Could a melanoma gene be patented?

Dr. Mole, while a resident in dermatology at the University of Melanoma, did some high-powered research on detecting an isolated gene that would predict those individuals who will contract malignant melanoma without any family history of dysplastic nevi or melanoma. He did his work while working under the supervision of Dr. Genius.

Ultimately, Dr. Mole finished his training and continued his research in his own facility (Melanoma Labs) funded by venture capital. Dr. Genius took his work to another university. The University of Melanoma also hired new researchers who also continued to look for the “melanoma gene.” All three groups spent the next five years in a race for a discovery with enormous medical and financial implications.

Melanoma Labs won. They found the gene and received the U.S. patent for the gene. With this announcement financial pundits suggested that Melanoma Labs may now be valued at billions of dollars. Immediately, both Dr. Genius and the University of Melanoma sued. Their argument is that such a gene cannot be patented. Alternatively, they argue that at the very least, all three parties should be on the patent. After all, Dr. Mole began his initial research under Dr. Genius while a resident at the University of Melanoma. What will happen?

Gene discoveries

There is precedent for this scenario with the development of testing for the BRCA breast and ovarian genes. In this case, Myriad Laboratories expended an enormous amount of effort in isolating the DNA containing the BRCA 1 and BRCA 2 genes. Although genetic sequencing is a well-understood technique used by molecular biologists, the initial sequencing of a target DNA is clearly a process requiring great ability.

Before the disclosure of Myriad’s patents, the region surrounding BRCA 1 was not well mapped and there were few markers. Using a large inventory of DNA samples from families with histories of breast and ovarian cancers, Myriad correlated cancer in individual familiar members with certain marker DNA sequences. Myriad mapped the BRCA 1 and BRCA 2 gene by defining flanking genetic markers around the BRCA 1 locus. In short, Myriad contributed to the state of the art by narrowing the BRCA1 region to a small enough region to allow isolation and characterization of the BRCA 1 locus.

Nonetheless, the discovery of the BRCA 1 and BRCA 2 genes was the cumulative result of scientific research conducted by seven major research teams spanning five countries. The hunt for genes correlating with breast cancer started as an internationally competitive project called the International Breast Cancer Linkage Consortium in 1988. This research was funded by numerous private and public sources, including a funding grant from the National Institutes of Health (NIH).

An American research team led by Mary-Claire King, Ph.D., from the University of California, Berkeley, was the first to discover and announce the location of the BRCA 1 gene on chromosome 17. But Dr. King’s team did not acquire the BRCA 1 patent, because researchers needed to determine both the normal and mutated sequences of the gene in order to obtain the patent.

Patent winner

A team led by Marc Skolnick, Ph.D., founder of Myriad Genetics, won the race to do so - with the help of a direct $5 million grant from the NIH, and a $2.8 million investment from Eli Lilly, Myriad filed its patent application for BRCA 1 sequences and mutations in August 1994, and, after subsequent revisions, was granted a patent in December 1997 covering 47 different mutations of the BRCA 1 gene.

The location of BRCA 2 was first announced by a U.K.-based research team led by Michael Stratton in September 1994 and funded by the Cancer Research Campaign charity. The team published the genetic sequence in December 1995. Mysteriously, Myriad filed its patent application for the BRCA 2 gene a day before the study was published, and successfully received the patent grant.

After obtaining its patents, Myriad began to market the “BRACAnalysis” test at three levels: a complete BRCA 1 and BRCA 2 sequence test, a single-site test, and a three-mutation multisite test (for mutations prevalent in Ashkenazi Jewish population). Shortly after this, the Genetics Diagnostics Laboratory of the University of Pennsylvania, and the Genetics and IVF Institute independently developed tests that rivaled, and in some ways surpassed Myriad’s.

The Genetics and IVF Institute used different methods that had the advantage of picking up on large rearrangement and deletion mutations that Myriad’s sequencing method did not always detect. Not only did Myriad’s sequencing method occasionally fail to detect mutations, the results would sometimes be inconclusive. BRACAnalysis results would sometimes contain “variants of unknown significance,” which are genetic mutations for which susceptibility to cancer were unknown. Instead of granting licenses to these other firms so that women may obtain needed second opinion testing, Myriad threatened to sue these other innovative, alternative diagnostic test providers for patent infringement.

Isolated DNA patenting ‘trick’

Despite the fact that Myriad expended millions of dollars and enormous effort to isolate the BRCA genes, Myriad utilized well-established techniques already known in the field to isolate the DNA, which already existed in nature. Many scientists in the molecular biology and genomics fields consider the patenting of isolated DNA as a “lawyer’s trick” to circumvent the prohibitions on the direct patenting of genomic DNA, and perhaps rightly so.

The practical effect of Myriad’s patent of the isolated DNA containing the BRCA genes is the same as if Myriad patented genomic DNA in the human body itself. For the duration of Myriad’s BRCA 1 and BRCA 2 patents, Myriad may prevent anyone from offering any diagnostic test to a patient to determine if they have BRCA 1 or BRCA 2 mutations. The issuance of the BRCA 1 and BRCA 2 patents to Myriad arguably undermine the purpose of the patenting scheme by causing preemptive effects on further innovation in BRCA testing.

In 2009, various associations of physicians, geneticists, researchers, clinicians, doctors, and patients filed suit against Myriad Genetics, the University of Utah Research Foundation, and the PTO alleging that 15 of Myriad’s claims under seven of its patents were invalid as unpatentable subject matter. The challenged patents covered isolated DNA and cDNA containing BRCA 1 and BRCA 2 genes, and methods for analyzing or comparing segments of isolated DNA to detect mutations.

Court weighs in

In Ass'n for Molecular Pathology v. Myriad Genetics, Inc, the District Court held that Myriad’s patent claims of isolated DNA covered products of nature, and were therefore unpatentable. The court applied the “markedly different” standard to determine whether there was any patentable modification or alteration in the isolated DNA not present in native DNA.

The District Court took a biological perspective, comparing the information content of the DNA in the body vis-à-vis the isolated form. The court concluded that the information content of the isolated DNA and native DNA was identical; therefore the isolated DNA was not patentable subject matter.

The Federal Circuit reversed the District Court’s finding and found that the isolated gene was “markedly different” from native DNA. The Federal Circuit used a chemical perspective, focusing on the change in physical structure rather than information content of the patented DNA as compared to native DNA.

On March 26, 2012, the U.S. Supreme Court granted certiorari for the Myriad case, vacating the Federal Circuit’s judgment and remanding the case to the Federal Circuit to be reconsidered in light of its recent holding in Mayo Collaborative Servs. v. Prometheus. Mayo involved a patent on a method of drug dose optimization by measuring certain metabolites in the patient’s blood after the drug was administered. The Supreme Court described requirements for transforming unpatentable natural laws into patent eligible applications of those laws - focusing the analysis heavily on whether a process involving a natural law contained a sufficient “inventive concept” such that “the patent in practice amounts to significantly more than patent upon the natural law itself.”

Decisions in the Myriad case will have a substantial impact on Dr. Mole’s ability to enforce his melanoma patent.