Gene patents are a class of intellectual property that give the patentee rights to the specific sequences in the claims of a patent, providing the exclusive right to make, use, sell, and import a molecule consisting of a claimed sequence. In 2001, the US patent office issued formal guidelines on what is acceptable patent material in the human genome. It stated that DNA is eligible if it is 'isolated from its natural state and processed through purifying steps that separate the gene from other molecules naturally associated with it.' These guidelines specified that any gene or sequence patent also needs to show 'specific, credible, and substantial utility' [1]. To date, there are over 40,000 patents on DNA molecules [2, 3], including those on the breast and ovarian cancer genes BRCA1 and BRCA2 [4], indicating that patents on DNA are a widespread and significant class of intellectual property that have increased consistently since the 1980s (Figure 1).
Some DNA patents are for a very specific series of nucleotides (such as 5'-ATGCGACGGATCGATC-3') or an exact chemical structure (such as a DNA molecule modified with a fluorescent probe), but diagnostic DNA-based patents have broader claims [5]. These patents are used to find mutations in various disease-related genes, and the specified DNA sequence as well as any other similar sequence are often covered within the patent claim. This is because there are many (at least [(2N) - 1]) possible combinations of mutations for a gene [6]. Diagnostic gene patents are therefore written to find any known or unknown variation of a gene. For example, in the Association of Molecular Pathologists (AMP) v. Myriad case, the broadest intellectual property rights on BRCA sequences come from several related claims in patent 5,747,282:
Claim #1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2 (the BRCA1 cDNA).
Claim #2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1 (the BRCA1 gene).
Claim #5. An isolated DNA having at least 15 nucleotides of the DNA of claim 1
Claim #6. An isolated DNA having at least 15 nucleotides of the DNA of claim 2.
In 2010, in the first ruling on AMP v. Myriad, a US District Court stated that all of these patent claims were invalid and that isolated DNA is 'not patentable subject matter'. Then, in 2011, the US Court of Appeals for the Federal Circuit overturned this ruling (2 to 1 decision) and stated that an isolated DNA molecule is 'markedly different' from native genomic DNA and that fragments of the BRCA genes can be patented. After a re-hearing in light of another case (Mayo v. Prometheus), the same decision was issued by the Federal Circuit in August 2012. Recently, the Supreme Court decided to hear arguments in the case, opening a re-examination of the lower courts' decisions and rationale on these gene patents and their claims.
Notably, the Federal Circuit's decision declared that even a short, isolated DNA molecule such as 'ACGT' is different from the 'NNNNN-ACGT-NNNNN' present within a chromosome (AMP v. Myriad, Federal Circuit 2012), because it will not be connected to a sugar via a phosphodiester bond and will have a hydroxyl group instead of a bond to a phosphate (Figure 2). Thus, even a 15 nucleotide fragment of DNA in Claim #6 from Patent '282 is claimed to be 'markedly different'. However, we observe that the Court's ruling is overly broad for at least three reasons. First, it relies on the sequences having chemical features and side-chains that are not actually present in the patents (Figure 2): the claims are for a linear series of nucleotides, not a specific chemical structure. Second, if allowed to be so broad, these claims could also create a monopoly on all epigenetic and chemical variations of these sequences. Third, and perhaps most importantly, the non-specificity of 15mer sequences creates unclear infringement liability that has been even noted by the Court. Specifically, Judge Bryson declared that claim 6 'is so broad that it includes products of nature (the BRCA1 exons) and portions of other genes. ... The other claim to a short segment of DNA, claim 5 of the '282 patent, is breathtakingly broad' (AMP v. Myriad, Federal Circuit 2012). To date, however, there has not been a genome-wide analysis of the uniqueness of 15mer sequences in patented genes.
Establishing the uniqueness of gene patents in DNA and cDNA could potentially have a large impact on the interpretation of these patents [7, 8]. Previous work has examined Claim #5 with respect to other cDNAs on one chromosome (Chr1), and used these data to estimate that 15 infringing 15mers might exist for any cDNA [9]. However, these studies compared the likely uniqueness of cDNAs on the basis of an average degeneracy of the genetic code, leaving open the issue of exact DNA matches in the coding regions of genes and the genome. Also, a first estimate, made in 2005, calculated that 18% of human genes were patented [10], but many new DNA patents have emerged since (Figure 1). These results have been challenged in recent work [8], which has demonstrated that some gene patents for genetic sequences do not contain the DNA fragments within the actual claims. Thus, we sought to examine the current landscape of gene patents using empirical, exact matches to known genes that were confirmed to be present in patent claims, ranging from sequences of 15 nucleotides (15mers) to the full lengths of all patented DNA fragments.