Cornell University et al v. Illumina Inc.
Filing
449
REPORT AND RECOMMENDATIONS re claim construction. Please note that when filing Objections pursuant to Federal Rule of Civil Procedure 72(b)(2), briefing consists solely of the Objections (no longer than twenty-five (25) pages) and the Response to the Objections (no longer than twenty-five (25) pages). No further briefing shall be permitted with respect to objections without leave of the Court. Objections to R&R due by 5/23/2016. Signed by Judge Mary Pat Thynge on 5/6/16. (cak)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE
CORNELL UNIVERSITY, CORNELL
RESEARCH FOUNDATION, INC., LIFE
TECHNOLOGIES CORPORATION, and
APPLIED BIOSYSTEMS, LLC,
Plaintiffs,
v.
ILLUMINA, INC.,
Defendant.
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C. A. No. 10-433-LPS-MPT
REPORT AND RECOMMENDATION
I. INTRODUCTION
On May 10, 2010, Cornell University, Cornell Research Foundation, Inc.
(collectively, “Cornell”), Life Technologies Corporation (“Life Technologies”), and
Applied Biosystems, LLC (“Applied Biosystems”) (collectively, “plaintiffs”) brought this
action against Illumina, Inc. (“Illumina” or “defendant”), alleging infringement of several
patents.1 The currently asserted patents are in two distinct patent families, the Array
Patent family and the LDR-PCR Patent family. The patents in the Array Patent family
are U.S. Patent Nos. 7,083,917 (“the ‘917 patent”), 7,892,746 (“the ‘746 patent”),
7,893,233 (“the ‘233 patent), 8,288,521 (‘the ‘521 patent”), 8,624,016 (“the ‘016 patent”),
and 8,703,928 (“the ‘928 patent”).2 The patents in the LDR-PCR Patent family are U.S.
1
D.I. 1. Plaintiffs filed a First Amended Complaint on August 19, 2011 (D.I. 63),
a Second Amended Complaint on April 28, 2015 (D.I. 274), and a Third Amended
Complaint on August 7, 2015 (D.I. 298).
2
D.I. 419 at 1 n.1. The specifications of the Array Patent family are identical in
substance, and citations to the common specification are generally made to the ‘917
Patent Nos. 6,797,470 (“the ‘470 patent”), 7,166,434 (“the ‘434 patent”), 7,312,039 (“the
‘039 patent”), 7,332,285 (“the ‘285 patent”), and 7,429,453 (“the ‘453 patent”).3 The
remaining asserted claims are: claim 4 of the ‘470 patent; claims 1, 2, and 18 of the
‘917 patent; claim 5 of the ‘434 patent; claim 5 of the ‘039 patent; claim 3 of the ‘285
patent; claim 10 of the ‘453 patent; claims 1 and 2 of the ‘746 patent; claims 1, 2, 4, 5,
7, 8, 13, 15, and 26 of the ‘233 patent; claims 18 and 19 of the ‘521 patent; claims 1, 2,
3, 5, 13, and 18 of the ‘016 patent; and claims 1, 2, and 3 of the ‘928 patent.4
A Markman hearing was held on February 22, 2016. The court’s construction of
disputed claim terms is set forth below.
II.
CLAIM CONSTRUCTION
The asserted patents cover instruments and methods for determining whether a
certain DNA sequence is present in a sample. The Abstract of the Array Patent family
recites:
The present invention describes a method for identifying one or more of a
plurality of sequences differing by one or more single base changes,
insertions, deletions, or translocations in a plurality of target nucleotide
sequences. The method includes a ligation phase, a capture phase, and
a detection phase. The ligation phase utilizes a ligation detection reaction
between one oligonucleotide probe, which has a target sequence-specific
portion, and a second oligonucleotide probe, having a target sequencespecific portion and a detectable label. After the ligation phase, the
capture phase is carried out by hybridizing the ligated oligonucleotide
probes to a solid support with an array of immobilized capture
oligonucleotides at least some of which are complementary to the
addressable array-specific portion. Following completion of the capture
patent.
3
Id. at 1 n.2. The specifications of the LCR-PCR Patent family are identical in
substance, and citations to the common specification are generally made to the ‘470
patent.
4
Id. at 1 n.3.
2
phase, a detection phase is carried out to detect the labels of ligated
oligonucleotide probes hybridized to the solid support. The ligation phase
can be preceded by an amplifications process. The present invention also
relates to a kit for practicing this method, a method of forming arrays on
solid supports, and the supports themselves.5
The Abstract of the LDR-PCR Patent family recites:
The present invention relates to the detection of nucleic acid sequence
differences using coupled ligase detection reaction and polymerase chain
reaction. One aspect of the present invention involves use of a ligase
detection reaction coupled to a polymerase chain reaction. Another
aspect of the present invention relates to the use of a primary polymerase
chain reaction coupled to a secondary polymerase chain reaction coupled
to a ligase detection reaction. A third aspect of the present invention
involves a primary polymerase chain reaction coupled to a secondary
polymerase chain reaction. Such coupling of the ligase detection reaction
and the polymerase chain reaction permits multiplex detection of nucleic
acid sequence differences.6
The parties agree to the construction of the following claim terms.
“Oligonucleotide probe set(s)” means “oligonucleotide sequences that hybridize
to a target sequence in a ligase detection reaction.”
“Primer-specific portion” means “portion of an oligonucleotide capable of
hybridizing to a nucleotide sequence used to initiate PCR amplification.”
“Ligation product sequence(s)” and “ligation product(s)” mean “oligonucleotide
sequence(s) resulting from a ligase detection reaction.”
“Composite oligonucleotides” means “an oligonucleotide having to or more
portions.”
Based on the parties’ agreement as to the meaning of those terms, the court
adopts the parties’ proposed constructions.
5
6
‘917 patent, Abstract.
‘470 patent, Abstract.
3
The meanings of the following claim terms are in dispute.
1.
“solid support”
Representative claim 1 of the ‘917 patent recites:
1. A device comprising:
a solid support having an array of positions each suitable for attachment of
an oligonucleotide probe;
a linker suitable for coupling an oligonucleotide probe to the solid support
at each of the array positions; and
an array of capture oligonucleotide probes on the solid support at the
array positions, said capture oligonucleotide probes each having greater
than sixteen nucleotides and able to bind to complementary nucleic acids
at uniform hybridization conditions, wherein each capture oligonucleotide
probe of the array differs in sequence from its adjacent capture
oligonucleotide probe, when aligned to each other by at least 25% of the
nucleotides.7
Plaintiffs’ proposed construction is: “solid-phase substrate.”
Defendant’s proposed construction is: “a single unitary substrate.”
The parties agree the construction of “solid support” includes “substrate,” but
disagree whether the substrate comprises one or more components or structures
(plaintiffs) or just a “single unitary” structure (defendant).8
Plaintiffs state the specification provides for beads or slides to be used
individually or together as supports and describes coupling oligonucleotides to a solid
support via another solid support.9 They argue, therefore, that a combination of
supports is within the scope of the claims.10 Defendant maintains a person of ordinary
7
‘917 patent, claim 1 (emphasis added).
D.I. 419 at 32.
9
Id. at 34.
10
Id.
8
4
skill in the art reading the intrinsic evidence, including the prosecution history, would
understand the claims do not cover the use of intermediate supports coupling the
oligonucleotide to the solid support.11 The court agrees with defendant that the “solid
support” is “a single unitary substrate.”
In support of their position, plaintiffs rely on the specification’s statement that
“[t]he solid support can be made from a wide variety of materials. The substrate may be
biological, nonbiological, organic, inorganic, or a combination of any of these, existing
as particles, strands, precipitates, gels, sheets, tubing, spheres, containers, capillaries,
pads, slices, films, plates, slides, discs, membranes, etc.”12 As defendant explained
during the Markman hearing, however, the “combined” reference is to composite
materials, for instance a slide coated with a polymer, which is nevertheless a unitary
structure like a piece of plywood is a unitary structure.13 The specification describes
such composite: “[p]olymer-coated slides were tested for their capture capacity of
addressable oligonucleotide probes following different procedures for immobilization of
capture oligonucleotides.”14 Those “polymer-coated slides” are a unitary structure.
Plaintiffs also rely on the specification’s statement that:
Yet another aspect of the present invention relates to an array of
oligonucleotides on a solid support per se. The solid support has an array
of positions each suitable for attachment of an oligonucleotide. A linker or
support (which can be non-hydrolyzable), suitable for coupling an
oligonucleotide to the solid support, is attached to the solid support at
11
Id.
‘917 patent, 22:1-6 (emphasis added).
13
Markman Tr. at 65:6-19; see also D.I. 419 at 40 n.12.
14
‘917 patent, 51:15-17; see also ‘917 patent, 22:34-35 (“Surfaces on the solid
substrate will usually, though not always, be composed of the same material as the
substrate.”).
12
5
each of the array positions.15
That passage indicates the “linker” or “support” for coupling an oligonucleotide to
the “solid support” are distinct, separate, structures; not that “support” is a species of
“linker” as plaintiffs suggest.16 The specification thus contemplates use of a linker or a
support to couple an oligonucleotide to the solid support. That use of an intervening
support structure, however, was foreclosed during prosecution. The patentees
originally attempted to claim either a linker or a support for oligonucleotide coupling.
During prosecution, claim 120 of the application leading to the ‘917 patent claimed “a
linker or support for coupling an oligonucleotide to the solid support attached to the solid
support at each of the array positions.”17 The examiner rejected that claim as indefinite,
stating:
Claim 120 is indefinite by reciting “a linker or support suitable for coupling
an oligonucleotide probe to the solid support . . .”, it is not clear what does
applicants [sic] mean by support suitable for coupling to the solid support.
Does applicants mean the oligonucleotide is coupled to the solid support
by using a different support[?] Applicants are requested to amend the
claim.18
In response to that rejection, the patentees amended the claims to remove the words
“or support” from the limitation clarifying that the oligonucleotides are coupled to the
solid support using only a “linker”19 and stated to the patent office “[t]he rejection of
15
‘917 patent, 6:37-43 (emphasis added).
Elsewhere in the specification, “supports” and “linkers” are also distinguished.
See, e.g., ‘917 patent, 26:13-18 (“DNA oligonucleotides can be synthesized and
terminated with a residue of the amino acid tryptophan, and conjugated efficiently to
supports that have been modified by tris(alkoxy)benzyl ester (hypersensitive acid labile
(‘HAL’)) or tris(alkoxy)benzylamide (‘PAL’) linkers.”) (emphasis added).
17
D.I. 421 at A1548 (emphasis added).
18
Id. at A1399-1400.
19
Id. at 1416.
16
6
claims 120-125, 128, and 136-137 under 35 U.S.C. § 112 (2nd para.) for indefiniteness
is respectfully traversed in view of the above amendments.”20 The court agrees with
defendant that, in addition to reviewing the specification, the amendment removing “or
support” in response to the examiner’s question of whether the original language of
application claim 120 was meant to indicate an oligonucleotide was coupled to the solid
support by using a different support, a person of ordinary skill in the art would
understand that a “solid support” means a single unitary object without any intermediate
supports.21
The court adopts defendant’s proposed construction that “solid support” means
“a single unitary substrate.”
2.
“array of positions”
Representative claim 1 of the ‘928 patent recites:
1. An instrument comprising:
a solid support comprising at least 25 types of capture oligonucleotides
immobilized on the solid support at an array of positions, wherein each
type of capture oligonucleotide is greater than 16 oligonucleotides and
differs in nucleotide sequence, when aligned to another type of capture
oligonucleotide on an adjacent position of said solid support, by at least
25%;
20
Id. at 1424.
See, e.g., Tr. of Columbia Univ. v. Symantec Corp., 811 F.3d 1359, 1363 (Fed.
Cir. 2016) (“Our case law does not require explicit redefinition or disavowal. See., e.g.
Aventis Pharma S.A. v. Hospira, Inc., 675 F.3d 1324, 1330 (Fed. Cir. 2012) (‘This clear
expression need not be in haec verba but may be inferred from clear limiting
descriptions of the invention in the specification or prosecution history.’).”); Schindler
Elevator Corp. v. Otis Elevator Co., 593 F.3d 1275, 1285 (Fed. Cir. 2010) (“[A]n
amendment that clearly narrows the scope of a claim, such as by the addition of a new
claim limitation, constitutes a disclaimer of any claim interpretation that would effectively
eliminate the limitation or that would otherwise recapture the claim’s original scope.”).
21
7
one or more nucleic acid molecules hybridized to complementary portions
of the one or more capture oligonucleotides on said solid support, wherein
the capture oligonucleotides hybridize to the complementary portions of
the nucleic acid molecules under uniform hybridization conditions; and
an imager configured to detect the hybridized nucleic acid molecules.22
Plaintiffs’ proposed construction is: “arrangement of positions”
Defendant’s proposed construction is: “positions organized in known locations.”
The parties disagree whether the positions of the array can be either random or
pre-defined (plaintiffs) or must be pre-defined (defendant).23
Plaintiffs contend defendant’s proposed construction improperly imposes a
temporal requirement on the “array of positions,” i.e. that the positions of each
oligonucleotide be known before they are attached to the solid support.24 They maintain
nothing in the patent requires the oligonucleotides to be placed at a pre-determined
location rather than at a location determined after the solid support is manufactured.25
In briefing, plaintiffs also maintained that “Illumina correctly states that, by having
discrete locations for attachment on the array, a spacial relationship can be observed
between the oligonucleotides attached to the solid support,” but reiterated “the specific
identity and position of the oligonucleotides at each discrete spot can be determined
before or after the oligonucleotides are attached to the array.”26 At the Markman
hearing they stated there was no dispute that when an array is used one must know
22
‘928 patent, claim 1 (emphasis added).
D.I. 419 at 42.
24
Id. at 46.
25
Id.
26
Id. at 48.
23
8
which oligonucleotide is where on the array.27
At the hearing, defendant explained its proposed construction did not require the
positions be pre-determined, just that those positions are known.28 It also stated its
construction was not about how the arrays are manufactured.29
Because the parties agree that when the arrays are used the positions of the
oligonucleotides must be known, and with defendant’s representation that its
construction does not set a temporal limit (does not require pre-determination of
oligonucleotide positions) or relate to how the solid supports are manufactured, the
court adopts defendant’s proposed construction of “array of positions” to mean
“positions organized in known locations.”
3.
Claim Terms Related to the Connection of Oligonucleotides to the Solid Support
This group of terms relate to oligonucleotides being connected to a solid
support.30
a.
“linker”
Representative claim 1 of the ‘917 patent recites:
27
Markman Tr. at 71:15-17 (“There’s no dispute that when you use the array, you
have to know which oligonucleotide is where.”); 72:3-4 (“So there’s no dispute that when
you use the array you have to know which one is there.”); 72:15-17 (“They have to be
known before you use them, but they don’t have to be known before you put them on
the array.”); 75:17-20 (“In fact, before any of those arrays are used, they determine
where the positions are. It’s just not a known location ahead of time . . . .”).
28
Markman Tr. at 73:21-22 (“We’re not saying pre-determined our proposal is
known.”); 74:10-14 (“So we’re not asking the Court to construe it to be pre-determined,
but they do have to me known, fixed locations as an array of positions because that’s
how the whole patent makes sense.”).
29
Markman Tr. at 74:23-75:2 (“We’re not talking about how it’s manufactured.
We’re talking about the idea of known locations”).
30
D.I. 419 at 51.
9
1. A device comprising:
a solid support having an array of positions each suitable for attachment of
an oligonucleotide probe;
a linker suitable for coupling an oligonucleotide probe to the solid support
and attachment to the solid support at each of the array positions; and
an array of capture oligonucleotide probes on the solid support at the
array positions, said capture oligonucleotide probes each having greater
than sixteen nucleotides and able to bind to complementary nucleic acids
at uniform hybridization conditions, wherein each capture oligonucleotide
probe of the array differs in sequence from its adjacent capture
oligonucleotide probe, when aligned to each other by at least 25% of the
nucleotides.31
Representative claim 15 of the ‘233 patent recites:
15. The device according to claim 7, wherein a linker couples the capture
oligonucleotides to the solid support.32
Plaintiffs’ proposed construction is: “feature that connects an oligonucleotide to a
solid support.”
Defendant’s proposed construction is: “a molecule that covalently binds an
oligonucleotide to the solid support without an intervening support.”
Defendant states the critical difference in the parties’ proposed constructions is
whether a “linker” is a chemical molecule (defendant) or a “feature” which would allow a
linker to be something else, such as an intervening solid structure, like a bead, between
the oligonucleotide and the solid support (plaintiffs).33
Defendant’s proposed construction defines a linker as “a molecule that covalently
31
‘917 patent, claim 1 (emphasis added).
‘233 patent, claim 15 (emphasis added).
33
D.I. 419 at 53.
32
10
binds an oligonucleotide to the solid support without an intervening support.”34 Plaintiffs
note the specification discloses linkers that result in both covalent and non-covalent
interactions. The specification describes covalent linkages when stating “linker
molecules can be attached to the substrate via carbon–carbon bonds . . . or, preferably,
by siloxane bonds” or as parts of a polymer on the substrate.35 It also discloses noncovalent linkages in “alternative embodiments” where “the linker molecules are
absorbed to the surface of the substrate.”36 Plaintiffs argue their construction provides
for linkers that result in both covalent and non-covalent interactions.37 They state that
construction also embraces intervening structures for connecting oligonucleotides to
solid supports.38
The court has determined in its construction of the term “solid support,” above,
that the claims do not cover intervening structures, like an additional support, for
connecting oligonucleotides to solid supports. As plaintiffs’ proposed constructions for
“linker” and the other terms in this group would cover intervening structures, the court
rejects those proposed constructions. The court now addresses plaintiffs’ additional
criticisms of defendant’s proposed constructions.
In addition to the purportedly improper exclusion of non-covalent connections,
the disclosed absorption of the linker molecules to the surface of the substrate, plaintiffs
argue defendant improperly limits the claimed linkers to “linker molecules.” That
34
Emphasis added.
‘917 patent, 25:44-52.
36
‘917 patent, 25:52-54. Defendant acknowledges that absorption is different
from covalent bonding and hybridization. D.I. 419 at 57 n.20.
37
D.I. 419 at 51.
38
Id.
35
11
criticism is based on plaintiffs’ contention that in addition to linker molecules which can
only be attached to a solid support through “chemical” linkers, plaintiffs assert
attachment may be made through an “intervening solid structure.” The court has
rejected that argument.39 Because there is no other description in the patent of linkers
other than linker molecules attached to the support through chemical bonds, the court
adopts defendant’s proposed constructions for linker and the other terms in this group.
The court modifies defendant’s proposed constructions for “linker” and “attached” to
reflect the possibility of absorption in light of the specification’s recitation that “[i]n
alternative embodiments, the linker molecules are absorbed to the surface of the
substrate.”40
The court adopts defendant’s proposed construction of “linker,” as modified, to
mean “a molecule that covalently binds an oligonucleotide to the solid support, or is
absorbed thereto, without an intervening structure.”
b.
“immobilized”
Plaintiffs’ proposed construction is: “restricted in mobility.”
39
In further support of their contention that linkers can be either solid or chemical,
plaintiffs cite the statement in the specification that the inventors contemplated “great
flexibility in . . . attachment [of oligonucleotides] to solid supports.” D.I. 419 at 51, 58
(quoting ‘917 patent, 43:12-14). As defendant points out, however, the entire passage
refers not to flexibility in designing a linker as a solid support, but rather to flexibility in
manufacturing oligonucleotides either on or off the support, and then subsequently
attaching them to the solid support. The full passage reads: “The present invention
also affords great flexibility in the synthesis of oligonucleotides and their attachment to
solid supports. Oligonucleotides can be synthesized off of the solid support and then
attached to unique surfaces on the support. Segments of multimers or oligonucleotides,
which do not require intermediate backbone protection (e.g., PNA), can be synthesized
and linked onto the solid support.” ‘917 patent, 43:12-18 (emphasis added).
40
‘917 patent, 26:52-54.
12
Defendant’s proposed construction is: “covalently bound or bound via
hybridization.”
Court’s construction: “covalently bound or bound via hybridization.”
c.
“attached”
Plaintiffs’ proposed construction is: “connected.”
Defendant’s proposed construction is: “covalently bound.”
Court’s construction: “covalently bound or absorbed.”
d.
“suitable for attachment”
Plaintiffs’ proposed construction is: “capable of being connected.”
Defendant’s proposed construction is: “functionalized to permit covalent
bonding.”
Court’s construction: “functionalized to permit covalent bonding.”
e.
“coupled to”
Plaintiffs’ proposed construction is: “connected to.”
Defendant’s proposed construction is: “covalently bound or bound via
hybridization.”
Court’s construction: “covalently bound or bound via hybridization.”
4.
“capture oligonucleotide probes” / “capture oligonucleotide(s)” / “capturing said
one or more amplification product to a solid support”
Representative claim 1 of the ‘917 patent recites:
1. A device comprising:
a solid support having an array of positions each suitable for attachment of
an oligonucleotide probe;
a linker suitable for coupling an oligonucleotide probe to the solid support
13
at each of the array positions; and
an array of capture oligonucleotide probes on the solid support at the
array positions, said capture oligonucleotide probes each having greater
than sixteen nucleotides and able to bind to complementary nucleic acids
at uniform hybridization conditions, wherein each capture oligonucleotide
probe of the array differs in sequence from its adjacent capture
oligonucleotide probe, when aligned to each other by at least 25% of the
nucleotides.41
Representative claim 1 of the ‘746 patent recites:
1. A method comprising:
providing an array of a plurality of capture oligonucleotides wherein each
type of capture oligonucleotide is greater than 16 nucleotides and differs in
nucleotide sequence, when aligned to another type of capture
oligonucleotide, by at least 25%, wherein said capture oligonucleotides are
coupled to a support;
providing a sample comprising a plurality of target oligonucleotides, each
target oligonucleotide comprising (i) an addressable array-specific portion,
(ii) a further nucleotide sequence, and (iii) a detectable reporter label;
contacting the sample comprising the plurality of target oligonucleotides
with the array of capture oligonucleotides under uniform hybridization
conditions effective to hybridize the addressable array-specific portion of
each target oligonucleotide to its complementary capture oligonucleotide;
and
detecting the reporter labels of one or more of the plurality of target
oligonucleotides hybridized to their complementary capture
oligonucleotides on the solid support.42
a.
“capture oligonucleotide probes” / “capture oligonucleotide(s)”
Plaintiffs’ proposed construction is: “oligonucleotide capable of hybridizing to a
complementary nucleic acid.”
Defendant’s proposed construction is: “oligonucleotide [probe] which has no
41
42
‘917 patent, claim 1 (emphasis added).
‘746 patent, claim 1 (emphasis added).
14
homology to a target sequence and is complementary to the addressable array specific
portion of an oligonucleotide containing an addressable array specific portion and a
target specific portion.”
The parties disagree whether the capture oligonucleotide (probe) can be any
sequence capable of hybridizing to a complementary nucleic acid (plaintiff) or must be a
sequence that lacks homology43 to a target sequence and only hybridizes to a specific
portion of an oligonucleotide of the array (defendant).44
The Federal Circuit recently reiterated “[t]he only meaning that matters in claim
construction is the meaning in the context of the patent.”45 “‘[W]hen the scope of the
invention is clearly stated in the specification, and is described as the advantage and
distinction of the invention it is not necessary to disavow explicitly a different scope.’”46
Plaintiffs argue the claim language supports their construction because the term
“homology” is never used in any of the claims and not all of the asserted claims include
the requirement that the capture oligonucleotide hybridizes to the addressable arrayspecific portion of the target oligonucleotide.
That none of the asserted claims recite the term “homology” is not determinative
43
“Homology” refers to the level of similarity between two nucleotide sequences.
D.I. 419 at 66 n.22.
44
Id. at 64.
45
Tr. of Columbia Univ. v. Symantec Corp., 811 F.3d 1359, 1363 (Fed. Cir. 2016)
(citation omitted); see also Netword, LLC v. Centraal Corp., 242 F.3d 1347, 1352 (Fed.
Cir. 2001) (“The claims are directed to the invention that is described in the
specification; they do not have meaning removed from the context from which they
arose.”).
46
Columbia Univ., 811 F.3d at 1364 (alteration in original) (quoting On Demand
Mach. Corp. v. Ingram Indus., Inc., 442 F.3d 1331, 1340 (Fed. Cir. 2006)).
15
as the claims “must be read in view of the specification, of which they are a part.”47
“[T]he specification is always highly relevant to the claim construction analysis. Usually
it is dispositive; it is the single best guide to the meaning of a disputed term.”48
Plaintiffs also state Illumina’s proposed construction requiring the “oligonucleotide
[probe] . . . [to be] complementary to the addressable array specific portion of an
oligonucleotide containing an addressable array specific portion and a target specific
portion” might be appropriate if all the asserted claims included such limitations, as does
representative claim 1 of the ‘746 patent.49 All asserted claims, however, do not recite
those limitations. For instance, representative claim 1 of the ‘917 patent does not
require the oligonucleotide probe to have those limitations and asserted claim 18 of ‘917
patent, depending from claim 1, merely requires the “capture oligonucleotide probes”
need only “hybridize” to other oligonucleotides.50 Similarly, claim 1 of the ‘233 patent
recites the “capture oligonucleotide” hybridizes to any “nucleic acid molecule” that has
“a complementary nucleotide sequence.”51 The differences in the recited limitations of
the claims plaintiffs cite are also not determinative. To the extent plaintiffs basing their
argument on the doctrine of claim differentiation, that doctrine is not a “hard and fast
rule of construction” and “cannot broaden claims beyond their correct scope,
47
Phillips v. AWH Corp., 415 F.3d 1303, 1315 (Fed. Cir. 2005) (en banc) (citation
and internal quotation marks omitted).
48
Id. (citation an internal quotation marks omitted).
49
D.I. 419 at 64-65.
50
‘917 patent, claim 18 (“The device according to claim 1, wherein the array is
reusable for repeatedly hybridizing oligonucleotides to the array of capture
oligonucleotides probes on the solid support.”).
51
‘233 patent, claim 1 (“[E]ach capture oligonucleotide of the collection hybridizes
to a nucleic acid molecule comprising a complementary nucleotide sequence under
uniform hybridization conditions.”).
16
determined in light of the specification and the prosecution history and any relevant
extrinsic evidence.”52 Whether or not plaintiffs are basing their argument on that
doctrine:
Ultimately, the interpretation to be given a term can only be determined and
confirmed with a full understanding of what the inventors actually invented and
intended to envelop with the claim. The construction that stays true to the claim
language and most naturally aligns with the patent’s description of the invention
will be, in the end, the correct construction.53
The intrinsic record demonstrates the claimed invention was an addressable, or
universal, array and was meant to improve on prior detection techniques using
hybridization arrays where false positive and false negative results could occur due to
cross-hybridization. The ‘917 patent is titled “Detection of Nucleic Acid Sequence
Differences Using the Ligase Detection Reaction with Addressable Arrays,” and the
specification states “[t]he array of the present invention will be universal, making it
useful for detection of cancer mutations, inherited (germline) mutations, and infectious
diseases.”54 During prosecution, the applicants touted the advantage of the claimed
invention over prior art hybridization arrays. “In a direct hybridization array, the capture
probes, which are covalently linked to the array surface, are complementary to
52
Seachange Int’l, Inc. v. C-COR Inc., 413 F.3d 1361, 1369 (Fed. Cir. 2005)
(citation omitted); see also Atlas IP, LLC v. Medtronic, Inc., 809 F.3d 599, 606-07 (Fed.
Cir. 2015) (“[W]e have been cautious in assessing the force of claim differentiation in
particular settings, recognizing that patentees often use different language to capture
the same invention, discounting it where it is invoked based on independent claims
rather than the relation of an independent and dependent claim, and not permitting it to
override the strong evidence of meaning supplied by the specification.”).
53
Phillips, 415 F.3d at 1316 (emphasis added) (citation omitted).
54
‘917 patent, 43:7-9.
17
sequences within the gene or target nucleotides to be interrogated.”55
The present invention is directed to the use of an array designed to
overcome the problems associated with false positive and false negative
results generated by direct hybridization arrays when using LDR. An
addressable array uses capture probes that are de novo sequences
separate and distinct from the nucleic sequences of interest.56
The applicants repeatedly distinguished their addressable arrays from prior art
hybridization arrays that they viewed as unsatisfactory.
I am presenting this declaration to demonstrate how the efforts of others in
the art to develop a hybridization array-based detection assay to meet this
need[, accurate detection of cancer related mutations,] have failed, and
continue to fail, and how the method of my present application has
overcome these failures and successfully resolved this unmet and long-felt
need.57
Chee teaches arrays of nucleic acid probes on biological chips that are
useful for determining whether a target nucleic acid is identical to or
different from a specific reference nucleic acid sequence. The array
contains probes that are exactly complementary to the reference
sequence, as well as probes that differ by one or more bases from the
exactly complementary sequence. The Chee array is exemplary of the
direct hybridization arrays discussed in paragraphs 8-9 above and subject
to the constraints of these arrays as discussed in paragraphs 10-22.58
The implications of Pozhitkov’s and Naiser’s findings are that direct
hybridization methods which attempt to simultaneously discriminate and
detect nucleic acid sequence variations are inadequate because of the
unpredictable cross-hybridization between target sequence and
mismatched or perfect match probe sequences.59
55
D.I. 421 at A1758 (‘981 FH 10/31/07 Gerry Decl. at ¶ 27 (“10/31/07 Gerry
Decl.”)). Dr. Norman Gerry was a Post-Doctoral Research Associate in Francis
Barany’s Laboratory from September 1996 until June 2001 and submitted a declaration
as an “expert” during prosecution of the ‘981 patent. Id. at A1751 (10/31/07 Garry Decl.
at ¶ 3). Dr. Francis Barany is a named inventor of the patents-in-suit.
56
Id. at A1761 (10/31/07 Gerry Decl. at ¶ 31).
57
Id. at A1616-17 (‘981 FH 2/25/10 Barany Decl. at ¶ 5 (“2/25/10 Barany Decl.”)).
58
Id. at A1627 (2/25/10 Barany Decl. at ¶ 25) (emphasis added).
59
Id. at A1625 (2/25/10 Barany Decl. at ¶ 22) (emphasis added); see also id. at
A1754 (10/31/07 Gerry Decl. at ¶ 11) (“Therefore, it is logical that Barany contemplated
18
The applicants again touted the superiority of the claimed invention over
hybridization arrays.
The present invention teaches a method of identifying one or more
sequences, differing by one or more single base changes, insertions,
deletions, or translocations, in a sample containing a plurality of target
nucleotide sequence that avoids all of the aforementioned problems
associated with typical hybridization arrays (i.e., target-capture probe
cross-hybridization and false-positive/negative signal generation).60
Plaintiffs’ proposed construction of the “capture oligonucleotides” terms is
“oligonucleotide capable of hybridizing to a complementary nucleic acid.” They
characterize that construction as meaning “the capture oligonucleotide (probe) can be
any sequence capable of hybridizing to a complementary nucleic acid.”61 That
construction would cover hybridization arrays that were repeatedly distinguished during
prosecution as not being what was described and claimed in the Array Patent family.
Consequently, plaintiffs’ proposed construction is rejected. The court will next
determine whether defendant’s construction requiring no homology and
complementarity is supported by the intrinsic evidence.
The intrinsic evidence, and extrinsic evidence in the form of deposition testimony
using the target DNA sequence itself to capture the target sequence (i.e. direct
hybridization) as describe by others.”) (distinguishing prior art Barany reference); id. at
A1757 (10/31/07 Gerry Decl. at ¶ 22) (“This embodiment of Bouma, in which an
immobilized hybridization probe having sequence complementarity to the target
sequence directs the capture and detection of the target, is characteristic of a direct
hybridization array.”) (distinguishing prior art Bouma reference); id. at A1758 (10/31/07
Gerry Decl. at ¶ 25) (“Like Bouma, the terminal sorting embodiment of Chetverin is
similar to a direct hybridization array where hybridization of the target sequence to an
immobilized probe occurs via a target specific sequence.”) (distinguishing prior art
Chetverin reference).
60
Id. at A1630 (2/25/10 Barany Decl. at ¶ 30) (emphasis added).
61
D.I. 419 at 64 (emphasis added).
19
of named inventor Dr. George Barany, support defendant’s argument that the capture
oligonucleotides have no homology to a target sequence. The ‘917 patent specification
states:
The 1,000 different addresses can be unique capture oligonucleotide
sequences (e.g., 24-mer) linked covalently to the target-specific sequence
(e.g., approximately 20- to 25-mer) of a LDR oligonucleotide probe. A
capture oligonucleotide sequence does not have any homology to either
the target sequence or to other sequences on genomes which may be
present in the sample. This oligonucleotide probe is then captured by its
addressable array-specific portion, a sequence complementary to the
capture oligonucleotide on the addressable solid support array.62
That there be no homology was made clear during the prosecution of the ‘917
patent family. Dr. Barany stated “array hybridization is carried out using divergent
capture probe sequences that are not homologous to the target sequence being
detected or any other known genomic sequence.”63 Dr. Gerry also noted “[a]n
addressable array uses capture probes that are de novo sequences separate and
distinct from the nucleic acid sequences of interest.”64
Finally, Dr. Barany testified it was the inventors’ goal to design around the
problems associated with hybridization arrays.
Q.
What do you mean by “minimal sequence homology with the
natural genome”?
A.
So one of the problems is–of hybridization technologies before our
invention of the universal arrays was that the–the detection step
62
‘917 patent, 20:62-21:4 (emphasis added).
D.I. 421 at A1630 (2/25/10 Barany Decl. at ¶ 30).
64
Id. at A1761 (10/31/07 Gerry Decl. at ¶ 31); see also id. at A1760 (10/31/07
Gerry Decl. at ¶ 29) (“Sequence homology between the capture probes and likewise
between the target sequences can jeopardize the specificity of target/probe
hybridization and lead to the generation of both false positive and false negative results
as illustrated in Figure 3 below.”).
63
20
was–was closely coupled to the–biological questions being asked.
So–so you had–had something on the array and you had
something complementary that had–may or may not have the
mutation. It was supposed to hybridize. And–so it was very easy
for–for you to get false positives and false negatives because it was
non-orthogonal. You were testing something that had tremendous
sequence homology with the natural genome. And so mistakes
were happening all the time, and so this is what we–we got around
with–with the–with our invention.65
The court determines, therefore, that the scope of the invention is limited to
capture oligonucleotides having no homology to a target sequence.
The court also determines the intrinsic record supports defendant’s construction
requiring the capture oligonucleotide to the be “complementary to the addressable array
specific portion of an oligonucleotide.” In the Summary of the Invention, the ‘917 patent
specification states:
The present invention relates to a method for identifying one or more of a
plurality of sequences differing by one or more single base changes,
insertions, deletions, or translocations in a plurality of target nucleotide
sequences. The method includes a ligation phase, a capture phase, and
a detection phase. . . . The next phase of the process is the capture
phase. This phase involves providing a solid support with capture
oligonucleotides immobilized at particular sites. The capture
oligonucleotides are complementary to the addressable array-specific
portions. The mixture, after being subjected to the ligation phase, is
contacted with the solid support under conditions effective to hybridize the
addressable array-specific portions to the capture oligonucleotides in a
base-specific manner. As a result, the addressable array-specific portions
are captured on the solid support at the site with the complementary
capture oligonucleotides.66
65
D.I. 422 at A2040-41 (G. Barany Tr. at 86:11-87:4).
‘917 patent, 5:32-37, 6:3-13 (emphasis added); see also ‘917 patent, 9:4-9,
9:44-46 (same language in Detailed Description of the Invention and Drawings).
Plaintiffs cites the Abstract describing the invention as including “a solid support with an
array of immobilized capture oligonucleotides at least some of which are complementary
to the addressable array-specific portion” of an oligonucleotide as demonstrating that in
some arrays not all of the capture oligonucleotides comprise a portion complementary
66
21
According to defendant, this statement describes the invention as a whole and thus
carries particular weight.67
The prosecution history also supports defendant’s proposed construction. During
prosecution of the ‘917 patent family, Dr. Barany represented to the PTO that “[t]hese
claims further require that the capture probes have nucleotide sequence complementary
to the addressable array specific portions of the oligonucleotide probes.”68 Dr. Gerry
likewise explained “[t]he addressable array-specific portion of a ligation product is
complementary to a capture oligonucleotide immobilized on a solid support.”69
to an addressable array-specific portion of an oligonucleotide. D.I. 419 at 65 (quoting
‘917 patent, Abstract) (emphasis added by plaintiff). Plaintiffs do not site corresponding
language in the specification and, nevertheless, the court must determine “what the
inventors actually invented and intended to envelop with the claim.” Phillips, 415 F.3d
at 1316.
67
D.I. 419 at 69 (citing Verizon Servs. Corp. v. Vonage Holdings Corp., 503 F.3d
1295, 1308 (Fed. Cir. 2007) (“When a patent thus describes the features of the ‘present
invention’ as a whole, this description limits the scope of the invention.”)); see also C.R.
Bard, Inc. v. U.S. Surgical Corp., 388 F.3d 858, 864 (Fed. Cir. 2004) (“Although a
statement’s location is not ‘determinative,’ the location can signal the likelihood that the
statement will support a limiting definition of a claim term. Statements that describe the
invention as a whole, rather than statements that describe only preferred embodiments,
are more likely to support a limiting definition of a claim term.”); Microsoft Corp. v. MultiTech Sys., Inc., 357 F.3d 1340, 1348 (Fed. Cir. 2004) (“Those statements, some of
which are found in the ‘Summary of the Invention’ portion of the specification, are not
limited to describing a preferred embodiment, but more broadly describe the overall
inventions of all three patents.”), cert. denied, 543 U.S. 521 (2004).
68
D.I. 421 at 1639-40 (‘981 FH 7/15/09 Pre-Appeal Brief Request for Review at
1-2); see also id. at 1640 (explaining that the capture oligonucleotides are
“oligonucleotides designed to bind to the addressable array specific portions on the
oligonucleotide probes which are designed to ligate together.”); id. at A1327-38 (‘527
App. FH 5/14/07 Barany Decl. at ¶ 19 (“5/14/07 Barany Decl.”)) (“[E]ach ligation product
of the LDR process is provided with an addressable array-specific portion which is
selectively captured by a complementary capture probe at a particular location on the
solid support.”).
69
Id. at A1753 (10/31/07 Gerry Decl. at ¶ 8).
22
The court concludes that the “capture oligonucleotides” are limited to those
“complementary to the addressable array specific portion of an oligonucleotide
containing an addressable array specific portion and a target specific portion.” The
court determines, therefore, that defendant’s proposed constructions are consistent with
the terms’ “meaning in the context of the patent” and supported by the prosecution
history and the specification’s description of the “advantage and distinction of the
invention” over the prior art. Defendant’s proposed construction thus reflects “what the
inventors actually invented.”70 The court adopts defendant’s proposed construction that
“capture oligonucleotide probes” and “capture oligonucleotide” mean “oligonucleotide
[probe] which has no homology to a target sequence and is complementary to the
addressable array specific portion of an oligonucleotide containing an addressable array
specific portion and a target specific portion.”
b.
“capturing said one or more amplification products to a solid support”
70
In reaching that conclusion, the court rejects plaintiffs’ assertion that
defendant’s proposed construction improperly imports limitations from particular
embodiments. “Although . . . the claims are not limited to the preferred embodiment of
the invention, neither do the claims enlarge what is patented beyond what the inventor
has described as the invention.” Netword, LLC v. Centraal Corp., 242 F.3d 1347, 1352
(Fed. Cir. 2001) (internal citation omitted); see also Digital Biometrics, Inc. v. Identix,
Inc., 149 F.3d 1335, 1347 (Fed. Cir. 1998) (relying on “global comments made to
distinguish the applicants’ ‘claimed invention’ from the prior art” during the prosecution
of the patent in construing a claim term). Plaintiffs also criticize the intrinsic evidence
relied upon by defendant as relating to descriptions of LDR methods which should not
be imported as necessary features of every capture oligonucleotide. D.I. 419 at 75-76.
The court agrees with the argument defendant made at the Markman hearing, that
during prosecution the applicants were distinguishing the nature of the array of the
invention from the prior art hybridization arrays by arguing the claimed
universal/addressable arrays had certain fundamental features. Markman Tr. at 132:18134:1.
23
Representative claim 10 of the ‘453 patent recites:
10. A method for identifying one or more of a plurality of sequences
differing by one or more single-base changes, insertions, deletions, or
translocations in a plurality of target nucleotide sequences comprising:
producing one or more ligation products from a reaction mixture, wherein
said reaction mixture comprises:
a ligase;
one or more target nucleotide sequences; and
one or more oligonucleotide probe sets, each probe set including (a) a first
oligonucleotide probe comprising a first target-specific portion capable of
hybridizing to a corresponding target nucleotide sequence and (b) a
second oligonucleotide probe comprising a second target-specific portion
capable of hybridizing to said corresponding target nucleotide sequence,
wherein a ligation product comprising the first and the second targetspecific portions is capable of being produced after the first and the
second target-specific portions are hybridized to said corresponding target
nucleotide sequence, but is not produced when the first and the second
target-specific portions are hybridized with one or more mismatches to a
nucleotide sequence present in said reaction mixture, wherein each of
said one or more ligation products comprises a ligated sequence which
includes (1) the first target-specific portion of the first oligonucleotide
probe in a corresponding probe set and (2) the second target-specific
portion of the second oligonucleotide probe in said corresponding probe
set, or complements thereof;
subjecting said one or more ligation products to one or more polymerase
chain reaction cycles to produce one or more amplification products, each
amplification product comprising (1) the ligated sequence of a
corresponding ligation product from which said amplification product is
amplified, (2) a reporter label, and (3) an addressable array-specific
portion, wherein said reporter label and said addressable array-specific
portion distinguish said amplification product from other amplification
products that comprise other ligated sequences or complements thereof;
capturing said one or more amplification products to a solid support; and
detecting the reporter labels and the identities of the addressable arrayspecific portions in said captured amplification products to indicate the
presence of one or more target nucleotide sequences in said reaction
24
mixture.71
Plaintiffs’ proposed construction is: “hybridizing the one or more amplification
products to an oligonucleotide immobilized on a solid support.”
Defendant’s proposed construction is: “hybridizing the amplification products to
capture oligonucleotides attached on the solid support.”
The parties agree that “capture” means the amplification product hybridizes to an
oligonucleotide on a solid support.72 According to defendant, the parties’ disagreement
over this term is whether the amplification products may hybridize to any oligonucleotide
on the solid support, as plaintiffs contend, or whether those products must be hybridized
to capture oligonucleotides.73 The court agrees with defendant.
The specification of the ‘917 patent is incorporated by reference in the ‘453
specification: “use of a solid support with an array of capture oligonucleotides is fully
disclosed in the pending provisional U.S. Patent Application Ser. No. 60/011,359
[resulting in the ‘917 patent], which is hereby incorporated by reference.”74 Therefore,
the “capturing” of claim 10 of the ‘453 patent is accomplished according to the
understanding of the meaning of “capture” as it modifies “oligonucleotide” in the ‘917
patent. The court determined that “capture oligonucleotides” have specific
characteristics because the applicants argued those characteristics distinguished their
universal array from hybridization arrays. The ‘453 patent incorporated those
71
‘453 patent, claim 1 (emphasis added).
D.I. 419 at 76.
73
Id. at 67. “Amplification products” are the same as LDR-PCR products. Id. at
67 n.24.
74
‘453 patent, 35:53-56.
72
25
characteristics. The court adopts defendant’s proposed construction of “capturing said
one or more amplification products to a solid support” to mean “hybridizing the
amplification products to capture oligonucleotides attached on the solid support.”
5.
Claim Terms Related to Hybridization of Oligonucleotides to Their
Complementary Sequences
These terms are considered together because they all relate to the hybridization
of oligonucleotides–or portions of oligonucleotides–with each other.75
a.
“each [type of] capture oligonucleotide hybridizes to a nucleic acid
molecule comprising a complementary nucleotide sequence” / “the
capture oligonucleotides hybridize to complementary portions of the target
nucleic acid molecules”
Representative claim 1 of the ‘233 patent recites:
1. A collection of capture oligonucleotides, wherein each type of capture
oligonucleotide of the collection has greater than sixteen nucleotides and
comprises a nucleotide sequence that differs from the nucleotide
sequence of other types of capture oligonucleotides by at least 25% when
aligned, and wherein each [type of] capture oligonucleotide of the
collection hybridizes to a nucleic acid molecule comprising a
complementary nucleotide sequence under uniform hybridization
conditions.76
Representative claim 7 of the ‘233 patent recites:
7. A device comprising:
a solid support having an array of positions each suitable for attachment of
a capture oligonucleotide;
an array of capture oligonucleotides on the solid support at the array of
positions, wherein each type of capture oligonucleotide on the solid
support comprises a nucleotide sequence that is greater than sixteen
nucleotides with a nucleotide sequence that differs from the nucleotide
sequence of other types of capture oligonucleotides on the solid support
75
76
D.I. 419 at 82.
‘233 patent, claim 1 (emphasis added).
26
by at least 25% when aligned; and
one or more target nucleic acid molecules hybridized to complementary
portions of the capture oligonucleotides on the solid support, wherein the
capture oligonucleotides hybridize to the complementary portions of the
target nucleic acid molecules under uniform hybridization conditions.77
Plaintiffs’ proposed construction is: “each capture oligonucleotide hybridizes to
an oligonucleotide containing a complementary nucleotide sequence.”
Defendant’s proposed construction is: “each capture oligonucleotide hybridizes
to an oligonucleotide containing a complement to the entire capture oligonucleotide
sequence.”
The parties dispute whether the terms allow an oligonucleotide and its
complementary sequence to be partially hybridized with or without complete
complementarity (plaintiffs) or, instead, require that the oligonucleotide be hybridized to
the entire capture sequence (defendant).78
Plaintiffs base their arguments with respect to this term (and the others in this
group of terms) on the doctrine of claim differentiation. 35 U.S.C. § 112, ¶ 4 states “a
claim in dependent form shall contain a reference” to the claim from which it depends
“and then specify a further limitation of the subject matter claimed.”79 Under the doctrine
of claim differentiation, a dependent claim that adds a limitation gives rise to the
presumption that the claim from which it depends is not so restricted.80 As noted above,
“[w]hile the doctrine of claim differentiation is not a hard and fast rule of construction, it
77
‘233 patent, claim 7 (emphasis added).
D.I. 419 at 82.
79
35 U.S.C. § 112, ¶ 4.
80
SunRace Roots Enter. Co., LTD v. Sram Corp., 336 F.3d 1298, 1303 (Fed. Cir.
78
2003).
27
does create a presumption that each claim in the patent has a different scope.”81 “This
presumption is especially strong where ‘there is a dispute over whether a limitation
found in a dependent claim should be read into an independent claim, and that limitation
is the only meaningful difference between the two claims.’”82
Claim 1 of the ‘746 patent, one of the selected claims, sets forth a method that
includes the step of contacting a sample with:
the array of capture oligonucleotides under uniform hybridization
conditions effective to hybridize the addressable array-specific portion of
each target oligonucleotide to its complementary capture oligonucleotide
. . . .83
Dependent claim 4 of the ‘746 patent requires capture oligonucleotides with complete
complementarity to a portion of the target oligonucleotides:
The method according to claim 1, wherein the addressable array-specific portions of the
target oligonucleotides hybridize to their complementary capture nucleotides with
complete complementarity.84
Similarly, claim 5 of the ‘746 patent includes a step of contacting a sample with:
the collection of capture oligonucleotides under uniform hybridization
conditions effective to hybridize the address-specific portion of each target
oligonucleotide to its complementary capture oligonucleotide . . . . 85
81
Comark Commc’ns, Inc. v. Harris Corp., 156 F.3d 1182, 1187 (Fed. Cir. 1998).
Ecolab Inc. v. Paraclipse, Inc., 285 F.3d 1362, 1375 (Fed. Cir. 2002) (quoting
Intermatic Inc. v. Lamson & Sessions Co., 273 F.3d 1355, 1364 (Fed. Cir. 2001)); see
also Comark, 156 F.3d at 1187 (“‘There is presumed to be a difference in meaning and
scope when different words or phrases are used in separate claims. To the extent that
the absence of such difference in meaning and scope would make a claim superfluous,
the doctrine of claim differentiation states the presumption that difference between
claims is significant.’”) (quoting Tandon Corp. v. United States Int’l Trade Comm’n, 831
F.2d 1017, 1023 (Fed. Cir. 1987)).
83
‘746 patent, claim 1.
84
‘746 patent, claim 4 (emphasis added).
85
‘746 patent, claim 5.
82
28
Dependent claim 8 of the ‘746 patent likewise requires capture oligonucleotides with
complete complementarity to a portion of the target oligonucleotides:
The method according to claim 5, wherein the address-specific portions of
the target oligonucleotides hybridize to the complementary capture
oligonucleotides with complete complementarity.86
Thus, claims 1 and 5 require target oligonucleotides to “hybridize the
addressable array-specific portion of each target oligonucleotide to its complementary
capture oligonucleotide.” Claims 4 and 8 add that the hybridization be “with complete
complementarity.” That additional requirement is the only meaningful difference added
by dependent claims 4 and 8. To include the “complete complementarity” requirement
to claims not reciting that requirement would render those dependent claims
superfluous. The court therefore rejects defendant’s proposed constructions for each of
the terms in this group and adopts plaintiffs’ proposed constructions for those terms.87
The court defines “each [type of] capture oligonucleotide hybridizes to a nucleic acid
molecule comprising a complementary nucleotide sequence” / “the capture
oligonucleotides hybridize to complementary portions of the target nucleic acid
86
‘746 patent, claim 8 (emphasis added).
The court is not persuaded by defendant’s argument that plaintiffs’
constructions must be rejected because those constructions would defeat the purpose
of the ‘917 patent family: to prevent cross-hybridization of an addressable array specific
portion to the wrong oligonucleotide. D.I. 419 at 84. One of the citations defendant
directs the court to suggests some cross-hybridization can occur with the claimed
inventions: “Capture specific probe sequences designed to differ by 25% or more to
minimize cross-hybridization.” Id. at 85 (quoting D.I. 421 at A1358) (emphasis added).
Minimization of cross-hybridization with universal arrays was, indeed, a major advance
touted by the patentees over prior art hybridization arrays. Here, however, the court
determines defendant’s arguments do not overcome the presumption created by the
doctrine of claim differentiation that dependent claims adding only a single meaningful
difference from the claims from which they depend have a different meaning than those
independent claims.
87
29
molecules” to mean “each capture oligonucleotide hybridizes to an oligonucleotide
containing a complementary nucleotide sequence.”
b.
“one or more target nucleic acid molecules hybridized [to complementary
portions of the capture oligonucleotides on the solid support]”
Plaintiffs’ proposed construction is: “one or more nucleic acid molecules are
hybridized to one or more complementary nucleic acid molecules on a solid support.”
Defendant’s proposed construction is: “one or more nucleic acid molecules are
hybridized [to complementary portions of the capture oligonucleotides on the solid
support].”
Court’s construction: “one or more nucleic acid molecules are hybridized to one
or more complementary nucleic acid molecules on a solid support.”
c.
“each type of capture oligonucleotide . . . hybridizes to its complement”
Plaintiffs’ proposed construction is: “at least a portion of each capture
oligonucleotide hybridizes to its complement.”
Defendant’s proposed construction is: “each type of capture oligonucleotide
hybridizes to an oligonucleotide containing a complement to the entire capture
oligonucleotide sequence.”
Court’s construction: “at least a portion of each capture oligonucleotide
hybridizes to its complement.”
d.
“wherein the zip code portion of each of the composite oligonucleotides
. . . hybridizes to its complement”
Plaintiffs’ proposed construction is: “wherein an address portion of each of the
composite oligonucleotides, or a portion thereof, hybridizes to its complement.”
Defendant’s proposed construction is: “wherein the zip code portion of each of
30
the composite oligonucleotides hybridizes to an oligonucleotide containing a
complement to the entire zip code portion.”
Court’s construction: “wherein an address portion of each of the composite
oligonucleotides, or a portion thereof, hybridizes to its complement.”
e.
“the capture oligonucleotides hybridize to the complementary portions of
the nucleic acid molecules”
Plaintiffs’ proposed construction is: “at least a portion of each capture
oligonucleotide hybridizes to a complementary portion of a nucleic acid molecule.”
Defendant’s proposed construction is: “each capture oligonucleotide hybridizes
to one or more oligonucleotides containing a complement to the entire capture
oligonucleotide sequence.”
Court’s construction: “at least a portion of each capture oligonucleotide
hybridizes to a complementary portion of a nucleic acid molecule.”
6.
Claim Terms that Relate to Differences between Oligonucleotide Sequences
The following terms are considered together because they relate to differences in
sequence between oligonucleotides or portions of oligonucleotides. The parties
disagree whether the each limitation is satisfied when one oligonucleotide differs in
sequence from “its adjacent” sequence, “another” sequence, “another type of”
sequence, or “other types of sequences” by at least 25% (plaintiff) or whether all of
these limitations mean the same thing by requiring an oligonucleotide sequence to be at
least 25% different from “every” other oligonucleotide sequence (defendant).88
The court agrees with defendant that the intrinsic record supports its proposed
88
D.I. 419 at 93.
31
constructions. For instance, each claim of the ‘233 patents requires “each type of
capture oligonucleotide . . . differs from the nucleotide sequence of other types of
oligonucleotides” by at least 25%.89 Claim 1 of the ‘746 patent requires that “each type
of capture oligonucleotide . . . differs in nucleotide sequence when aligned to another
type of capture oligonucleotide, by at least 25%.”90 This language leads to the
conclusion that each capture oligonucleotide differs from every other type of capture
oligonucleotide, not just one other type as plaintiffs’ construction allows. Claim 1 of the
‘917 patent requires that “each capture oligonucleotide probe of the array differs in
sequence from its adjacent capture oligonucleotide, when aligned to each other by at
least 25% of the nucleotides.”91 Plaintiffs argue that because the ‘917 patent uses the
singular form, the limitation is satisfied when the capture oligonucleotide differs in
sequence from “just one other oligonucleotide sequence.”92 As a general rule of
construction, however, use of the singular form includes the plural form.93 Therefore,
that singular form does not require the interpretation put forth by plaintiffs.
The specification also supports defendant’s position. As discussed above, the
patentees sought to avoid the problem of cross-hybridization experienced in prior art
arrays. To accomplish this, “[e]ach of the capture oligonucleotides have substantial
89
Id. at 96 (quoting ‘233 patent, claims 4, 7) (emphasis added by defendant).
Id. (quoting ‘746 patent, claim 1) (emphasis added by defendant).
91
‘917 patent, claim 1 (emphasis added).
92
D.I. 419 at 94.
93
See, e.g., TiVo, Inc. v. EchoStar Commc’ns Corp., 516 F.3d 1290, 1303 (Fed.
Cir. 2008) (“As a general rule, the words ‘a’ or ‘an’ in a patent claim carry the meaning
of ‘one or more.’”); 01 Communique Lab., Inc. v. LogMeln, Inc., 687 F.3d 1292, 1297
(Fed. Cir. 2012) (“The patent’s use of words such as ‘a,’ ‘its,’ and ‘the’ in the claim is
insufficient to limit the meaning of ‘locator server computer’ to a single physical
computer.”).
90
32
sequence differences to minimize any chances of cross-reactivity.”94 The specification
also explains that:
Since each address is designed by alternating tetramer addition in three
rows and three columns, a given address will differ by at least three
tetramers from its neighbor. Since each tetramer differs from every other
tetramer by at least 2 bases, a given address will differ from another
address by at least 6 bases. However, in practice most addresses will
differ from most other addresses by considerably more bases.95
Since each 24-mer differs from its neighbor by three tetramers and each
tetramer differs from another by at least 2 bases, then each 24mer differs
from another by at least 6 bases (i.e., 25% of the nucleotides differ).
Thus, a wrong address would have 6 mismatches in just 24 bases and,
therefore, would not be captured at the wrong address, especially under
75-80E C.96
During prosecution, the applicants told the PTO the capture oligonucleotides
were substantially different from each other.
The plurality of capture oligonucleotides immobilized on a solid are
designed to differ substantially from each other in their nucleotide
sequence, yet all have the same or similar melting temperature. This
design strategy drastically minimizes any chance of cross-hybridization
leading to false-positive signals, while allowing for simultaneous capture of
a plurality ligation products, by their addressable sequence, under uniform
hybridization conditions across the array.97
In explaining the claimed invention, Dr. Gerry told the PTO:
An addressable array uses capture probes that are de novo sequences
separate and distinct from the nucleic acid sequences of interest. . . .
Because the addresses are de novo sequences, they can be designed to
have as little homology to each other or to any other genomic sequence
as possible, while having very similar thermodynamic properties (e.g.,
94
‘917 patent, 35:41-43 (emphasis added). During prosecution, Dr. Barany told
the PTO “[c]apture probe sequences [are] designed to differ by 25% or more to
minimize cross-hybridization.” D.I. 421 at A1358.
95
‘917 patent, 36:63-37:3 (emphasis added).
96
‘917 patent, 37:63-38:2 (emphasis added).
97
‘D.I. 421 at A1176 (emphasis added).
33
melting temperature). This combination results in high stringency
hybridization across the array with no cross hybridization.98
Finally, named inventor Dr. Robert Hammer testified that the capture
oligonucleotides all needed to be different.
Q. And in order to avoid cross hybridization, you wanted to design each
zip code sequence to be different from every other zip code sequence on
the array, right?
A. Yeah, whatever the–whatever the detection scheme, the idea was to
make it so they wouldn’t cross react with the other, you know, positions on
the array.99
Because the intrinsic records supports defendant’s proposed constructions, the
court adopts those construction for the terms in this group.
a.
“each capture oligonucleotide probe of the array differs in sequence from
its adjacent capture oligonucleotide probe, when aligned to each other by
at least 25%”
Plaintiffs’ proposed construction is: “each capture oligonucleotide probe of the
array differs in sequence from an adjacent capture oligonucleotide probe, when aligned,
by at least 25% in nucleotide sequence.”
Defendant’s proposed construction is: “each capture oligonucleotide probe [of
the array] differs in sequence from every adjacent capture oligonucleotide probe, when
aligned, by at least 25% in nucleotide sequence.”
Court’s construction: “each capture oligonucleotide probe [of the array] differs in
sequence from every adjacent capture oligonucleotide probe, when aligned, by at least
98
Id. at A1761 (emphasis added); see also id. at 1760 (“Sequence homology
between the capture probes and likewise between the target sequences can jeopardize
the specificity of target/probe hybridization and lead to the generation of both false
positive and false negative results as illustrated in Figure 3 below.”) (emphasis added).
99
D.I. 422 at A2046-47 (emphasis added).
34
25% in nucleotide sequence.”
b.
“each type of capture oligonucleotide . . . differs in nucleotide sequence,
when aligned to another type of capture oligonucleotide that is located on
an adjacent position of said solid support, by at least 25%”
Plaintiffs’ proposed construction is: “each capture oligonucleotide probe of the
array differs in sequence from an adjacent capture oligonucleotide probe, when aligned,
by at least 25% in nucleotide sequence.”
Defendant’s proposed construction is: “each capture oligonucleotide probe [of
the array] differs in sequence from every adjacent capture oligonucleotide probe, when
aligned, by at least 25% in nucleotide sequence.”
Court’s construction: “each capture oligonucleotide probe [of the array] differs in
sequence from every adjacent capture oligonucleotide probe, when aligned, by at least
25% in nucleotide sequence.”
c.
“each type of capture oligonucleotide . . . differs in nucleotide sequence,
when aligned to another type of capture oligonucleotide, by at least 25%” /
“each type of capture oligonucleotide . . . differs by at least 25% in
nucleotide sequence, when aligned to another type of capture
oligonucleotide”
Plaintiffs’ proposed construction is: “each type of capture oligonucleotide probe
of the array differs in sequence from another type of capture oligonucleotide probe,
when aligned, by at least 25% in nucleotide sequence.”
Defendant’s proposed construction is: “each type of capture oligonucleotide
differs by at least 25% in nucleotide sequence, when aligned, to every other type of
capture oligonucleotide.”
Court’s construction: “each type of capture oligonucleotide differs by at least
25% in nucleotide sequence, when aligned, to every other type of capture
35
oligonucleotide.”
d.
“each type of capture oligonucleotide . . . comprises a nucleotide
sequence that differs from the nucleotide sequence of other types of
capture oligonucleotides in the collection by at least 25% when aligned” /
“each type of capture oligonucleotide . . . comprising nucleotide sequence
that differs from the nucleotide sequence of other types of capture
oligonucleotide of the collection by at least 25% when aligned” / “each
type of capture nucleotide . . . with a nucleotide sequence that differs from
the nucleotide sequence of other types of capture oligonucleotides on the
solid support by at least 25% when aligned”
Plaintiffs’ proposed construction is: “each type of capture oligonucleotide probe
differs in sequence from other types of capture oligonucleotide probes, when aligned, by
at least 25% in nucleotide sequence.”
Defendant’s proposed construction is: “each type of capture oligonucleotide . . .
differs by at least 25% in nucleotide sequence, when aligned, to every other type of
capture oligonucleotide.”
Court’s construction: “each type of capture oligonucleotide . . . differs by at least
25% in nucleotide sequence, when aligned, to every other type of capture
oligonucleotide.”
7.
“uniform hybridization conditions”
Representative claim 1 of the ‘917 patent recites:
1. A device comprising:
a solid support having an array of positions each suitable for attachment of
an oligonucleotide probe;
a linker suitable for coupling an oligonucleotide probe to the solid support
at each of the array positions; and
an array of capture oligonucleotide probes on the solid support at the
array positions, said capture oligonucleotide probes each having greater
than sixteen nucleotides and able to bind to complementary nucleic acids
36
at uniform hybridization conditions, wherein each capture oligonucleotide
probe of the array differs in sequence from its adjacent capture
oligonucleotide probe, when aligned to each other by at least 25% of the
nucleotides.100
Plaintiffs’ proposed construction is: “common conditions at which different
oligonucleotides are capable of hybridizing to complementary nucleic acids.”
Defendant contends this term is indefinite.
“Because a patent is presumed to be valid, the evidentiary burden to show facts
supporting a conclusion of invalidity is one of clear and convincing evidence.”101
Section 112 ¶ 2 provides: “[t]he specification shall conclude with one or more
claims particularly pointing out and distinctly claiming the subject matter which the
inventor or a joint inventor regards as the invention.”102 “[A] patent is invalid for
indefiniteness if its claims, read in light of the specification delineating the patent, and
the prosecution history, fail to inform, with reasonable certainty, those skilled in the art
about the scope of the invention.”103 “[A] claim must be ‘sufficiently definite to inform the
public of the bounds of the protected invention, i.e., what subject matter is covered by
the exclusive rights of the patent.’”104 The parties disagree as to whether the
specification meets these requirements.
The specification states that prior art arrays required hybridization conditions
optimized for each nucleotide sequence of interest: “existing methods in the prior art
100
‘917 patent, claim 1 (emphasis added).
Young v. Lumenis, Inc., 492 F.3d 1336, 1345 (Fed. Cir. 2007) (citing AK Steel
Corp. v. Sollac & Ugine, 344 F.3d 1234, 1338-39 (Fed. Cir. 2003)).
102
35 U.S.C. § 112 ¶ 2.
103
Nautilus, Inc. v. Biosig Instruments, Inc., 134 S. Ct. 2120, 2124 (2014).
104
Ancora Techs., Inc. v. Apple, Inc., 744 F.3d 732, 737 (Fed. Cir. 2014) (quoting
Halliburton Energy Servs., Inc. v. M–I LLC, 514 F.3d 1244, 1249 (Fed. Cir. 2008)).
101
37
relying on allele-specific PCR, differential hybridization, or sequencing-by-hybridization
methods must have hybridization conditions optimized for each new sequence being
analyzed. When attempting to detect multiple mutations simultaneously, it becomes
difficult or impossible to optimize hybridization conditions.”105
The claimed universal array addressed that difficulty by selecting array
sequences that enabled hybridization of a plurality of oligonucleotides to occur under
common conditions: “the present invention is a general method for high specificity
detection of correct signal, independent of the target sequence, and under uniform
conditions.”106
Plaintiffs state the specification discloses exemplary common hybridization
conditions in which oligonucleotides of the array hybridize to complementary sequences
in solution.107 For instance, in Example 3, capture oligonucleotides were hybridized with
their complements under identical conditions.108 Plaintiffs maintain from those and other
disclosures, a person of ordinary skill in the art would understand that “uniform
hybridization conditions” means “common conditions at which different oligonucleotides
are capable of hybridizing to complementary nucleic acids” and fully appreciate the
“scope of the invention with reasonable certainty.”109
Defendant argues the scope of the invention in not reasonably certain. It
contends the specification provides no guidance as to when hybridization conditions
105
‘917 patent, 42:60-66.
‘917 patent, 42:67-43:2.
107
D.I. 419 at 111.
108
Id. (citing ‘917 patent 47:30-48:25; 48:24-25 (“Hybridizations were performed
for 15 min[utes] at 70C”)).
109
Id.
106
38
must be uniform, i.e. can the hybridization conditions vary over time?110 Likewise, the
specification does not describe which hybridization conditions must be uniform.111
According to defendant, without knowing those parameters, it is impossible to
understand the bounds of the claims in order to avoid infringement.112
In light of the purpose of the claimed invention, the court agrees with plaintiffs
that defendant’s argument is mis-focused. The purpose of the invention was to
overcome the difficulty in the prior art of detecting multiple sequences simultaneously.
The prior art required optimization of conditions for each different oligonucleotide
sequence being analyzed. Because of that requirement, “attempting to detect multiple
mutations simultaneously, . . . becomes difficult or impossible to optimize hybridization
conditions.”113 The claimed invention sought to detect multiple, sometimes thousands,
of sequences on the same array and, using zip codes, accomplished that goal whereby
all of the oligonucleotides are exposed to the same conditions, i.e., different conditions
did not have to be optimized for each sequence. Put another way, the multiple
oligonucleotides are detected in a hybridization solution having uniform, or common,
conditions.114 If some of those conditions, e.g. temperature, vary during the reaction,
each different oligonucleotide is still exposed to the same common condition.
The court, therefore, determines defendant has not shown by clear and
convincing evidence that this term is indefinite and adopts plaintiffs’ construction of
110
Id. at 113, 116-17.
Id.
112
Id. at 113-14.
113
‘917 patent, 42:64-66 (emphasis added).
114
See, e.g., ‘917 patent, 42
111
39
“uniform hybridization conditions” as meaning “common conditions at which different
oligonucleotides are capable of hybridizing to complementary nucleic acids.”
8.
“addressable array-specific portion” / “address-specific portion” / “zip code
portion”
Representative claim 1 of the ‘746 patent recites:
1. A method comprising:
providing an array of a plurality of capture oligonucleotides wherein each
type of capture oligonucleotide is greater than 16 nucleotides and differs in
nucleotide sequence, when aligned to another type of capture
oligonucleotide, by at least 25%, wherein said capture oligonucleotides are
coupled to a support;
providing a sample comprising a plurality of target oligonucleotides, each
target oligonucleotide comprising (i) an addressable array-specific portion,
(ii) a further nucleotide sequence, and (iii) a detectable reporter label;
contacting the sample comprising the plurality of target oligonucleotides
with the array of capture oligonucleotides under uniform hybridization
conditions effective to hybridize the addressable array-specific portion of
each target oligonucleotide to its complementary capture oligonucleotide;
and
detecting the reporter labels of one or more of the plurality of target
oligonucleotides hybridized to their complementary capture
oligonucleotides on the solid support.115
Representative claim 18 of the ‘521 patent recites:
18. A kit for identifying one or more of a plurality of target nucleotide
sequences in a sample comprising:
a ligase;
a plurality of oligonucleotide probe sets, each set characterized by (a) a
first oligonucleotide probe, having a target-specific portion and an
address-specific portion and (b) a second oligonucleotide probe, having a
target-specific portion; and
115
‘746 patent, claim 1 (emphasis added).
40
a collection of capture oligonucleotide wherein each type of capture
oligonucleotide in the collection comprises a nucleotide sequence
complementary to an address-specific portion, wherein the addressspecific portion is comprised of a nucleotide sequence which is distinct
from that of the target-specific portions, and wherein each type of capture
oligonucleotide in the collection hybridizes to its complement under
uniform hybridization conditions but differs by at least 25% in nucleotide
sequence, when aligned to another type of capture oligonucleotide in the
collection.116
Representative claim 1 of the ‘016 patent recites:
1. An apparatus comprising:
a solid support having an array of positions;
composite oligonucleotides coupled to the solid support at the array of
positions, each of said composite oligonucleotides characterized by having
a target-specific portion and a zip code portion, wherein the zip code
portion of each of the composite oligonucleotides comprises a nucleotide
sequence of greater than sixteen nucleotides that differs for each different
target-specific portion and hybridizes to its complement under uniform
hybridization conditions, wherein the nucleotide sequence of one zip code
portion differs from the nucleotide sequence of another zip code portion,
when aligned with each other, by at least 25% of the nucleotides; and
one or more detectable labels coupled to at least one of the composite
oligonucleotide, thereby facilitating detection of the composite
oligonucleotide and its zip code portion.117
The following terms relate to portions of the oligonucleotide sequences in the
Array Patents. The parties agree these terms are directed to the portion of the
composite oligonucleotide that hybridizes to the complementary capture oligonucleotide
on the array.118 Parties disagree as to whether the terms should be construed to
prohibit the recited “portions” of oligonucleotides from hybridizing to naturally occurring
116
‘521 patent, claim 18 (emphasis added).
‘016 patent, claim 1 (emphasis added).
118
D.I. 419 at 119.
117
41
nucleic acids and other oligonucleotides of the array (defendant) or not (plaintiff).119
Plaintiffs contend nothing in the claims or specification supports defendant’s proposed
prohibition.120 Defendant argues this prohibition follows from the fundamental objective
stated in the specification: to prevent cross-hybridization.121 The parties each reference
their arguments concerning the “capture oligonucleotide probe” / “capture
oligonucleotide(s)” terms as being applicable here.122 Plaintiffs also state defendant’s
proposed constructions are also based on its purportedly incorrect arguments with
respect to the “25% difference” terms.123
According to the specification, “[t]he capture oligonucleotides are complementary
to the addressable array-specific portions”124 and “[t]his oligonucleotide probe is then
119
Id. at 118.
Id.
121
Id. at 119-20.
122
Id. at 119 (Plaintiffs’ analysis above for “capture oligonucleotide probe” and
“capture oligonucleotide(s) applies with equal force here.”) (emphasis added); id. at 120
(“[T]he lack of homology to the target or other natural DNA, and to other
oligonucleotides located on the array, is fundamental to the claimed invention and is
characteristic of the “capture oligonucleotides” as described in the specification”)
(emphasis added); id. at 122 (Like it did for the “capture oligonucleotide” terms above,
Illumina is trying to further limit these claim elements to require the absence of
hybridization to naturally occurring nucleic acids to other oligonucleotides on an
array. . . . Illumina generally relies on the same incorrect arguments it made to support
its construction of the capture oligonucleotide terms. . . . For the same reasons already
explained, there is no reason to restrict the “address” terms as Illumina proposes.”)
(emphasis added); id. at 123 (“As described in [defendant’s arguments with respect to
the ‘capture oligonucleotide’ terms and ‘25% difference’ terms] . . . the patentees were
concerned with the problems associated with cross-hybridization, and the patents are
directed to methods and technologies designed to eliminate such problems. The
arguments made in those sections apply with equal force here.”) (emphasis added).
123
Id. at 123 (“Illumina’s argument that there must be no hybridization to other
oligonucleotides on the array is another attempt to require every oligonucleotide on the
array to be different from every other. But that is incorrect, as described above in the
context of the “25% difference” terms.”) (emphasis added).
124
‘917 patent, 6:5-7 (emphasis added).
120
42
captured by its addressable array-specific portion, a sequence complementary to the
capture oligonucleotide on the addressable solid support array.”125 The addressable
array-specific portion is complementary to the capture oligonucleotide. Because the
parties each rely on their arguments concerning the “capture oligonucleotide” terms and
the “25% difference” terms with respect to these terms, and the court adopted
defendant’s proposed construction of those groups of terms, the court adopts
defendant’s construction of these terms for the reasons explained in those sections.
a.
“addressable array-specific portion”
Plaintiffs’ proposed construction is: “a portion of oligonucleotide that hybridizes
to a complementary oligonucleotide, or portion thereof, at a particular location on an
array.”
Defendant’s proposed construction is: “portion of an oligonucleotide that
selectively hybridizes to a complementary oligonucleotide located on an array, and does
not hybridize to naturally occurring nucleic acids or to other oligonucleotides located on
the array.”
Court’s construction: “portion of an oligonucleotide that selectively hybridizes to
a complementary oligonucleotide located on an array, and does not hybridize to
naturally occurring nucleic acids or to other oligonucleotides located on the array.”
b.
“address-specific portion”
Plaintiffs’ proposed construction is: “a portion of oligonucleotide that hybridizes
to a complementary oligonucleotide, or portion thereof, at a particular location on an
125
‘917 patent, 27:1-4 (emphasis added).
43
array.”
Defendant’s proposed construction is: “portion of an oligonucleotide that
selectively hybridizes to a complementary oligonucleotide located on an array, and does
not hybridize to naturally occurring nucleic acids or to other oligonucleotides located on
an array.”
Court’s construction: “portion of an oligonucleotide that selectively hybridizes to
a complementary oligonucleotide located on an array, and does not hybridize to
naturally occurring nucleic acids or to other oligonucleotides located on an array.”
c.
“zip code portion”
Plaintiffs’ proposed construction is: “a portion of oligonucleotide that hybridizes
on an array to a complementary oligonucleotide.”
Defendant’s proposed construction is: “portion of an oligonucleotide that
selectively hybridizes to a complementary oligonucleotide located on an array, and does
not hybridize to naturally occurring nucleic acids or to other oligonucleotides located on
an array.”
Court’s construction: “portion of an oligonucleotide that selectively hybridizes to
a complementary oligonucleotide located on an array, and does not hybridize to
naturally occurring nucleic acids or to other oligonucleotides located on an array.”
9.
“unique nucleotide sequence” / “unique nucleotide sequence portions”
Representative claim 4 of the ‘470 patent recites:
4. A method according to claim 1, wherein the oligonucleotide probes in
each set are configured so that the sequence of the ligation product
sequence from each oligonucleotide probe set is unique and can be
distinguished from other nucleic acids in the polymerase chain reaction
mixture, said method further comprising:
44
providing a solid support with different capture oligonucleotides
immobilized at different particular sites, wherein the capture
oligonucleotides have nucleotide sequences complementary to the unique
nucleotide sequences of given probe sets;
contacting the polymerase chain reaction mixture, after said subjecting it
to one or more polymerase chain reaction cycles with the solid support
under conditions effective to hybridize the extension product to the capture
oligonucleotide in a base-specific manner, wherein said detecting
indicates the presence of extension products captured using the unique
nucleotide sequence portions to identify one or more target nucleotide
sequences in the sample.126
Plaintiffs’ proposed construction is: “a sequence that is different for each locus.”
Defendant’s proposed construction is: “portion(s) of a ligation product that
hybridizes to a complementary address sequence on an addressable array that does
not exist in ligation products resulting from any other target sequence.”
The parties dispute whether every ligation product has to have a portion that
hybridizes to the array and is different from every other ligation product (defendant) or
whether such a portion need only be different for each locus analyzed (plaintiffs).127
The parties competing constructions differ based upon whether the claims cover
the embodiments illustrated in Figures 13B and 13C of the ‘917 patent, as plaintiffs
contend, or are limited to covering only the Figure 13B embodiment, as defendant
contends.
With respect to Figure 13B, on which defendant relies, the specification recites:
FIGS. 13A-B shows two LDR primers that are designed to discriminate
wild type and mutant p53 by containing the discriminating base C or T at
the 3' end. In the presence of the correct target DNA and Tth ligase, the
discriminating probe is covalently attached to a common downstream
126
127
‘470 patent, claim 4 (emphasis added).
D.I. 419 at 124.
45
oligonucleotide. The downstream oligonucleotide is fluorescently labeled.
The discriminating oligonucleotides are distinguished by the presence of
unique addressable array-specific portions, Z1 and Z2, at each of their 5'
ends.128
With respect to Figure 13C, which plaintiffs rely on, the specification recites:
FIG. 13C shows the discriminating signals may be quantified using a
fluorescent imager. This format uses a unique address where
oligonucleotide probes are distinguished by having different fluorescent
groups, F1 and F2, on their 5' end. Either oligonucleotide probe may be
ligated to a common downstream oligonucleotide probe containing an
addressable array-specific portion Z1 on its 3' end. In this format, both
wild type and mutant LDR products are captured at the same address on
the array, and are distinguished by their different fluorescence. This
format allows for a more efficient use of the array and may be preferred
when trying to detect hundreds of potential germline mutations.129
Defendant acknowledges that Figure 13C is described as allowing a capture
probe to have more than one corresponding type of assay product. It maintains that
while the independent claims of the asserted ‘470 patent family cover both
embodiments, the asserted dependent claims, through their use of the term “unique,”
cover only the embodiment depicted in Figure 13B.130 The court disagrees with
defendant. Each embodiment describes a “unique” address or portion. The court
declines to exclude the Figure 13C embodiment from the construction of these terms
and adopts plaintiffs proposed construction of “unique nucleotide sequence” and
“unique nucleotide sequence portions” to mean “a sequence that is different for each
locus.”
10.
“ligase detection reaction” / “ligase detection reaction cycles” / “suitable for
ligation together”
128
‘917 patent, 21:28-37 (emphasis added).
‘917 patent, 21:56-67 (emphasis added).
130
D.I. 419 at 128.
129
46
Representative claim 1 of the ‘285 patent recites:
1. A method for identifying one or more different target nucleotide
sequences comprising:
providing a sample potentially containing one or more target nucleotide
sequences comprising sequence differences;
performing a ligase detection reaction to form a ligation product
comprising a first target specific portion complementary to the target
nucleotide sequence and a second target specific portion complementary
to the target nucleotide sequence, wherein the ligation product further
comprises a 5' upstream primer-specific portion and a 3' downstream
primer-specific portion, wherein the first target specific portion and the
second target specific portion are located between the 3' down
downstream primer-specific portion and the 5' upstream primer specific
portion;
providing an oligonucleotide primer set comprising (a) an upstream primer
containing the same sequence as the 5' upstream primer-specific portion
of the ligation product sequence and (b) a downstream primer
complementary to the 3' downstream primer-specific portion of the ligation
product sequence;
performing a polymerase chain reaction to form extension products
comprising the ligation product sequence and/or complements thereof;
and
detecting the extension products to identify one or more target nucleotide
sequences in the sample.131
Representative claim 1 of the ‘470 patent recites:
1. A method for identifying one or more different target nucleotide
sequences comprising:
providing a sample potentially containing one or more target nucleotide
sequences comprising sequence differences;
providing one or more oligonucleotide probe sets, each set comprising (a)
a first oligonucleotide probe comprising a target-specific portion and a 5'
upstream primer-specific portion and (b) a second oligonucleotide probe
131
‘285 patent, claims 1 (emphasis added).
47
comprising a target-specific portion and 3' downstream primer-specific
portions, wherein the first and second oligonucleotide probes in each
particular set are suitable for ligation together when hybridized on a
corresponding target nucleotide sequence, but have a mismatch which
interferes with such ligation when first and second oligonucleotide are
hybridized to any other nucleotide sequence present in the sample;
providing a ligase;
blending the sample, the one or more oligonucleotide probe sets, and the
ligase to form a ligase detection reaction mixture;
subjecting the ligase detection reaction mixture to one or more ligase
detection reaction cycles to form a ligation product sequence comprising
(a) the 5' upstream primer specific portion, (b) the target-specific portions,
and (c) the 3' downstream primer-specific portion, when the respective
target nucleotide sequence of the corresponding oligonucleotide probe set
is present in the sample;
providing one or a plurality of oligonucleotide primer sets, each comprising
(a) an upstream primer containing the same sequence as the 5' upstream
primer-specific portion of the ligation product sequence and (b) a
downstream primer complementary to the 3' downstream primer-specific
portion of the ligation product sequence;
providing a polymerase;
blending the ligase detection reaction mixture with the one or a plurality of
oligonucleotide primer sets, and the polymerase to form a polymerase
chain reaction mixture;
subjecting the polymerase chain reaction mixture to one or more
polymerase chain reaction cycles to form extension products comprising
the ligation product sequence and/or complements thereof; and
detecting the extension products to identify one or more target nucleotide
sequences in the sample.132
a.
“ligase detection reaction”
Plaintiffs’ proposed construction is: “reaction capable of forming a ligation
132
‘470 patent, claim 1 (emphasis added).
48
product that can be detected.”
Defendant’s proposed construction is: “reaction which detects the presence of
target nucleotide sequence in a sample by using a ligase and one or more sets of two
oligonucleotide probes in which the ligase joins the two oligonucleotide probes only if
they are hybridized at adjacent positions on a target nucleotide sequence.”
b.
“suitable for ligation together”
Plaintiffs’ proposed construction is: “capable of forming a ligation product.”
Defendant’s proposed construction is: “able to be ligated together only when
hybridized adjacent to one another on the target nucleotide sequence.”
c.
“ligase detection cycles”
Plaintiffs’ proposed construction is: “cycles comprising at least the following
steps: denaturation, hybridization, and ligation, with the denaturation step occurring at
the beginning or the end.”
Defendant’s proposed construction is: “ligase detection reaction comprising: (1)
denaturation; (2) hybridization of the oligonucleotide probe set; and (3) ligation of
adjacently hybridized oligonucleotide probe sets.”
The Parties have two disputes about these terms. First, is whether a ligation
detection reaction requires that the oligonucleotides must hybridize adjacent or abutting
each other (defendant) or do not have to (plaintiff).133 The second dispute relates to
whether a “ligase detection cycle” requires a denaturation step to be at the beginning of
the cycle (defendant) or whether it can be at the end, after the oligonucleotide probes
133
D.I. 419 at 132.
49
are hybridized and (some) are ligated (plaintiff).134
Beginning with the first dispute, plaintiffs primarily rely a claim differentiation
argument.
Claim 1 of the ‘039 patent recites:
1. A method for identifying a target nucleotide sequence comprising:
forming a ligation product on a target nucleotide sequence in a ligation
detection reaction mixture, wherein the ligation product comprises an
upstream primer portion and a downstream primer portion, wherein the
upstream primer portion and the downstream primer portion are not
complementary with the target nucleotide sequence;
amplifying the ligation product to form an amplified ligation product in a
polymerase chain reaction (PCR) mixture, wherein the PCR mixture
comprises an upstream primer and a downstream primer; and
detecting the amplified ligation product to identify the target nucleotide
sequence.135
Claim 2 of the ‘039 patent depends from claim 1 and recites:
2. The method according to claim 1 wherein the ligation detection reaction
mixture comprises adjacently hybridizing ligation probes.136
Because claim 2 adds the “adjacently hybridizing” requirement, plaintiffs maintain
it would be improper to impose that requirement on claims not explicitly requiring
adjacency.137 However, “[i]t is axiomatic that the claim construction process entails
more than viewing the claim language in isolation. Claim language must always be read
134
Id. at 134.
‘039 patent, claim 1 (emphasis added).
136
‘039 patent, claim 2 (emphasis added). Plaintiffs also note, independent claim
10 of the ‘453 patent recites that a ligation product is formed after oligonucleotides “are
hybridized to said corresponding target nucleotide sequence,” without requiring
adjacency, while independent claim 11 requires the ligation product be formed by
ligation probes “hybridized adjacent to one another.” D.I. 419 at 134.
137
D.I. 419 at 133.
135
50
in view of the written description and any presumption created by the doctrine of claim
differentiation will be overcome by a contrary construction dictated by the written
description or prosecution history.”138
The court determines that in this case the presumption is overcome. The ‘470
specification incorporates by reference the definition of “ligase detection reaction” in the
disclosure of Barany’s prior art patent application WO 91/17239. The specification
states “[t]he ligase detection reaction is described generally in WO 9[1]/17239 to Barany
et al. . . . , the disclosures of which are hereby incorporated by reference.”139 That
application recites:
In order to avoid any misunderstandings as to what is being referenced,
and to provide the reader with a clear understanding of what is being
described, the following definitions will be used: . . . . “Ligase detection
reaction (LDR)” refers to the use of two adjacent oligonucleotides for the
detection of specific sequences with the aid of a thermophilic ligase with
linear product amplification.140
When the specification “reveal[s] a special definition given to a claim term by the
patentee . . . the inventor’s lexicography governs.”141 This includes definitions included
in documents incorporated by reference.142
138
Retractable Techs., Inc v. Becton, Dickinson & Co., 663 F.3d 1296, 1305
(Fed. Cir. 2011) (citations and internal quotation marks omitted).
139
‘470 patent, 32:13-20.
140
D.I. 422 at A2191, A2196 (emphasis added).
141
Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005) (en banc).
142
See Cook Biotech Inc. v. Acell, Inc., 460 F.3d 1365, 1376 (Fed. Cir. 2006)
(construing a term based on the specification of a prior art patent incorporated by
reference); see also id. (“‘Incorporation by reference provides a method for integrating
material from various documents into a host document . . . by citing such material in a
manner that makes clear that the material is effectively part of the host document as if it
were explicitly contained therein.’”) (quoting Advanced Display Sys., Inc. v. Kent State
Univ., 212 F.3d 1272, 1282 (Fed. Cir. 2000)).
51
The specification consistently and exclusively describes the ligase detection
reaction of the invention as requiring adjacent hybridization:
A second aspect of the present invention relates to a method for
identifying one or more of a plurality of sequences differing by one or more
single-base changes, insertions, deletions or translocations in a plurality of
target nucleotide sequences. . . . In the ligate detection reaction phase
one or more oligonucleotide probe sets are provided. . . . The
oligonucleotide probes in a particular set are suitable for ligation together
when hybridized adjacent to one another on a corresponding target
nucleotide sequence. However, there is a mismatch which interferes with
such ligation when they are hybridized to any other nucleotide sequence
present in the sample. . . . The ligase detection reaction mixture is
subjected to one or more ligase detection reaction cycles. These cycles
include a denaturation treatment and a hybridization treatment. . . . The
hybridization treatment causes the oligonucleotide probe sets to hybridize
at adjacent positions . . . . Once hybridized, the oligonucleotide probe sets
ligate to one another to form a ligation product sequence.143
Figure 16 of the ‘470 patent illustrates successful ligation where the
oligonucleotide probes are adjacently hybridized and unsuccessful ligation where there
is a gap between the hybridized probes.144 Describing Figure 16, the specification
143
‘470 patent, 9:19-52 (emphasis added); see also, e.g., ‘470 patent, 7:1:25
(“The last phase of this aspect of the present invention involves a ligase detection
reaction process. . . . The ligase detection reaction mixture is subjected to one or more
ligase detection reaction cycles having a denaturation treatment and a hybridization
treatment . . . . In the hybridization treatment, the oligonucleotide probe sets hybridize
at adjacent positions in a base-specific manner to the respective secondary extension
products if present.”) (emphasis added); ‘470 patent, 25:8:12 (“[P]airs of oligonucleotide
probes, having a target-specific portion and a primer-specific portion, are allowed to
anneal adjacent to each other on target nucleic acids and ligate to one another (in the
absence of mismatches.”) (emphasis added); ‘470 patent, 18:54-57 (“During LDR,
oligonucleotide probes ligate to their adjacent oligonucleotide probes only in the
presence of target sequence which give perfect complementarity at the junction cite.”)
(emphasis added); ‘470 patent, 23:27-32 (“The oligonucleotide probes in a particular set
are suitable for ligation together when hybridized adjacent to one another on a
corresponding target nucleotide sequence. However, there is a mismatch which
interferes with such ligation when they are hybridized to any other nucleotide sequence
present in the sample.”) (emphasis added).
144
‘470 patent, Figure 16.
52
states “LDR products are only formed on the correct length target sequence, and thus
the presence of that target is distinguished (step 4).”145 Named inventor Dr. Matthew
Lubin confirmed in deposition that Figure 16 illustrates unsuccessful ligation where there
is a gap between the hybridized oligonucleotide probes:
Q. So, in this case, what is being shown as the mismatch in figure 16
preventing ligation is the gap of a single A between the spots of
hybridization for the two LDR primers; correct?
A. That’s what is described.146
The specification distinguishes prior art gap ligase chain reaction methods.
Jou, et al., “Deletion Detection in Dystrophia Gene by Multiplex Gap
Ligase Chain Reaction and Immunochromatographic Technology,” Human
Mutation 5:86-93 (1995) relates to the use of so called “gap ligase chain
reaction” process to amplify simultaneously selected regions of multiple
exons with the amplified products being read on an
immunochromatographic strip having antibodies specific to the different
haptens on the probes for each exon. . . . However, the prior-art methods
described above are not readily adaptable for use in detecting multiple
selected sequences in a convenient, automated single-assay format.147
The gap ligase chain reaction process requires an additional
step–polymerase extension. The use of probes with distinctive ratios of
charge/translation frictional drag for a more complex multiplex will either
require longer electrophoresis times or the use of an alternate form of
detection. The need thus remains for a rapid single assay format to detect
the presence or absence of multiple selected sequences in a
polynucleotide sample.148
During prosecution, Dr. Barany also distinguished the gap ligase chain reaction
disclosed in prior art by Zaun:
[T]he LCR procedure utilized by Zaun . . . is known as gap-LCR. . . . [M]y
145
‘470 patent, 27:61-63.
D.I. 422 at A2757.
147
‘470 patent, 2:51-3:5 (emphasis added).
148
‘470 patent, 3:59-67 (emphasis added).
146
53
LCR procedure involves use of oligonucleotide probe sets which hybridize
to a target nucleic acid in abutting relationship, and, if there is perfect
complementarity at their junction, these oligonucleotides can be joined
with ligase. By contrast, in gap-LCR, the oligonucleotide probe sets do
not hybridize to a target nucleic acid in abutting relation and, therefore, are
not potentially suitable for immediate ligation. Instead, there is a gap
which must be closed using polymerase before any ligation can occur.
The claims of the present application clearly refer to an LDR procedure to
distinguish single nucleotide differences and require that the
oligonucleotide probe be configured to hybridize “adjacent to one another”
on a corresponding target nucleotide sequence. Since they do not involve
LCR or filling a gap, these claims are readily distinguishable from Zaun.149
Based on the foregoing evidence, the court concludes the claims require the two
oligonucleotide probe to hybridize at adjacent positions. Therefore, the court construes
“ligase detection reaction” to mean “reaction which detects the presence of target
nucleotide sequence in a sample by using a ligase and one or more sets of two
oligonucleotide probes in which the ligase joins the two oligonucleotide probes only if
they are hybridized at adjacent positions on a target nucleotide sequence” and “suitable
for ligation together” to mean “able to be ligated together only when hybridized adjacent
to one another on the target nucleotide sequence.”
The parties’ second dispute with whether a ligase detection reaction cycle
requires a denaturation step at the beginning of the cycle or whether it can be at the
end, after oligonucleotide probes are hybridized and (some) are ligated.
“[A] claim requires an ordering of steps when the claim language, as a matter of
logic or grammar, requires that the steps be performed in the order written, or the
149
D.I. 421 at A1310-11 (emphasis added). The ‘470 patent specification
describes a ligase chain reaction (“LCR”) as a method of LDR using two sets of
complementary oligonucleotides. ‘470 patent, 32:20-25.
54
specification directly or implicitly requires an order of steps.”150
Defendant does not disagree that an additional denaturation step may be
included in a ligase detection reaction cycle but insists an initial denaturation step is
required for separation of double stranded DNA to create a single stranded target.151 It
points to the figures in the patent and the related descriptions of those figures for its
position. For example defendant notes Figure 10 illustrates the cycle, and is described
in the specification, in a manner consistent with its proposed order of steps.
FIG. 10 is a schematic diagram depicting an LDR/PCR process for
multiplex detection of gene amplifications and deletions. . . . Following
denaturation of DNA at 94E C., pairs of oligonucleotide probes, having a
target-specific portion and a primer-portion, a allowed to anneal adjacent
to each other on the target nucleic acids and ligate to one another (in the
absence of mismatches).152
That and the other figures defendant cites in its brief do require denaturation of
double stranded DNA at the beginning of the cycle. Those figures, and related
descriptions, are specific embodiments. Plaintiffs, however, note that if the reaction
starts with a single-stranded target, such as a strand of RNA, there is nothing to
denature as a first step.153 The court agrees with plaintiffs that in that case, an initial
denaturation step is not required as defendant’s proposed construction does.
Consequently the court adopts plaintiffs’ proposed construction of “ligase detection
reaction cycle” to mean “cycles comprising at least the following steps: denaturation,
hybridization, and ligation, with the denaturation step occurring at the beginning or the
150
mFormation Tech., Inc. v. Research in Motion Ltd., 764 F.3d 1392, 1398 (Fed.
Cir. 2014) (internal quotation marks omitted).
151
D.I. 419 at 149.
152
‘470 patent, 25:3-11 (emphasis added).
153
D.I. 419 at 146.
55
end.”
11.
“ligase detection reaction mixture” / “ligation detection reaction mixture” /
“reaction mixture” / “polymerase chain reaction (PCR) mixture”
Representative claim 1 of the ‘470 patent recites:
1. A method for identifying one or more different target nucleotide
sequences comprising:
providing a sample potentially containing one or more target nucleotide
sequences comprising sequence differences;
providing one or more oligonucleotide probe sets, each set comprising (a)
a first oligonucleotide probe comprising a target-specific portion and a 5'
upstream primer-specific portion and (b) a second oligonucleotide probe
comprising a target-specific portion and 3' downstream primer-specific
portions, wherein the first and second oligonucleotide probes in each
particular set are suitable for ligation together when hybridized on a
corresponding target nucleotide sequence, but have a mismatch which
interferes with such ligation when first and second oligonucleotide are
hybridized to any other nucleotide sequence present in the sample;
providing a ligase;
blending the sample, the one or more oligonucleotide probe sets, and the
ligase to form a ligase detection reaction mixture;
subjecting the ligase detection reaction mixture to one or more ligase
detection reaction cycles to form a ligation product sequence comprising
(a) the 5' upstream primer specific portion, (b) the target-specific portions,
and (c) the 3' downstream primer-specific portion, when the respective
target nucleotide sequence of the corresponding oligonucleotide probe set
is present in the sample;
providing one or a plurality of oligonucleotide primer sets, each comprising
(a) an upstream primer containing the same sequence as the 5' upstream
primer-specific portion of the ligation product sequence and (b) a
downstream primer complementary to the 3' downstream primer-specific
portion of the ligation product sequence;
providing a polymerase;
blending the ligase detection reaction mixture with the one or a plurality of
oligonucleotide primer sets, and the polymerase to form a polymerase
56
chain reaction mixture;
subjecting the polymerase chain reaction mixture to one or more
polymerase chain reaction cycles to form extension products comprising
the ligation product sequence and/or complements thereof; and
detecting the extension products to identify one or more target nucleotide
sequences in the sample.154
a.
“ligase detection reaction mixture’ / “ligation detection reaction mixture” /
“reaction mixture”
Plaintiffs’ proposed construction is: “mixture containing the components or
products of a ligase detection reaction.”
Defendant’s proposed construction is: “mixture that contains all of the
components used to perform a ligase detection reaction, including a sample, a ligase
and one or more oligonucleotide probe sets, in either ligated or unligated form.”
b.
“polymerase chain reaction (PRC) mixture”
Plaintiffs’ proposed construction is: “mixture containing the components or
products of a polymerase chain reaction.”
Defendant’s proposed construction is: “mixture that contains all of the
components used to perform a polymerase chain reaction, including a polymerase, a
template sequence, and unextended and/or extended primer sequences containing
sequences that are the same as, and sequences that are complementary to, the
template sequence.”
These terms relate to mixtures of components at stages of the claimed methods.
The parties’ dispute is whether the components used in a reaction must still be present
154
‘470 patent, claim 1 (emphasis added).
57
after the reaction has been performed.155
Plaintiffs contend each of these mixtures refer to two mixtures that necessarily
contain different components.156 According to plaintiffs, the first ligase reaction mixture
contains the components that are input into the ligase detection reaction and the second
ligase detection reaction mixture contains the output of the ligase detection mixture than
is, in turn, input into the PCR reaction.157 They make the same argument regarding the
polymerase chain reaction mixture. These arguments are contrary to the claim
language and the specification.
Claim 1 of the ‘470 patent introduces “a ligase detection reaction mixture” and
then twice refers back to “the ligase reaction mixture.” The meaning of “a ligase
detection reaction mixture” does not change in the claim to include a product of the
reaction. Also, the claims recites “subjecting the ligase detection reaction mixture to
one or more ligase detection reaction cycles to form a ligation product sequence,”
making clear the “ligase detection reaction mixture” is distinct from “a ligation product.”
Furthermore, the ligase detection mixture is subjected to “one or more ligase detection
reaction cycles.” For there to be more than one cycle, at least some of each of the
original components necessarily must be present.
The same analysis applies to polymerase chain reaction mixture. The claim
introduces “a polymerase chain reaction mixture” and refers back to “the polymerase
chain reaction mixture.” And again, the polymerase chain reaction mixture is subject to
155
D.I. 419 at 153.
Id. at 152.
157
Id.
156
58
“one or more polymerase chain reaction cycles to form extension products.” As with the
ligase detection reaction mixture, the polymerase chain reaction mixture is different than
the product of the polymerase chain reaction. Because the mixture is subjected to “one
or more” cycles, at least some of each of the original components necessarily must be
present.
Moreover, the specification describes both mixtures consistent with the above
understanding: “[t]he sample, the plurality of oligonucleotide probe sets, and a ligase
are blended together to form a ligase detection reaction mixture”158 and “[t]he ligase
detection reaction mixture is blended with the one or a plurality of oligonucleotide primer
sets and the polymerase to form a polymerase chain reaction mixture.”159 Neither
description includes the products of LCR/PCR reactions as part of the reaction mixtures.
Because defendant’s proposed constructions are consistent with the claim
language and the specification, the court construes “ligase detection reaction mixture’ /
“ligation detection reaction mixture” / “reaction mixture” to mean “mixture that contains
all of the components used to perform a ligase detection reaction, including a sample, a
ligase and one or more oligonucleotide probe sets, in either ligated or unligated form”
and “polymerase chain reaction (PRC) mixture” to mean “mixture that contains all of the
components used to perform a polymerase chain reaction, including a polymerase, a
template sequence, and unextended and/or extended primer sequences containing
sequences that are the same as, and sequences that are complementary to, the
template sequence.”
158
159
‘470 patent, 23:32-35.
‘470 patent, 23:63-65.
59
12.
“target-specific portion(s)”
Representative claim 18 of the ‘521 patent recites:
18. A kit for identifying one or more of a plurality of target nucleotide
sequences in a sample comprising:
a ligase;
a plurality of oligonucleotide probe sets, each set characterized by (a) a
first oligonucleotide probe, having a target-specific portion and an
address-specific portion and (b) a second oligonucleotide probe, having a
target-specific portion; and
a collection of capture oligonucleotides wherein each type of capture
oligonucleotide in the collection comprises a nucleotide sequence
complementary to an address-specific portion, wherein the addressspecific portion is comprised of a nucleotide sequence which is distinct
from that of the target-specific portions, and wherein each type of capture
oligonucleotide in the collection hybridizes to its complement under
uniform hybridization conditions but differs by at least 25% in nucleotide
sequence, when aligned to another type of capture oligonucleotide in the
collection.160
Plaintiffs’ proposed construction is: “portion of oligonucleotide capable of
hybridizing to a target nucleic acid.”
Defendant’s proposed construction is: “portion of an oligonucleotide capable of
hybridizing to a target nucleic acid sequence of interest from naturally occurring nucleic
acids.”
The parties’ dispute is whether the “target nucleic acid” that hybridizes to a
“portion of an oligonucleotide” is restricted to “naturally occurring nucleic acids”
(defendant) or not (plaintiffs). In support of such restriction, defendant notes the
specification repeatedly describes target nucleic acids as naturally occurring and
160
‘521 patent, claim 18 (emphasis added).
60
contains no description of target-specific portions hybridizing to artificial target nucleic
acids.161 It also points to the specification’s description of the invention as being used to
detect cancer and other human diseases where the target nucleic acids in the sample
are naturally occurring: “[t]he array of the present invention will be universal, making it
useful for detection of cancer mutations, inherited (germline) mutations, and infectious
diseases.”162 Defendant also cites statements made during prosecution and in
depositions relating to use of the invention in disease detection. During prosecution, Dr.
Barany submitted a declaration describing how the claimed invention “provides a rapid
and reliable method for the detection of genomic mutations (e.g., genetic disease
mutations and cancer related mutations), promoter methylation, and infectious diseases
(e.g., bacterial, fungal and viral infections.”163 At deposition, Dr. Barany testified that
“detection of cancer mutations, inherited (germline) mutations, and infectious diseases”
was “a very important part of the invention.”164
Although disease detection, using naturally occurring nucleic acids, is an
important focus of the invention, the evidence defendant relies on does not convince the
court there was a clear and unambiguous disavowal of detection of non-naturally
occurring nucleic acids.165 Therefore, the court adopts plaintiffs’ proposed construction
of “target-specific portion(s)” as meaning “portion of oligonucleotide capable of
161
D.I. 419 at 161.
‘917 patent, 43:7-9.
163
D.I. 421 at A1633.
164
D.I. 422 at A2043 (emphasis added).
165
Home Diagnostics, Inc. v. LifeScan, Inc., 381 F.3d 1352, 1357 (Fed. Cir.
2004) (The “choice to describe only a single embodiment does not mean that the patent
clearly and unambiguously disavowed other embodiments.”).
162
61
hybridizing to a target nucleic acid.”
Order: The Court’s Claim Construction
At Wilmington, this 6th day of May, 2016, having heard oral argument, having
reviewed the papers submitted with the parties’ proposed claim constructions, and
having considered all of the parties’ arguments (whether or not explicitly discussed
herein);
IT IS ORDERED that the disputed claim language in asserted claims of the
patent-in-suit, as identified by the parties, shall be construed below consistent with the
tenets of claim construction set forth by the United States Court of Appeals for the
Federal Circuit in Phillips v. AWH Corp.,166 as follows:
Claim Term
Construction
oligonucleotide probe set(s)
oligonucleotide sequences that hybridize
to a target sequence in a ligase detection
reaction
primer-specific portion
portion of an oligonucleotide capable of
hybridizing to a nucleotide sequence
used to initiate PCR amplification
ligation product sequence(s)
oligonucleotide sequence(s) resulting
from a ligase detection reaction
ligation products
composite oligonucleotide
an oligonucleotide having two or more
portions
solid support
a single unitary substrate
an array of positions
positions organized in known locations
166
415 F.3d 1303 (Fed. Cir. 2005) (en banc).
62
Claim Term
Construction
linker
a molecule that covalently binds an
oligonucleotide to the solid support, or is
absorbed thereto, without an intervening
structure
immobilized
covalently bound or bound via
hybridization
attached
covalently bound or absorbed
suitable for attachment
functionalized to permit covalent bonding
coupled to
covalently bound or bound via
hybridization
capture oligonucleotide probes
oligonucleotide [probe] which has no
homology to a target sequence and is
complementary to the addressable array
specific portion of an oligonucleotide
containing an addressable array specific
portion and a target specific portion
capture oligonucleotide(s)
capturing said one or more amplification
products to a solid support
hybridizing the amplification products to
capture oligonucleotides attached on the
solid support
each [type of] capture oligonucleotide
hybridizes to a nucleic acid molecule
comprising a complementary nucleotide
sequence
each capture oligonucleotide hybridizes
to an oligonucleotide containing a
complementary nucleotide sequence
the capture oligonucleotides hybridize to
complementary portions of the target
nucleic acid molecules
one or more target nucleic acid
molecules hybridized [to complementary
portions of the capture oligonucleotides
on the solid support]
one or more nucleic acid molecules are
hybridized to one or more complementary
nucleic acid molecules on a solid support
each type of capture oligonucleotide . . .
hybridizes to its complement
at least a portion of each capture
oligonucleotide hybridizes to its
complement
63
Claim Term
Construction
wherein the zip code portion of each of
the composite oligonucleotides . . .
hybridizes to its complement
wherein an address portion of each of the
composite oligonucleotides, or a portion
thereof, hybridizes to its complement
the capture oligonucleotides hybridize to
the complementary portions of the
nucleic acid molecules
at least a portion of each capture
oligonucleotide hybridizes to a
complementary portion of a nucleic acid
molecule
each capture oligonucleotide probe of the
array differs in sequence from its
adjacent capture oligonucleotide probe,
when aligned to each other by at least
25%
each capture oligonucleotide probe [of
the array] differs in sequence from every
adjacent capture oligonucleotide probe,
when aligned, by at least 25% in
nucleotide sequence
each type of capture oligonucleotide . . .
differs in nucleotide sequence, when
aligned to another type of capture
oligonucleotide that is located on an
adjacent position of said solid support, by
at least 25%
each capture oligonucleotide probe [of
the array] differs in sequence from every
adjacent capture oligonucleotide probe,
when aligned, by at least 25% in
nucleotide sequence
each type of capture oligonucleotide . . .
differs in nucleotide sequence, when
aligned to another type of capture
oligonucleotide, by at least 25%”
each type of capture oligonucleotide
differs by at least 25% in nucleotide
sequence, when aligned, to every other
type of capture oligonucleotide
each type of capture oligonucleotide . . .
differs by at least 25% in nucleotide
sequence, when aligned to another type
of capture oligonucleotide
64
Claim Term
Construction
each type of capture oligonucleotide . . .
comprises a nucleotide sequence that
differs from the nucleotide sequence of
other types of capture oligonucleotides in
the collection by at least 25% when
aligned
each type of capture oligonucleotide . . .
differs by at least 25% in nucleotide
sequence, when aligned, to every other
type of capture oligonucleotide
each type of capture oligonucleotide . . .
comprising nucleotide sequence that
differs from the nucleotide sequence of
other types of capture oligonucleotide of
the collection by at least 25% when
aligned
each type of capture nucleotide . . . with a
nucleotide sequence that differs from the
nucleotide sequence of other types of
capture oligonucleotides on the solid
support by at least 25% when aligned
uniform hybridization conditions
common conditions at which different
oligonucleotides are capable of
hybridizing to complementary nucleic
acids
addressable array specific portion
portion of an oligonucleotide that
selectively hybridizes to a complementary
oligonucleotide located on an array, and
does not hybridize to naturally occurring
nucleic acids or to other oligonucleotides
located on the array
address-specific portion
portion of an oligonucleotide that
selectively hybridizes to a complementary
oligonucleotide located on an array, and
does not hybridize to naturally occurring
nucleic acids or to other oligonucleotides
located on an array
65
Claim Term
Construction
zip code portion
portion of an oligonucleotide that
selectively hybridizes to a complementary
oligonucleotide located on an array, and
does not hybridize to naturally occurring
nucleic acids or to other oligonucleotides
located on an array
unique nucleotide sequence
a sequence that is different for each
locus
unique nucleotide portion
ligase detection reaction
reaction which detects the presence of
target nucleotide sequence in a sample
by using a ligase and one or more sets of
two oligonucleotide probes in which the
ligase joins the two oligonucleotide
probes only if they are hybridized at
adjacent positions on a target nucleotide
sequence
suitable for ligation together
able to be ligated together only when
hybridized adjacent to one another on the
target nucleotide sequence
ligase detection reaction cycles
cycles comprising at least the following
steps: denaturation, hybridization, and
ligation, with the denaturation step
occurring at the beginning or the end
ligase detection reaction mixture
mixture that contains all of the
components used to perform a ligase
detection reaction, including a sample, a
ligase and one or more oligonucleotide
probe sets, in either ligated or unligated
form
ligation detection reaction mixture
reaction mixture
66
Claim Term
Construction
polymerase chain reaction (PCR) mixture
mixture that contains all of the
components used to perform a
polymerase chain reaction, including a
polymerase, a template sequence, and
unextended and/or extended primer
sequences containing sequences that are
the same as, and sequences that are
complementary to, the template
sequence
PCR mixture
target-specific portion(s)
portion of oligonucleotide capable of
hybridizing to a target nucleic acid
Pursuant to 28 U.S.C. § 636(b)(1)(B), FED. R. CIV. P. 72 (b)(1), and D. DEL. LR
72.1, any objections to the Report and Recommendation shall be filed within fourteen
(14) days limited to twenty-five (25) pages after being served with the same. Any
response shall be limited to twenty-five (25) pages.
The parties are directed to the Court’s Standing Order in Non-Pro Se Matters for
Objections Filed under FED. R. CIV. P. 72 dated November 16, 2009, a copy of which is
found on the Court’s website (www.ded.uscourts.gov.)
/s/ Mary Pat Thynge
UNITED STATES MAGISTRATE JUDGE
67
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