Gene patents remain controversial in biomedical research
Authors: Carrie Arnold
Journal: The Lancet (2013)

A recent US Supreme Court ruling and the outbreak of a novel coronavirus has put gene patenting under the spotlight. Carrie Arnold asks researchers their views about this contentious issue. The gene was just a tiny fragment of DNA on the long arm of chromosome 17. To biotech insiders, however, this snippet of DNA was a potential gold mine. The gene researchers were looking at was BRCA1, which can increase a woman's lifetime risk of breast cancer to nearly 80% if she carries certain variants of this gene or its cousin, BRCA2. In 1994, university researchers along with a group of geneticists at the Utah-based biotech company Myriad Genetics cloned the BRCA1 gene, publishing their results in Science. Just hours before a UK research group published the sequence of BRCA2 in Nature in December, 1995, Myriad scientists posted the sequences of both BRCA1 and BRCA2 to GenBank and immediately filed for a patent with the US Government. Although litigation almost immediately challenged the idea that genes were patentable, Myriad's patent was still worth tens of millions of dollars to the company. In 2012, the company's estimated worth was US$500 million, much of it from their exclusive BRCA testing, marketed as BRCAnalysis. The test cost around $3000, though geneticists say the actual cost of sequencing the gene had fallen in recent years to just a few hundred dollars. Since Myriad controlled the BRCA testing market, however, consumers were forced to pay up if they wanted to find out if they carried the high-risk alleles. All of that changed in June this year when the US Supreme Court ruled on Association for Molecular Pathology vs Myriad Genetics. In the landmark, 9–0 decision, Justice Clarence Thomas wrote in the majority opinion that “A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA [complementary DNA] is patent eligible because it is not naturally occurring…Myriad did not create anything. To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.” Inventors have long-used patents, trademarks, and copyrights to protect their creations, their defence being intellectual property. But the Supreme Court ruled that genes were not, in fact, anyone's property. This ruling did not, however, resolve all of the patent issues currently facing the biomedical research community. Other Supreme Court cases, such as Mayo vs Prometheus, stated that certain diagnostic tests weren't patentable. Meanwhile, in the Netherlands, virologists have controversially moved to patent parts of the emerging Middle East respiratory syndrome coronavirus (MERS-CoV). How these issues are resolved will have major effects on research in the coming years. That scientists have been looking for a resolution to these issues can be seen from their response to the Myriad Supreme Court ruling. Most opinions expressed on this case concurred with the ruling: sequencing a gene doesn't require an inventive step if researchers used established methods, which is what the Myriad scientists did. Myriad's patents, and other similar gene patents, “are a blatant grab at making money”, Steven Salzberg, a bioinformaticist at Johns Hopkins University, MD, USA, tells The Lancet. “I realise people want and need to make money, but it shouldn't be at the expense of your overall goal of advancing science.” Not all scientists were pleased about the details of the ruling, however. “From a policy standpoint, it seemed like the Supreme Court was trying to give something to everyone”, says Dan Burk, a biologist and law professor at the University of California, CA, USA. Scientists got the benefit of knowing genes couldn't be patented, but keeping the patentability of cDNA meant that the biotech industry would also be protected, he explains. “Some of us believe that the better outcome would have been for the Supreme Court to say okay, all these genes, all this DNA is patentable, but we're going to place a research exemption”, says Burk. This exception would have allowed researchers undertaking basic scientific research to use the patented genes, proteins, and other material without having to pay royalties. Commercial enterprises, however, would be subject to these fees. Salzberg also caught several mistakes in the beginning of the ruling, including the mixing up of basic details like the difference between introns and protein-coding exons. The fact that the Supreme Court ruled that cDNA was patentable also showed that they really didn't understand what cDNA was or how it was made. cDNA is synthesised by the enzyme reverse transcriptase, which is found in retroviruses. Reverse transcriptase converts messenger RNA back into DNA, but with all of the gene's introns spliced out. It's useful in making proteins because the introns are already gone. In their ruling, the Supreme Court effectively said that cDNA was not naturally occurring, when in fact it is, says Salzberg. “It's how retroviruses reproduce. RNA gets copied back into DNA by a natural process. The only thing artificial is that we can direct the reverse transcriptase to a specific location on the genome”, he says. Although some biotech firms rejoiced at the ability to continue using their patented cDNA to make their products, others worried that this ruling could also potentially impede biomedical research. Eileen Kane, a molecular biologist turned intellectual property attorney and currently a law professor at Penn State University, PA, USA, says that this ruling was likely to bring about its own set of litigation. “The decision is really a mixed bag”, she says. The courts failed to answer exactly how much researchers can modify a gene before it becomes patent eligible, nor did it determine whether the legal system should look at DNA based on its specific chemical structure or based on the information it encodes. Just as the Myriad case wound down, WHO raised questions about the actions of a team of Dutch researchers who had applied for a patent on use of parts of MERS-CoV. Virologists at Erasmus Medical Center, Netherlands, including Ron Fouchier and Ab Osterhaus, filed a patent on use of the sequence and host receptor data of the novel coronavirus late last year. Margaret Chan, Director-General of WHO, criticised these patents harshly. Virus patents have the potential to impede public health. Researchers might not be as willing to share information and virus samples if they have an eye on future profits rather than immediate epidemiological concerns. “These issues actually have real negative public health consequences. Countries don't want to share their viruses, and then all of the epidemiology and public health surveillance is getting weighed down by that. So this has a major impact on whether we even know the status of outbreaks around the world”, says Kane. Osterhaus tells The Lancet that the move to patent parts of MERS-CoV was motivated not by money, but by ultimate public health concerns. Vaccines are expensive to create, and without the potential for a serious profit, drug companies will be hesitant to invest the tens or hundreds of millions of dollars to create a vaccine, he explains. Osterhaus adds that his laboratory is currently working on a vaccine and he is open to both private and public collaborations. Although it is unclear exactly which parts of the virus Osterhaus and colleagues have filed a patent on, Kane says that it is likely that the patent covers various receptors and other surface proteins on the virus. These proteins are likely to be immunogenic and therefore chief candidates in vaccine development. Osterhaus says that such patenting is a common occurrence in research circles and shouldn't be construed as an attempt to inhibit research. “We want to collaborate as much as possible in the name of public health. We are sharing all our information for diagnostic purposes”, he says. “It's all for the benefit of public health.” Anecdotal reports from other researchers also working on MERS-CoV haven't reported any problems receiving samples from the Dutch researchers. Osterhaus denied that he had delayed or withheld samples from Saudi researchers who were also working on the virus. The irony is, in fact, that Saudi researchers had to ask the Dutch scientists for samples of a virus that was causing an outbreak in their own country. If a vaccine is ever developed, it is likely that people in the Middle East will be dependent on a vaccine that is produced by Europeans. Even if the patents aren't harming public health now, they could have a substantial effect in the future, says Kane. Most disease outbreaks tend to occur in resource-poor countries, and the local physicians who first make the diagnosis frequently send samples of the pathogens to scientists in other countries with better-equipped laboratories. It is the scientists in these laboratories that frequently file for virus patents and profit if a vaccine is ultimately sold back to the country in which the outbreak originated. Sorting out these issues will likely require several more rounds of litigation in various countries. The scientific and legal establishments will have to find ways to protect intellectual property while not overly impeding scientific research. It's perilous ground, since the legal system handles advances in thinking and changes of opinion far differently than science. “The law is very different from science. It's also very conservative and very slow to fix its mistakes”, says Salzberg.