Myriad
Genetics v. Ambry Genetics Corp. and Myriad Genetics v. Gene By Gene Ltd.

By Kevin E. Noonan —

Last month, Ambry Genetics and
Gene By Gene responded to Myriad's motion for preliminary injunction in a 109
page brief that sets out its invalidity case as well as the basis for its
antitrust counterclaims.  Supported by
declarations from numerous luminaries and illuminaries in the gene patenting
debate (including several of the individual plaintiffs in the Myriad case, and
anti-gene patenting economist and Nobel Prize winner Joseph Stiglitz), the
brief makes its points good and bad in an exhaustive fashion.  Not surprisingly, the brief focuses on the
Supreme Court's decision in the AMP v. Myriad Genetics case, categorical
exclusion being the easiest and most direct for the defendants to prevail.  The brief also alleges invalidity for
anticipation or obviousness and non-infringement, as well as challenging Myriad's
claims of irreparable harm, the balance of the hardships and the public
interest, the latter based on the generic testing being "critical to
patient care" (indeed, as in AMP, the intuitively persuasive argument is that patients will benefit, regardless
of the evidence for or against that proposition).

The brief leads with its most
compelling argument:  that the Supreme Court's Myriad decision drew the patent
eligibility line at whether a claimed DNA molecule had the same sequence as the
molecule as it is found in nature, not whether the molecule was
synthesized in the laboratory (the latter argument was persuasive to Judge
Moore at the Federal Circuit).  Less so
is their reading of the applicability of the Court's Mayo decision, which defendants' argue invalidate Myriad's claims
because the steps of amplifying and sequencing DNA was "well-understood,
routine and conventional."  While
certainly not yet settled, Myriad's method claims are expressly outside the
Supreme Court's Myriad decision and
could fall within the scope of "applications"
of the determination of the BRCA gene sequences the Court seemed to view with
considerably more favor that the genomic DNA claims in the Myriad decision.

The brief challenges Myriad even as to
the statement of facts, in enumerated fashion and asserts its own Statement of
Facts, supported by several declarations by putative experts.  Many of these facts reconstruct the
development of genetic diagnostic testing in the early 1990's, purporting that
such testing was "widely used" and that the genetic variation in the
BRCA genes was known prior to Myriad's patents (providing part of the factual
bases for defendants' invalidity contentions).  Additional facts include mapping
studies that located the BRCA 1 and BRCA 2 genes to within 2-6 centiMorgans of
chromosome-specific markers.  (The
speciousness of this argument is illustrated by the following graphic
illustrating imperfectly the differences in scale between kilobases and
centiMorgans):

Interestingly, Gene By Gene's factual
statement is framed in what the company "intends" to do, rather than
is actually doing with regard to BRCA testing.  The defendants also assert so-called "equitable" factual
considerations regarding harm to them if enjoined, the fact that Myriad has not
sued other putative providers, and that many patients "who want BRCA 1/2
testing cannot afford Myriad's BRCA 1/2 test price," and that Myriad's
tests do not identify up to 10% of (rearrangement) mutations (begging the
question of whether Myriad's asserted claims encompass such testing).  And the brief cites San Francisco geneticist
Robert Nussbaum regarding Myriad's proprietary genetic mutation database to
support its argument that Myriad's frequency of variant of unknown significance
cannot be verified.

Defendants' legal arguments regarding
Myriad's asserted composition of matter (probes and primer) claims start (and
could end) with the Supreme Court's Myriad
decision as the underpinnings of their argument that Myriad is not likely to
prevail on the merits.  Defendants'
interpretation of the Supreme Court's Myriad
decision (if correct, which it likely is) is dispositive:

If the DNA primer nucleotide
sequence created in the lab corresponds to a natural DNA nucleotide sequence,
then it is an unpatentable product of nature under Myriad.

Defendants cite portions of the
specifications of the patents-in-suit as well as Myriad's arguments before the District Court, Federal Circuit, and Supreme Court to establish the distinction
between natural and non-naturally occurring DNA, with genomic DNA and
oligonucleotide primers in the former category and cDNA in the latter
category.  Under this analysis, the
primers and probes recited in Myriad's asserted composition of matter claims
fall within the scope of patent-ineligible subject matter according to the
Supreme Court's Myriad decision.  In this way, defendants argue that claims 29
and 30 of the '492 patent and claims 16 and 17 of the '282 patent are invalid
as being directed to patent-ineligible subject matter (albeit based on one of
the more strikingly inaccurate quotes from the Court's Myriad decision, no doubt being one of the factors that prompted
Justice Scalia's concurrence).  Unfortunately, the brief also reiterates the Court's misjudgment
regarding the significance of the informational content of the primers as being
dispositive, which might be compelling if the genetic information was itself
either patent eligible or patented.

Turning
to the method claims, defendants' arguments focus on the Court's Mayo v. Prometheus decision, in a manner
that ignores portions of the Myriad
decision that arguably distinguish Mayo from Myriad's asserted method
claims.  According to defendants, Myriad's
method claims are patent-ineligible for reciting a law of nature using only "well-understood,
routine and conventional methods," specifically PCR amplification and
nucleotide sequencing.  In defendants'
view, they are merely an "artifice of patent drafting" (proving if
nothing else that Supreme Court Justices should avoid dicta illustrating their
prejudices more than illuminating the law), arguing that as dependent claims
from method claims invalidated by the District Court and Federal Circuit (and
not reviewed by the Supreme Court), these claims are also patent
ineligible.  Defendants analogize the
BRCA genes with previously unknown laws of nature, which are then analyzed
using "well-understood, routine and conventional" PCR and sequencing
methods.  Where this analysis falls
apart, of course, is that the subject matter of the Mayo claims was in all
aspects "well-understood, routine and conventional."  Here, the "law
of nature" is that some mutations are associated with disease and others
are not; the distinction with the Mayo claims is that the isolated BRCA genes
themselves were not in the prior art, in contrast with the step of administering
6-thioguanine to Crohn's disease patients.  And there is no support for the proposition that, because the isolated
BRCA genes themselves are not patent-eligible the method for determining a risk
of disease by detecting certain mutations would not be.  Importantly, the Supreme Court suggested that
these types of claims may be patent eligible precisely because Myriad was the
first to identify the BRCA genes:

[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 [including the
ones asserted in Myriad's complaint against Ambry and Gene By Gene] are limited
to such applications."

It
is also relevant that defendants attempt to bootstrap the District Court
decision on claims arguably much broader and less specific than the
now-asserted claims against Myriad, which would reward defendants for the AMP plaintiffs' strategic decision not to include these claims in its
complaint.

Defendants
also argue that Myriad's asserted composition of matter claims are invalid
under §§ 102, 103 and/or 112.  Regarding § 102, defendants first
assert particular priority dates for specific claims based on the presence of
specific disclosure in various applications in the priority chain of Myriad's
asserted patents.  Defendants then assert
prior art, available at these several dates, in support of their anticipation
arguments.  None of this art discloses isolated
human chromosomal DNA within the scope of the patent claims, i.e., that were
sufficiently circumscribed in the vicinity of the BRCA genes that would have
permitted the genes to be sequenced with the technology available in the
1992-1996 time frame.  And indeed, the
BRCA genes were not; ironically, one of the arguments asserted against Myriad
in other contexts is that Myriad was not the first to isolate the BRCA 2 gene
and that there is some question about its priority over Mary Claire King's lab
regarding the BRCA 1 gene.  However,
because the asserted claims recite primers that amplify "all or a portion"
of the BRCA 1 gene, some of these allegations are sufficiently specific
regarding disclosure of primers for chromosome 17 markers that turned out to be
portions of the BRCA genes that they may support a determination that Myriad
has not shown a likelihood of success on the merits with regard to the
assertion of these claims.  In this
regard, the arguments for the BRCA 1 claims are more likely to be persuasive
than the arguments for the BRCA 2 claims, insofar as the primers for the
chromosome 13 marker disclosed in the prior art are located entirely within an
intron.

Defendants
direct their obviousness attack under § 103 to Myriad's method
claims.  Here, the argument is that the
amplifying and sequencing steps would have been obvious as a solution to the
problem of identifying disease-associated BRCA 1 and BRCA 2 gene
mutations.  The obviousness of the BRCA
genes is indicated by the knowledge in the art that there were genes on
chromosomes 13 and 17 associated by genetic linkage analysis with a higher risk
of developing ovarian and breast cancer, respectively.  Finding the genes amounted to nothing more
than "tedious, but straightforward [] mapping of human traits,"
according to plaintiffs.  Most of this
argument is precatory in nature "[h]aving stood on the shoulders of
giants, Plaintiffs sought to claim the kingdom," and defendants reiterate
their mantra of "using well-understood, routine and conventional"
methods to isolate BRCA genomic DNA.  This is not the test, however; indeed, the argument runs contrary to the
express language of the statute, wherein "[p]atentability shall not be
negatived by the manner in which an invention is made."  The conventionality vel non of the methods would certainly be relevant for claims to
methods of isolating BRCA gene DNA, but the methods themselves are irrelevant
to the non-obviousness of the genes themselves.  (It is amusing that defendants contend that "[t]he sizable
investment by Plaintiffs' corporate partners and the federal government
evidences (sic) Plaintiff's
reasonable expectation of success in isolating the BRCA genes.")  And In
re Kubin is not to the contrary (despite defendants' argument), insofar as
the facts in that case involved a next generation of cDNA (not genomic) cloning
and had the benefit of specific antibodies to the gene product not present for
the BRCA genes.  Having asserted the
obviousness of the genes themselves, defendants then assert that the methods
claimed by Myriad would also have been obvious (again equated with the "well-understood,
routine and conventional").

With
regard to certain claims (including claim 5 of the '721 patent) defendants
argue that the existence in the prior art of methods that detected variants in
the BRCA1 gene not associated with
disease renders obvious claims directed to variants that are associated with disease, "because it would have been
obvious to identify additional polymorphisms."  And Myriad's own '282 patent is cites as § 102(e)
prior art in asserting some of these obviousness arguments.  Whatever else can be said about this
litigation, it is clear that Myriad's claims will get a full assessment of
their patentability under the substantive portions of the patent statute.

Finally,
defendants argue that certain of Myriad's asserted patent claims (including
claim 7 of the '282 patent and claim 30 of the '492 patent) are invalid under § 112
for indefiniteness for being insolubly ambiguous with regard to amplification
of exons and introns.  Claim 4 of the '155
patent is asserted to be invalid for failure to satisfy the written description
requirement (by reciting only variants that do
not lead to an increase susceptibility for cancer).

Turning
to non-infringement, defendants allege that Myriad has not "pinpointed
specific evidence" to support infringement of its asserted composition of
matter claims, characterizing Myriad's assertions as "speculations"
regarding defendants' allegedly infringing activities.  Defendants argue, for example, that the composition
claim term that the primers are "derived from" or "isolated from"
the human BRCA genes to mean "wholly derived from" (of "wholly
isolated from") and thus the presence of heterologous sequences in Ambry's
and Gene By Gene's primers place their methods outside the scope of literal
infringement.  Regarding the method
claims, defendants argue that there is a similar lack of specificity regarding
evidence of infringement.  And insofar as
Myriad's claims are directed to analyzing mRNA or cDNA (as in claim 8 of the '441
patent and claim 4 of the '857 patent), defendants argue that neither one of
them determines BRCA gene sequences from that source, and in other instances
(claim 5 of the '721 patent and claims 2 and 4 of the '155 patent) defendants
argue that they don't "compare patient sequences to contiguous cDNA
sequences."  In their most
interesting argument, defendants assert that they do not infringe because "they
do not use or intend to use probes specific for any known variations of BRCA1
that predispose a patient to certain cancers," "[t]hat is, the
probes that Ambry and Gene by Gene uses or will use will only identify BRCA1
and are not specific for any particular allele, as required by the claim."

In
the final portion of the brief, defendants turn to the other requirements for
obtaining a preliminary injunction:  irreparable harm, the balance of the
hardships tipping in favor of Myriad, and the public interest.  The irreparable harm argument emphasizes
Myriad's position as a "monopolist" and the amount of money Myriad
has made (and cites Myriad's Dr. Skolnick's unfortunate interview with a POV
journalist enshrined in the documentary film "In the Family").  Defendants also cite the institutional
inertia attendant upon Myriad's agreements with insurance companies and other
providers that are not capable of shifting providers quickly (although the
price difference could certainly be expected to do so, and slow adoption has
not been the case with other examples, such as generic replacement of patented
drugs).  Defendants emphasize the
benefits their lower priced tests confer on patients, and the possibility of "meaningful second opinion testing"
(emphasis in brief).  Defendants
challenge Myriad's assertion of the risk of "reputational" harm, and
further argue that Myriad's "inconsistent" enforcement of its
patents (Myriad allegedly is permitting "at least five other laboratories"
to provide BRCA gene testing) mitigates against its allegations of "irreparable
harm."  The balance of the
hardships, according to defendants is not with Myriad, due to its profits over
the past 17 years, but with Ambry and Gene By Gene, who will lose the "first
mover" advantage of their early entry into the market and Ambry's $46.7
million investment (an argument undercut by their earlier argument that "at
least five other laboratories" are providing BRCA gene testing).

Defendants
of course emphasize the public interest in this "life-saving technology":

This is precisely the kind of case where
consideration of the public interest compels denial of injunctive relief.  Indeed, courts have rejected injunctive relief on public interest grounds where
removal of the accused product or process could have serious consequences on
public heath — even when the patentee has satisfied its burden as to the other
factors.  See, e.g., Hybritech, Inc. v. Abbott Labs., 849 F.2d 1446,
1458 (Fed. Cir. 1988).

This
argument is followed by statistics on the number of women at risk of breast
cancer and the number who are expected to die from the disease.

Somewhat
curiously, defendants argue that the Court should deny the injunction because
doctors and patients prefer their testing over Myriad's (despite their earlier
contention that Gene By Gene is not yet offering the test).  The basis for this "preference" is
that Ambry and Gene By Gene will offer "multi-gene" testing, which
defendants characterize as "comprehensive testing."  In their final argument, defendants assert
that Myriad does not offer "transparency, access and affordability"
in its testing, which defendants will offer to the public's benefit.

Unfortunately,
the brief ends with citations to arguments that Myriad's patents have harmed
innovation because they have "blocked important follow on scientific
research, hindered collaborative data collection and sharing, halted patient screenings
at cancer diagnostic facilities, and prevented others from developing and/or
offering additional, alternative, and more affordable technologies."  The bases for at least some of these
arguments are that Myriad enforced its patents against academic medicine that
intended to charge its patients, activities clearly constituting infringement.  And these assertions fly in the face of the
more than 10,000 scientific research papers on the BRCA genes while Myriad's
patents have been in force.

Myriad
has replied, and that brief will be the subject of a future post.