Supreme Court rules natural genes not patentable

Unanimous decision against BRCA breast cancer susceptibility gene patents in Association for Molecular Pathology v. Myriad Genetics, Inc.

by Liza Lester, ESA communications officer

The Supreme Court ruled unanimously on Thursday, June 13th, that Myriad Genomics Inc. may not retain exclusive rights to the use of DNA sequence information for breast cancer associated genes BRCA1 and BRCA2, stating that Myriad had not created anything new in identifying the genes. Known mutations in the BRCA genes dramatically increase the risk of breast and ovarian cancer for people who carry them. Actress Angelina Jolie drew wide attention to familial breast cancer testing when she announced her preventative double mastectomy in a New York Times editorial last month, after learning she carried a risky variant of BRCA1. Jolie’s mother died of ovarian cancer at 56. Myriad has held sole rights to medical testing for these traits.

The ACLU and the Public Patent Foundation challenged those rights, filing suit against Myriad on behalf of 150,000 doctors, medical scientists, and patients. Thursday’s decision brought an end to four years of legal battles, and may have a powerful effect on biotechnology patents going forward, though the court was careful to limit the scope of its ruling.

Justice Clarence Thomas delivered the decision, reading from his opinion, “Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA. 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.  Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the [patent law] inquiry.” Myriad had argued that because it synthesized a complementary DNA (cDNA) copy of the gene in the process of identifying it, their patent was not based on a naturally-occurring phenomenon, but on a synthetic, isolated sequence.

Natural phenomena are excluded from patent protection.

The Thomas opinion starts off with a brief definition of DNA – it’s awkward and odd, and I recommend reading it for yourself. During testimony for the case, the justices dwelled at length on various analogies that might help them frame the question in a more familiar context.

The court agreed that cDNA is not naturally-occurring, and therefore is patent eligible, but rejected Myriad’s argument, commenting that  that Myriad’s claims “focus on the genetic information encoded in the BRCA1 and BRCA2 genes” and not the technical process of RNA isolation, reverse transcription, and sequencing. The court held that genetic information could not be patented, no matter how much work Myriad’s scientists invested in obtaining it.

Mark Capone, president of Myriad Genetics Laboratories, said (as reported by Nina Totenberg for NPR News) “What Myriad was able to do is sort through all those 20,000 genes [in the human body] and find the two that were highly linked to hereditary breast and ovarian cancer.”

But this is not what Myriad’s scientists did.

It is true, as Gregory Castanias, Myriad’s lawyer, said, that they took “the final step in an extraordinarily complicated set of inventive actions that led to the creation of this molecule, which had never been available to the world before.” Other scientists had done the hard work of demonstrating, in a small number of families, a genetic predisposition to develop breast cancer, and narrowing the source to a relatively small region of the human genome.

Mary-Claire King looks at old school sanger sequencing films, circa 1996. Credit, University of Washington.

Mary-Claire King looks at old school Sanger sequencing films, circa 1996. Credit, University of Washington.

Mary-Claire King had been looking for a breast cancer gene since 1974 – before the Human Genome Project began laying out a map of the genome, before automated sequencing, before PCR (a simple and now-ubiquitous technique for exponentially copying a short stretch of DNA). Molecular biology was slow and laborious, and the very idea of familial cancer was considered kind of crackpot by many medical scientists in the ‘70s. While a professor at the University of California at Berkeley, King tracked inherited susceptibility to breast cancer to chromosome 17q21 with the cooperation of 22 extended families suffering from a high incidence of early-onset (younger than 45) breast and ovarian cancer, and a relatively high incidence of the disease in men. Her research team published the results in a classic paper in Science in 1990.

Even though King had not tracked down the exact gene, linking breast cancer to a chromosomal location was an important feat. The diseases that had been genetically mapped up to that point were simple, like cystic fibrosis or Huntington’s disease, for which having the disease genotype means you will manifest the disease, and if you do not have the genotype, you will not develop the disease spontaneously. Breast cancer is not simple. The BRCA1 and BRCA2 mutations are rare. Most (~95%) breast cancers occur in women who do not have those particular genetic risk factors. Not everyone who has a genetic susceptibility to breast cancer becomes ill during their lifetime. All of these characteristics made the work of demonstrating an inherited susceptibility to breast cancer, and locating the gene(s) responsible, difficult. Demonstrating a genetic predisposition for cancer was a huge breakthough.

To get to the linkage analysis stage, King’s team examined 1500 families for evidence of a major gene component underlying the development of early onset breast cancer. Her search was complicated by the existence of a second breast cancer susceptibility gene, which confounded association of disease with a single genetic locus (a complication she eventually deduced and worked around). An international research team based at the Institute for Cancer Research in the UK mapped BRCA2 to chromosome 13 in 1994 by (early-onset breast cancer has now been associated with 13 genes).

breast cancer families - from Hall et al (1990) Linkage of early onset familial breast cancer to chromosome 17q21. Science 250, 1684.

Breast cancer in families – from Hall et al (1990) Linkage of early onset familial breast cancer to chromosome 17q21. Science 250, 1684.

Once King produced the map, pinpointing the gene was a matter of brute force digging. After King’s group published in 1990, many research groups set about attempting to identify the specific gene, dubbed BRCA1, located somewhere within band 1, region 2 of chromosome 17. In 1994, a large group of researchers working at the University of Utah, NIH, McGill, and Eli Lilly won the race to sequence a candidate gene. The senior author of this group, Mark Skolnick of the University of Utah, had incorporated as Myriad Genetics in 1991. In a Cold Spring Harbor interview, King talked about how she felt when she heard the news:

“When I heard Myriad’s announcement I was reading sequence. And I first heard it from a journalist who had heard it from Myriad and I said I want to know, you know, what’s the data. And the data was very quick in coming and of course we all knew the region so well that it, that we would be either very quickly convinced or it would be obvious immediately that they were wrong. And we were quickly convinced they were right, and all that played out within several hours. And I remember feeling, it’s been found, gosh, now we can get on with it and try to go to the next step. And in the previous years I had anticipated that if some other group found it, that I would just be devastated. And when I learned that Myriad had, I kept waiting to feel devastated, and I never felt devastated.”

Myriad Genetics Inc and the University of Utah filed patents for BRCA1 and BRCA2 in 1994 and 1995, respectively.

Hundreds of sequence variations have been found in BRCA1 and BRCA2. Some are associated with increased risk of cancer, with varying depth of evidence and investigation. In part, the patent controversy grew out of the frustrations of other medical practitioners, because Myriad tests only a subset of BRCA mutations, they said, yet considers examination of patient sequences for other variants, or development of alternative testing methods, to be infringement. The plaintiffs argued that the patents stifled ingenuity and discovery, rather than encouraging investment in new technology.

King and colleagues at the University of Washington have developed a test called BROCA that screens many genes at once, using next-generation sequencing. They will now be able to include BRCA1 and BRCA2 results in their analysis.

The court has worded its decision finely. By holding that cDNA is not naturally-occurring, the court seems to be declaring that genes may not be patented, while protecting the ability of the biotech industry to patent altered and manipulated genetic material, which hews more to process. It will be interesting to watch how this plays out for the thousands of other gene patents currently in play.

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  • Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L., Ding, W., & et, A. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1 Science, 266 (5182), 66-71 DOI: 10.1126/science.7545954
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