by Lizzie Stark
Andrews also points out that, as genetic sequencing becomes easier and cheaper, the patents become more cumbersome. “We’re moving toward the thousand-dollar genome test,” she says. We couldn’t do that if every gene had a royalty on it. If patients had to pay even a very modest fee, say $10 for each gene in the genome, she explains, that would add $220,000 to a patient’s test. Similarly, the plaintiffs argued that Myriad’s monopoly meant that it could control access to the test financially by setting the test’s price and deciding what insurance it would accept. Myriad, as it turns out, has a program to offer free testing to uninsured patients, as well as offering a no-interest financing program to allow patients to pay out-of-pocket costs over up to twenty-four months.
On the other hand, the scale of Myriad’s low-income help, in the form of free and low-cost tests, compared to its profits is difficult to uncover. In 2012 Myriad told the Patent Office that some one million patients had been tested for BRCA, and that over the last five years it had provided free tests for some four thousand patients, a comparatively small number. Those four thousand tests had a value of about $13.3 million, if each of the patients would have otherwise paid the current list price of $3,340. Compared to the more than $2 billion the company has raked in over the last fifteen years, $13.3 million over five years doesn’t sound like a whole lot. A 2014 opinion by a judge in another legal matter gives the much higher number of thirty-five thousand patients helped over the last five years but lumps together free and reduced-cost testing, as well as Myriad’s interest-free financing programs.
That’s the anti-gene patenting ethical case in an extremely reductive nutshell: limiting scientific research and failing patients by creating cost barriers and preventing the rivalry that might make companies vie to create more accurate and cheaper tests.
To make an ethical case for gene patenting, I turned to Noonan, since despite my numerous requests over several months, representatives from Myriad said they were too busy to talk to me. Though Noonan wasn’t directly involved in the case, he follows patent law like a hawk and filed an amicus brief supporting Myriad’s position. He reminded me that the methods used to sequence BRCA genes were—at the time of the genes’ discovery—much more expensive and cumbersome than they are now. He asks me to imagine a world without Myriad. Let’s say the genes are discovered anyway, and the person who does so publishes their sequences but doesn’t patent them. In all likelihood, the test will still be available; the question is whether doctors and patients will be informed about its existence and whether insurance will cover the diagnostic. Noonan argues that Myriad, because it had a business interest in spreading the test far and wide, was able to make it more widely available. As a business, it devoted time and resources to explain the significance of its findings to loads of ob-gyns, it argued with insurance companies to get them to cover the test, and it talked to state legislatures. “It’s not because they’re altruistic, it’s not because they’re wonderful people, it’s because they want to make money,” he says. Some people “might say that sucks,” he admits, but well, “that’s capitalism.” In our capitalist system, profit provides the motives. Implied is the idea that if we remove gene patenting, if we don’t provide companies with intellectual protection to invest large sums of money in spreading life-saving research, they might not do it. Without patent law and the profit incentive, the BRCA test might not have received the marketing and insurance coverage needed to reach many patients.
As a scientist, Noonan also recognizes some larger implications for gene patenting. “BRCA is really an anomaly because most cancers don’t develop from one mutation” but rather develop from the complex interaction of various genes and environmental factors, the mechanism of which is not yet fully understood. His worry is “that if you say you can’t protect it [a test for cancer predisposition] by patenting,” then people won’t disclose their methods, and science will stall or won’t move as fast as it has in the last few decades. The next cancer test might be concealed as a trade secret, just like the recipe for Coca-Cola has remained secret all these years.
There’s the ethical case for gene patenting: it provides profit motives to companies to sink research money into discovering genes that affect heritable diseases and into dealing with all the bureaucratic red tape needed to make the relevant tests available across the country. It also incentivizes disclosure of discoveries. Without gene patents, maybe we wouldn’t have a BRCA test at all.
In some way, the ethical case hinges on how much you believe in profit motives. If Skolnick hadn’t mobilized his millions in investment capital, would one of the other labs in the race, such as King’s, eventually have found and set free the BRCA mutations? And if they had, would the test have become commercially successful enough for someone to turn out a quality product without the assurance of patent protection?
The legal issues the case raised are a good deal more arcane. The ACLU and PUBPAT challenged only a handful of Myriad’s numerous patents relating to the BRCA genes. According to Cook-Deegan, there were fifteen claims at issue contained in seven patents, while Myriad has over 250 claims in twenty-four patents relating to the BRCA genes. The case challenged five of Myriad’s broad claims on methods for examining the genes, as well as nine claims relating to composition of matter—the DNA itself. The plaintiffs won their suit on method claims—claims on ways of comparing DNA sequences to one another—in the appeals court, and Myriad did not appeal that part of the ruling; so the Supreme Court case dealt primarily with the composition claims, the claims that related to the actual genes in isolation themselves. The core question of the case became: Are the BRCA genes a product of nature or human ingenuity?
In the time it takes for a patent case to settle, you could eat five whole hams with chopsticks—by the time a case concludes, it feels like the patents in question might have expired anyway. But still, the issue is an important one. As cocounsel Park puts it, “A lot of folks have tried to portray this as an issue that will go away—getting patents closely related to what we think is not patentable,” but “Myriad is continuing to get patents related to genes that are problematic.” The clock ticking on the patents in question, though, made the plaintiffs’ legal strategy ballsy. Park explains, “We dreamed big from the beginning because we knew that the only way we would win is by getting to the Supreme Court.” In other words, successfully trying this case was a long shot because the Supreme Court takes so few cases, and the court with jurisdiction immediately below it—the court of appeals—tends to favor patent holders. Still, the ACLU and PUBPAT tried to shoot the moon, and they succeeded. They won their first court case, lost their appeals case, and applied to the Supreme Court, which kicked the case back down to the appeals court again and asked it to decide the case a second time based on a recent Supreme Court ruling. After the second go-round with the appeals court, which yielded the same result—a ruling in favor of Myriad—the plaintiffs again applied to the Supreme Court, and this time, it agreed to hear the case. By that time, the consortium of plaintiffs had been knocked down to a single individual, medical geneticist Dr. Harry Ostrer. More than fifty individuals and groups filed amicus briefs, illustrating the case’s importance to scientists, researchers, law professors, businesses, and patients.
It was a battle of analogies drawn from earlier Supreme Court cases. Is a gene snipped out of its native DNA by restriction enzymes more like an oil-eating bacterium, or a fruit whose skin has been treated with borax? A mix of bacteria used to fertilize crops, or adrenaline extracted from the suprarenal glands of animals? Cellulose refined from wood pulp, or purified tungsten or uranium? A medicinal leaf plucked off an Amazonian plant, or a baseball bat carved out of a tree limb?
Myriad, naturally, argued that the isolated DNA sequences concerned in the patents were products of human ingenuity. I mean, we can’t isolate DNA sequences in our kitchens—it requires a substantial level of technical skill and equipment. Myriad’s attorneys argued that their patents were for manmade molecules, b
ecause isolating a gene from its native DNA sequence created a new chemical entity, one produced by human intervention, a molecule useful in its capacity as a screening tool for hereditary cancer syndrome. They found cases that revolved around purification of natural substances to be helpful to their cause. Myriad’s brief argued that “the established rule for over 100 years has been that isolates or extracts from natural materials that reflect human invention are eligible for patents.” For example, in the 1911 case Parke-Davis & Co. v. H. K. Mulford Co., the court ruled that purified adrenaline made from the adrenal glands of animals was patent eligible. If you extract the molecule that gives strawberries their distinctive taste and smell, or purify the prostaglandin hormone, or make concentrated vitamin B12 from bacteria, all these are patent eligible according to the courts, Myriad argued in its brief. The BRCA genes are simply a natural product that has been purified into a more useful state. Similarly, Myriad’s brief cited the Chakrabarty case, in which the courts ruled that bacteria genetically engineered to consume crude oil could be patented, according to the brief, because “although the molecules were derived from natural materials, those materials in a state of nature provided none of the benefits of the claimed molecules.” Similarly, the brief argues, “Without Myriad’s work, there is no indication whether these particular molecules, and the valuable uses to which they have been put, would ever have come about.”
The plaintiffs argued that human DNA—even isolated DNA—is a product of nature and that Myriad’s isolation of the BRCA genes did not rise to the level of innovation demanded to change something from a natural product into a product of human ingenuity. They cited the Funk Brothers case, in which the Supreme Court ruled that mixing together several sorts of natural bacteria as a fertilizer wasn’t enough to warrant a patent because “their qualities were the work of nature, not the patentee.” They also cited the American Fruit Growers case, in which the court overturned a patent on fruit that had been treated with borax to resist mold. Even though borax-treated fruit doesn’t exist in nature, the fruit’s primary use—as food—remained the same. So too, they argued, isolating a segment of DNA does not change its structure or function—it still codes for the same proteins, and it’s still got that double-helix shape. They also used Chakrabarty to support their position, arguing that isolating genomic DNA did not rise to the levels of innovation required for a patent. By the same token, they argued, the purification argument didn’t work. They cited the Gen. Elec. Co. v. De Forest Radio Co. case of 1928, in which the court ruled that superpurified tungsten couldn’t receive a patent, because in the words of the court, “Naturally we inquire who created pure tungsten. Coolidge? No. It existed in nature and doubtless has existed there for centuries. The fact that no one before Coolidge found it there does not negative its origin or existence.” In the same way, the plaintiffs’ lawyers argued, “Myriad did not invent the isolated DNA. Myriad did not invent any of the characteristics of DNA that are incidental to its isolation. Myriad did not invent the length, composition, or function of the BRCA1 or BRCA2 genes; human biology determined these qualities of the two genes.”
The oral arguments before the Supreme Court show the justices carefully grappling with where the line between a natural product and human invention lies. Myriad’s attorneys try to sell them on this baseball bat analogy—that clipping a BRCA gene out of DNA is like refining a baseball bat from a tree branch; the human mind has to create the shape of the bat before it can be carved down. The plaintiffs’ attorneys try to sell the justices on an Amazonian plant leaf analogy. Plucking a medicinal leaf off a plant doesn’t entitle one to a patent on the plant. Just as plucking the BRCA genes—genes decided by biology, not human invention—out of the genome doesn’t entitle one to a patent on the genes themselves. And the Justice Department made an unusual appearance to advocate a middle path, namely that human DNA is not patentable but cDNA is.
cDNA is a sort of lab-created DNA that occurs in nature only very rarely. Here’s a quick and dirty take on how it’s made. In order to regulate cell function, DNA unzips itself and makes molecules of RNA, which is chemically slightly different from DNA and codes for proteins. The RNA then gets edited—our DNA has lots of good stuff that codes for important things (exons) and lots of irrelevant junk (introns). During RNA splicing, the introns get edited out until only the exons—the important protein-coding stuff—remain. In a laboratory, scientists can then take this finished RNA molecule and create a strand of cDNA from it. The resulting cDNA differs from the original DNA in that it has the irrelevant stuff edited out.
The Justice Department argued that cDNA may be patentable because it’s genetically engineered, just like the oil-eating bacteria in Chakrabarty. Cocounsel Park tells me that it’s unclear whether Myriad’s patents covered cDNA and points out that the government’s position was that cDNA is not a product of nature. Even if that is true, cDNA may still not be patentable on the grounds that it is obvious, but in this particular case that was not at issue. Noonan says the Justice Department argument gave the Supreme Court “a nice simple sheep-and-goats dividing line that would theoretically make everybody happy.”
The Supreme Court had to balance the considerations of facilitating free scientific research with the concerns of industry—not just from an economic perspective, but because pharmaceutical companies do good stuff like isolate natural extracts and turn them into, among other things, aspirin and chemotherapy drugs. The justices unanimously overturned Myriad’s patents on genomic DNA while leaving the door open to patents on cDNA, and their brief largely followed the Justice Department’s logic. Isolated DNA is a product of nature and thus unpatentable, while cDNA is the product of significant human creativity and may thus be patentable.
As far as the impact of the decision, both Noonan (who authored an amicus brief supporting Myriad) and Cook-Deegan (who authored an amicus supporting neither party) agree that the immediate impact will likely be modest. Noonan calls the ruling a “narrow” and “split-the-baby” decision that gave something to both plaintiffs and respondents. Cook-Deegan points out that to his knowledge only two companies, Myriad and Athena Diagnostics, currently operate on a service-monopoly model relying on gene patents. “Pretty much everybody else isn’t going to do that,” he says. He thinks the decision will change how people write their patent claims, but that it won’t fundamentally change “the kinds of patents that really matter in the real world of biotech.” Grotesquely broad patent strategies will be reined in, but that’s it.
Still, in a legal system that operates based on precedent, Noonan argues, the implications of a Supreme Court decision don’t merely lie in the matter of law the case decides but in how that case is later used by other litigants. He expects the decision to ripple outward. “Litigants being litigants, and lawyers being lawyers,” he tells me, he believes that the Myriad decision, while narrow, “will be called to cover lots of things, and then the question is how successful will those efforts be?” Already, he says, the case is being cited in a stem cell suit that does not pertain to genetics.
In the meantime, the bottom line may not change all that much for BRCA patients. Myriad still has its vast database of genetic mutations that it can use to predict particular risk. Not all BRCA1 and BRCA2 mutations necessarily connote the same level of risk, because some genes are more penetrant than others. “Penetrant” is another way of talking about probability. When a gene is highly penetrant its effect will show up in a large number of people with that gene. So, some BRCA1 and BRCA2 mutations are highly penetrant, meaning that most of the people carrying those mutations will get breast or ovarian cancer. Other BRCA1 and BRCA2 mutations are not so penetrant, meaning that most of the people who carry those specific mutations will probably not get cancer, or at least, not because of the mutations. As the sole provider of the BRCA test, Myriad has more data points when it comes to estimating customized disease risk. Cook-Deegan points out that this is a double-edged sword. Normally, he says, such scientific results would
be validated independently, but since Myriad’s database is proprietary, “We don’t know how valid the interpretations are. There is no reason to doubt them, but there is equally no reason to believe them because they aren’t published and they aren’t publicly available.” ACLU cocounsel Park concedes that Myriad does “have an advantage because they have the largest database about the genes and they’ve refused to share that information,” but she argues that “from the experts I’ve spoken to, that advantage should be considered in the right context.” She believes that the database is mainly an advantage for very rare mutations. “But for most patients, that’s not going to matter for them,” she explains, and over time the advantage should dissipate as more labs develop their own databases. Noonan, on the other hand, points out that the patent suit has made Myriad less likely to share its results, possibly penalizing scientific progress by disincentivizing sharing. “They are very personally offended by all this,” he says, comparing the situation to the story of the little red hen who worked so hard to make the bread. “They did all this stuff, and at the end of the day they get the bread, and now everyone wants a piece.”
