Myriad BRCA Patents Nixed: What Happens Next?

Roxanne Nelson

June 21, 2013

Last week a Supreme Court ruling brought a multiyear legal battle to a close, with its unanimous decision that "products of nature" cannot be patented. At the heart of the ruling were the BRCA1 and BRCA2 genes, which were patented by Myriad Genetics in the late 1990s.

But as the ink dries and the dust settles, the bigger question looms: what does this really mean for oncology practice and cancer patients, in both the long and short term?

To backtrack, the Supreme Court ruled that isolated genomic DNA is not patent-eligible under section 101 of the Patent Act, but that complementary DNA (cDNA), a form of DNA artificially synthesized from a messenger RNA template and used in genetic engineering to produce gene clones, is patentable. Myriad Genetics had claimed patents on the isolated BRCA genes along with cDNA, but the ruling essentially invalidated the patents held by Myriad for the BRCA1 and BRCA2 genes.

The decision was applauded by professional organizations and advocacy groups and was viewed positively by many in the scientific and medical community. Francis S. Collins, MD, PhD, director of the National Institutes of Health, issued a statement shortly after the ruling, saying that he was pleased with the decision and that it "represents a victory for all those eagerly awaiting more individualized, gene-based approaches to medical care."

"The right to control exclusively the use of a patient's genes could have made it more difficult to access new tests and treatments that rely on novel technologies that can quickly determine the sequence of any of the estimated 20,000 genes in the human genome," he said. "Such approaches form the cornerstone of the rapidly emerging field of personalized medicine, in which diagnostic, therapeutic, and preventive strategies can be tailored to each person's unique genetic makeup."

Mary-Claire King, PhD, the geneticist who discovered the BRCA1 gene, also expressed her satisfaction with the ruling. In an interview with Slate, she stated that she was "delighted" that the court had invalidated the patents.

"This is a fabulous result for patients, physicians, scientists, and common sense," said Dr. King, professor of genome sciences and of medicine at the University of Washington School of Medicine, Seattle. "When I was working on it from 1974 to 1994, it did not cross my mind that a legal case that would end up in the Supreme Court would be the consequence of my work."

But it did, she added, and after so many years, it was a relief to have a decision..."and I'm so gratified that it was a unanimous decision."

The Price Tag

One of the most anticipated and immediate changes resulting from the Supreme Court decision was the break of Myriad's monopoly on BRCA testing. The ruling invalidated 5 patent claims held by Myriad, which underlie their BRACAnalysis test that comes with a price tag of about $4000.

The ruling now essentially opens the market to competition, and with that, lower costs, explained Beth Y. Karlan MD, director of the Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute at Cedar's Sinai Medical Center, Los Angeles, California.

"Acutely, what we are seeing is a drop in prices, down from $4000 to $995 for the same test, in less than 1 week," Dr. Karlan told Medscape Medical News.

In fact, on the same day as the Supreme Court announced its decision, DNATraits, a division of Houston-based genomics and genetics testing company Gene By Gene, Ltd, reported that it would be offering testing for the BRCA1 and BRCA2 genes for $995. Another company, Ambry Genetics, also announced that it will be offering BRCA1 and BRCA2 analysis for approximately $2200.

But even with Myriad's high price tag, many women did have access to testing, Kenneth Offit, MD, MPH, chief, Clinical Genetics Service at Memorial Sloan-Kettring Cancer Center in New York City, pointed out. "In terms of cost, I can say in general terms that from the vantage point of a provider of genetic testing in the setting of large cancer center, reimbursement by insurers, including federal and state coverage, has helped provide BRCA testing where it is most needed," said Dr. Offit.

Although insurers generally picked up all or at least most of the tab for eligible women, the high cost was still there. "One of the claims that Myriad had was that insurance would pay for testing," said Jeffrey Rosenfeld, PhD, an assistant professor of medicine at the University of Medicine and Dentistry of New Jersey, in Newark, and a member of the High Performance and Research Computing Group. "The problem is that even if insurance is covering it, someone is still paying for it, and the money has to come from somewhere. If the prices for everything would drop in half, then insurance premiums would decrease."

Although the BRCA genes were certainly not the first ones to be patented, the controversy over gene patenting heightened when Myriad Genetics obtained their patents and then refused to license the technology to other laboratories. Testing was essentially kept in house, and Myriad was able to set a price in the absence of competition. Conversely, most patent holders of other genes have not aggressively enforced their patent rights, and few have refused to license them to other companies.

This exclusive licensing has placed limits on patient access to testing as well as research, Dr. Rosenfeld said in an interview. "They have come after researchers, sending them cease and desist notices," he said. "How can you research breast cancer without the BRCA genes?"

But now it will be like any other gene, and specifically, this ruling gives the patient more options, he noted. "You can now get a second opinion." Dr. Rosenfeld said.

"Prior to the ruling, there was no legal way to get a second opinion, and you had no way to recheck the results," Dr. Rosenfeld added. "And this option can be very important to a woman who is contemplating a double mastectomy."

The Next Generation

Next-generation sequencing is a technology that analyzes multiple genes at once, and these panels are becoming increasingly utilized. Academics as well as commercial laboratories were working toward BRCA testing by next-generation panels, Dr. Offit pointed out, even before the court decision, although "that approach was of unclear relationship to the Myriad patents."

But many believe that the removal of patents will allow for improved and more comprehensive testing. Increased market competition will allow individuals, facilities, and payors to select among a variety of BRCA tests, and medical facilities and companies offering multigene assays can now add BRCA testing to the panel.

"There will be greater access," said Dr. Karlan, "but opening the field to competition really allows game-changing improvements in the testing."

An example of this, continued Dr. Karlan, is data that were presented at this year's annual meeting of the American Society of Clinical Oncology that showed that black women with breast cancer are more likely than those in the general population to have genetic mutations linked to their disease. As reported by Medscape Medical News at that time, these mutations were most prevalent in women with early-onset disease, triple-negative disease, or a family history of breast, ovarian, or pancreatic cancer. Importantly, a significant proportion of those mutations extended beyond the common BRCA1 and BRCA2 mutations.

"This kind of testing is done out of Mary-Claire King's lab at the University of Washington and offers about 40 genes for about $300," said Dr. Karlan. "With the patents lifted, the competition not only brings greater accessibility to many men, women and families but allows the headliners — the BRCA genes — to be included in these panels."

Dr. King has recently developed a 40-gene panel called BROCA, which also includes BRCA1 and BRCA2, and testing can be ordered for a single gene or subset of genes on the panel. In an interview with the Scientist, she stated that this test has "been used for months, but until today we had to mask BRCA1 and BRCA2. The Supreme Court ruling removes the illogical situation of being able to test all genes but having to mask some."

Another company, GeneDx, plans to offer a 27-gene panel for breast and ovarian cancers, as well as next-generation sequencing–based multigene panels for gastrointestinal and colorectal cancers, pancreatic cancer, endometrial cancer, and renal cell carcinoma. They intend to introduce all of these panels as early as August 1, 2013.

Ambry Genetics will also launch a new high-risk hereditary breast cancer panel (BRCAplus) that simultaneously analyzes 6 clinically actionable genes: BRCA1, BRCA2, CDH1, PTEN, STK11, and TP53. And in the wake of the Supreme Court ruling, even Myriad has thrown in the towel and announced that they will be phasing out the BRACAnalysis test in favor of a new assay that will analyze 25 genes for a range of cancers, including those of the breast, colon, ovary, and pancreas.

Oncology Practice

So what does this ruling mean for the practicing oncologist?

Well, at least in the immediate future, the Supreme Court decision is not likely to have a substantial impact on oncology practice, Dr. Offit and colleagues comment in an article published online June 13, in the Journal of Clinical Oncology. They write that "Myriad's broad diagnostic methods claims to detect breast cancer susceptibility were already rejected by the Federal Circuit and will not be revisited by the Supreme Court," although this "new legal standard remains to be tested." And even if the BRCA patents had been upheld, isolated DNA patent claims would almost certainly not inhibit next-generation sequencing of entire genomes.

"In the post genome sequence era, very broad DNA patients based on newly discovered sequence, like the patents Myriad filed in the mid 1990's, are no longer common," Dr. Offit told Medscape Medical News.

As far as the development of anticancer agents, the ruling will have little immediate impact. "The ruling is of little relevance to therapeutics, since these generally involve cellular methods," he said.

The court upheld patent claims for isolated cDNA but not genomic DNA or oligonucleotides, inasmuch as cDNA patents generally are based on cellular and protein applications, write Dr. Offit and coauthors. "A nuanced and narrowly crafted decision allowing patent protection for cDNA and not human genomic DNA could ameliorate most of the adverse impact on the biotechnology industry."

In addition, the Supreme Court decision will not force Myriad to release its data on BRCA genetic sequence variants. "Myriad's withholding of its mutation database of 300,000 cases from public access compromises clinicians' and researchers' ability to independently characterize missense variants, despite two reports from the National Academies calling for public depositing of data," they note.

Standards Haven't Changed

Angelina Jolie brought BRCA mutations into the spotlight when she announced that she had undergone a prophylactic double mastectomy to reduce her cancer risk. But just because access may now be increased and prices lowered, it is not a call for everyone to be tested, emphasized Jane Carleton, MD, an oncologist at the North Shore–LIJ Cancer Institute in Lake Success, New York.

"It may be possible that more people will be getting tested, including those who don't need to be," she said in an interview. "But the same criteria that are already in place should be used."

There are those who may ask to be tested, just because they heard about the test, but no testing should be done if it's entirely inappropriate, Dr. Carleton pointed out. "And I have had patients ask about Angelina Jolie, and I've had to explain to them that given their history, it won't help them to do the BRCA test."

"We have fairly generous criteria for this test, but only 5% of breast cancers can be attributed to the BRCA gene," Dr. Carleton continued. "And in fact, only 15% of breast cancer is related to some type of familial vulnerability. So that means that about 85% of women do not need to be tested."

It is very important that every test be weighed, she added. "Is it beneficial? Is it reasonable? Is it appropriate?" As human genome sequencing has become less expensive, something that was once considered inconceivable is now becoming a reality. "In the next 10 to 20 years, it could become routine and part of normal health maintenance," Dr. Carleton said. "It's not science fiction, and it's not going to happen in the next 5 years, because we don't have all of the information. We don't have enough data, for instance, to differentiate between a variation and a mutation."

Obtaining the information in and of itself also is not sufficient if action cannot be taken. "For example," she said, "if we were able to recognize an increased susceptibility to colon cancer, a person could get colonoscopies at more frequent intervals. Or even with the BRCA gene, there are steps that can be taken."

"It will take some time for the practicalities to catch up with testing," Dr. Carleton added.


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