Wednesday, 12 October 2011

Patent protection for the BRCA1 gene and genetic diagnostic methods in the USA

Author: Eddy D. Ventose Faculty of Law, Cave Hill Campus, University of the West Indies, Barbados)

Association for Molecular Pathology v United States Patent and Trademark Office (Fed. Cir. 2011), 29 July 2011

Journal of Intellectual Property Law & Practice (2011), doi: 10.1093/jiplp/jpr171, first published online: October 12, 2011

Protein structure of BRCA1 
In AMP v USPTO, the Federal Circuit Court of Appeal considered whether Myriad's claim for, inter alia, an isolated DNA coding for a BRCA1 polypeptide was patentable under section 101 and applied its recent decision in Prometheus v Mayo, relating to a species of ‘dosage regime’, and the most recent consideration of patent-eligibility by the US Supreme Court in Bilski v Kappos, to find that, while claims to genetic diagnostic methods were unpatentable, claims to genetic screening methods were patentable.

Legal context

The claims at issue related to three broad types:

an isolated DNA coding for a BRCA1 polypeptide; the isolated DNA of claim 1 and an isolated DNA having at least 15 nucleotides of the DNA of claim 1 (the ‘composition of matter’ claims);

  • a method for detecting a germline alteration in a BRCA1 gene (the ‘genetic diagnostic method’ claim);
  • a method for screening potential cancer therapeutics (the ‘screening method’ claim).

Were these product and process claims patent-eligible under section 101 of the Patents Act? In the District Court, Judge Sweet claimed that the issue was whether the isolated DNA was patentable under section 101. Relying principally on Supreme Court decisions of Funk Brothers Seed Co. v Kalo Inoculant Co. 333 US 127 (1948) and Diamond v Chakrabarty 447 US 303 (1980), he noted that the mere purification of a product of nature could not transform it into patentable subject matter: the purified product most possess ‘markedly different characteristics’ in order to satisfy the requirement of section 101. Myriad's focus on the chemical nature of DNA failed to acknowledge the unique characteristics of DNA that differentiated it from other chemical compounds. Accordingly, since the claimed isolated DNA was not markedly different from native DNA as it existed in nature, it constituted unpatentable subject matter under section 101. This was the same for all the composition of matter claims.

In relation to the genetic diagnostic method claims, Judge Sweet held that the claims which were directed only to the process of ‘analysing’ a BRCA1 sequence and noting whether or not the specified naturally occurring mutations existed, they were invalid under section 101. He then distinguished the District Court decision in Prometheus Laboratories Inc. v Mayo Collaborative Services 581 F.3d 1336 (Fed. Cir. 2009) on the basis that the claims in that decision were found transformative because the act of ‘determining the metabolite levels’ was construed to include the extraction and measurement of metabolite concentrations, such as high pressure liquid chromatography. However, in the case before him, the ordinary meaning of the terms ‘analysing’ or ‘comparing’ established that the claimed methods were directed only to the abstract mental process of ‘comparing’ or ‘analysing’ gene sequences. Additionally, the claim directed to ‘comparing’ the growth rate of cells in the presence of a potential cancer therapeutic was not patentable under section 101 because it sought simply to patent a basic scientific principle: that a slower rate of cell grown in the presence of a compound indicated that the compound might be a cancer therapeutic.

The opinion of the Federal Circuit

The Federal Circuit's opinion in AMP v USPTO is fascinating because of the three different approaches adopted by the judges who formed the Panel. Judge Lourie wrote the majority opinion. Judge Moore concurred with this opinion but only in respect of certain aspects, while agreeing with the result. Judge Bryson concurred in part and dissented in part with the ‘majority’ opinion of Judge Lourie. While there was unanimity as to whether the genetic diagnostic and screening methods were patent-eligible, the patentability of the isolated DNA produced three different approaches.

Composition of matter claims

The majority opinion

In relation to the isolated DNA, Judge Lourie accepted that the distinction between a product of nature and a human-made invention for purposes of section 101 turned on a change in the claimed composition's identity compared with what existed in nature; noting that the Supreme Court in Funk Brothers and Chakrabarty had drawn a line between compositions that, even if combined or altered in a manner not found in nature, had similar characteristics as in nature, and compositions that human intervention had given ‘markedly different’, or ‘distinctive’, characteristics. The distinction between a product of nature and a human-made invention for purposes of section 101 turned on a change in the claimed composition's identity compared with what existed in nature. After examining the differences between native DNA and isolated DNA, he concluded that BRCA1 and BRCA2, in their isolated state, were not the same molecules as DNA as it existed in the body; and human intervention in cleaving or synthesizing a portion of a native chromosomal DNA imparted on that isolated DNA a distinctive chemical identity from that possessed by native DNA. Judge Lourie claimed that it was the distinctive nature of DNA molecules as isolated compositions of matter, rather than their physiological use or benefit, which determined their patent eligibility, adding that the claimed isolated DNA molecules were distinct from their natural existence as portions of larger entities, and their informational content was irrelevant. The District Court had held that isolated DNA molecules were not patent-eligible because their only genetic function was to transmit information; however, he rejected this reasoning claiming that patent eligibility was not negated because it had similar information properties to a different, more complex natural material that embodies it. Focusing on the actual structure of the isolated molecules rather than their function, he held such isolated DNA molecules patent-eligible under section 101. Applying the test Funk Brothers and Chakrabarty to the isolated DNAs, the claims were drawn to patentable subject matter because they covered molecules that were markedly different—had a distinctive chemical identity and nature—from molecules that existed in nature. He added that the majority decision that isolated DNA molecules were patent-eligible was in line with the longstanding practice of the USPTO. If the law were to be changed, and DNA inventions excluded from the broad scope of section 101, contrary to the settled expectation of the inventing community, the decision must come not from the courts, but from Congress.

Concurring opinion of Judge Moore

Judge Moore noted that courts had long applied the principles articulated in Funk Brothers and Chakrabarty to different factual scenarios in order to determine whether an invention, as claimed, fell into the laws of nature exception. She saw no reason to deviate here from this longstanding flexible approach. Concurring with the majority, she reached some of the same conclusions by a different route. Joining the majority with respect to claims to isolated cDNA sequences, she concurred in the judgment with respect to the remaining sequences and then examined the isolated DNA claims to determine whether, in accordance with Funk Brothers and Chakrabarty, they had markedly different characteristics with the potential for significant utility, for example, an enlargement of the range of utility as compared to nature. The cDNA claims presented the easiest analysis since, although the District Court held that cDNA fell within the ‘laws of nature’ exception to section 101 patentability, she could not reconcile this argument with the fact that the claimed cDNA sequences did not exist in nature; cDNA sequences have a distinctive name, character, and use, with markedly different chemical characteristics from either the naturally occurring RNA or any continuous DNA sequence found on the chromosome. The claimed isolated cDNA sequences were thus the creation of man, made using biological tools and the naturally occurring mRNA as a template. Judge Lourie's analysis had focused on the ‘markedly different chemical structure’ of isolated DNAs, as compared to the corresponding native DNA, which, for her, suggested that isolated DNA was not a product of nature but that this difference alone did not necessarily make isolated DNA so ‘markedly different’ from chromosomal DNA so as to be per se patentable subject matter.

Judge Moore held that DNA sequences that had the same pattern of DNA bases as a natural gene, in whole or in part, presented a more difficult issue. Unlike the isolated cDNA molecules, whose sequence was not present in nature, those kinds of isolated DNA claims included nucleotide sequences which were found in the human body, albeit as part of a much larger molecule, the chromosome. The different chemical structure suggested that isolated DNA was not a product of nature, Judge Moore did not think that that difference alone necessarily made isolated DNA so ‘markedly different’ from native DNA so as to be per se patentable subject matter. Accordingly, given the differences, the Federal Circuit should, as precedent instructs, consider whether these differences imparted a new utility which made the molecules markedly different from nature. The claimed isolated DNA molecules, which were truncations (with different ends) of the naturally occurring DNA found as part of the chromosome in nature, were not naturally produced without the intervention of man. In her view, the isolated DNA could be used as a primer in order to selectively detect the presence of the BRCA1 gene or BRCA1 gene mutation in a patient. Accordingly, because the different chemical structure of the isolated DNA, which was a product of the intervention of man, led to a different and beneficial utility, isolated DNA fragments were patentable subject matter.

The judge then cautioned that, if she was deciding the case on a blank canvas, she might have concluded that an isolated DNA sequence that included most or all of a gene was not patentable subject matter: despite the literal chemical difference, the isolated full-length gene did not clearly have a new utility and appeared simply to serve the same ends devised by nature by acting as a gene encoding a protein sequence. However, she claimed (like Judge Lourie) that the case came to court ‘with a substantial historical background’. Congress had for centuries authorized an expansive scope of patentable subject matter, while the USPTO had allowed patents on isolated DNA sequences for decades and patents on purified natural products for centuries. With thousands of patents with claims to isolated DNA, and some unknown (but certainly large) number of patents to purified natural products or fragments thereof, Judge Moore pointed out that this meant that the Federal Circuit must be particularly wary of expanding the judicial exception to patentable subject matter where both settled expectations and extensive property rights were involved. Therefore, in addition to the belief that the Federal Circuit should defer to Congress, these settled expectations tipped the scale in favour of patentability.

Dissenting opinion of Judge Bryson

Judge Bryson dissented from the majority's holding that Myriad's BRCA gene claims and its claims to gene fragments were patent-eligible, claiming that those claims were not directed to patentable subject matter and that, if sustained, the Federal Circuit's decision would likely have broad consequences, such as pre-empting methods for whole-genome sequencing. The isolated BRCA genes fell clearly on the ‘unpatentable’ side of the line drawn in Chakrabarty because Myriad claimed the genes themselves, which appeared in nature on the chromosomes of living human beings. The only material change made to those genes from their natural state was the change that was necessarily incidental to the extraction of the genes from their natural environment. The isolated genes were not materially different from the native genes and the composition claims were not defined by any particular chemical formula. Judge Bryson explained that, from a genetic perspective, the claim covered one ‘composition of matter’—the BRCA1 gene: first, the isolated BRCA genes were identical to the BRCA genes; secondly, they had the same sequence, they coded for the same proteins, and they represented the same units of heredity; thirdly, the only difference between the naturally occurring BRCA genes during transcription and the claimed isolated DNA was that the claimed genes had been isolated according to nature's predefined boundaries, that is, at points that preserved the ability of the gene to express the protein for which it was coded.

Judge Bryson claimed that the test employed by the Supreme Court in Chakrabarty required the Federal Circuit to focus on two things: the similarity in structure between what was claimed and what was found in nature and the similarity in utility between what was claimed and what was found in nature. What was claimed in the BRCA genes was the genetic coding material; that material was the same, structurally and functionally, in both the native gene and the isolated form of the gene. As a result, the isolation of the naturally occurring genetic material did not make the claims to the isolated BRCA genes patent-eligible. He agreed, however, with the majority that the claims to BRCA cDNA were eligible for patenting. The cDNA could not be isolated from nature, but instead must be created in the laboratory. However, he disagreed in relation to the two claims to short segments of DNA having at least 15 nucleotides. Because small sequences of DNA were repeated throughout the three billion nucleotides of the human genome, the claim covered portions of the cDNA of more than 4 per cent of human genes and covered portions of the DNA of nearly all human genes. These, in his opinion, were not patent-eligible.

The genetic diagnostic method claims

In relation to the claims to methods of ‘comparing’ or ‘analysing’ BRCA sequences, Judge Lourie, with whom Judges Moore and Bryson agreed, concluded that Myriad's claims to ‘comparing’ or ‘analysing’ two gene sequences fall outside the scope of section 101 because they claimed only abstract mental processes. He noted that the claims recited, for example, a ‘method for screening a tumor sample’, by ‘comparing’ a first BRCA1 sequence from a tumour sample and a second BRCA1 sequence from a non-tumour sample, wherein a difference in sequence indicates an alteration in the tumour sample. In his view, the claims recited nothing more than the abstract mental steps necessary to compare two different nucleotide sequences: look at the first position in a first sequence; determine the nucleotide sequence at that first position; look at the first position in a second sequence; determine the nucleotide sequence at that first position; determine if the nucleotide at the first position in the first sequence and the first position in the second sequence are the same or different, wherein the latter indicates an alternation; and repeat for the next position. After citing from Supreme Court decisions of Flook, Diehr, and Bilski, Judge Lourie argued that, although the application of a formula or abstract idea in a process might describe patentable subject matter, Myriad's claims did not apply the step of comparing two nucleotide sequences in a process; rather, the step of comparing two DNA sequences was the entire process claimed.

Judge Lourie held that the method claims in this case were distinguishable from the claims upheld by the Federal Circuit under section 101 in Prometheus Laboratories Inc. v Mayo Collaborative Services 628 F.3d 1347 (Fed. Cir. 2010). In that decision, the patents claimed methods for optimizing the dosage of thiopurine drugs administered to patients with gastrointestinal disorders. There, the claimed methods included the steps of ‘administering’ a thiopurine drug to a subject and/or ‘determining’ the drug's metabolites levels in the subject, wherein the measured metabolite levels were compared with predetermined levels to optimize drug dosage. Judge Lourie claimed that the Federal Circuit in Prometheus held that, in addition to the ‘administering’ step being transformative, the ‘determining’ step was both transformative and central to the purpose of the claims. The same case held that because the metabolite levels could not be determined by mere inspection, the determining step necessarily required a transformation, and that this transformation was not just insignificant extra-solution activity or necessary data-gathering steps, but was central to the claims in that: determining the metabolite levels was what enabled the optimization of drug dosage. However, in his view, the Myriad claims did not include the step of ‘determining’ the sequence of BRCA genes by, for example, isolating the genes from a blood sample and sequencing them, or any other necessarily transformative step; rather, the comparison between the two sequences could be accomplished by mere inspection alone. He accordingly held that Myriad's claimed methods of comparing or analysing nucleotide sequences failed to satisfy the machine-or-transformation test, being instead directed to the abstract mental process of comparing two nucleotide sequences. The claims thus failed to claim a patent-eligible process under section 101.

The screening method claim

The plaintiffs argued that this claim was directed to the abstract idea of comparing the growth rates of two cell populations and pre-empted a basic scientific principle—that a slower growth rate in the presence of a potential therapeutic compound suggested that the compound was a cancer therapeutic. Judge Lourie, with whom Judges Moore and Bryson agreed, took as his starting point the machine-or-transformation test: the claim included transformative steps, an ‘important clue’ that it was drawn to a patent-eligible process. The claim recited a method that comprised the steps of: ‘growing’ host cells transformed with an altered BRCA1 gene in the presence or absence of a potential cancer therapeutic; ‘determining’ the growth rate of the host cells with or without the potential therapeutic and ‘comparing’ the growth rate of the host cells. This claim included more than the abstract mental step of looking at two numbers and ‘comparing’ two host cells' growth rates. In his view, the claim included the steps of ‘growing’ transformed cells in the presence or absence of a potential cancer therapeutic, an inherently transformative step involving the manipulation of the cells and their growth medium, and the step of ‘determining’ the cells' growth rates, a step that also necessarily involved physical manipulation of the cells. These steps were central to the purpose of the claimed process.

Judge Lourie also held that the claim was not so ‘manifestly abstract’ as to claim only a scientific principle, and not a patent-eligible process. The claim did not cover all cells, all compounds, or all methods of determining the therapeutic effect of a compound; rather, it was tied to specific host cells transformed with specific genes and grown in the presence or absence of a specific type of therapeutic. Observing that the claim was tied to measuring a therapeutic effect on the cells solely by changes in the cells' growth rate, it represented ‘functional and palpable applications’ in the field of biotechnology, thereby satisfying the requirement of patentable subject matter under section 101.

Practical significance

The majority of the Federal Circuit in AMP v USPTO ruled that isolated DNA molecules are in principle patentable because human intervention resulted in the creation of an isolated DNA with a distinctive chemical identity from that possessed by native DNA molecules. Thus, to be patent-eligible, isolated DNA molecules must be ‘markedly different’, or have ‘distinctive’ characteristics from the native DNA molecules. The biotechnology industry would be relieved that claims to isolated DNA and DNA itself remain patent-eligible. In addition, the majority opinion made it clear that genetic diagnostic methods that simply contain abstract mental steps necessary to compare two different nucleotide sequences would not be patent-eligible; whereas those which contain transformative steps central to the purpose of the claimed process would be patentable under section 101. However, the real difficulty remains with the methods claims, in particular, determining whether such claims are transformational at all.

1 comment:

  1. Your photo is a heterodimer of the BRCA1 and BARD1 RING finger domains. Not BRCA1 itself.