By Turna Ray
How broad can the claims in a gene patent be without impeding research and still be of financial value to the patent holder? While a US district court judge in a pending high-profile anti-gene patenting case is currently mulling over the answer to this very question, researchers from Duke University used bioinformatics to estimate the reach of a claim from one of Myriad Genetics' patents on the BRCA1 gene.
In an analysis of the scope of patent 5,747,282, entitled "17Q-linked breast and ovarian cancer susceptibility gene," the Duke researchers compared a 15-mer oligonucleotide in the BRCA1 gene described by one of the patent's claims against gene sequences in GenBank and found that 80 percent of cDNA and mRNA in the database contain at least one oligonucleotide covered by the claim. Additionally, around 300,000 oligonucleotides in chromosome 1, which does not contain the BRCA1 gene, would be covered by the claim, the researchers found.
"Any 'isolated' DNA molecules that include such 15bp nucleotide sequences would fall under the claim as granted by the US Patent and Trademark Office," Duke’s Thomas Kepler, Colin Crossman, and Robert Cook-Deegan conclude in their paper published in the March 9 issue of Genomics. "Anyone making, using, selling, or importing such a molecule for any purpose within the United States would thus be infringing the claim."
Furthermore, based on the timing of Myriad's application for patent '282 and a patent application by the National Institutes of Health that had previously been rejected due to the claimed 15-mer oligonucleotide being identified in existing DNA sequences, the researchers conclude that the USPTO may have erred in granting Myriad claim 5.
The findings of this study come as US District Court Judge Robert Sweet is in the midst of ruling on Association for Molecular Pathology, et al. v. United States Patent and Trademark Office, et al., a case that the American Civil Liberties Union and the Public Patent Foundation filed in May 2009 on behalf of scientific organizations representing numerous medical professionals, researchers, women's health groups, and individual women, challenging the legality and constitutionality of seven BRCA patents held by Myriad and the University of Utah [see PGx Reporter 05-13-2009].
The USPTO is also a defendant in the case. The plaintiffs assert that the patent office's policy of issuing gene-related patents violates Article I, Section 8, Clause 8 of the Constitution, or the "IP Clause," and the First Amendment of the Constitution. However, the USPTO has requested the judge to dismiss the case against it, arguing that the question of the validity of Myriad's patents is a statutory question, not a constitutional one.
The Secretary's Advisory Committee on Genetics, Health, and Society sent a report to HHS Secretary Kathleen Sebelius recommending the HHS advocate a statutory exemption from infringement liability for genetic test developers that use genes patented by another party, and supports exemptions for scientists who wish to use patent-protected genes for research.
One of the authors of the study published in Genomics, Cook-Deegan, led a research team that gathered public comments and provided research that formed the basis of the SACGHS' recommendations. A few members within the committee, as well as industry stakeholders, disagreed with SACGHS' recommendations and felt that there wasn't enough evidence confirming that gene-association patents restrict research.
However, in reviewing the breadth of claims in Myriad's '282 patent, Kepler, Crossman, and Cook-Deegan determined that although Myriad may not be enforcing its patents against researchers, such broad patents make a vast proportion of genetic research vulnerable to patent infringement.
We "do not oppose gene patents, indeed [we] believe DNA patents can encourage development of new drugs, therapies, and scientific instruments," the researchers said in a statement announcing the publication of their paper. "In diagnostics, however, broad patent claims such as the one studied here make it nearly impossible to pursue alternative ways to get at the information contained within patented genes, conferring a testing monopoly for the term of the patent that cannot be invented around."
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Patent '282 is one of the seven patents challenged in the ACLU's anti-gene patenting case, and reviewed by the Duke researchers in the Genomics paper. "The patent itself is complex and makes several different claims," the researchers note. "One of these claims seemed to us particularly broad, so we investigated it, doing simple calculations to estimate its reach, and testing our findings by direct analysis of the extent of its reach within parts of the human genome."
The researchers' investigations led to the conclusion that certain claims, particularly claim 5, were so broad that the '282 patent could be enforced to cover portions of most genes in the human genome and likely most genes in nature.
Claim 5 covers "an isolated DNA having at least 15 nucleotides" in the BRCA1 polypeptide — language that is essentially "a claim on any 15-mer oligonucleotide found in any such sequence," Kepler and colleagues point out. They further estimate that within the human genome there are more than 1 million oligonucleotides covered by claim 5, while most human genes contain one to several oligonucleotides in the claim.
"This claim and others like it turn out, on examination, to be surprisingly broad, and if enforced would have substantial implications for medical practice and scientific research," the researchers state.
The US Patent and Trademark Office granted Myriad and the University of Utah the '282 patent in 1998 but Myriad filed its patent application in 1995. A survey of GenBank performed by the Duke researchers showed that 568 of 713 mRNA coding sequences deposited in GenBank in 1994 contain at least one BRCA1-derived 15-mer oligonucleotide.
"These findings suggest that there were already many sequences in GenBank covered by claim 5 at the time the patent application was filed," the authors point out. "This further suggests that the claim should not have been granted, based on section 102 of the Patent Act (novelty)."
The criteria for discerning patentable subject matter in the US require it to be novel, non-obvious, and to have an industrial application. Section 102 of the US Patent Act sets out the criteria for patentability based on novelty.
Another mark against the USPTO, according to the Duke team, is the fact that a patent application by the NIH, filed four years before Myriad's '282 patent, was rejected precisely because the patent claimed 15-mer oligonucleotides found to exist in other DNA sequences.
This finding, involving an expressed sequence tag application filed by the NIH, was published in 1992 and the NIH abandoned its application two years later. Based on USPTO examiner James Martinell's estimation at the time, a full examination of all the oligonucleotide claims in the EST patent would have taken until 2035 "because of the computational time required to search for matches in over 700,000 15-mers claimed."
According to Kepler et al., this comprises "roughly half the number of molecules covered by claim 5 of Myriad's '282 patent."
While improvements in bioinformatics and computer hardware have made sequence comparisons much easier than they were in the early 1990s, the study authors arrive at no conclusions about why the USPTO granted Myriad claim 5 in patent '282 and not NIH's EST patent.
"The reason that sequence identity in prior art was not identified as a bar to claim 5 by a different examiner for US Patent '282 when it was being examined between 1995 and 1998 is not clear in the ‘282 patent's prosecution history," the authors state in the paper, noting that there is "no indication" of a search on 15-mer sequences being performed as part of the patent prosecution.
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"I simply have no idea why one examiner would notice the problem with 15-mer claiming and another would not," Cook-Deegan told Pharmacogenomics Reporter via e-mail this week.
One reason for the different decisions may be the experience of the patent examiners assigned to each case. Cook-Deegan described Martinell as a senior examiner "with lots of experience and a strong molecular biology background" whose examination of the EST patent in the early 90s sparked a lot of controversy and attracted a good deal of public attention.
"The examiner who allowed the 15-mer claim [in Myriad's patent 5,747,282] probably just didn't think through it, and he's not alone," Cook-Deegan said. "We see some similar claims in other patents examined by other examiners."
Daniel Ravicher, executive director of the Public Patent Foundation, which, along with the ACLU, represents the plaintiffs in the court case challenging Myriad's patents, has criticized the USPTO for being a "rubber stamp" granting a green light to anyone willing to pay [see PGx Reporter 02-24-2010].
According to Patstats, a web service from the University of Houston Law Center that provides quarterly and annual statistics for rulings on major patent cases, 40 percent of all patents challenged in court were found invalid in 2008.
In the researchers' view, invalidation of claim 5 would have minimal impact on the totality of Myriad's patent suite for the BRCA1 gene and it wouldn't invalidate other claims in patent '282. However, such a move might stir companies to investigate such broad claims in public patent databases.
The researchers acknowledged that the broad impact on research of claim 5 in the '282 patent is "very difficult to assess." The claim was "clearly structured" to capture oligonucleotides for hybridization assays and PCR-based diagnostic methods. As such, commonly used PCR-based diagnostic methods used to analyze segments of the BRCA1 and BRCA2 genes would likely infringe claim 5 and possibly other claims in the '282 patent, the researchers believe.
"[We] believe the astounding breadth of the claim coupled with the fact that the DNA was already well known to researchers leaves this claim of the patent vulnerable to a court challenge," the researchers said in a statement.
Indeed, the Duke team determined that not only can Myriad's claim be "significantly narrowed," but that many genetic patents are similarly broad. This is particularly worrisome to Kepler and colleagues as full-genome sequencing becomes more widespread, because any kind of genomic sequencing will likely infringe such broad patents.
However, Myriad and legal analysts in support of the company in the ACLU's anti-gene patenting case have maintained that the large number of published studies on BRCA genes show that despite Myriad's strong patent position, the company has not exercised these patents to thwart research.
While the Duke researchers credit Myriad for not aggressively enforcing its patent rights against basic research and most clinical research, they feel that the company's broad patents force researchers to operate in an uncertain environment and at Myriad's mercy.
"The simplest conclusion about the effect of claim 5 and Myriad's other BRCA1 patents on research and clinical testing is that Myriad has only rarely enforced its patents in research, has vigorously enforced its patents against commercial genetic testing, and has selectively enforced its patents in clinical research," the researchers note.
However, following the conclusions in the Genomics paper about the reach of claim 5 and the widespread potential for patent infringement, the researchers called for a review of the patenting process to ensure such broad patents are not granted.
"Almost all research on the BRCA1 gene that has taken place in the United States since 1998 infringes this claim or other very broad claims in patents held by Myriad," the researchers said in a statement. "Research is not exempt from patent infringement liability under US law, and so BRCA1 research has proceeded only with the company's voluntary indulgence.
"While Myriad has stated publicly that it has not enforced its patents against basic research, it has not stated it will not do so in the future," they note in the paper.