Assoc. Molec. Pathol. v. USPTO, Myriad Genetics et al., 10-1406 (Fed. Cir., July 29, 2011) In a decision long awaited by the biotechnology industry, the Federal Circuit has held that claims to isolated DNA are patent-eligible subject matter under 35 USC §101 as compositions of matter that do not occur in nature, reversing the lower court ruling. Assoc. Molec. Pathol. v. USPTO (Myriad Genetics), 10-1406 (Fed. Cir. July 29, 2011). The asserted composition claims are directed to isolated DNA related to the BRCA1 or BRCA2 gene. Mutations or alterations in the BRCA genes have been found to be associated with particular types of breast cancer, and the characterization and isolation of the genes was critical in developing diagnostic screens for cancer and potential therapeutic products.

Summary

While all members of the Myriad panel agreed that cDNA was patent eligible subject matter because it is man-made in the laboratory and does not include the non-coding introns, the panel did not agree entirely on whether or why isolated DNA was statutory subject matter under §101, hence the decision is a plurality decision; the decision includes the opinion of the Court (J. Lourie), a concurrence (J. Moore) and a dissent (J. Bryson). The opinion of the Myriad Court relies on the observation that isolated DNA is cleaved from the larger native (chromosomal) DNA by breaking chemical bonds and therefore exists in a distinct chemical form. The Court determined that isolated DNA molecules are markedly different from DNA molecules that exist in nature. The Court opinion and concurring opinions relied in part on the long-standing Patent Office practice of issuing patents for isolated DNA, stating: “The Supreme Court has repeatedly stated that changes to longstanding practice should come from Congress, not the courts.” Slip Op. at 47 (citation omitted). The concurrence found the composition claims to cDNA to be an easy analysis in favor of patent eligible subject matter, claims to short fragments of isolated DNA to be a bit more difficult, and claims to isolated DNA containing a full gene sequence to potentially fall either way, because while technically a different structure, its utility is tied up in the parent structure. The dissent did not find the fact that covalent bonds had to be cleaved to extract a gene from a genome to be a compelling basis for finding the isolated DNA to be a “different material” under §101 compared to what is found in nature. Rather, the dissent opined that isolating a gene was “akin to snapping a leaf from a tree,” because the boundaries of the gene are predefined by nature, which determines in the transcription process the starting and stopping point for the gene. The Myriad panel agreed: (1) that at least one plaintiff had standing to challenge the validity of Myriad’s patents and satisfy the jurisdictional requirements for declaratory judgment actions, (2) to affirm that the claimed methods for comparing or analyzing steps fall outside the scope of patent eligibility under §101 because they included no transformation and were merely directed to abstract mental processes, and (3) to reverse the holding that a claim to a method for screening which included “growing” and a “determining” steps in addition to a “comparing” step, was not statutory subject matter under §101.

Background

The Supreme Court has stated that §101 should be construed broadly. “Congress intended statutory subject matter to ‘include anything under the sun that is made by man.’ ” Diamond v. Chakrabarty, 447 U.S. 303, 309 (1980) (emphasis added). The Supreme Court has added three exceptions to subject matter eligibility: “laws of nature, physical phenomena, and abstract ideas,” describing them as “part of the storehouse of knowledge of all men ... free to all men and reserved exclusively to none.” Chakrabarty, 447 U.S. at 309 (quoting Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948). These exceptions also preclude the patenting of “products of nature”, “phenomena of nature”, and “mental processes”. Id. at 313; Gottschalk v. Benson, 409 U.S. 63, 37 (1972). In the multi-decade boom of biotechnology, the issue of whether particular forms of DNA – the building blocks  of life – are statutory subject matter has now been directly addressed by the Federal Circuit. By way of background, isolated DNA is a particular portion of native DNA that has been excised, or extracted, from the whole. It is the location of the ends in the nucleotide sequence and the length of the sequence that represent the greatest differences between isolated DNA and native DNA. Generally, an entire isolated gene (and certain fragments thereof) will include introns (the non-coding portion of the sequence) and exons (the coding portion of the sequence). By contrast, so-called cDNA will contain no introns, because it is reconstructed in the lab by reverse transcription from “messenger RNA,” which by definition do not contain introns. Myriad involved fifteen claims in seven patents, directed to isolated DNA molecules including 5 full length genes, short fragments and cDNAs, as well as methods of using the DNAs. The composition claims to isolated full length gene DNAs were most hotly contested, and the Plaintiffs raised the possibility of ethical issues, as did some amici curiae and the district court: “[h]ow this genomic information is best harnessed for the greater good presents difficult questions touching upon innovation policy, social policy, medical ethics, economic policy, and the ownership of what some view as our common heritage.” 702 F. Supp. 2d 181, 193 (S.D.N.Y. 2009); Three of the asserted patents included composition claims for “isolated DNA”: U.S. 5,693,473 (‘473) claim 1, U.S. 5,747,282 (‘282), claims 1, 2, 5-7, and U.S. 5,837,492 (‘492), claim 1. Exemplary are claims 1 and 2 of the ‘282 patent:

1. An isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2.

2. The isolated DNA of claim 1, wherein said DNA has the nucleotide sequence set forth in SEQ ID NO:1.

The SEQ ID Nos 1 and 2 encompassed the full length and genes.

Claims 2, 6 and 7 of the ‘282 patent, claim 1 of the ‘473 patent, and claim 7 of the ‘491 patent are limited to cDNA. These cDNA sequences do not exist in nature. Claim 7 of the ‘492 patent recites an isolated DNA molecule that has “a mutated nucleotide sequence set forth in SEQ ID NO:1,” but SEQ ID NO:1 is the open reading frame of the BRCA2 gene, not a mutated form of the BRCA2 gene. Claims 1 and 5 of the ‘282 patent are directed to an isolated DNA molecule that “codes for” the BRCA1 polypeptide having the sequence set forth in SEQ ID NO:2; claims 1 and 6 of the ‘492 patent are directed to an isolated DNA molecule that “codes for” the BRCA2 polypeptide having the sequence set forth in SEQ ID NO:2 of that patent, or a mutated form thereof. These claims are not limited to cDNA but may include any “isolated DNA molecule” provided it can encode the identified polypeptide.

Isolated DNA is not a product of nature and therefore is patent eligible subject matter

Holding of the Court

Writing the opinion of the Court, Judge Lourie said the distinction “between a product of nature and a human – made invention for purposes of § 101 turns on a change in the claimed composition’s identity compared with what exists in nature.” Slip. Op. at 41. Specifically, a distinction is drawn between compositions that have “similar characteristic as in nature” and composition that human intervention has given “markedly different” of “distinctive” characteristics. (citing Hartranft, 121 U.S. at 615; see also Am. Fruit Growers v. Brogdex Co., 283 U.S. 1, 11 (1931). Slip. Op. at 41. Judge Lourie described the difference between native (genomic) DNA found in chromosomes, isolated DNA and cDNA, and various types of mutations that can occur in DNA to illustrate the differences in structure of the molecules. Focusing on the differences between chromosomal DNA – native DNA packaged into chromosomes – and isolated DNA, which has been extracted from the native DNA, Judge Lourie observed that an isolated DNA molecule is not the same structure as native (chromosomal) DNA, because it is cleaved from the larger structure.. . . we conclude that the challenged claims are drawn to patentable subject matter because the claims cover molecules that are markedly different—have a distinctive chemical identity and nature— from molecules that exist in nature. It is undisputed that Myriad’s claimed isolated DNAs exist in a distinctive chemical form—as distinctive chemical molecules— from DNAs in the human body, i.e., native DNA. ... Isolated DNA ... is a free-standing portion of a native DNA molecule, frequently a single gene. Isolated DNA has been cleaved (i.e., had covalent bonds in its backbone chemically severed) or synthesized to consist of just a fraction of a naturally occurring DNA molecule.

Slip Op. at 41-42. The Court further explained that “isolated DNA” is not a “purified” form of native DNA. While it is “removed from its native cellular and chromosomal environment, [isolated DNA] has also been manipulated chemically so as to produce a molecule that is markedly different from that which exists in the body.” Slip Op. at 42. In response to plaintiffs’ argument that isolated DNAs retain the same nucleotide sequence as native DNA, and do not have any markedly different characteristics, the Court opinion stated that “it is the distinctive nature of DNA molecules as isolated compositions of matter that determines their patent eligibility rather than their physiological use or benefit.” Slip Op. at 44. In other words, isolated DNA is a “markedly different” structure from the naturally occurring, larger structure, even if it has the same utility. The Court further explained, “the patent eligibility of an isolated DNA is not negated because it has similar informational properties to a different, more complex natural material that embodies it.” Id. Finally, the Court noted the long-standing practice of the USPTO of issuing patents to isolated DNA and the responsibility of Congress, not the courts, to change that practice. The Court stated “the PTO has issued patents directed to DNA molecules for almost thirty years. ... It is estimated that the PTO has issued 2,645 patents claiming ‘isolated DNA’ over the past twenty-nine years ... and Congress has not indicated that the PTO’s position is inconsistent with §101.” Slip Op. at 48.

The Concurrence

Writing the concurring opinion, Judge Moore said “. . . Funk Brothers and Chakrabarty do not stake out the exact bounds of patentable subject matter. Instead, each applies a flexible test . . .” Concurrence at 5. Judge Moore found a different basis for patent eligibility: isolating a DNA sequence “results in a substantially smaller molecule compared to the naturally occurring sequence as part of the chromosome.” As a result, isolated DNA leads to additional utility, in particular for smaller fragments. Judge Moore found cDNA patentable because “the claimed cDNA sequences do not exist in nature. Moreover, since a cDNA has all of the introns removed, thereby containing only coding nucleotides, it can be used to express a protein in a cell which does not normally produce it” in accordance with Chakrabarty. Concurrence at 13. Thus, cDNA sequences are distinctive in name, character and use and have markedly different chemical characteristics from any continuous native DNA sequence, even if inspired by the natural template. Concurrence at 14.  Judge Moore found the class of isolated DNA that encompasses full length gene sequence and shorter fragments, both of which have sequences found on the chromosome, to be a more difficult case. These sequences do technically have a different chemical structure, because the structural “ends” of the isolated DNA molecules are not found in nature. Concurrence at 9-11. However, Judge Moore had difficulty characterizing these structures as so “markedly different,” as to make them per se patentable subject matter. Concurrence at 14. She found, however, that having the same sequence as a portion the native DNA does not render isolated DNA “per se a law of nature [product of nature] and remove it from the scope of patentable subject matter” – they are “not naturally produced without the intervention of man”. Concurrence at 15. The shorter sequences have a utility not found in nature, namely using the molecules as a basis for diagnostic genetic testing. While using a property devised by nature – the ability of a single DNA strand to interact with a complementary strand – diagnostic testing itself is not a naturally occurring utility. Concurrence at 16. Thus it can be said that the new structural properties – e.g., being truncated – confer a new and significant utility, because the same sequence within the native DNA cannot be used in the same manner, at least with regard to the shorter isolated sequences which may be used as primers or probes. Concurrence at 16-17. Ultimately, for the long isolated DNA and full gene sequence DNA, the concurrence deferred to long-standing patent office policy. The concurrence cites the overwhelming number of patents issued on isolated DNA over the past 30 years and the precedent of over a hundred years of patent eligibility of chemical compounds isolated or purified from larger structures found in nature. Concurrence at 18, 20-21. According to Patent Office policy, “isolated DNA is no different from the isolated natural products” which also “ ‘do[] not occur in that isolated form in nature.’ ” Concurrence at 20 (citation omitted). Judge Moore also strongly emphasized the deference owed to Congress in deciding such issues, stating “the judiciary is ill-suited to determine whether the claims at issue promote or inhibit science and useful arts in all but the clearest cases”. Concurrence at 27; see also Concurrence at 19 (“Congress has, for centuries, authorized an expansive scope of patentable subject matter.”); Concurrence at 31 (“The patents in this case might well deserve to be excluded from the patent system, but that is a debate for Congress to resolve.”). With regard to the ethical and moral issues raised by amici curiae and the Plaintiffs, Judge Moore made the following salient comments: This case typifies an observation by the late Chief Judge Markey, our first Chief Judge, that “[o]nly God works from nothing. Men must work with old elements.” ... Human DNA is, for better or worse, one of the old elements bequeathed to men to use in their work.

Concurrence at 30 (citations omitted).

The Dissent

Writing the dissent, Judge Bryson took the position that “the discovery of the [BRCA gene] sequences is an unprotectable fact” although applications of that discovery may be protectable subject matter, and some of the unasserted claims fall into the latter category. Dissent at 3-4. Because the claimed sequences exist in nature, according to Judge Bryson, allowing them to be patented prevents others from sequencing the BRCA genes or any other genome that may include the gene or claimed fragments thereof, for example to search for additional mutations. Judge Bryson argued that Myriad could have claimed these segments more narrowly in alignment with their utility – for example tagged segments to achieve the probe function, or the particular segments that would actually function as primers. Dissent at 15. The dissent criticized the opinion of the Court for framing the question as one of breaking covalent bonds linking the BRCA genes to the rest of the DNA. Judge Bryson did not find this turns the isolated genes into “different materials.” Dissent at 7. Focusing on the issue of the method of “isolating” the subject matter as determining whether the product was patent eligible, the dissent presented a different analysis with respect to molecules and elements, using lithium as an example.

Once isolated, lithium has many industrial applications, and in order to isolate lithium, it is necessary to break ionic bonds in the lithium compounds that are found in nature.

Dissent at 8. According to the dissent, the boundaries of the isolated DNA are defined by nature “at points that preserve the ability of the gene to express the protein from which it is coded.” Dissent at 10. The dissent therefore analogized extracting a gene to “snapping a leaf from a tree” because a leaf “has a natural starting and stopping point.

It buds during spring from the same place that it breaks off and falls during autumn. Yet prematurely plucking the leaf would not turn it into a human made invention.” Id. Judge Bryson dismissed any deference owed to the decades of Patent Office practice, stating that the Patent Office does not have substantive rulemaking authority to issues of “patentability” and its position in not granting patents on live organisms was given no weight by the Supreme Court in Chakrabarty. Dissent at 17. With regard to deferring changes to long-standing Patent Office practice to Congress, the dissent pointed out that the Chakrabarty Court did not agree that the scope of statutory subject matter should be left to Congress. “Congress has performed its constitutional role in defining patentable subject matter in §101; we perform ours in construing the language Congress has employed.” Id., quoting Chakrabarty, 477 US at 315.

Commentary

What is clear from Myriad is that recombinant DNA and cDNA appear to be safely within the scope of §101. The Myriad demarcation also provides some certainty with respect to “isolated DNA.” It leaves a clean demarcation around “isolated DNA” as patent eligible subject matter, and avoids categorically excluding inventions in this area of molecular science. Whether this clean line preserving, claims for “isolated DNA” stands up to further judicial review, and then to the test of time remains to be seen. Plaintiff filed a petition for panel rehearing which was denied on September 13, 2011. Defendant has filed a petition for panel rehearing on the standing issue which has not yet been decided.