Now that a recent U.S. Supreme Court decision has struck down most gene patents, geneticists and many labs hope it will decisively open up the market for testing BRCA1, BRCA2, and other patented genes that were licensed exclusively.
The unanimous June 13 ruling in Association for Molecular Pathology v. Myriad Genetics, Inc. says that patents on naturally occurring genes including BRCA1 and BRCA2 are invalid because DNA segments are products of nature and not patent-eligible merely because they have been isolated. But manmade “strands of nucleotides known as composite DNA (cDNA)” may be patented because they do not occur naturally, the decision says.
Although breast cancer is an adult onset disease, knowledge of BRCA1 and BRCA2 testing is important for medical geneticists and genetic counselors in all areas of the field because guidelines from the American College of Medical Genetics (ACMG)—a plaintiff in the case— direct labs to return with each genomic sequencing report pathogenic BRCA1 and BRCA2 mutations [American College of Medical Genetics, ].
Additionally, certain genes that cause rare diseases and disorders in children— such as hearing loss, spinal muscular atrophy, spinocerebellar ataxia, Duchenne muscular dystrophy, tuberous sclerosis, and long QT syndrome—were also affected by exclusive licensing of patents, thus complicating diagnoses because those genes could not be included in panel tests.
Athena Diagnostics of Worcester, Massachusetts, which holds many of the exclusive licenses on testing for rare genetic diseases affecting children, is perhaps less impacted by the decision than Salt Lake City-based Myriad Genetics because its business is based on a larger array of rare diseases that aren't as profitable, says Robert Cook-Deegan, MD, Director of the Center of Genome Ethics, Law and Policy at the Duke University Institute for Genome Science and Policy in Durham, North Carolina.
Myriad Fights Back
However, the degree of victory for the Supreme Court plaintiffs may be contingent on the outcomes of two BRCA1 and BRCA2 patent infringement lawsuits filed by Myriad, the University of Utah Research Foundation in Salt Lake City, the University of Pennsylvania in Philadelphia, HSC Research and Development in Belfast, Ireland, and Endorecherche Inc. in Quebec, Canada. Filed July 9 and 10, respectively, the suits against rival labs Ambry Genetics of Aliso Viejo, California, and Gene by Gene Ltd.'s subsidiary, DNATraits of Houston, Texas, raise questions about the ability of these and other labs to offer their new BRCA tests in the long term.
The lawsuits could leave “plaintiffs (including breast cancer patients) without the full and complete remedy they no doubt were promised,” writes patent lawyer Kevin Noonan, a partner with McDonnell Boehnen Hulbert & Berghoff LLP, in a post on July 9 to the biotechnology law blog PatentDocs.org. In a subsequent post on July 10, Mr. Noonan writes, “The genetic diagnostics community awaits the identity of the next of its members who announced plans to market BRCA gene testing that Myriad decides to sue.”
The lawsuits against Ambry and Gene by Gene are “big developments … but it's not clear what the significance will be unless they scare off other competitors,” says Dr. Cook-Deegan, adding that the cases are obviously disruptive for defendants. “To win, Myriad and other plaintiffs must convince the court and/ or a jury that discovering a gene means you can claim polymerase chain reaction (PCR) amplification of that gene, even if it's only one among many, based on using the sequence information from the cloned or sequenced gene,” he says.
Prior to the high court decision and its subsequent suits against Ambry and Gene by Gene, Myriad Genetics had begun relying on trade secrets to protect its business. While Myriad reported variants to a public National Institutes of Health (NIH) database until 2004, it has since maintained variant data in a proprietary database. Industry observers say this move protected its profits in advance of the 2014 expiration of many of the company's patents.
Some geneticists think that database gives Myriad a diagnostic edge over other labs. While labs new to BRCA1 and BRCA2 testing will have no problem interpreting results of the vast majority of tests, about 10% will yield variants of unknown significance (VUS), meaning the lab cannot interpret them and offer information regarding breast cancer risk, notes James P. Evans, MD, PhD, Professor of Genetics and Medicine at University of North Carolina at Chapel Hill and chair of the gene patent task force implemented by the now disbanded U.S. Department of Health and Human Services Secretary's Advisory Committee on Society, Health, and Genetics. Last year, Myriad publicly announced a VUS rate of 2.9%, although it did not publish a study saying so.
“For the time being, Myriad can still do the best interpretation,” maintains Wayne Grody, MD, PhD, immediate past president of ACMG and Director of the Molecular Diagnostic Laboratories and Clinical Genomics Center at UCLA School of Medicine in Los Angeles. “Other labs are good options for second opinions on results—especially as they compete on price—but their interpretations of risk posed by VUS are of less value,” Dr. Grody adds.
Gaithersburg, Maryland-based lab GeneDx won't take long to get BRCA1 and BRCA2 data equivalent to Myriad's, maintains Sherri Bale, PhD, the company's managing director. That's because GeneDx has an incidental database of normal controls gathered through clinical diagnostic whole exome sequencing for patients with various genetic disorders.
Other molecular labs have their own troves of data from genomic sequencing and can access the data Myriad made public—more than 10,000 published research papers on BRCA1 and BRCA2, plus other BRCA databases in Europe, says Harry Ostrer, MD, Director of Genetic and Genomic Testing at Montefiore Medical Center in New York and a plaintiff in the Supreme Court case.
Circumventing the Myriad Database
Meanwhile, a grassroots effort aims to get geneticists, oncologists, and patients to submit de-identified BRCA1 and BRCA2 mutation information so the project can make it publicly available. The Sharing Clinical Reports Project (SCRP), a volunteer initiative with the slogan “Free the Data,” aims to put BRCA variants reported by Myriad to cancer clinics since 2006 into the National Institute of Health's new ClinVar database.
While he applauds the effort, Dr. Evans calls it a “long slog.” Meanwhile, Myriad's own interpretations of particular variants have changed over time, Dr. Grody adds, questioning how complete ClinVar's information would be. He notes that Myriad has contacted him a few times to say its interpretation of a variant had changed.
A potential scenario for influencing Myriad to release database information would involve the Centers for Medicare & Medicare Services (CMS), which routinely pays for BRCA1 and BRCA2 testing, and other insurers, Dr. Evans suggests. If CMS refused to pay for a test it can't evaluate on the basis of performance characteristics and the way in which results are interpreted, “Myriad would have to make a choice: forego third-party payment, or show the data,” he says.
What about cDNA?
Geneticists and laboratory directors say continued cDNA patenting will have little effect on them. “Since much of the diagnostic testing is based on whole-gene analysis, not RNA, this is not a big deal,” Dr. Ostrer explains.
cDNA is more important to proteins and peptides, says Dr. Bale, adding that related patents may be an issue in cancer diagnostics because labs make cDNA from RNA to sequence tumors. Because cDNA is used in gene therapy to make vectors, it might be important if gene therapies become viable, says Dr. Cook-Deegan. By the time cDNA proves clinically useful, “the BRCA cDNA patents will very likely have expired,” he adds.
Meanwhile, despite Myriad's new lawsuits, the demise of patents on naturally occurring human genes apparently removes many legal complications for genomic testing, geneticists point out. “We should have pretty unfettered access to the genome now,” says Dr. Ostrer. Moreover, adds Dr. Evans, “You and your patients will have more options regarding testing.”
The demise of patents on naturally occurring human genes apparently removes many legal complications for genomic testing, say geneticists.