United States: DNA Primers: The Trouble With Being Short

In BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig. v. Ambry Genetics Corp. (Ambry), the Federal Circuit invalidated Myriad's claims to short synthetic DNAs. Myriad sued Ambry shortly after the Supreme Court held in Association for Molecular Pathology v. Myriad (Myriad) that Myriad's claims to cDNAs were patent eligible as long as the cDNAs did not have the same sequence as natural DNAs, but that Myriad's claims to isolated genomic DNA (DNA with the same sequence as natural DNA) were not patentable. While commentators have argued that Ambry unnecessarily expands the Supreme Court's holding in Myriad, Ambry flows directly from Myriad's test for patentable subject matter. After Myriad, short synthetic DNAs are not patentable if they have the same sequence as natural DNA.

Ambry involves the medically important BRCA1 and BRCA2 genes that Myriad discovered and isolated. Mutations in these genes are linked to hereditary breast and ovarian cancers. Myriad developed tests for detecting mutations in the BRCA genes, allowing doctors to determine a woman's susceptibility to breast and ovarian cancer. After the Supreme Court invalidated Myriad's claims to isolated BRCA DNAs, competitors including Ambry entered the market with their own tests for BRCA mutations. Just as Myriad, Ambry employs DNA primers patented by Myriad to test for BRCA mutations. These primers – short synthetic DNAs – make it possible to synthesize a patient's BRCA genes using polymerase chain reaction (PCR) and to identify mutations.

Myriad sued Ambry asserting claims in Myriad's patents that were not before the Supreme Court in Myriad. These included claims to a pair of single-stranded DNA primers for PCR so that all or a portion of a woman's BRCA genes could be synthesized and the sequence determined. Although the primers are synthetic and do not occur in nature, the Federal Circuit held that Myriad's claims were invalid. In doing so, the Federal Circuit explained that the primers "necessarily contain the identical sequence of the BRCA sequence directly opposite to the strand to which they are designed to bind."

Following the Supreme Court's decision in Myriad, the Federal Circuit was dismissive of Myriad's argument that primers were patent eligible "because single-stranded DNA cannot be found in the human body." The Federal Circuit emphasized that "[a]s the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible." It held that "it makes no difference that the identified gene sequences are synthetically replicated."

Myriad also argued that primers have a fundamentally different function than natural DNA sequences and should be patentable for that reason. Here too the Federal Circuit disagreed. It gave no import to the fact that primers make possible the highly unnatural and beneficial amplification of regions of a patient's DNA through PCR. Instead, the Federal Circuit focused on the fact that "just as in nature, primers utilize the innate ability of DNA to bind to itself."

The decision in Ambry follows rather than expands Myriad. Although Myriad upheld the patentability of synthetic BRCA cDNA – DNA synthesized from RNA which only has sequences that code for proteins (exons) and no intervening noncoding sequences (introns) – it did not do so on the basis of cDNA being synthetically created. Rather, the Supreme Court relied on the fact that cDNA is an "exons-only molecule" and therefore has a different sequence than natural DNA, i.e., DNA with both exons and introns.

The Supreme Court also noted that "cDNA is not a 'product of nature' and is patent eligible under §101, except insofar as very short series of DNA may have no intervening introns to remove when creating cDNA." According to the Court, "[i]n that situation, a short strand of cDNA may be indistinguishable from natural DNA." This is the situation in Ambry and why the Federal Circuit's decision, although important, is not surprising in view of Myriad.

After the Supreme Court's decision in Myriad, only short DNAs that span at least two exons with the intervening intron removed are patentable subject matter. This is because such short DNAs do not have the sequence of natural DNAs; they are missing at least one intron. Most short DNAs do not meet these criteria. Moreover, short DNAs do not compensate for being short (and not spanning two exons) through being synthetically created. Nor do they avoid the consequences of being short by making possible reactions that do not occur in our cells, such as PCR. While PCR has changed the practice of medicine and revolutionized biotechnology, Ambry shows that it does not save short DNAs. After its DNA primer claims were invalidated, Myriad settled with Ambry and many of its other competitors.

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