Guest Post by Sean Brennan --
As we all know by now, the Supreme Court last month decided that isolated genes are not eligible for patenting. Although seemingly drawing a clear-cut distinction between DNA molecules having the same sequence as that which occurs in nature (genes), and DNA molecules having different sequences from those that occur in nature (cDNA) (see Patent Docs posts here and here), the decision leaves a host of unsettled questions about the patent-eligibility of numerous biologicals. Although ostensibly concerned with human genes, the reasoning supporting the decision could be used to call into question the patent-eligibility of compositions ranging from purified metabolites (such as antibiotics) to isolated proteins to procaryotic genes.
Although the question addressed by the Court was "Are human genes patentable?", in its decision the Court couldn't seem to decide whether its decision applied strictly to human genes or to genes in general. In framing the question, the Court stated that the case "requires us to resolve whether a naturally occurring segment of . . . DNA is patent eligible . . . by virtue of its isolation from the rest of the human genome." (Slip. Op. at 1, emphasis added). But in announcing its decision, the Court appeared to have lost sight of the "human" limitation when it stated: "we hold that a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated" (Id.); "separating [a] gene from its surrounding genetic material is not an act of invention" (Id. at 12); and "[w]e merely hold that genes and the information they encode are not patent eligible under § 101 simply because they have been isolated from the surrounding genetic material" (Id. at 18).
Thus, the decision leaves open the question of whether it is only human genes that are not patent-eligible (i.e., did the Supreme Court buy the "you can't patent my body" argument?) or is any gene, from any organism, barred from patent eligibility? It is difficult to understand how the Court could justify one standard for human genes and another for genes of other species.
This being the case, the decision would seem to doom the patent-eligibility of procaryotic genes; the vast majority of which do not contain introns. Although it is possible to reverse-transcribe a procaryotic mRNA molecule to generate a cDNA from a procaryotic gene, such a nucleic acid molecule would not have a sequence different from the sequence of the gene as it occurs in nature.
This result would be unfortunate, since new bacterial species are being discovered every day, and many of these contain genes encoding proteins that are useful for processes such as pesticide production and bioremediation. It would also set up a technology-specific distinction between biotechnological and pharmaceutical practice, in which it is typical to obtain composition claims for the first disclosure of a new compound.
If it is no longer possible to claim an isolated gene per se, might we still be able to claim a gene sequence as a component of a vector? Unfortunately, the decision provided no guidance on this point, because none of Myriad's claims reciting BRCA genes as components of a vector or expression system (e.g., claims 8-11 of U.S. Patent No. 5,747,282) were at issue. Although it is undisputed that the combination of a gene with one or more of a heterologous promoter, termination site, regulatory sequence(s), replication origin, or antibiotic resistance marker is a composition that does not occur in nature; I worry that, given the current judicial climate (see Mayo v. Prometheus), addition of heterologous sequences to a newly isolated gene will be dismissed as "insignificant post-solution activity." After all, cloning vectors and expression vectors are standard materials that can be purchased from any one of a dozen or more suppliers. Then again, it could turn out that certain vectors (and/or heterologous sequences) will be considered standard and others not, so that the patent eligibility of a gene might end up depending upon what other sequences are attached to it. A good deal of biotech practice over the next few years may well involve figuring out how much we need to "dress up" a gene before it can be "taken out" into the realm of patent-eligibility.
The Court seemed to imply that identity of informational content between a cloned gene and a naturally-occurring gene is what renders gene sequences patent-ineligible; and not the (supposed) identity of chemical structure between the two: "Myriad's claims are simply not expressed in terms of chemical composition, nor do they rely in any way on the chemical changes that result from the isolation of a particular section of DNA. Instead, the claims understandably focus on the genetic information encoded in the BRCA1 and BRCA2 genes." (Slip Op. at 14-15). "Myriad . . . is concerned primarily with the information contained in the genetic sequence, not with the specific chemical composition of a particular molecule." (Id. at 15, emphasis in original).
If this is the case, I wonder why even cDNA was found to be patent-eligible. Inasmuch as the informational content of most DNA molecules resides in their ability to encode a polypeptide sequence, a cDNA is no different in this respect from the intron-containing gene sequence from which it is derived.
At the risk of presenting a somewhat far-fetched example to make another point, I note that it is possible to create recombinant gene sequences that do not have the same chemical structure, but nonetheless contain the same informational content, as a naturally-occurring gene. For instance, certain bacteriophages contain hydroxymethyluracil (HMU) instead of thymine in their DNA. Imagine an enterprising geneticist who develops a cloning system, based on this bacteriophage, that generates cloned DNA containing HMU instead of thymidine. The cloned gene now has a structure that does not occur in the natural gene -- is it patent eligible? It would seem to depend on whether the criterion is a different chemical structure or a different information content. Unfortunately the decision, while leaning toward informational content, failed to provide a clear criterion.
Another biological fact that seemed to get lost in the Myriad case is that naturally occurring DNA sequences contain epigenetic informational content (the most well-known example being methylation of cytosine residues) that is generally not present in an isolated cloned gene. Consequently, there are both structural (e.g., methyl groups) and informational (gene methylation generally signals transcriptional repression) differences between certain isolated genes and their naturally-occurring counterparts. This being so, whatever the Court's criterion for eligibility (structural difference or informational difference), it would appear that at least some isolated DNA molecules remain patent-eligible.
What is a mutant?
The Court punted on the question of whether mutated sequences are patent-eligible and, to make matters worse, provided scant guidance as to what types of sequences they considered mutant and, thereby, at least potentially patent-eligible. The decision failed to comment specifically on claims that recited naturally-occurring mutant BRCA sequences (claim 7 of the '282 patent and claim 1 of U.S. Patent No. 5,693,473). But following the Court's "product of nature" reasoning would lead to the conclusion that naturally-occurring alleles of a gene (some of which might be "mutants" in the classical sense of encoding a gene product with altered function) would not be patent-eligible.
On the other hand, isolated genes whose sequences have been altered in the laboratory would appear to escape at least the "product of nature" barrier to eligibility. The question then arises as to whether a gene with a change in a single nucleotide (that does not alter the amino acid sequence of the encoded polypeptide) would be considered a "mutant." What about a single nucleotide change that did result in an amino acid change? Would it make any difference if the new amino acid encoded by the mutant sequence was a conservative or a non-conservative substitution? Eventually, we may need to know how large or significant a change in sequence is necessary to confer "mutant" status on an isolated nucleic acid.
A further complication is that assessing whether a laboratory-altered sequence is different from a naturally-occurring sequence can present the patent applicant with a moving target. Consider the hypothetical heartbreaker in which an applicant constructs a mutant sequence in vitro that is found to be both patent-eligible and patentable. Years after the patent is granted, the same sequence is discovered in nature. Does the patentee's claimed mutant sequence become retroactively ineligible?
What about a claim to a gene sequence that has been introduced into a heterologous cell? Surely, this is a composition that does not occur in nature. Although such claims (e.g., claims 12 and 13 of the '282 patent) were not at issue in Myriad, it was just such a composition that was validated as patent eligible by the Supreme Court in Chakrabarty (albeit the cell in that case comprised more than one heterologous nucleic acid), which was cited favorably by the Myriad Court. It's possible that, in the end, this may be as close as we'll be able to get to a composition claim to a newly-isolated gene. In many cases, this may be good enough, since the principal use for most cloned genes is to express their gene product and, in order to do so, the gene is often placed into a heterologous cell for expression.
The Court's proscription of naturally-occurring substances would also seem to rule out patent eligibility for isolated polypeptides. In most cases, the amino acid sequence of a purified protein is exactly the same as the amino acid sequence of the naturally-occurring protein. One normally doesn't even have to break any chemical bonds to purify a protein (thus failing the test for eligibility set forth by Judge Lourie in the decision below). In the same way that "Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes" and "[t]he location and order of the nucleotides existed in nature before Myriad found them"; the amino acid sequence of a protein exists in nature before that protein is purified, and it is generally not altered by the purification procedure.
Does this mean that isolated proteins are also no longer patent-eligible? Maybe not, since, in some cases, there are structural differences between isolated and naturally-occurring proteins (assuming structural distinction is sufficient for eligibility -- see above). For example, if an isolated protein is obtained through expression of a recombinant nucleic acid, it often lacks certain naturally-occurring post-translational modifications, such as glycosylation or phosphorylation. This is particularly true of a eukaryotic protein expressed in a procaryotic host cell. Thus, it may be possible to obtain a claim to a polypeptide that lacks certain post-translational modifications, or contains additional modifications not present on the naturally-occurring protein. Whether such a claim will have any value will depend, of course, on whether the isolated protein, containing more or fewer post-translational modifications than its naturally occurring counterpart, functions effectively for its intended purpose.
Antibiotics and other naturally-occurring compounds
Denial of patent-eligibility to an isolated biological molecule, based on identity to its naturally-occurring counterpart, will have repercussions well beyond the field of molecular biology. As other commentators have already pointed out, the Myriad decision could sound the death knell for patent eligibility of all purified naturally-occurring substances (such as antibiotics, certain chemotherapeutics, and bacterial metabolites). In a worst-case scenario, even chocolate chip cookies and baseball bats could become patent-ineligible.
The Myriad decision leaves me with a lot to be pessimistic about. But on the bright side, keeping my expectations low will at least minimize the chance that I'll be disappointed. I give the Court credit for trying to limit the breadth of its decision. Presumably, they wanted to come-up with a clear-cut answer to a clear-cut question and thought they had done so by accepting the Solicitor's and Judge Bryson's distinction between genomic DNA and cDNA. But in so doing, the Court let not just one, but a whole herd of elephants into the room. I have a feeling we'll be shoveling for quite a while.
Dr. Brennan is a Patent Agent with Brennan IP Services. He received a Ph.D. in Molecular Biology from the University of California, San Diego in 1982, and prior to becoming a patent practitioner, Dr. Brennan was a faculty member at the University of Connecticut School of Medicine and the University of Southern California.