Originally published Nov. 1.
By Turna Ray
The US Department of Justice last week added an unexpected twist in the ongoing legal battle to determine the patentability of genetic discoveries by taking the position that merely isolating a DNA strand from its natural state is not an invention that can be patented.
The DoJ, which until now has not made its position known about the patentability of genes, issued an amicus brief in Association for Molecular Pathology et al. vs. the United States Patent and Trademark Office et al. In its statement to the US Court of Appeals for the Federal Circuit, the DoJ attempted to strike a balance between rewarding inventions that result from genomic discoveries, and ensuring that discoveries of natural phenomena remain in the "storehouse of knowledge of all men." As examples of the latter, the DoJ cited Albert Einstein's equation describing mass-energy equivalence and Isaac Newton's law of gravity.
While the DoJ believes that the New York Southern District Court in March wrongly invalidated Myriad Genetics' composition claims "directed solely to cDNAs," the government agrees with the lower court that genes as they occur in the body are not products of human invention worthy of a patent. "Crossing the threshold of [patentability under 35 USC] Section 101 … requires something more than identifying and isolating what has always existed in nature, no matter how difficult or useful that discovery may be," the DoJ stated.
In the brief, the government also asserts that genotype-phenotype associations as they occur in the body, such as a gene mutation's association to a person's likelihood of getting cancer, cannot be claimed as intellectual property. "The fact that particular natural mutations [in a chain of chemical base pairs] increase a woman's chance of contracting breast or ovarian cancer" is not patentable, the DoJ stated.
The New York Southern District Court earlier this year invalidated 15 claims in seven patents held by Myriad on BRCA genes conferring susceptibility to the hereditary risk of breast and ovarian cancer (PGx Reporter 03/31/10). In that decision, federal district court Judge Robert Sweet determined that isolated DNA containing BRCA1/2 gene sequences could not be patented as described in Myriad's claims because such gene sequences were not markedly different from those sequences naturally occurring in the body in function or in the information they contain. Furthermore, Sweet found that comparisons of DNA sequences are abstract mental processes, which are also unpatentable under section 101.
Myriad in June appealed Judge Sweet's determination in the federal court of appeals, asking the higher court to overturn the lower court's finding that its patents are invalid, and that isolated DNA is a product of nature.
The DoJ's statements, submitted to the appeals court, seemed to take the life sciences industry by surprise, and raised concerns that the DoJ's interpretation of gene patenting laws would harm drug developers and test makers. However, for the time being the USPTO is unlikely to end its practice of granting patents on isolated genes. "The USPTO will maintain the status quo while this matter is pending resolution by the Federal Circuit," a patent office spokesperson told PGx Reporter.
Although the brief stands to be influential, it remains to be seen whether the DoJ's legal interpretations will translate into case law. However, the fact that an arm of the government disagrees with the district court's view regarding the patent eligibility of cDNA — but not when it comes to naturally occurring isolated DNA — effectively blurs Myriad's prospects for a clear-cut victory in the federal appeals court.
The DoJ's argument is "only about composition of matter claims to DNA molecules, not method claims or kits or others," Robert Cook-Deegan, director of Duke University's Center for Genome Ethics, Law & Policy, pointed out. "The upshot would be some but not all claims in gene patents going away."
Although the DoJ's position wasn't filed in support of the plaintiffs or the defendants in the ongoing case challenging Myriad's BRCA patents, the brief nonetheless is being hailed by the American Civil Liberties Union and the Public Patent Foundation as a confirmation of their main position that isolated gene sequences are not patentable.
The ACLU and PUBPAT filed their case challenging the patentability of genes over a year ago on behalf of scientific organizations representing medical professionals, researchers, women's health groups, and individual women, who allege that the BRCA gene patents held by the University of Utah Research Foundation and exclusively licensed to Myriad stifle research and limit women's options for medical care (PGx Reporter 05/13/09).
"The US [government's] brief is a substantial confirmation of our views and Judge Sweet's decision," Daniel Ravicher, PUBPAT's executive director, told PGx Reporter via e-mail.
"Patents are intended to promote progress, and because patents have both an incentivizing and chilling effect on the public, including investments in research and development, it is important to draw the line carefully between those things that are patentable (true man-made inventions) and those that are not (things that are merely manifestations of laws of nature and natural phenomenon)," Ravicher said. "The line drawn by the [DoJ] in their brief is a substantial positive movement towards a more balanced approach, which will enable researchers and businesses who want to use basic genetic information to do so, while also providing true inventors the patent rights they deserve."
Myriad did not comment on the DoJ brief for this article. However, in its appeal, Myriad asserts that if companies are no longer allowed to patent genes, innovation in the drug and diagnostics industries will be thwarted.
"Myriad's BRCA DNA testing could not even have gotten off the ground" without patents, the company states in its appeal. As such, if the lower court's decision is not reversed, "valuable future developments will slow or cease, or be driven underground so that their developers can maintain trade-secret protection without disclosing them," Myriad warns.
As an example of the types of innovation that the district court's decision would block, Myriad cites US Patent No. 4,703,008, which is a patent for Amgen's blockbuster anemia drug Epogen that claims "a purified and isolated DNA sequence encoding erythropoietin." In Myriad's opinion the gene claims in the Epogen '008 patent are similar to some of Myriad's claims on isolated BRCA gene sequences.
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However, by the DoJ's reasoning, since the Epogen '008 also includes claims on cDNA, that patent would not be rendered invalid.
"The government is arguing that purification and isolation don't change the nature or function of the DNA, whereas splicing out the introns matters because you can thereby manufacture a protein in cells, so a cDNA is patentable," Cook-Deegan said. As such, the DoJ would consider the Epogen patent valid "because cDNAs of individual cloned genes don't exist in nature and … involve the hand of man."
In support of Myriad's patents, the Biotechnology Industry Organization, which represents more than 1,200 companies, academic institutiosn and biotech centers, filed a statement to the district court last year, in which it urged Judge Sweet to deny the plaintiff's motion. According to BIO, "claiming isolated DNA molecules are among the cornerstones of intellectual property portfolios of many, if not most, of [its] members," which include Fortune 500 companies and biotech start-ups. As such, a decision invalidating gene patenting, "would frustrate decades of investments in research and development undertaken in reliance of DNA patents … and would destroy perhaps the most important incentive for investing in DNA-based inventions," BIO wrote in its brief to the district court.
Cook-Deegan disagrees that if the DoJ's stance were to be incorporated into law it would have a devastating impact on the drug and diagnostics industry. Instead, he noted, the DoJ's position would make it less risky, from a patent infringement standpoint, for diagnostic companies to advance multi-gene pharmacogenomic, prognostic, and whole-genome sequencing analysis tests. "The current jurisprudence and current business models cast a dark shadow of uncertainty on some really important future diagnostics that will almost certainly require substantial private R&D investment … This would clean out a thicket of very broad patent claims," he said.
The DoJ's reasoning, if adopted by the US courts, "would weaken patents that have been enforced in diagnostics, and it would therefore affect Myriad, Athena, and Clinical Data — the three main companies that are pursuing a business strategy that depends heavily on patent enforcement of broad claims in diagnostics," Cook-Deegan told PGx Reporter. "But it would not affect very many other companies," he added.
The ACLU and PUBPAT had considered challenging Athena Diagnostics' gene patents when trying to decide on a test case upon which to hang a legal assault on the patentability of genes, but decided in the end to take on Myriad's patents.
Drawing a Line
In its brief, the US DoJ distinguishes between cDNA, which researchers must generate in a laboratory as a tool for biotechnological and diagnostic applications, from naturally occurring genes that are isolated from the body but unaltered.
Examples of patentable gene discoveries, according to the DoJ, include cDNAs, vectors, recombinant plasmids, chimeric proteins, vaccines, and genetically modified crops. Conversely, the link between gene mutations and the increased risk of breast and ovarian cancer as it occurs in the body is not an invention, but a natural phenomenon, and thus cannot be patented, the government maintains.
The DoJ uses Myriad's US Patent No. 5,747,282, entitled "17Q-linked breast and ovarian cancer susceptibility gene," to point out the claims it believes are patent eligible under section 101 of the Patent Act, and those that are not. According to the brief, '282 contains both claims "limited to" cDNAs that encode BRCA proteins, while other claims "encompass isolated but otherwise unmodified human genomic DNA itself."
Claim 1 of '282 describes "an isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2." In this claim, the term "isolated DNA" includes cDNAs, but also "genomic DNA" that has been "merely … removed from its naturally occurring environment."
"Accordingly, claim 1 of the '282 patent encompasses any isolated DNA molecule whose nucleotide sequence codes for the natural BRCA1 protein," the DoJ wrote. "This would include an ordinary BRCA gene isolated from a tissue sample taken from a woman in a hospital."
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Researchers that are challenging Myriad's patents assert that the company's claims on isolated BRCA sequences restrict them from even looking at the particular stretch of DNA for research purposes without Myriad's permission. Myriad in turn, has argued that the numerous independently conducted studies in the published literature investigating the link between BRCA gene mutations and hereditary breast and ovarian cancer suggest that the company has not enforced its patents to the detriment of basic research.
Meanwhile, claim 2 of '282 — for "the isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1" — is a claim on cDNA that is patent eligible, in the government's view.
The DoJ cites Diamond v. Chakrabarty as legal precedent supporting its view of patentable and unpatentable genetic discoveries. Chakrabarty was a 1980 landmark case in which the Supreme Court decided that genetically modified microorganisms were patentable. "Unlike the genetically engineered microorganism in Chakrabarty, the unique chain of chemical base pairs that induces a human cell to express a BRCA protein is not a 'human-made invention,'" the DoJ reasoned.
Cook-Deegan suspects, however, that the DoJ's position "may not carry the day" in the appeals case because it doesn't go far enough in discussing how its argument against the patentability of isolated gene sequences fits with current case law on biological products that are discovered rather than invented.
With regard to certain antibiotics, vaccines, proteins, and even Chakrabarty's genetically modified microorganisms, "the argument could be made … about why [the DoJ's] interpretation for DNA would not necessarily set precedents for those other biological products," Cook-Deegan pointed out. The circuit court of appeals will "have to do all the work on why this case would not change precedents for the other cases it has decided."
In the end, it is Cook-Deegan's view that if the DoJ's position were to hold up in appeals court, Myriad would retain claim 2 and maybe even claim 1 in the '282 patent, if it involved making a protein in cells. "But it would lose claim 1 in '282 if used in inferring the DNA sequence from a cell found in nature, and all the claims that hang off of claim 1 (which is most of them)," he explained via e-mail. Based on the DoJ's reasoning, Myriad stands to "surely lose claims 5 and 6 and the PCR claims."
Claims 5 and 6 of the '282 patent describe "an isolated DNA having at least 15 nucleotides" of the BRCA1 gene. Claim 16 discusses "a pair of single-stranded DNA primers for determination of a nucleotide sequence of a BRCA1 gene by a polymerase chain reaction, the sequence of said primers being derived from human chromosome 17q, wherein the use of said primers in a polymerase chain reaction results in the synthesis of DNA having all or part of the sequence of the BRCA1 gene."
If the appeals court agrees with the DoJ and invalidates the above claims, it could effectively restrict overly broad patent claims on genes.
Cook-Deegan has been an outspoken critic of the USPTO's practice of granting patents claiming large chunks of DNA linked to disease susceptibility. In an analysis of the scope of Myriad's '282 patent, Cook-Deegan and his colleagues at Duke compared the claims on a 15-mer oligonucleotide in the BRCA1 gene against gene sequences in GenBank.
They discovered that 80 percent of cDNA and mRNA in the database contain at least one oligonucleotide covered by the '282 claims. Additionally, around 300,000 oligonucleotides in chromosome 1, which does not contain the BRCA1 gene, would be covered by the claim, the researchers found.
Because any isolated DNA molecule included in this 15bp nucleotide sequence would be circumscribed by this broad claim, "anyone making, using, selling, or importing such a molecule for any purpose within the United States would thus be infringing the claim," the Duke researchers concluded in a paper published in the Mar. 9 issue of Genomics (PGx Reporter 03/24/10).
Counter to those who would argue that the DoJ's position would have a deleterious impact on the biotech and diagnostics industry, Cook-Deegan worries that broad patent claims on isolated gene sequences, like those described above, are discouraging investment in multi-gene cancer screens and cheap diagnostics that might be useful in nations such as India and China as public health tools.
"I'm more worried about underinvestment in promising but nascent genomic technologies other than DNA sequencing itself, attributable to the legacy of very broad patent claims," he said.
The Work Ahead
Another touchy area in the DoJ's brief, which the courts will have to iron out, is to what extent genotype/phenotype associations can be patented.
"Indeed, the relationship between a naturally occurring nucleotide sequence and the molecule it expresses in a human cell — that is the genotype and phenotype — is simply a law of nature," the DoJ explains in its brief. "The chemical structure of native human genes is a product of nature, and it is no less a product of nature when that structure is 'isolated' from its natural environment than are cotton fibers that have been separated from cotton seeds or coal that has been extracted from the earth."
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The DoJ is clear that naturally occurring isolated DNA and its association to disease, in and of themselves, are not patentable. However, this composition of matter assertion doesn't have any bearing on method claims.
Furthermore, the DoJ doesn't say anything about how current patent laws would deal with whole-genome sequencing tests that yield a person's full genome data and reveal the presence of gene mutations claimed in awarded patents. Whole-genome sequencing tests in this case are "still infringing a patent claim — one not addressed by the government brief," Cook-Deegan said. "But that claim could also fall if the composition of matter claims [to DNA molecules] go away, but it would require a new layer of arguments, and it's not a slam dunk that it would follow."
The blank spots for the court of appeals to figure out — and not addressed in the DoJ brief — have to do with how an invalidation of "isolated genes" would impact previously granted patents in the drug and biotech sector.
"The courts need to hear why recognizing that about DNA would not spill over to overturn all sorts of precedents for other biological molecules that can be patented — they need to have a line they can defend," Cook-Deegan said. "I'm not sure any of us has helped them draw that line, or even given them the tools to do so. So, if they do it, they'll have to do it on their own. That's very hard intellectual work, and I hope it gets done."
Cook-Deegan and Chris Holman, a gene patenting expert and a professor at the University of Missouri-Kansas City School of Law, submitted an amicus brief in AMP et al. vs. the USPTO et al. in appeals court, in which they asserted that instead of trying to decide a gene patent application on the basis of patent-eligibility, the USPTO should evaluate patent claims on the grounds of obviousness, novelty, enablement, or written description criteria.
For example, claim 5 and 6 of Myriad's '282 patent for "an isolated DNA having at least 15 nucleotides" of BRCA1 would fail under the novelty criteria since such a large portion of cDNA and mRNA sequences contributed to GenBank would be encompassed by these claims. "That's much less elegant," than the patent-eligibility argument, "but might have the same practical result," Cook-Deegan said.
Meanwhile, Luigi Palombi, director of the Genetic Sequence Right project at the Australian National University and a gene patenting scholar, believes the court of appeals will have to review the patent eligibility of cDNA under all the indices of what constitutes an invention derived from naturally occurring biological materials, not just on the grounds of "artificiality" or that cDNA is a manmade construct.
In Chakarabarty, the Supreme Court said that an "invention must display (a) 'markedly different characteristics from anything found in nature' and (b) have 'the potential for significant utility,'" Palombi told PGx Reporter via e-mail. Palombi is working with Cancer Voices Australia, the law firm Maurice Blackburn, and breast cancer patient Yvonne D'Arcy to challenge Myriad's BRCA patents in Australia.
"cDNA will not satisfy the first part of the Chakrabarty test because cDNA contains nothing more than the protein-coding region of a natural gene spliced together. Its characteristics, far from being markedly different, are markedly similar to the corresponding DNA in the natural gene," Palombi said, agreeing with Judge Sweet's decision on Myriad's patents.
Furthermore, Palombi argued that cDNA is not useful in and of itself. "It is possible [that] cDNA, as a component, may have a role to play in the context of the scientific instrument, device, or apparatus within which it is incorporated, but not by itself," he reasoned. "cDNA is no more useful as DNA in that it contains genetic information, but, taken out of context, it does not have any significant utility above and beyond corresponding natural DNA."
In Australia, Myriad has offered to surrender the contested BRCA patent in an effort to avoid erosion of its legal position in the US (PGx Reporter 10/06/10). Even if the patent challenge ends there, the DoJ brief can still influence the status of gene patenting in the country as the Australian parliament and senate investigate the issue.
BIO, on the other hand, has argued that cDNAs are markedly different from naturally occurring genes in the body and are critically useful in developing innovative, new treatments. "From the mass production of life-saving medicines by cell cultures to the screening of our blood supply for life-threatening viruses, patented isolated DNA molecules have been put to countless uses that have benefited society — uses not possible with the sequences as they exist in nature," BIO said in an amicus brief filed with the district court in AMP et al. vs. the USPTO et al. "Such uses distinguish isolated DNA molecules in kind from their counterpart naturally occurring sequences, and compel their patent-eligibility."
Question of Great Importance
The DoJ said in its amicus brief that the extent to which genetic discoveries may be patented "is a question of great importance to the national economy, to medical science, and to the public health."
The DoJ acknowledged that Myriad's appeal of the federal district court's decision "implicates the expertise and responsibilities of a wide array of federal agencies and components," including the US Patent and Trademark Office, the National Institutes of Health, the Centers for Disease Control and Prevention, the Office of Science and Technology Policy, and others.
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The DoJ's brief follows a report by the HHS Secretary's Advisory Committee on Genetics, Health, and Society that recommended HHS Secretary Kathleen Sebelius advocate a statutory exemption for genetic researchers and commercial test developers from gene patent infringement liability (PGx Reporter 10/14/09).
Cook-Deegan led a research team that gathered public comments and provided the case studies for that report. The research, supported by a grant from the National Human Genome Research Institute and the US Department of Energy, found no conclusive evidence that gene patents restrict research or have a widespread impact on limiting patients' access to genetic tests.
The DoJ admitted in its brief that its position is counter to the USPTO, NIH, and other government agencies' "longstanding practice" of awarding and obtaining patents on isolated DNA sequences.
In its appeal to the federal circuit court, Myriad estimates that in nearly three decades, the USPTO has issued approximately 2,645 patents with claims to “isolated DNA” and green lighted 50,000 patents containing at least one claim directed to a nucleic acid sequence, derived from humans, animals, plants, and bacteria.
The DoJ acknowledged in its brief that the scope of the law describing patent-eligible subject matter is "purposefully wide" and therefore "its threshold is not difficult to cross." However, the law does not restrict the patenting of new methods of isolating, extracting, or using genetic information, according to the DoJ. Furthermore, the brief lays out the types of discoveries that would continue to be supported by existing patent laws, including gene replacement therapies, engineered biologic drugs, methods of modifying the properties of plants or generating biofuels, or advanced applications of biotechnology.
"Nearly every biotechnological or pharmaceutical application of genomic DNA will involve a welter of potentially patentable products and methods: engineered DNA molecules, including cDNAs; processes of extraction and purification; optimized pharmaceutical compounds (pills, vaccines); methods of preparing and administering the same; and so on," the DoJ wrote. "These may include very broad and fundamental claims (e.g., 'method of treating cancer by administering an effective amount of compound X'). Claims directed to such 'human-made inventions,' properly capture what the inventor has in fact contributed to society, without precluding the public’s access to 'the basic tools of scientific and technological work.'"