in Aug. 5, 2011 issue of The Cancer Letter.
Q: What do baseball bats, cancer-fighting tree sap from Amazonian plants, and chocolate chip cookies have in common?
A: They were all analogies that Supreme Court justices used to probe the question before them in oral arguments in Association of Molecular Pathology vs. Myriad Genetics (S. Ct. 12-398) on April 15. The oral arguments addressed one deceptively simple question: “are human genes patentable?”
The pantheon of molecular biology was there: Eric Lander, professor of biology at MIT, and DNA co-discoverer James Watson had written two of the 49 amicus curiae briefs.
NIH Director Francis Collins, NCI Director Harold Varmus, and Eric Green, director of the National Human Genome Research Institute, were just a few of the molecular biological luminaries in the audience.
It is always perilous to predict Supreme Court outcomes based on the questions in an hour of seemingly Brownian motion, with questions half-answered before careening off to address a new one.
Every judge except Clarence Thomas asked many questions. All were fully engaged. The attorneys were regularly asked questions that rested on science, and demonstrated the limits of simplifying arcana of molecular genetics to an audience of legal generalists.
Harold Varmus visibly winced, for example, when Greg Castanias, the Jones Day attorney arguing the case for Myriad, declared that scientists had decided where the gene started and ended, and nature had not determined such parameters until the scientists decided the matter. Ouch.
When Justice Kagan drew him out on whether a chromosome, or a liver, or a part of a liver would be patentable if extracted from the body, to his credit Mr. Castanias stuck to his guns and said yes, they would be patent-eligible (but not necessary meet the other patent criteria), but he may have been aiming his guns at the deck of his already fragile life raft.
The general drift of the questions left little doubt that a majority of justices—at least in their questions—wanted to understand why the magical word “isolated” would turn something unpatentable into something patentable, and were not persuaded it made much sense. But they also strongly signaled discomfort with a sweeping decision that might undermine investment incentives in biotechnology.
When Justice Kagan asked Chris Hansen, the ACLU attorney representing the petitioners (those challenging 15 claims in seven of Myriad’s patents), why a company would invest in funding such useful R&D without a patent incentive, the body language was clear from one end of the bench to the other: the justices are not going to be satisfied that academic reputation, NIH grants, and Nobel Prizes will supply all the incentives they want to see in place. They also want the patent incentive to induce private R&D investment in medical products and services.
There was almost no attention to why “human” was in the question, or how decisions in this case might spill over to patents on nucleic acid sequences from other organisms. And nothing at all about who can sue whom in such a patent lawsuit (the question of standing had been removed from questions under consideration, but a justice might nonetheless have asked a question if this were still a lingering concern).
Predictions among those dissecting the proceedings in venues across Washington, D.C., after the event fell into a surprisingly narrow range. The justices seem likely to rule in a way that tracks closely to the arguments of the U.S. government’s top lawyer, the solicitor general, who had 10 minutes to make his argument.
The solicitor general’s office mediated an often contentious process for deciding that U.S. Patent and Trademark Office practices of granting patents on “isolated” DNA over the past three decades do not comport with the law.
USPTO did not sign onto the solicitor general’s brief, but the solicitor general is nonetheless represents the official view of the United States government. The solicitor general’s logic appears likely to carry the day: DNA is not patentable subject matter if the only intervention is “isolating” it (whatever that means, and we got no guidance on Monday).
If it is engineered—for example, by removing exons via reverse transcription into cDNA from mRNA, or by tagging it or engineering it, through insertion into a vector, addition of promoters or enhancers, etc.—then it is patent-eligible.
For now, such conclusions are speculative, but the ruling will be apparent soon enough. The case will be decided in the current term, which ends June 30. Since this case was heard in the last two weeks of arguments for the term, the ruling is likewise apt to appear just before the end of the term.
We will have a ruling from the Supreme Court by July.