By Donald Zuhn —

In an article published in
the current issue of Genome Medicine,
Jeffrey Rosenfeld of the University of Medicine & Dentistry of New Jersey
and Christopher Mason of Cornell University contend that due to the
non-specificity of sequence uniqueness across the genome and the broad scope of
claims to nucleotide sequences, the Supreme Court and Congress should limit the
patenting of existing nucleotide sequences ("Pervasive sequence patents cover the entire human genome," Genome Medicine 5:27 (2013)).  According to the two researchers, the Association for Molecular Pathology v.
Myriad Genetics, Inc. case affords the Supreme Court with an opportunity to
resolve the "sharp conflict between the public goods of medical knowledge and
improved health and the private goods of rewarding innovation and entrepreneurial
risk-taking" that is presented by gene patents.

The
authors begin by stating that "the broadest intellectual property rights
on BRCA sequences" come from four claims in Myriad's U.S. Patent No.
5,747,282:

1.  An
isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino
acid sequence set forth in SEQ ID NO:2.

2.  The isolated DNA of claim 1, wherein said DNA
has the nucleotide sequence set forth in SEQ ID NO:1.

5.  An isolated DNA having at least 15
nucleotides of the DNA of claim 1.

6.  An isolated DNA having at least 15
nucleotides of the DNA of claim 2.

The
article takes the Federal Circuit to task for (twice) "declar[ing] that even
a short, isolated DNA molecule such as 'ACGT' is different from the
'NNNNN-ACGT-NNNNN' present within a chromosome (AMP v. Myriad, Federal Circuit 2012), because it will not be
connected to sugar via a phosphodiester bond and will have a hydroxyl group instead
of a bond to a phosphate."  According
to the authors, the Federal Circuit's ruling means that "even a 15
nucleotide fragment of DNA in Claim #6 from Patent '282 is claimed to be
'markedly different'."

The
authors, however, find the Federal Circuit's ruling to be overly broad for
three reasons:

First, it relies on the sequences having chemical
features and side-chains that are not actually present in the patents . . . :
the claims are for a linear series of nucleotides, not a specific chemical
structure.  Second, if allowed to be so
broad, these claims could also create a monopoly on all epigenetic and chemical
variations of these sequences. Third, and perhaps most importantly, the
non-specificity of 15mer sequences creates unclear infringement liability that
has been even noted by the Court.

To
investigate this last point, the authors examined the incidence with which
15mers from a given gene matched 15mers in other genes using the Consensus
Coding Sequences (CCDS) database of 18,382 high-confidence genes.  This analysis showed that "every gene in
the CCDS database had a 15mer that matched the sequence of at least one other
gene," with the "[t]he number of matching genes ranged from as few as
5 (for MTRNR2L7) or 689 (for BRCA1) to as high as 7,688 (for TTN),
corresponding to 0.01%, 4%, and 42% of all genes in the human genome."  The authors note that 99.999% of 15mers in
the human genome are repeated at least twice.

According
to the authors, this analysis "demonstrate[s] that short patent sequences
are extremely non-specific and that a 15mer patent claim from one gene will
always 'cross-match' and patent a portion of another gene as well."  In support of this point, the authors
identified 58 patents whose claims covered at least 10% of the bases of all human
genes, with the claimed sequences of U.S. Patent No. 7,795,422
matching 91.5% of human genes, and the claimed bovine sequences of U.S. Patent
No. 7,468,248
matching 84% of human genes.  Arguing
that "[t]he demonstrated non-specificity of sequence uniqueness across the
genome suggests that the Supreme Court should use [the Myriad] case to clarify the law on gene patents," the authors
contend that "[i]f patent claims that use these 15mer or other short k-mer
sizes are enforced, it could potentially create a situation where a piece of
every gene in the human genome is patented by a phalanx of competing patents,
with potentially harmful consequences for genetic testing laboratories and
research groups performing targeted sequencing on any gene, in virtually all
species."

The
authors' conclusion regarding the broad scope of Myriad's 15mer claims,
however, is not particularly ground-breaking given that Kepler et al. similarly concluded in a 2010 Genomics paper that claim 5 of the '282
patent was "exceptionally broad" (see
"Caught in a Time Warp: The (In)validity of BRCA1 Oligonucleotide Claims").  Kepler et
al. suggested that "if human genes were random strings of nucleotides,
one would expect a human gene to contain an average of 15 15-mers claimed under
the ['282] patent," and in fact found that 80% of 713 human mRNAs
deposited in 1994 (the earliest effective filing date of the '282 patent is August 12, 1994) contained at least one of the claimed 15mers.  Thus, Kepler et al. indicates that claims 5 and 6 are sufficiently overbroad as
to be easily invalidated.  Because the analysis of Kepler et al. and Rosenfeld and Mason suggest that claims 5 and 6 of the '282 patent (and perhaps 15mer claims
in other patents) would likely not withstand an invalidity challenge, it is
unlikely that these claims will have the adverse impact on the "medical
good" suggested by the authors of the Genome
Medicine article.

One
interesting result presented in the Genome
Medicine article is that even longer nucleotide fragments from known genes
matched the sequence of sequences in other genes.  In particular, the paper points out that
"even 1,000 nucleotide fragments from known genes could still match 117
other genes."  However, the paper does not
present any additional information regarding the 1,000 nucleotide fragment (or
fragments) that yielded such matches.

Finally,
it should be noted that Dr. Mason submitted two declarations when the Myriad case was before the District
Court.  In a Supplemental Declaration
submitted in response to Myriad's brief and Statement of Material Facts, Dr.
Mason stated that claim 6 of the '282 patent was "so broad that it
includes at least 4% and as much as 100% of the genes in the human genome."