Editor’s Note: We are pleased to share a guest post by Nicholson Price, an
Academic Fellow at the Petrie-Flom Center for Health Law Policy, Biotechnology
and Bioethics at Harvard Law School.
December 10, 2012 : W. Nicholson Price II : What happens when, during the course of whole-genome
sequencing (WGS) a patient or research subject, an investigator sequences and
analyzes a disease gene that has been patented? The U.S. Supreme Court will
shed some light on this question next year when it issues its ruling in the
long-running Myriad Genetics saga.
Last month, the Supreme Court voted to hear the case of Association for Molecular Pathology v.
Myriad Genetics to consider the question whether human genes are
patentable. The plaintiffs -- doctors, patients, researchers, and the American
Civil Liberties Union – have challenged
Myriad’s patents on the breast cancer genes BRCA1
and BRCA2, which cover, among
other things, isolated DNA molecules with the sequences of those genes. A
federal district court in New York ruled that the patent claims on isolated DNA
molecules were invalid, but that ruling was reversed on appeal by the Federal
Circuit in D.C. The Supreme Court decided to review the Federal Circuit’s
decision and will likely rule on whether isolated human gene sequences are
patentable next summer.
This case has profound implications for biotechnology, and
diagnostics, as well as the emerging field of personalized medicine. Among the fascinating
issues that will likely be addressed is whether WGS—an essential foundation for
truly personalized medicine—violates human gene patents.
As WGS involves determining the sequence of an individual’s
entire genome, there is concern in many quarters that WGS could violate
essentially every patent covering an isolated human DNA sequence – of which
there are thousands. Indeed, this concern has been raised by scholars, policy
analysts and lawyers, including before the Federal Circuit and in the arguments
over whether the Supreme Court should hear the case.
However, a closer look at the technology suggests that,
rather than violating thousands of gene patents, WGS methods violate few, if
any, existing gene patents. Whatever the Supreme Court decides next summer, the
widespread adoption of clinical WGS is not particularly threatened by gene
patents.
Patents and WGS
Gene patents, it is worth emphasizing, do not mean that the patentee owns the
gene, in all forms and for all uses. Instead, a patentee has only the ability
to prevent others from making or using what is specifically claimed in a
patent; the patent claims determine the precise boundaries of the protected
invention. While it is impossible to analyze comprehensively all the claims in all
gene patents, an analysis
by law professor Christopher Holman of a set of representative gene patents
(including those at stake in the Myriad case) suggests that most claims in gene
patents will not be infringed by WGS.
The claims in gene patents generally fall into two
categories: (1) composition of matter claims, which claim physical isolated DNA
molecules; and (2) method claims, which claim methods of comparing the sequence
of an individual with known reference sequences, and sometimes using that
information to draw medical conclusions.
Method claims are not especially problematic for WGS. Myriad’s
method claims were held invalid by the district court; the Federal Circuit
affirmed (relying on Mayo Collaborative
Services v. Prometheus Laboratories, Inc., a March 2012 Supreme Court case
which invalidated simple diagnostic correlation patents). Diagnostic methods
patents thus have a somewhat uncertain future; it is unclear what genetic
methods patents require to be valid. More importantly for the development of personalized
medicine, diagnostic patents lack the same sort of potential hold-up problems
as patents on isolated DNA. If any individual valid diagnostic patent covers a
particular gene’s correlation with a disease and the patent is too hard or
expensive for the person performing WGS to license, that result could just be
left out of a WGS analysis without blocking the sequencing and the rest of the
analysis.
Composition claims, on the other hand, are the real source
of worries for WGS and are squarely at issue in the Myriad case. Two
characteristics of composition of matter claims are relevant: they claim
physical DNA molecules which are (1) “isolated” and (2) generally quite
long. Because WGS typically does not
make or use long isolated DNA molecules, it is unlikely to infringe composition
claims.
Composition claims in gene patents almost always claim “isolated”
or “purified” DNA molecules with the specified gene sequence (or a set of
related sequences). The claims are limited to isolated molecules because
otherwise they would cover the gene as found in nature, and would thus be
invalid as including unpatentable subject matter. The term “isolated” is ambiguous,
and no court has laid out a generally applicable definition. (Indeed, since
each patent can define its own term, the exact contours of “isolated” cannot be
precisely determined for the whole class of gene patents.) However, “isolated”
must have a relatively narrow meaning to avoid patent claims which are too broad
and thus invalid. At the least, to avoid claiming genes as found in nature, “isolated”
must mean that the claimed DNA is largely separated from other cellular
components and flanking DNA sequences.
The second relevant characteristic relates to the size of
the claimed molecules. Most composition claims are for whole genes, or at least
portions of genes long enough to encode functional proteins; in other words, composition
claims generally cover lengthy DNA molecules of thousands of bases. (A handful of
other claims cover all molecules containing a very short specified sequence—generally
15 or so bases—but these claims are almost certainly invalid as too broad and
as anticipated by early public disclosures of matching DNA molecules.)
In Violation
To violate gene patents, then, WGS would need to make or use
long, isolated DNA sequences. But most WGS techniques do not rely on such DNA
molecules. Shotgun sequencing generally reads very short DNA molecules,
frequently in the tens to hundreds of bases; while these molecules are
isolated, they are usually too short to include the full sequence of most
claimed DNA sequences. And next-generation WGS methods avoid even that
possibility. Techniques that do not rely on PCR amplification almost certainly
do not create “isolated” DNA molecules, and neither do techniques like the Pacific
Biosciences platform or nanopore sequencing, which in theory sequences very
long molecules of many kilobases—much longer than the approximately gene-length
sequences claimed by most gene patents.
Note that isolating the informational
sequence of a particular gene—after the whole genome has been sequenced—does
not violate composition claims because those claims cover physical molecules,
and WGS never makes or uses the physical
isolated DNA molecule containing that sequence. Thus, while there may be some residual
uncertainty in this analysis from the sheer number of gene patents and their
variation—and, as
Robert Cook-Deegan has argued in Science,
uncertainty itself can prevent innovative technologies from being adopted—it
seems that WGS, especially next-generation WGS, likely infringes very few if
any patents on isolated human gene sequences.
(The same analysis applies to whole-exome sequencing (WES), even
though initially the technique appears more likely to violate composition
claims. However, as in WGS, the genome is broken into very short fragments
prior to WES. The method thus never makes or uses the physical isolated gene-length DNA
fragments claimed in gene patent composition claims, and likely infringes as
few patents as WGS.)
In addition to the legal analysis, there are some practical
considerations that make it unlikely that gene patents will block widespread
WGS. Most significantly, WGS has been going on for several years, and there
have been no reports of specific gene patent holders trying to extract licenses
or block WGS. Indeed, given that gene patents cover only very small portions of
the genome, any successful infringement lawsuit would likely result only in
small required royalty payments, rather than an injunction blocking the
sequencing, making such a lawsuit not worth the time and cost of bringing it. Finally,
of course, patents are granted for a limited time, many gene patents have
expired, and it is much harder to get new gene patents. Gene patents, while
still important, are a dying breed.
Overall, several important issues may turn on the outcome of
the closely-followed Myriad case. But
the future of whole-genome sequencing is not one of them.
Editor’s note: This article is based on a more detailed analysis by the author
published in 2012 in the Cardozo Law Review.