By
Donald Zuhn --
On
March 26, the Federal Circuit reversed the judgment of the District Court for
the District of Connecticut that U.S. Patent Nos. 5,328,824 and 5,449,767 are
invalid, affirmed the judgment of the District Court that U.S. Patent No.
5,476,928 is anticipated, and affirmed the judgment of the District Court that
5,082,830 is not infringed.
The
'824, '767, '928, and '830 patents, which are owned by Plaintiffs-Appellants
Enzo Biochem, Inc., Enzo Life Sciences, Inc., and Yale University
("Enzo"), are directed to various techniques for labeling and
detecting nucleic acids. More
particularly, the '824, '767, and '928 patents are directed to a compound, or a
method of using that compound as a detection probe. In this compound (shown below), a nitrogenous base B is
covalently attached, either directly or through a "linkage group"
(dotted line), to a chemical moiety A.
In
the asserted claims, the linkage group is recited functionally (rather than
structurally) as "not interfering substantially" with both
hybridization and detection (in the '824 and '767 patents) or detection alone (in the '928
patent). Chemical moiety A is
a label that facilitates detection, "compris[ing] at least three carbon
atoms and represent[ing] at least one component of a signalling moiety capable
of producing a detectable signal" (claim 1 of the '824 and '767 patents)
or "represent[ing] at least three carbon atoms and an indicator molecule
selected from the group consisting of fluorescent dyes, electron-dense
reagents, enzymes which can be reacted with a substrate to produce a visually
detectable reaction product, and radioisotopes" (claim 1 of the '928
patent). The '830 patent is
directed to a compound and a method of detection using a compound, wherein
the claimed compound is a nucleotide labeled with "at least one
non-radioactive moiety directly or indirectly attached to each of the 5′ and 3′
end nucleotides thereof," and the detection method is accomplished using a
"preformed detectable molecular complex."
In
June 2004, Enzo brought suit against Defendants-Appellees Applera Corp. and
Tropix, Inc. ("Applera") for infringement of the '824, '767, '928,
and '830 patents (as well as U.S. Patent Nos. 4,711,955 and 4,994,373, which
were not at issue in the appeal).
In October 2006, the District Court issued a claim construction ruling,
determining that the "not interfering substantially" functional language
for the linkage group means that "the linkage group neither substantially
interferes with the ability of the compound to hybridize with the nucleic acid
nor substantially interferes with the ability of [moiety] A to be detected." As for moiety A, the District Court
determined that for the '824 and '767 patents, "[moiety] A may be a part
of or the entire signalling moiety"; for the '928 patent, the plain
language of the patent "precludes a construction where A is the entire
[indicator] molecule"; and for the '830 patent, the term
"non-radioactive moiety" means "a moiety that is utilized in
indirect detection, i.e., a moiety that can be detected with a preformed
detectable molecular complex."
Enzo
conceded that under the District Court's construction, it could not prove
infringement of the '830 patent, and the District Court granted summary judgment of
noninfringement to Applera.
Applera then moved for summary judgment of lack of written description, lack of enablement, indefiniteness, and anticipation with respect to the three
remaining patents. The District
Court granted summary judgment of indefiniteness and anticipation, finding the
"not interfering substantially" language in the asserted claims to be
indefinite because "[t]he specifications neither set forth how one would
gauge substantial interference, nor delimit the threshold at which interference
with the procedure prevents [the claimed] method from being implemented,"
and determining that the asserted claims were anticipated by three references (Kasai
et al., 1979; Pingoud et al., 1977; and Bauman, 1980).
Indefiniteness
On
appeal, Enzo argued that the District Court incorrectly determined that the
"not interfering substantially" language in the '824, '767, and '928
patents is indefinite. In
particular, Enzo argued that the specifications provide specific examples of
linkage groups that do not substantially interfere with hybridization and
detection and a test for measuring the degree of interference (i.e., comparing the melting temperature
of a modified polynucleotide with that of an unmodified polynucleotide). Applera countered that nothing in the
patents explains how to measure "interference" or how to determine
whether such interference is "substantial."
In
determining that the claims of the '824 and '767 patents are not indefinite,
the Federal Circuit noted that "[t]he claims in this case provide at least
some guidance as to how much interference will be tolerated." Pointing to a dependent claim that
recites the structure –CH=CH–CH2–NH–,
the panel observed that "[a] person of ordinary skill would presume that a
structure recited in a dependent claim will perform a function required of that
structure in an independent claim," and "[t]hus, it may be presumed
that the term 'not interfering substantially' in the independent claims allows
for at least as much interference as that exhibited when the linkage group has
the structure specified in the dependent claims."
The panel also looked to examples of suitable
linkage groups, as well as criteria for selecting such linkage groups, disclosed
in the specification. For example,
the specification discloses that more preferred chemical linkage groups be
derived from a primary amine and have the structure –CH2–NH–, and
further, that thermal denaturation profiles and hybridization properties of a
polynucleotide can be used to measure the degree to which a linkage group
interferes with hybridization. In
view of the teachings in the specification, the panel concluded that the
specification indicates that "when a linkage group is incorporated into a
DNA strand having a length and sequence similar to those used in the
specification, a decrease in Tm of up to 5 oC implies that
the linkage group does not 'substantially interfere' with hybridization, and a
decrease of up to 15 oC is acceptable if the degree of cooperativity
and the extent of hyperchromicity are the same for the modified and unmodified
strands."
Finally, the panel noted that during the
prosecution of the patents, Enzo overcame an indefiniteness rejection by submitting
a declaration under 37 C.F.R. § 1.132 listing eight specific linkage groups,
including the –CH=CH–CH2–NH– group listed in the
patents' dependent claims. Thus,
the panel concluded that:
Because the intrinsic evidence here provides "a general guideline
and examples sufficient to enable a person of ordinary skill in the art to
determine [the scope of the claims]," the claims are not indefinite even
though the construction of the term "not interfering substantially" defines
the term without reference to a precise numerical measurement. When deciding whether a particular
linkage group is or is not "substantially" interfering with
hybridization within the meaning of the district court's construction, a person
of ordinary skill would likely look to the thermal denaturation profiles and
hybridization properties (including Tm) of the modified nucleotide,
to see whether they fall within the range of exemplary values disclosed in the
intrinsic evidence.
(citations omitted).
The Federal Circuit similarly found the claim
language not indefinite with respect to detection (Wherein the '824 and '767 patents
concern the effect of the linkage group on hybridization and detection, the
'928 patent only concerns the effect of the linkage group on detection.) In support of this additional finding,
the panel noted that the eight linkage groups listed in the declaration "were
said not to 'interfere[] with the ability of biotin in an oligo- or
polynucleotide probe of this invention to form a detectable complex with one of
avidin, streptavidin or antibodies to biotin or iminobiotin.'" Thus, the panel concluded that:
So long as moiety A can be detected within the level of detection
achieved by the applicants using the exemplary linkage groups disclosed in the
intrinsic evidence, a person of ordinary skill would understand that a
different linkage group (one that is not disclosed in the intrinsic evidence)
likewise does not "substantially interfere" with the detection of
moiety A.
Anticipation
The Federal Circuit next addressed the issue of
anticipation, finding that Enzo had raised a genuine issue of material fact as
to the Kasai et al. and Pingoud et al. references sufficient to survive
summary judgment of anticipation of the '824 and '767 patents, but that Enzo had failed
to raise a genuine issue of material fact with respect to the Bauman reference
and '928 patent. Looking at the
first two references, the panel noted that each "employ[s] a –CH2–NH–
linkage group, which arguably belongs to the set of linkage groups disclosed in
the patents-in-suit as 'even more preferred' embodiments," adding that
"[i]f unopposed, this evidence would entitle Applera to judgment as a
matter of law." At trial,
Enzo responded by offering an expert declaration stating that the –CH2–NH–
linkage group of Kasai et al. "would
not provide sufficient rigidity to prevent significant interference with
hybridization of a complementary polynucleotide," and "[i]ndeed, one
would predict based on the flexibility of this functional group and the
concomitant high degree of motion, there would be significant interference due
to free rotation about the single bonds."
On appeal, Applera argued that Enzo's expert declaration
could not be credited because it conflicted with Enzo's Rule 132 declaration,
and further, because Enzo's expert offered no support for his assertion that
Kasai et al. would substantially
interfere. The Federal Circuit,
however, determined that:
Viewing the [expert] declaration in a light most favorable to Enzo
requires that [the expert's] explanation be read as limited to the specific
one-carbon aminomethyl group [i.e., –CH2–NH–] disclosed in Kasai and
not as a sweeping condemnation of single bonds or an unyielding requirement of
double bonds. . . . [The expert's] statement that the
aminomethyl group disclosed in Kasai would substantially interfere and [the
Rule 132 declaration's] statement that a six-carbon diamine group would not are
not inconsistent, particularly when viewed in a light most favorable to Enzo,
as it must be.
The panel also noted that while Enzo's expert
focused on the impact of the nature of the bonds in the linkage group (i.e., single or double) on hybridization
and detection, the specification also recognizes that the length of linkage
group impacts hybridization and detection.
Lastly, the panel addressed Applera's argument that the –CH2–NH–
linkage group, which is described in Kasai et
al., was also within Enzo's "even most preferred" embodiments. In response, the Court determined that
Enzo's counterargument that "the 'even more preferred' language is
properly read as describing a subset of the preferred embodiments -- i.e.,
those with carbon-carbon double bonds at the α-positition -- such that the most
preferred embodiments have both a carbon-carbon double bond at the α-position,
and are derived from a primary amine and include a –CH2–NH– group,"
was reasonable and should have been credited on summary judgment.
Turning to Pingoud et al., the Court noted that "[o]n its face, Pingoud notes
that there was substantial interference with hybridization." In particular, the panel pointed to a
statement in the reference that "[c]odon-anticodon interaction . . . is
severely affected by the [fluorescent labeling] modification," stating
that "'[c]odon-anticodon interaction' is indicative of hybridization, and
'severely affected' suggests substantial interference." The panel therefore concluded that
there was a genuine issue of material fact as to whether the linkage group disclosed
in Pingoud et al. substantially
interferes with hybridization. The
Court also rejected Applera's argument that the –CH2–NH– linkage
group, which is similarly described in Pingoud et al., was within Enzo's "even most preferred"
embodiment.
Turning to the final reference, the panel noted
that in Bauman, hybridization is performed before moiety A is attached to base
B via the linkage group. Enzo
argued that in view of this chronology, Bauman did not anticipate the '928
patent. However, the Court
determined that "[i]t is irrelevant, for purposes of anticipation, what
method is used, much less what order of steps is used, to attach both moiety A
and the linkage group to base B."
The Court also noted that because the '928 patent is silent as to
hybridization, "[a]ll that is required of this particular linkage group is
that it not substantially interfere with the ability of A to be detected."
Infringement
Addressing the last issue on appeal (i.e., infringement of the '830 patent),
the Federal Circuit first reviewed the District Court's construction of the
term "non-radioactive moiety," which the lower court had found to
mean "a moiety that is utilized in indirect detection, i.e., a moiety that
can be detected with a preformed detectable molecular complex." The Federal Circuit found the District Court's construction to be reasonable, and affirmed the lower court's
judgment of noninfringement with respect to the '830 patent. In response to Enzo's argument that the
District Court's construction violated the doctrine of claim differentiation
because dependent claim 14 adds "a preformed detectable molecular
complex" to claim 1, the panel stated that:
[T]he district court's construction
imposes no requirement that a preformed detectable molecular complex is
actually present in claim 1; rather, it simply requires the "non-radioactive
moiety" to be capable of performing a function: "can be detected with a preformed detectable
molecular complex." Claim
Construction, 2006 WL 2927500, at *11 (emphasis added). Claim 1, unlike claim 14, is infringed
even in the absence of a preformed detectable molecular complex.
Enzo Biochem, Inc. v.
Applera Corp. (Fed. Cir. 2010)
Panel:
Chief Judge Michel and Circuit Judges Plager and Linn
Opinion
by Circuit Judge Linn
