2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

The majority of gene-related discoveries have been made
by federally funded academic researchers, for whom patents
are unlikely to have provided primary or even significant
motivation. 7 Further, given the relative ease by which
molecular pathology procedures are introduced into practice,
patents are unnecessary for the clinical implementation
of molecular pathologic discoveries. Rather, enforcement of
gene patents in the diagnostic realm results in the elimination
of already existing services and dissuades laboratories
from adding new ones. 8 The resultant elimination of competition
is likely to result in higher prices, decreased quality,
reduced innovation, and diminished patient access to these
important medical services. Moreover, loss of academic
providers will adversely affect training and related clinical
research.
Greater interest in companion diagnostic development by
the pharmaceutical industry may alter the preceding dynamics.
Control of companion diagnostics could allow drug
manufacturers to ensure assay standardization, enforce
specific quality requirements, and provide additional
sources of revenue. Companion diagnostics could serve as
vehicles by which companies preserve market share for
linked drugs, assuming they avoid patent misuse or antitrust
violations. Under this model, gene-related patents may
create incentives for marker discovery and in vitro diagnostic
commercialization. However, such patents could prove a
double-edged sword by creating holdout problems for drug
vendors who do not own the underlying molecular pathologic
relationships.
Thousands of U.S. patents have been issued on human
gene sequences and genotype-phenotype associations, but
their legal status remains uncertain. Several cases presently
making their way through the courts may clarify and add
reason to the law in this area.
Recent Legal Developments
In Mayo Collaborative Servs. v. Prometheus Labs., Inc., 9
Prometheus sued Mayo Clinic in the District Court for the
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KEY POINTS
● Personalized medicine in the form of targeted drug
therapies is already making important contributions
to oncology care.
● Patents on human gene sequences have likely helped
stimulate the introduction of novel biologics and
pharmaceutical agents.
● Conversely, patents on human gene sequences and
genotype-phenotype correlations appear to reduce
the availability of and patient access to already
existing diagnostic services, while increasing costs
and decreasing innovation in the development of
diagnostic methods.
● The intellectual property rules by which patents on
human genes and genotype-phenotype associations
are governed will have a profound impact on the
advancement of personalized cancer care.
● Several key legal cases now before the courts may add
clarity and guidance to the law governing this area.
ROGER D. KLEIN
Southern District of California for infringement of a process
patent covering the postadministration correlation between
thiopurine drug activity and side effects, and blood levels of
the metabolites 6-methyl mercaptopurine (6-MMP) and
6-thioguanine (6-TG). The patent claims at issue include
“administering a drug,” “determining the level” of a metabolite
of the drug, and correlating this level with therapeutic
efficacy or side effects.
The district court found as a matter of law that the patent,
which essentially claims the reference range for the drugs,
covered an unpatentable natural phenomenon. The Court of
Appeals for the Federal Circuit (CAFC), the national patent
appeals court, reversed the lower court, finding that the
patent covers a treatment method. Further, the CAFC held
that the in vivo metabolism of thiopurine agents constituted
a transformation of matter, consistent with a patentable
process on an application of a natural phenomenon as
opposed to a patent on the phenomenon itself.
The Prometheus Labs case was appealed to and accepted
by the U.S. Supreme Court. Oral arguments were held
before the Court on December 7, 2011. Of note, during oral
arguments, the attorney for Prometheus Labs acknowledged
that it had patented “a fact” they identified, and that
physicians can infringe the patent merely by thinking about
the biologic relationship between metabolite levels and patient
response. However, because the case involved an exogenously
administered drug rather than a genetic variant
intrinsic to a patient, and the CAFC considered the patent
a therapeutic method patent, and Prometheus defended
its validity on this basis, the implications for genotypephenotype
association patents are unclear.
In a case addressing legal standards for patent obviousness,
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007),
Teleflex sued KSR for infringement of a patent that claimed
the combination of an adjustable brake pedal and an electronic
sensor. The district court found the patent obvious,
but the CAFC reversed the lower court decision. The Supreme
Court in turn reversed the CAFC, ruling that the
patent was obvious. The CAFC, the high court stated, had
applied overly restrictive criteria in finding the patent
“nonobvious.” Importantly, the Supreme Court held that
“obviousness to try” a problem-solving approach can render
a patent obvious if there is a demonstrated need for a
discovery and a finite number of identified, predictable
solutions.
Many if not most patented genes were initially mapped
to a chromosomal region before discovery. Moreover, many
genes are involved in sequential biochemical pathways in
which disease-related changes were known before specific
genetic variations were identified. Therefore, for many of
these discoveries, it was arguably obvious to look for variants
in the potentially responsible genes among the finite
number of available solutions. As a result, under KSR Int’l
Co. v. Teleflex Inc. (KSR) many gene-related patents may be
subject to challenge on obviousness grounds. In an early
application of the KSR ruling, the USPTO refused to award
a patent on the gene sequence of the natural killer cell
activation–inducing ligand. Although the sequence had not
been previously described, the USPTO found it obvious in
light of the prior art. The CAFC upheld the USPTO’s
decision. 10
Finally, in Association for Molecular Pathology v. United
States Patent and Trademark Office, a lawsuit sponsored