Does the Myriad Decision Presage a Golden Age of Patent-Free Personalized Medicine?

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.

Comments

[Skeptical]

When I read "and no less a legal luminary than Nina Totenberg" I immediately become...

[EG]

Kevin,

Nice article. A Pyrrhic victory indeed! Maybe those media pundits, as well as the ACLU/PubPat should stop "crowing" about how they "won" in the Myriad decision.

[Bob Cook-Deegan]

Not so fast.

These claims are indeed specific and might well withstand the new post-Mayo, post-Myriad jurisprudence (who knows?). But see below.

Who knows if Myriad will sue, but deep-sequencing of multiple genes can be done many ways. Let's see how folks do their tests before deciding they're going to be infringing. No one is going to do a multi-gene deep sequencing test using Sanger or hybridization, and you don't do BRCA genotyping of patient samples on tumors (and several claims you cited are for tumor samples, see below).

Claim 4 of '857 would cover Sanger, but not NGS since NGS does not entail electrophoresis (step a).

Did you stitch together two claims in your editing of claim 9 of '441? One refers to genomic the other to tumor. The first half suffers the same fate as the claims invalidated by CAFC in its first (and affirmed in its second) ruling (the invalidated claims also included the language about sample origin--not sure why you italicized it). The second half (seemingly a different claim) is for tumor, and not relevant to Dx genotyping of a person.

Claims 3 and 4 from the '999 patent are method-specific and not infringed by NGS. One is hybridization; the other has amplification step and electrophoresis.

And claim 10 of '001 is for a tumor sample, again not genomic from a person's blood or cheek swab.

I don't think you've made your case. Or maybe I've missed something.

My sense of a subtractive algorithm: If it entails electrophoresis, can be worked around easily. If it involves tumor sample, not relevant for testing genomic DNA from an individual. If it involves hybridization, easy to work around.

It's gonna depend a lot on details of the methods. And here's a general heuristic. If the claims are so broad they cover NGS sequencing, they are likely to be so broad they fall afoul of Mayo, because no one foresaw NGS until recently. There may be an NGS-infringed claim on non-tumor BRCA testing, but I don't see it here.

Some of the later method claims might survive, but they will be to very specific mutations (check out the claims in US 7,993,835). I can't tell if that survives Mayo or not. But if so, it would be for one rare BRCA2 deletion and surely not gonna command an injunction, and damages would be restricted to hits on a very rare mutation so tiny percent of tests.

BCD

[EG]

"When I read "and no less a legal luminary than Nina Totenberg" I immediately become..." Skeptical

As do I, Skeptical.

[MP]

Yes, claim 9 in '441 is incorrectly transcribed. The correct version doesn't have any tumor language:

1. 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.
9. The method of claim 1 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.

This seems like the broadest protection Myriad has left, except that I'm not sure we know what cDNA means anymore. If cDNA can only be defined the way it is in the opinion: ~composite DNA with the introns removed, it's hardly useful in an assay that identifies fragments, since there are no introns to remove. The assays wouldn't use RNA in any case.

[Dell]

An excellent and interesting post, as always, Kevin--thanks. I am however wondering whether these claims would indeed be limited to covering only the particular mutations disclosed, as the plain language of, e.g., '441 claim 9 does not recite the names of the mutations. While Myriad might lose if trying to assert such a claim against a screen for a 'new' mutation for lack of enablement or written description, it also seems possible that they would win by virtue of having met those requirements by describing a sufficient number of examples. However, I have not looked at the prosecution history, so perhaps something in there is limiting.

[Moocow]

BCD, I don't think Kevin was making the case that the announced BRCA testing would inevitably infringe Myriad's remaining claims. My takeaway is that the Supreme Court decision didn't really change what Myriad's competitors are free to do or not. In my opinion, the ACLU won the case when the Federal Circuit struck down Myriad's broad "comparing" method claims. The ACLU could have stopped there because the rest of the challenged claims are irrelevant to its case. Why they persisted in challenging, for example, methods of drug screening when Harry Ostrer never expressed any interest in screening drugs is beyond me. Myriad's other claims, to full-length genomic sequences, can easily be designed around and we can assume that Myriad's competitors knew that all along. The upheld cDNA claims are likewise already being laughed off as irrelevant. And the fragment claims, under a PTO "broadest reasonable claim construction" are invalid anyway for other reasons and could have been wiped out in a simple ex parte reexamination.
So I think this whole Supreme Court appeal, from the ACLU's perspective, was just gravy. In the meantime there are companies that work in beverage manufacturing or industrial microbiology whose claims were just sacrificed by the hundreds, and who don't quite know what to think about the "we won!" banners that went up at Cardozo Law School.

[Shrivan]

I think Moocow is mostly right here.

On the other hand, I do wonder about claims 1 and 9 of the '441. Here's claim 1 with the "or" clauses removed.

"1. 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 ... with germline sequences of wild-type BRCA1 gene ... wherein a difference in the sequence of the BRCA1 gene ... from wild-type indicates an alteration in the BRCA1 gene in said subject."

I don't think that's an enforceable claim, for the same reasons that claim 1 of the '857 went down.

All claim 9 does is generically describe an old method for obtaining the sequence. That's not going to save it from ineligibility.

I'm curious as to whether anyone has thoughts about the eligibility of mixtures consisting only of individually ineligible polynucleotides (say, a new mixture of two ineligible primers). Does Myriad/Funk nix all such claims or ...?

[Kevin E. Noonan]

Dear Bob:

I am not saying that third parties will inevitably infringe any of these claims. Just that it is not the case that they inevitably will not. We shall see, but Moocow is correct that access to this technology for third party providers (as opposed to patients) was achieved when the broad method claims were invalidated. For the same reasons that these claims should remain patent eligible they are also easier to design around.

Thanks for the comment.

[Moocow]

Shrivan - to state it in a way Justice Thomas would understand: "Primer 1 is ineligible, primer 2 is ineligible, and primer 3 is also ineligible. Put them all in a vial, and they're all ineligible together."
Don't overanalyze the opinion. Just by asking your question you've probably expended more mental effort than what went into the decision :)

[Shrivan]

"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."

Regrettable? Are you sure you didn't mean "refreshing"?

[Mary]

Kevin, I have been in the trenches of attempting to obtain diagnostics methods claims since Prometheus. And I can tell you that it is unlikely that the USPTO would issue any of those methods claims noted above now. Currently, they are requiring a method of treatment step to follow the diagnosis step, even where the correlation is novel. I have tried to get claims directed to once the correlation is found, additional testing is performed, but USPTO will not allow those, I've found. They've very broadly construed Prometheus. Not that this matters all that much for the eventual Fed Circuit weigh-in of the Myriad diagnostics methods claims, but just thought I'd mention it. I guess my take on this is that the 101 eligibility of the Myriad-type diagnostics methods claims (where the correlation is actually novel)in the absence of a treatment step, really haven't been decided yet.