[author: Kevin E. Noonan]
One thing has become abundantly clear in the public debate about the patent-eligibility of isolated human DNA. That something is that there is a great deal of uninformed opinion extant, predominantly by well-educated people with scientific backgrounds, who believe wholeheartedly that patenting genes is pernicious because it has or will inhibit medical science and progress in the diagnosis or treatment of disease. But that doesn't appear to be the situation to those with a background in biotechnology patent law, and so exploring why the two groups have come to such diametrically opposite conclusions may be informative.
And, before we start, let's agree that we won't waste time accusing each other of being motivated by "hidden biases" or "self interest." Precious few doctors, hospitals, or medical societies have called for the practice of human genetic diagnostic methods to be performed free of charge, and it is well to remember that patenting, for all its arcane minutiae, is relatively straightforward. Protecting intellectual property in other ways, such as by trade secret, requires a great deal more cleverness, and patent lawyers are particularly adept at being clever (if you doubt this, ask Justice Breyer).
We begin, as we must, with the claims ("The name of the game is the claim," as Judge Rich famously noted). For most "gene patents," the claims have a canonical format, constructed over the last generation by the U.S. Patent and Trademark Office, on the one hand (who have been generally parsimonious in what is permitted to be patented, accusations by gene patent opponents to the contrary) and by patent applicants, who generally want claims that can be defended in a court of law when asserted against an infringer. These claims have the format:
An isolated (human) nucleic acid (or DNA molecule or gene (specified by name), encoding an amino acid sequence identified by SEQ ID NO: X.
(The portions of this claim in parentheses are optional, used in some cases but not necessary to properly recite the claimed subject matter.) Certain features of this claim merit further discussion. First, the Office has required the term "isolated" to be in the claim, for at least two reasons. First, under Diamond v. Chakrabarty, the claimed DNA must show "the hand of man" and be "markedly different." That standard was established during times where isolating a human gene was truly analogous to finding a needle in a haystack, where the needle was made of hay. While not based on a "sweat of the brow" requirement, the necessity for the "hand of man" was more evident during those times than (perhaps) it is now, when the entirety of the human genome exists (representationally at least) in computer databases worldwide. Second, a DNA molecule was required to be isolated so that the claim would not encompass ("read on" in patent geek speak) the molecule as it exists in nature. This is not a question, necessarily, of patent eligibility, but rather of novelty; the gene in nature is not novel until is isolated. This reasoning can be seen in early cases, such as Wood-Paper Patent, 90 U.S. 566 (1874), and Cochrane v. Badische Anilin Soda Fabrik, 111 U.S. 293 (1884). In the former case, the Supreme Court stated its reasoning for finding the claimed cellulose-based paper as follows:
It [the isolated cellulose] may have been in existence and in common use before the new means of obtaining it was invented, and possibly before it was known that it could be extracted from the subject to which the new process is applied. . . . If, then, the Watt & Burgess patent for a product is sustainable it must be because the product claimed, namely, "a pulp suitable for the manufacture of paper, made from wood or other vegetable substances," was unknown prior to their alleged invention. But we think it is shown satisfactorily that it had been produced and used in the manufacture of paper long before 1853, the year in which the original patent of Watt & Burgess was dated.
Similarly, in the Cochrane case the Court said:
According to the description in [the patents in suit], and the evidence, the article produced by the process described was the alizarine of madder, having the chemical formula C14H8O4. It was an old article. While a new process for producing it was patentable, the product itself could not be patented, even though it was a product made artificially for the first time, in contradistinction to being eliminated from the madder root. Calling it artificial alizarine did not make it a new composition of matter, and patentable as such, by reason of its having been prepared artificially, for the first time, from anthracine, if it was set forth as alizarine, a well-known substance. Wood Paper Patent, 23 Wall. 566, 593. There was therefore no foundation for reissue No. 4,321, for the product, because, on the description given, no patent for the product could have been taken out originally.
The same rationale explains why isolated DNA claims cannot be read to encompass the genes in chromosomal DNA "isolated" from cells (but otherwise unchanged); Frederich Mieschner "isolated" DNA to this level of purification in the 1880's and thus, any such interpretation of the term "isolated" in isolated DNA claims would render them unpatentable for lack of novelty.
Another feature of the representative claim set forth above is that, to infringe, it requires that the entire amino acid coding sequence be produced. The reason for this limitation stems from the purpose of such claims from the dawn of the biotechnology age: to be able to produce a protein having therapeutic or other beneficial uses. If an isolated gene was to be used to produce erythropoietin, or tissue plasminogen activator, or interferon, or insulin, or blood clotting factors VIII or IX, or any of the other patented human genes, it needed to be full-length or otherwise a truncated fragment would be produced that, even if it retained biological activity could perhaps differ in biological half-life, immunogenicity, or other important properties.
One more claim feature should be mentioned, which is present in almost all but the earliest-filed claims: the nucleic acid is claimed in terms of the protein that it encodes. This represents a compromise, because although the claim thus encompasses any nucleic acid that encodes a specific protein, the claim encompasses only those DNA molecules that have the specifically recited, identified sequence. Accordingly, literal infringement does not lie even if there are conservative amino acid substitutions, meaning that a Valine to Isoleucine substitution (a difference of a single methylene group, -CH2-) in a molecule having hundreds of amino acids does not infringe. In addition, the scope of these claims is further limited by Federal Circuit case law and PTO reactions to it, resulting in claims to unspecified "conservative" substitutions being held unpatentable under 35 U.S.C. § 112, first paragraph.
There are several consequences of these considerations regarding these claims. First, the claims are only infringed if someone without authorization makes, uses, sells, offers to sell or imports an isolated nucleic acid encoding the specified amino acid sequence. Typically, a "gene patent" identifies a cell or tissue source (and, frequently, identifies a plurality of cell or tissue sources as part of its characterization of a gene) that natively expresses the gene. Thus, anyone who uses such a cell or tissue source to study the gene without isolating it will not infringe. Second, portions of the gene can be isolated, sequenced, and characterized and not infringe, and such portions can be changed and then introduced into the gene to produce another gene that does not infringe. (The patentability of primers and probes selected from the gene sequence are not considered here; their patentability, rather than patent eligibility, has been called into question by others; see "Caught in a Time Warp: The (In)validity of BRCA1 Oligonucleotide Claims"). Third, the gene product (typically, a protein) can be isolated from the cell and studied without infringement, as can antibodies raised against the gene product. These antibodies can be used to detect under- or over-expression of the gene in cell or tissue sources for diagnostic purposes, and mutant forms of the gene product associated with disease can also be produced. All without infringing the gene claim.
Fourth, the sequence itself can be identified in individuals and compared to wildtype or disease-associated mutations without infringing unless the entire DNA is isolated intact (something that is unnecessary and unduly burdensome to do; portions can be sequenced and the entire sequence aligned in a computer). This is because (ACLU arguments to the contrary) the DNA sequence information is not protected by the patent claim. (Again, whether there can be crafted a valid method claim for making a diagnosis is not within the scope of this discussion; indeed, challenging the "gene" claims while eschewing a challenge to Myriad's several remaining method claims smacks of cynicism in an attempt to garner the most publicity rather than a honest effort to obtain genetic BRCA diagnostic testing for those women who cannot afford it.) This is also the reason why "whole genome sequencing" and other present or future genetic diagnostic methods are unaffected by the isolated DNA claims: practice of these diagnostic methods do not infringe the DNA claims.
The question remains what experiments will be impeded by the existence of claims to isolated human DNA. (It should be mentioned that there are more than 8,000 scientific research papers published in the BRCA genes since the grant dates of the patents.) Clinical testing may be one type, where a population is to be assessed for the prevalence of BRCA gene mutations, for example. Here, there are questions of whether the testing will be performed for free or whether the patients will be charged; it is difficult to defend a "study" where the research subjects pay for the privilege. But even in cases where there is a need for such a study it seems that countervailing practices should be able to reduce if not eliminate any negative effects of a gene patent claim. As discussed above, large-scale sequencing can be performed without incurring patent infringement liability as to the isolated DNA claims. Also, scientific research typically requires specialized reagents and services that are supported by grant monies. For example, there was a time when restriction endonucleases were not readily available but could be isolated from the particular bacteria that produced them, and lambda phage packaging extracts were routinely (albeit laboriously) produced from complementary cultures of mutant phage (one making the packaging protein but defective phage heads, the other making intact phage heads but not the packaging protein). The advent of commercially available preparations of more and more restriction enzymes and highly effective packaging extracts made these homemade efforts obsolete; similarly, engaging the patentee to perform the genetic testing would eliminate any risk of patent infringement liability as well as gaining for the project the reliability that such testing services provide.
Thus, there seems to be little empirical support for the contentions that "gene patents" are inhibiting research, despite the allegations from former Acting Solicitor General Neal Katyal, at this year's BIO conference, that his two weeks with NIH scientists convinced him (and, it seems, the rest of the Department of Justice) that gene patents raised such a "clear and present danger." However, because no one is infallible (here or at the NIH), it is possible that there are such instances or circumstances that have been overlooked. If so, please let us know. If not, perhaps it is time for those who argue without basis that gene patents do not "promote the progress" to make their arguments honestly, based on (legitimate) moral, religious, or political grounds. There is nothing to be ashamed of in making these types of arguments; but if that is the basis for principled opposition to patenting human DNA then perhaps the issues can be addressed in ways that can foster a solution rather than (as in so many things) mere partisanship. We welcome a response.