By Kevin E. Noonan --
The Supreme Court's decision in the Myriad case has been almost universally hailed as being a great victory for patients, doctors, personalized medicine, and research. Precluding patenting for "merely" isolated human DNA, while permitting cDNA to be patent-eligible, is seen as being a rational compromise ("The Supreme Court got it exactly right," according to amicus Eric Lander of the Broad Institute) and no less a legal luminary than Nina Totenberg has said that the decision has "enormous implications for the future of personalized medicine and in many ways is likely to shape the future of science and technology." Medical practitioners and media pundits agree: with this decision, the Court swept away a significant barrier to patient access for BRCA gene tests and, by implication, genetic testing more generally. Indeed, several genetic analysis companies (including Ambry Genetics, and of course Dr. Harry Ostrer, the only plaintiff with standing to sue), announced plans to offer BRCA gene testing.
The natural question to ask is: are all these "experts" correct? The answer may surprise you. During oral argument before the Federal Circuit the first time the case came before the appellate court, Gregory Castanias, representing Myriad, argued that the plaintiffs did not have standing to bring the lawsuit under the doctrine of redressability. The plaintiffs would not be able to perform genetic diagnostics on the BRCA genes, according to Mr. Castanias, because Myriad's patents contained additional method claims of different scope (other than the claims targeted by plaintiffs in their lawsuit) that Myriad could assert against Dr. Harry Ostrer. Specifically, the District Court and the Federal Circuit recognized that the claims put at issue by plaintiffs were generally directed broadly to "comparing" a patient's BRCA gene sequence with a wildtype sequence, which failed the then-prevailing "machine or transformation" test for patent-eligibility of method claims. Claim 1 of U.S. Patent No. 6,033,857 is illustrative of the invalidated claims:
1. A method for identifying a mutant BRCA2 nucleotide sequence in a suspected mutant BRCA2 allele which comprises comparing the nucleotide sequence of the suspected mutant BRCA2 allele with the wild-type BRCA2 nucleotide sequence, wherein a difference between the suspected mutant and the wild-type sequences identifies a mutant BRCA2 nucleotide sequence.
Whether Mr. Castanias is correct depends on how the Court's Mayo v. Prometheus and Myriad decisions affect the patent-eligibility of these remaining claims. These claims include claims 3, 4, and 9 of U.S. Patent 5,709,999:
3. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1, which comprises analyzing BRCA1 RNA from the subject and wherein a germline alteration is detected by hybridizing a BRCA1 gene probe which specifically hybridizes to nucleic acids containing at least one of said alterations and not to wild-type BRCA1 sequences to RNA isolated from said human sample and detecting the presence of a hybridization product, wherein the presence of said product indicates the presence of said alteration in said RNA and thereby the presence of said germline alteration in said sample.
4. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1,wherein a germline alteration is detected by obtaining a first BRCA1 gene fragment from a BRCA1 gene isolated from said human sample and a second BRCA1 gene fragment from a wild-type BRCA1 gene, said second fragment corresponding to said first fragment, forming single-stranded DNA from said first BRCA1 gene fragment and from said second BRCA1 gene fragment, electrophoresing said single-stranded DNAs on a non-denaturing polyacrylamide gel, comparing the mobility of said single-stranded DNAs on said gel to determine if said single-stranded DNA from said first BRCA1 gene fragment is shifted relative to said second BRCA1 gene fragment and sequencing said single-stranded DNA from said first BRCA1 gene fragment having a shift in mobility.
9. A method for detecting a germline alteration in a BRCA1 gene, said alteration selected from the group consisting of the alterations set forth in Tables 12A, 14, 18 or 19 in a human which comprises analyzing a sequence of a BRCA1 gene or BRCA1 RNA from a human sample or analyzing a sequence of BRCA1 cDNA made from mRNA from said human sample with the proviso that said germline alteration is not a deletion of 4 nucleotides corresponding to base numbers 4184-4187 of SEQ ID NO:1, wherein a germline alteration is detected by forming a heteroduplex consisting of a first strand of nucleic acid selected from the group consisting of BRCA1 gene genomic DNA fragment isolated from said sample, BRCA1 RNA fragment isolated from said sample and BRCA1 cDNA fragment made from mRNA from said sample and a second strand of a nucleic acid consisting of a corresponding human wild-type BRCA1 gene fragment, analyzing for the presence of a mismatch in said heteroduplex, and sequencing said first strand of nucleic acid having a mismatch.
Claim 10 from U.S. Patent No. 5,710,001:
10. A method for screening a tumor sample from a human subject for a somatic alteration in a BRCA1 gene in said tumor which comprises gene comparing a first sequence selected form the group consisting of a BRCA1 gene from said tumor sample, BRCA1 RNA from said tumor sample and BRCA1 cDNA made from mRNA from said tumor sample with a second sequence selected from the group consisting of BRCA1 gene from a nontumor sample of said subject, BRCA1 RNA from said nontumor sample and BRCA1 cDNA made from mRNA from said nontumor sample, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA from said tumor sample from the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA from said nontumor sample indicates a somatic alteration in the BRCA1 gene in said tumor sample, wherein the nucleic acid sequence is compared by molecularly cloning all or part of the BRCA1 gene from said tumor sample and from said nontumor sample to produce cloned nucleic acids and sequencing the cloned nucleic acids.
Claim 9 of U.S. Patent No. 5,753,441:
9. A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cDNA made from mRNA from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cDNA, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cDNA of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject, wherein a germline nucleic acid sequence is compared by amplifying all or part of a BRCA1 gene using a primer specific for a specific BRCA1 mutant allele and detecting the presence of an amplified product, wherein the presence of said product indicates the presence of said specific allele.
And claim 4 of U.S. Patent No. 6,033,857:
4. A method for diagnosing a
predisposition for breast cancer in a human subject which comprises comparing
the germline sequence of the BRCA2 gene or the
sequence of its mRNA [= cDNA] in a tissue sample from said subject with the
germline sequence of the wild-type BRCA2 gene or the sequence of its mRNA,
wherein an alteration in the germline sequence of the BRCA2 gene or the
sequence of its mRNA [= cDNA] of the subject indicates a predisposition to said
cancer, wherein the detection in the alteration in the germline sequence is
determined by an assay selected from the group consisting of
(a) observing shifts in electrophoretic mobility of single-stranded DNA on non-denaturing polyacrylamide gels,
(b) hybridizing a BRCA2 gene probe to genomic DNA isolated from said tissue sample,
(c) hybridizing an allele-specific probe to genomic DNA of the tissue sample,
(d) amplifying all or part of the BRCA2 gene from said tissue sample to produce an amplified sequence and sequencing the amplified sequence,
(e) amplifying all or part of the BRCA2 gene from said tissue sample using primers for a specific BRCA2 mutant allele,
(f) molecularly cloning all or part of the BRCA2 gene from said tissue sample to produce a cloned sequence and sequencing the cloned sequence,
(g) identifying a mismatch between (1) a BRCA2 gene or a BRCA2 mRNA isolated from said tissue sample, and (2) a nucleic acid probe complementary to the human wild-type BRCA2 gene sequence, when molecules (1) and (2) are hybridized to each other to form a duplex,
(h) amplification of BRCA2 gene sequences in said tissue sample and hybridization of the amplified sequences to nucleic acid probes which comprise wild-type BRCA2 gene sequences,
(i) amplification of BRCA2 gene sequences in said tissue sample and hybridization of the amplified sequences to nucleic acid probes which comprise mutant BRCA2 gene sequences,
(j) screening for a deletion mutation in said tissue sample,
(k) screening for a point mutation in said tissue sample,
(l) screening for an insertion mutation in said tissue sample, and
(m) in situ hybridization of the BRCA2 gene of said tissue sample with nucleic acid probes which comprise the BRCA2 gene.
The italicized portion of these claims constitute affirmative limitations that are more than merely comparing two sequences, the deficiency that formed the basis for the Federal Circuit to affirm the District Court's invalidation of these claims. As stated in Justice Thomas' opinion:
[T]his case does not involve patents on new applications of knowledge about the BRCA1 and BRCA2 genes. Judge Bryson aptly noted that, "[a]s the first party with knowledge of the [BRCA1 and BRCA2] sequences, Myriad was in an excellent position to claim applications of that knowledge. Many of its unchallenged claims are limited to such applications."
These methods are clearly "applications" of the "knowledge of the [BRCA1 and BRCA2] sequences" and constitute applications to which the unchallenged claims are limited. The Court's Myriad decision not only does not preclude patent-eligibility for these claims, it affirmatively suggests that claims to such applications (particularly when directed to using cDNA) are the type of claims the Court believes do not suffer from the deficiencies the Court found attached to claims to "merely" isolated genomic DNA.
But what of the effects of the Court's Mayo decision? Recall that Justice Breyer's opinion (like Myriad, for a unanimous Court) mandates that to be patent eligible a claim cannot merely recite a law of nature and direct that it be applied. Claims to "a process that focuses upon the use of a natural law must also contain other elements or a combination of elements, sometimes referred to as an 'inventive concept,' sufficient to ensure that the patent in practice amounts to significantly more than a patent upon the natural law itself." Here, the "law of nature" would putatively be the correlation between certain alterations in the sequence of the BRCA 1 or BRCA 2 genes with an increased risk or predilection for developing breast or ovarian cancer. An important part of the Court's reasoning concerning the patent-ineligibility of the claims at issue in Mayo is that the limitation(s) in the claims relating to detection methods were not specified or limited to any specific methods. Moreover, both administration of 6-thioguanine (6-TG) to patients and assaying blood from such patients for 6-TG or its metabolites was "well-understood, routine and conventional" and had been "previously engaged in by researchers in the field." In Mayo, "scientists already understood that the levels in a patient's blood of certain metabolites, including, in particular, 6-thioguanine and its nucleotides (6–TG) and 6-methyl-mercaptopurine (6–MMP), were correlated with the likelihood that a particular dosage of a thiopurine drug could cause harm or prove ineffective," circumstances that supported the Court's determination regarding what was "well-understood, routine and conventional."
Myriad's method claims differ in two important ways from the claims in Mayo with regard to these considerations. First, even the Supreme Court acknowledged that Myriad had "discovered the precise location and sequence of two human genes, mutations of which can substantially increase the risks of breast and ovarian cancer" and that this discovery was "a medical breakthrough." It seems evident that methods directed to previously undetected BRCA genes cannot be "well-understood, routine and conventional." And another aspect of the Court's decision in Mayo, that administering 6-TG to patients constituted a "pre-existing" audience (doctors) who had been performing the administration step in the prior art, cannot be the case here where the Court recognized that the BRCA genes were unknown prior to Myriad's "discovery."
In addition, unlike Myriad's invalidated method claims or the claims at issue in Mayo, how genetic alterations correlated with cancer risk are detected in the remaining Myriad method claims is recited with specificity. A consequence of this specificity is that Myriad's claims have a much more narrow scope and thus exert a much more restricted preclusive effect than the claims in Mayo.
And the Court's other concern in Mayo, that the claims at issue "threaten to inhibit the development of more refined treatment recommendations (like that embodied in Mayo's test), that combine Prometheus' correlations with later discovered features of metabolites, human physiology or individual patient characteristics" are contravened here because these claims are all limited to detecting specific mutations disclosed in Myriad's patent specifications. New mutations and their detection fall outside the scope of these remaining claims and thus what is "preempted" by Myriad in these claims is both properly within the scope of the patent disclosure and does not pose the impediment that raised concern with the Court in Mayo.
In view of these considerations, it should be clear that any "victory" claimed by the ACLU or Public Patent Foundation is of the Pyrrhic variety; tragically, the women patients, whose banner was used to engender sympathy and support from the public and press (with attendant publicity from The New York Times to People and Marie Clare) are in no better a position than they were before the Court's decision. As for Myriad, the fact that they can sue unlicensed purveyors of BRCA gene testing doesn't mean that they will. Under circumstances where asserting their patent rights throughout this case put the patent rights of many biotechnology companies at risk for patents Myriad itself admitted were not critically important to protect their commercial interests, it would be regrettable if Myriad did not defend their remaining method claims with the same vigor and tenacity.