Last week’s Supreme Court ruling threatens Myriad’s patent on breast cancer causing genes. But fuzzy interpretations about what types of DNA are patentable means the battle is far from over.
The U.S Supreme Court ruled last Thursday that DNA sequences occurring naturally within the human genome cannot be patented. This is a direct ruling against Myriad Genetics, Inc. of Salt Lake City, which holds patents on two genes they discovered, BRCA1 and BRCA2. The BRCA sequence patents held by Myriad were the basis for Myriad’s BRACAnalysis® genetic test, which tests for mutations in these genes that increase an individual’s risk up to 85% for developing breast and 60% for ovarian cancer. The unanimous Court ruling was made on the basis that isolating segments of naturally occurring DNA is not a new invention. As the Court wrote in their decision, “It is undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The location and order of the nucleotides existed in nature before Myriad found them. Nor did Myriad create or alter the genetic structure of DNA.”
Surprisingly, the Court’s decision has allowed a form of DNA, called cDNA (complementary DNA), to be patented because it is not a “product of nature.” cDNA is different from genomic sequence only in that it is exclusively comprised of gene sequences called exons, and other sequences called introns, are absent. Exons contribute to the final protein product of the gene, while introns do not. (See “Learn More: From DNA to cDNA” below).
This ruling threatens Myriad’s exclusive patent rights for the BRCA genes and raises many questions that further complicate the issue of patenting genetic information.
Is cDNA naturally occurring?
Scientists readily synthesize cDNA by adding a naturally occurring enzyme called reverse transcriptase that makes a DNA copy of other naturally occurring genetic sequences called mRNAs. These sequences are not unique nor are they new inventions. The technician is simply exploiting an existing and naturally occurring enzyme’s function to make a synthetic genetic sequence.
The Court acknowledges the naturalness of cDNA, saying, “…the nucleotide sequence of cDNA is dictated by nature, not by the lab technician.” Despite this, the Court ruled that the laboratory technician “unquestionably creates something new when cDNA is made.”
Complicating the issue further, cDNA actually does occur naturally within many biological systems. When certain viruses called retroviruses infect a cell, they use reverse transcriptase to convert their RNA genomes into DNA genomes. This viral DNA then integrates into the infected cell’s genome, and is replicated when the host cell divides. The Court gives brief mention to the biology of viruses, only noting that, “petitioners have failed to demonstrate that the [viral] gene [integration] consists of the same sequence as the BRCA1 cDNA.” In this statement the Court is simply saying that there is no sequence identical to BRCA1 cDNA in the human genome. However, this statement does not address the fact that cDNAs can occur naturally.
Despite these issues, it was ruled that cDNA is not naturally occurring, and thus Myriad’s BRCA1 and BRCA2 cDNA patents currently remain valid.
Do cDNAs meet the criteria for patentability?
Perhaps the most potent argument against cDNA patents comes under the restrictions for patent “obviousness.” Drawing from the unanimous Supreme Court decision of KSR Int'l Co. v. Teleflex, Inc., 550 U.S. 398, the precedent in patent law states that inventions are not patent eligible if the basis of the invention is “obvious to try.” In their decision, the Court defined that “the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results” and “the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” Yet in the lab, combining reverse transcriptase and a specific mRNA will essentially always yield the predicted cDNA sequence. In addition, existing computer programs can often easily predict cDNA sequence from genomic DNA sequence. The full sequencing of the human genome has also already annotated the intron and exon sequences for every gene in the human genome – allowing for easy prediction of cDNA sequences. cDNAs fail in the requirement of obviousness due to the fact that their generation does no more than yield a predicted result.
In the 2007 KSR decision, Justice Kennedy went one step further, saying, “If a person of ordinary skill can implement a predictable variation, § 103 [Guidelines for Determining Obviousness] likely bars its patentability.” In patent law, this has established the PHOSITA or, person having ordinary skill in the art, precedent. This precedent states that if any person familiar with the area of research can apply a technique to produce a predictable result, the result is not patent eligible. Any PHOSITA in a modern biology lab is capable of applying the techniques required to generate cDNA.
By the Supreme Court’s own precedent then cDNAs are not patent eligible due to the fact that their production is doing nothing more than yielding the predictable result and that they are easily generated by the average PHOSITA. If Myriad attempts to enforce it’s patents on cDNA, it is likely that will be challenged on the basis of obviousness.
Will Myriad's cDNA patents prevent other companies from developing BRCA1 and BRCA2 genetic tests?
The Court’s ruling also brings into question the usefulness of cDNA patents for current genetic tests. While the specific details of Myriad’s BRACAnalysis® test are confidential, the most logical approach Myriad and others will take will be to simply sequence the genomic DNA of BRCA1 and BRCA2. The possibility for Myriad to develop cDNA specific BRCA1 and BRCA2 genetic tests still exists, but remains unlikely due to the current ease of DNA sequencing. Sequencing genomic DNA will reveal mutations in both intron and exon sequences. It will likely be very difficult for Myriad to argue that their cDNA patents provide them the intellectual rights to mutations occurring in exon sequences, since these sequences also occur in genomic DNA. The Court’s decision very clearly stated that the intellectual rights of patents cannot be applied to naturally occurring genomic DNA sequences. As Clarence Thomas wrote in the ruling opinion, “We merely hold that genes and the information they encode are not patent eligible under §101 [Patent Act] simply because they have been isolated from the surrounding genetic material.”
A number of groups have made similar assessments. The University of Washington, Quest Diagnostics, and Ambry Genetics have all stated they will develop BRCA1 and BRCA2 tests, some claiming they can do it for much cheaper than Myriad. The race is on.
Learn More: From DNA to cDNA
DNA (deoxyribonucleic acid) is the building block of all life on Earth and is organized into functional units called genes. For genes to exert functions inside cells they must be transcribed into mRNA (messenger ribonucleic acid). Since the DNA sequence is used as a template, the mRNA sequence is complementary to the DNA sequence from which it was transcribed. The biggest difference between DNA and mRNA sequences is that mRNA sequences do not contain stretches of DNA sequence called introns. mRNA contains only exon sequences, sequences that code for proteins. cDNA is the DNA equivalent of mRNA and cDNA sequence is different from the genomic sequence only in that it does not contain non-protein coding (intron) sequences.
cDNA sequences can be readily generated in the lab by using the enzyme reverse transcriptase. Reverse transcriptase is capable of using an RNA template to make a DNA sequence. By subjecting mRNA from a cell to reverse transcriptase a researcher can generate a cDNA sequence for every mRNA present in the cell.
Both the process of transcription of DNA to mRNA and reverse transcription of cDNA from mRNA happen through the function of naturally occurring enzymes. In this sense, cDNA is just as naturally occurring as mRNA – a difference the Supreme Court failed to address in their decision.
