Guest
Post by Sean Brennan —
As
we all know by now, the Supreme Court last month decided that isolated genes
are not eligible for patenting. Although
seemingly drawing a clear-cut distinction between DNA molecules having the same
sequence as that which occurs in nature (genes), and DNA molecules having
different sequences from those that occur in nature (cDNA) (see
Patent Docs posts here
and here), the decision leaves
a host of unsettled questions about the patent-eligibility of numerous biologicals. Although ostensibly concerned with human
genes, the reasoning supporting the decision could be used to call into
question the patent-eligibility of compositions ranging from purified metabolites
(such as antibiotics) to isolated proteins to procaryotic genes.
Non-human
genes
Although
the question addressed by the Court was "Are human genes patentable?",
in its decision the Court couldn't seem to decide whether its decision applied strictly
to human genes or to genes in general. In framing the question, the Court stated that the case "requires
us to resolve whether a naturally occurring segment of . . . DNA is patent eligible . . . by virtue of its isolation from the rest of the human genome." (Slip.
Op. at 1, emphasis added). But in
announcing its decision, the Court appeared to have lost sight of the "human"
limitation when it stated: "we hold that a naturally occurring DNA segment
is a product of nature and not patent eligible merely because it has been
isolated" (Id.); "separating
[a] gene from its surrounding genetic material is not an act of invention"
(Id. at 12); and "[w]e merely
hold that genes and the information they encode are not patent eligible under §
101 simply because they have been isolated from the surrounding genetic
material" (Id. at 18).
Thus,
the decision leaves open the question of whether it is only human genes that
are not patent-eligible (i.e., did
the Supreme Court buy the "you can't patent my body" argument?) or is
any gene, from any organism, barred from patent eligibility? It is difficult to understand how the Court
could justify one standard for human genes and another for genes of other
species.
This
being the case, the decision would seem to doom the patent-eligibility of
procaryotic genes; the vast majority of which do not contain introns. Although it is possible to reverse-transcribe
a procaryotic mRNA molecule to generate a cDNA from a procaryotic gene, such a
nucleic acid molecule would not have a sequence different from the sequence of
the gene as it occurs in nature.
This
result would be unfortunate, since new bacterial species are being discovered
every day, and many of these contain genes encoding proteins that are useful
for processes such as pesticide production and bioremediation. It would also set up a technology-specific
distinction between biotechnological and pharmaceutical practice, in which it is
typical to obtain composition claims for the first disclosure of a new
compound.
Vectors
If
it is no longer possible to claim an isolated gene per se, might we still be able to claim a gene sequence as a
component of a vector? Unfortunately,
the decision provided no guidance on this point, because none of Myriad's
claims reciting BRCA genes as components of a vector or expression system (e.g., claims 8-11 of U.S. Patent No. 5,747,282)
were at issue. Although it is undisputed
that the combination of a gene with one or more of a heterologous promoter,
termination site, regulatory sequence(s), replication origin, or antibiotic
resistance marker is a composition that does not occur in nature; I worry that,
given the current judicial climate (see Mayo
v. Prometheus), addition of heterologous sequences to a newly isolated gene
will be dismissed as "insignificant post-solution activity." After all, cloning vectors and expression vectors
are standard materials that can be purchased from any one of a dozen or more
suppliers. Then again, it could turn out
that certain vectors (and/or heterologous sequences) will be considered
standard and others not, so that the patent eligibility of a gene might end up
depending upon what other sequences are attached to it. A good deal of biotech practice over the next
few years may well involve figuring out how much we need to "dress up"
a gene before it can be "taken out" into the realm of patent-eligibility.
Informational content
The
Court seemed to imply that identity of informational content
between a cloned gene and a naturally-occurring gene is what renders gene
sequences patent-ineligible; and not the (supposed) identity of chemical
structure between the two: "Myriad's
claims are simply not expressed in terms of chemical composition, nor do they
rely in any way on the chemical changes that result from the isolation of a
particular section of DNA. Instead, the
claims understandably focus on the genetic information encoded in the BRCA1 and
BRCA2 genes." (Slip Op. at 14-15). "Myriad . . . is concerned primarily with the information contained in the
genetic sequence, not with the
specific chemical composition of a particular molecule." (Id. at 15, emphasis in original).
If
this is the case, I wonder why even cDNA was found to be patent-eligible. Inasmuch as the informational content of most
DNA molecules resides in their ability to encode a polypeptide sequence, a cDNA
is no different in this respect from the intron-containing gene sequence from
which it is derived.
At
the risk of presenting a somewhat far-fetched example to make another point, I note
that it is possible to create recombinant gene sequences that do not have the
same chemical structure, but nonetheless contain the same informational
content, as a naturally-occurring gene.
For instance, certain bacteriophages contain hydroxymethyluracil (HMU)
instead of thymine in their DNA. Imagine
an enterprising geneticist who develops a cloning system, based on this
bacteriophage, that generates cloned DNA containing HMU instead of
thymidine. The cloned gene now has a
structure that does not occur in the natural gene — is it patent eligible? It would seem to depend on whether the criterion
is a different chemical structure or a different information content. Unfortunately the decision, while leaning
toward informational content, failed to provide a clear criterion.
Another
biological fact that seemed to get lost in the Myriad case is that naturally
occurring DNA sequences contain epigenetic informational content (the most
well-known example being methylation of cytosine residues) that is generally
not present in an isolated cloned gene. Consequently,
there are both structural (e.g., methyl
groups) and informational (gene methylation generally signals transcriptional repression)
differences between certain isolated genes and their naturally-occurring
counterparts. This being so, whatever
the Court's criterion for eligibility (structural difference or informational
difference), it would appear that at least some isolated DNA molecules remain
patent-eligible.
What is a mutant?
The
Court punted on the question of whether mutated sequences are patent-eligible
and, to make matters worse, provided scant guidance as to what types of sequences
they considered mutant and, thereby, at least potentially patent-eligible. The decision failed to comment specifically
on claims that recited naturally-occurring mutant BRCA sequences (claim 7 of
the '282 patent and claim 1 of U.S. Patent No. 5,693,473). But following the Court's "product of
nature" reasoning would lead to the conclusion that naturally-occurring
alleles of a gene (some of which might be "mutants" in the classical
sense of encoding a gene product with altered function) would not be
patent-eligible.
On
the other hand, isolated genes whose sequences have been altered in the
laboratory would appear to escape at least the "product of nature"
barrier to eligibility. The question
then arises as to whether a gene with a change in a single nucleotide (that
does not alter the amino acid sequence of the encoded polypeptide) would be
considered a "mutant." What
about a single nucleotide change that did result in an amino acid change? Would it make any difference if the new amino
acid encoded by the mutant sequence was a conservative or a non-conservative
substitution? Eventually, we may need to
know how large or significant a change in sequence is necessary to confer "mutant"
status on an isolated nucleic acid.
A
further complication is that assessing whether a laboratory-altered sequence is
different from a naturally-occurring sequence can present the patent applicant
with a moving target. Consider the
hypothetical heartbreaker in which an applicant constructs a mutant sequence in vitro that is found to be both
patent-eligible and patentable. Years
after the patent is granted, the same sequence is discovered in nature. Does the patentee's claimed mutant sequence
become retroactively ineligible?
Transformed cells
What
about a claim to a gene sequence that has been introduced into a heterologous
cell? Surely, this is a composition that
does not occur in nature. Although such
claims (e.g., claims 12 and 13 of the '282 patent) were not at issue in Myriad,
it was just such a composition that was validated as patent eligible by the
Supreme Court in Chakrabarty (albeit
the cell in that case comprised more than one heterologous nucleic acid), which
was cited favorably by the Myriad
Court. It's possible that, in the end,
this may be as close as we'll be able to get to a composition claim to a
newly-isolated gene. In many cases, this
may be good enough, since the principal use for most cloned genes is to express
their gene product and, in order to do so, the gene is often placed into a
heterologous cell for expression.
Proteins
The
Court's proscription of naturally-occurring substances would also seem to rule
out patent eligibility for isolated polypeptides. In most cases, the amino acid sequence of a
purified protein is exactly the same as the amino acid sequence of the
naturally-occurring protein. One
normally doesn't even have to break any chemical bonds to purify a protein
(thus failing the test for eligibility set forth by Judge Lourie in the
decision below). In the same way that "Myriad
did not create or alter any of the genetic information encoded in the BRCA1 and
BRCA2 genes" and "[t]he location and order of the nucleotides existed
in nature before Myriad found them"; the amino acid sequence of a
protein exists in nature before that protein is purified, and it is generally
not altered by the purification procedure.
Does
this mean that isolated proteins are also no longer patent-eligible? Maybe not, since, in some cases, there are
structural differences between isolated and naturally-occurring proteins
(assuming structural distinction is sufficient for eligibility — see above). For example, if an isolated protein is
obtained through expression of a recombinant nucleic acid, it often lacks certain
naturally-occurring post-translational modifications, such as glycosylation or
phosphorylation. This is particularly
true of a eukaryotic protein expressed in a procaryotic host cell. Thus, it may be possible to obtain a claim to
a polypeptide that lacks certain post-translational modifications, or contains
additional modifications not present on the naturally-occurring protein. Whether such a claim will have any value will
depend, of course, on whether the isolated protein, containing more or fewer
post-translational modifications than its naturally occurring counterpart,
functions effectively for its intended purpose.
Antibiotics and other naturally-occurring
compounds
Denial
of patent-eligibility to an isolated biological molecule, based on identity to
its naturally-occurring counterpart, will have repercussions well beyond the
field of molecular biology. As other
commentators have already pointed out, the Myriad
decision could sound the death knell for patent eligibility of all purified
naturally-occurring substances (such as antibiotics, certain chemotherapeutics,
and bacterial metabolites). In a
worst-case scenario, even chocolate chip cookies and baseball bats could become
patent-ineligible.
Conclusion
The
Myriad decision leaves me with a lot
to be pessimistic about. But on the
bright side, keeping my expectations low will at least minimize the chance that
I'll be disappointed. I give the Court
credit for trying to limit the breadth of its decision. Presumably, they wanted to come-up with a
clear-cut answer to a clear-cut question and thought they had done so by
accepting the Solicitor's and Judge Bryson's distinction between genomic DNA
and cDNA. But in so doing, the Court let
not just one, but a whole herd of elephants into the room. I have a feeling we'll be shoveling for quite
a while.
Dr.
Brennan is a Patent Agent with Brennan IP Services. He received a Ph.D. in Molecular Biology from
the University of California, San Diego in 1982, and prior to becoming a patent
practitioner, Dr. Brennan was a faculty member at the University of Connecticut
School of Medicine and the University of Southern California.
Patent Docs 
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