March 26, 2013 6:53 pm

Science: Custodians of the code

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Scientists and biotechnology companies are locked in a debate over the ethics of genetic patents

Joanna Hershey’s gut told her the news would be bad when she decided to undergo genetic testing to see if she was at high risk of breast cancer. Her grandmother had died of the disease. Her mother and two aunts had fought and survived it.

When the results came back, her fears were confirmed.

But she had a plan: relentless vigilance until the first possible sign of disease, at which point, she says, she will opt for a double mastectomy, even if such radical surgery is not immediately required.

“One sign of it, and they’re gone,” she says.

For now, the 31-year-old lawyer is participating in a screening programme for high-risk women at Memorial Sloan Kettering in New York, where she has either a mammogram or an MRI every six months.

“The only reason I’m in that programme is because I got the genetic testing done,” she says. “It has been drilled into my head that early detection is the key to surviving.”

Advancements in the scientific understanding of human genetics, and new tests such as the one that revealed Ms Hershey’s risk, are offering patients life-saving information – as well as groundbreaking medical treatments – to fight disease and live longer lives.

But for scores of scientists, doctors, and women’s health advocates, there is another side to the story, one that raises profound legal and even moral questions that will come before the US Supreme Court on April 15.

The gene mutations Ms Hershey shares with other women in her family are patented by Mark Skolnick, the scientist from the University of Utah who first isolated and sequenced them. That means that only one company, Myriad Genetics, which was co-founded by Mr Skolnick, has the exclusive right in the US to perform clinical tests or research on these genes, known as BRCA1 and BRCA2.

Myriad model falls apart outside the US

Myriad Genetics’ monopoly over the US market has been controversial but undoubtedly successful. The company is expected to generate total revenue of up to $565m this fiscal year on the back of its testing services. Its model has not worked as well around the world, however, reflecting stark differences in how gene patents are seen in other markets.

Myriad approached the international market much as it did the US. It sought patent rights internationally, then pursued licensee relationships in every country or region in which it wished to market its test for the BRCA genes. The BRCA gene test identifies mutations that make women more susceptible to breast cancer. It also insisted initially on performing the primary genetic test at its facilities in Utah.

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For the past 19 years, Myriad’s patents have raised questions about whether any single entity should control the rights to DNA and whether an individual – or company – that discovers a particular gene should be granted the same privileges and protections that Thomas Edison once sought for his lightbulb.

A legal challenge against Myriad by the American Civil Liberties Union, an activist group known for its defence of free speech, is forcing the high court to confront this question: can genes be patented?

The case could have sweeping implications for the $83bn biotechnology industry, which has argued that a whole range of patents that encourage private investment in start-ups could be at stake.

Legal scholars are closely watching the patent case, too. There is a suspicion – feared by some, celebrated by others – that the court is drawing important new distinctions about what constitutes an invention (which is patent-eligible) and what is simply a discovery of a naturally occurring phenomenon (which may not be patent-eligible, even if it represents cutting-edge science). In the age of genetics, when a gene found in a human is identical to one found in a fly, knowing the difference is more complex than it seems.

“The court appears to be narrowing the boundaries of patentable subject matter in a field that has long taken for granted the availability of patent protection,” says Rebecca Eisenberg, a professor at the University of Michigan Law School.

While the immediate focus is on the Supreme Court, European challenges to gene patents are also becoming important test cases.

This story begins in 1994. A race was under way to sequence cancer-causing mutations on a gene whose association with cancer had been discovered four years earlier by a geneticist named Mary-Claire King, then at the University of California, Berkeley.

Mr Skolnick won that race when he uncovered the BRCA1 sequence and later tied another group of researchers, led by Michael Stratton at the UK Institute of Cancer Research, to clone and sequence another set of mutations on the BRCA2 gene. A person carrying mutations for those genes has up to an 87 per cent risk of breast cancer.

Myriad Genetics’ new patents allowed it to become the only company in the US that could offer genetic testing for those mutations – even though some of its early research was helped by government funding. It also received funding from the drugmaker Eli Lilly.

It has long been held in patent law that a product or law of nature – like an element on the periodic table – cannot be patented. Nor can abstract ideas. But the decision by the US Patent and Trademark office to grant the BRCA patents in 1997 was based on earlier court decisions that found that patents on naturally occurring substances were allowed if – like a modified bacterium that was the subject of a landmark 1980 case – it had “markedly different characteristics” than any found in nature.

The question of whether isolated DNA molecules such as Myriad’s BRCA genes are indeed found in nature is at the heart of the challenge against the company’s patents.

“What the ACLU is trying to do is say that they are a product of nature. And our response is that this has not been the standard for 30 years,” says Rick Marsh, Myriad’s lawyer. The isolated fragments of DNA in question, he says, are only in existence because of the “handiwork of man”.

Some of the world’s most renowned scientists have weighed in on this question in briefs to the court, including Eric Lander, the genome pioneer.

Prof Lander took issue with a lower-court ruling that found that while a whole genome was not patentable because it was found in nature, that DNA fragments were patentable, because they were not found in nature. “It is well accepted in the scientific community that chromosomes are constantly being broken up into DNA fragments by natural biological processes ... these DNA fragments are ubiquitous in the human body,” he wrote, adding that the BRCA genes were “unambiguously” products of nature.

What worries many in the biotech industry is that this case could reach far beyond Myriad if its patents are invalidated.

“The legal reasoning in this case transfers directly to others. Scientifically, there’s no distinction. It is just DNA, whether it is found in a bacterial body or human body. There is no law or science that would allow the Supreme Court to say ‘we are just going to strike down patents in human DNA’,” says Hans Sauer, a lawyer at the Biotechnology Industry Organization, a trade group.

The BRCA genes in the human body are probably identical to the ones found in a chimp, Mr Sauer notes.

The implications also reach beyond the medical applications of genetics. Companies that own patents for DNA sequences of sugar cane and all sorts of innovations are growing nervous, incredulous that what Mr Sauer calls the “marketplace behaviour by a single diagnostic company” could draw them in to a legal storm.

But the ACLU says these concerns have been overblown, because they are not challenging the merits of patents on DNA that has in any way been transformed or altered, which is what often happens with genes used in therapies or for new functions.

Mr Lander agrees, saying that a narrowly crafted decision by the court that explicitly gave patent protection only to non-natural DNA molecules – as opposed to naturally occurring genomic DNA – would foster scientific progress by guaranteeing unfettered access to study a “remarkable product of nature”: the human genome.

But this case is about more than science. It is about the way Myriad exercised its patent rights to the detriment – the company’s critics allege – of medical advances.

In 1999, a scientist at the University of Pennsylvania named Arupa Ganguly was issued a cease-and-desist order from Myriad after she developed an alternative test to screen patients for the BRCA genes. “I could not believe that an academic lab was being prohibited from doing a test that was going to have so many implications,” she says. “We were cheaper and using a different technique.”

Myriad acknowledges it has blocked others from performing diagnostic tests for patients but insists that it has never obstructed research. Mr Marsh says Myriad abides by the unwritten rule that companies never enforce their patents against researchers. At the same time, however – and this is a sore point for scientists – Myriad has never explicitly assured those researchers that it would not claim in the future that they had infringed Myriad’s patent rights.

The ACLU contends that Myriad’s patents have limited the availability of genetic tests. Sandra Park, a lawyer for the ACLU, says a test developed by the University of Washington that looks at 20 genes that are correlated with breast and ovarian cancer excludes the BRCA genes, so patients who want a full diagnosis would have to undergo a separate genetic test from Myriad.

Myriad criticises the ACLU tactics, saying that its case was cherry-picked by the ACLU because of the emotional reaction people have to breast cancer. “If we had patent claims on isolated DNA for toe fungus, then they would not have brought this case against us. They wanted to hit a public nerve,” says Mr Marsh.

. . .

Robert Cook-Deegan, a research professor of genome ethics, law and policy at Duke University, is a man staking out the middle ground. Both sides, he says, have exaggerated the harms and the benefits of gene patents.

Yes, patents have encouraged private investment in biotech. But the benefits have been marginal. And yes, Myriad’s control of the BRCA patents has delayed some clinical research. However, given the thousands of research papers that have been published on the genes, it does not appear to have done real harm. The frequently cited high cost of Myriad’s test (about $3,300) is more of a reflection of the US healthcare system than it is of Myriad’s monopoly.

But there have been real-life harms from Myriad’s patents, he says, and here is one example. There are a small number of patients – about 3 per cent – who are tested for the BRCA mutations but do not get the clear-cut results that Ms Hershey did.

For patients who are told they have a “variant of unknown significance”, there are few options, because Myriad does not perform all the kinds of further testing that can be needed, Dr Cook-Deegan says. There are labs that do perform those tests, but they do so quietly, in a “world of shadows”, because they are infringing Myriad’s patents and could be liable. Patients must “know the right doctors” to get the answers they need.

“It is not just a patent law case. It is a lawsuit about who gets to decide questions about healthcare and whether patent law trumps all other things that people care about,” he says.

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