Opinion
No. C 10-5542 EDL
02-08-2012
ILLUMINA, INC and SOLEXA INC., Plaintiffs, v. COMPLETE GENOMICS, INC., Defendant.
CLAIM CONSTRUCTION ORDER
On December 9, 2011 and January 11, 2012, the Court held hearings on the parties' proposed construction of the disputed terms of United States Patent Number 6,306,597, pursuant to Markman v. Westview Instruments, Inc., 517 U.S. 370 (1996), preceded by a technology tutorial presented by the parties on November 30, 2011. Having carefully reviewed the papers and considered the arguments of counsel and the relevant legal authority, the Court hereby construes the claim terms as follows.
I. BACKGROUND
A. The Instant Action
Plaintiffs Illumina, Inc. and Solexa, Inc. (collectively, "Illumina") filed this patent infringement action against Defendant-Counterclaimant Complete Genomics, Inc. ("CGI") in the District Court for the District of Delaware on August 3, 2010. The parties are competitors in the field of DNA sequencing. Illumina designs, manufactures, and sells several platforms for high-throughput DNA sequencing, including its Genome Analyzer and HiSeq sequencing instruments. CGI offers DNA sequencing services to its customers through its Complete Genomics Analysis Service ("CGA™ Service"). In performing its CGA™ Service, CGI employs its Complete Genomics Analysis Platform ("CGA™ Platform"), which includes its Combinatorial Probe-Anchor Ligation (or "cPAL™") read technology. Illumina contends that through CGI's use of its CGA™ Platform to perform DNA sequencing services, CGI infringes Illumina U.S. Patent No. 6,306,597 ("the '597 patent"). Illumina also previously asserted U.S. Patent No. 7,232,656 ("the '656 patent"), and U.S. Patent No. 7,598,035 ("the '035 patent"), but the parties stipulated to dismissal without prejudice of all claims and counterclaims related to the '656 and '035 patents. Doc. no. 75.
CGI denies that it infringes any of the Illumina Patents. CGI further alleges that all of the Illumina Patents are invalid, and it alleges that the '597 patent is unenforceable due to inequitable conduct. CGI also claims that by filing its claim for infringement of the '597 patent against CGI, Illumina has violated Section 2 of the Sherman Act under the doctrine of Walker Process Equipment, Inc. v. Food Machine & Chemical Corp., 382 U.S. 172 (1965). Illumina denies that any of the Illumina patents are invalid and denies that it has violated the Sherman Act.
By order dated November 9, 2010, the court granted CGI's motion to transfer venue to the Northern District of California. Judge Alsup denied CGI's motion to consider whether this action is related to an earlier filed action, Applera-AB v. Illumina, No. C 07-02845 WHA. Doc. no. 42. Upon consent of the parties, this action was reassigned to this Court.
B. Prior Litigation of the '597 Patent
In Applera Corp. - Applied Biosystems Group v. Illumina, et al., No. C 07-02845 WHA, Applied Biosystems ("AB") filed suit against Illumina for ownership of the '597 patent and two related patents (U.S. Patent Nos. 5,750,341 and 5,969,119), alleging that the inventor, Dr. Macevicz, invented the subject matter of the patents while he was in-house patent counsel for AB and breached the terms of an Invention Agreement by, among other things, failing to disclose inventions to AB, applying for patents on the inventions in his own name, and purporting to assign the inventions and patents to Lynx, a spinoff corporation of AB, which subsequently merged with Solexa. AB alleged that Macevicz's conduct, as well as Illumina and Solexa's conduct, gave rise to claims for interference with contract, breach of fiduciary duty, constructive fraud, conversion, imposition of constructive trust, and unfair competition. Illumina countersued AB for infringement.
Judge Alsup issued a claim construction order on February 21, 2008, which construed terms from one of the '597 patent's sibling patents, some of which also appear in the '597 patent. See Applera-AB, Case No. 07-2845 WHA, doc. no. 133. See Labbe Decl., Ex. 5. Judge Alsup issued a supplemental claim construction on terms from Claim 1 of the '597 patent and the parties stipulated that AB infringed Claim 1 and that the Southern prior art reference rendered Claim 1 invalid. Applera-AB, doc. nos. 383-1, 384-1, 402 (order on stipulation re infringement and invalidity). See Labbe Decl., Ex. 5. The parties agree that Judge Alsup's construction of the terms also applies to the '597 patent. Opening Br. at 6-7; Resp. at 9. Following jury trial, on February 3, 2009, Judge Alsup entered judgment for Illumina on AB's claim of ownership of the Macevicz patents and entered judgment for AB on Illumina's claim that AB infringed the '119 patent.
On March 25, 2010, the Federal Circuit issued its decision affirming Judge Alsup's claim construction of the terms that were appealed and affirming "the court's judgment of noninfringement with respect to Applera's accused products, and the court's order, entered pursuant to stipulation, concerning invalidity." See Labbe Decl., Ex. 6 at 14-16. Mandate was issued on May 3, 2010.
C. Reexamination
While the litigation before Judge Alsup was pending, on June 30, 2008, AB filed a request for reexamination of the '597 patent. See Labbe Decl., Ex. 7. Three months after the jury trial before Judge Alsup, on May 28, 2009, the PTO issued a non-final Office Action rejecting claim 1 of the '597 patent as being anticipated by several prior art references, including Martinelli (U.S. Patent No. 5,800,994) and either Landegren (U.S. Patent No. 4,988,617) or Whitely (U.S. Patent No. 4,883,750) taken in view of Martinelli. Labbe Decl., Ex. 8. Illumina/Solexa held an interview with the Examiner on July 13, 2009, and filed a response to the office action on August 6, 2009, which included amendments to the claims. Labbe Decl., Exs. 9, 10.
The Examiner's interview summary indicates that he and Illumina/Solexa discussed whether the "Martinelli patent is 'repeating' steps a and b within the meaning of claim 1." Labbe Decl., Ex. 10. In its response to the PTO's Office Action, Illumina/Solexa summarized the interview as follows:
It was discussed that Martinelli did not disclose repeating steps (a) and (b) on the same polynucleotide that was operated on in the first cycleLabbe Decl., Ex. 9 at 11 (8/6/2009 Suppl. Amendment). According to Illumina, "Martinelli described its version of [oligonucleotide ligation assay] as a 'hybridization-ligation methodology (HLM),'" which involves binding two probes to a DNA sample to detect whether a mutation is present. Id. at 15; Opening Br. at 8. Under the Martinelli patent, according to Illumina, "[i]f the two
of the claimed method. It was discussed that claim 1 recites a method that is limited to repeating steps (a) and (b) on the same polynucleotide that was operated on in the first cycle of the method. It was agreed that an unequivocal statement by the Applicant that step (c) of claim 1 of the ' 597 patent requires repeating steps (a) and (b) on the same polynucleotide acted upon in the first cycle of the recited method would overcome the rejections based on Martinelli.
probes can be ligated, the identity of the nucleotide at the site in the sample where the two probes attach to each other can be determined, because ligation could only occur if the mutation is present." Opening Br. at 8. In response to the rejection of claim 1 as anticipated by Martinelli and obvious over Landegren and Whiteley in view of Martinelli, Illumina/Solexa distinguished Martinelli on the ground that Martinelli "did not disclose repeating the steps of its 'HLM' method . . . [and] expressly taught that the HLM reaction was intended to be performed for only one cycle." Labbe Decl., Ex. 9 at 15. In its amendment to Claim 1, Illumina made the following narrowing statement:
As discussed at the interview, the "repeating" step in the claimed method, step (c), requires the repetition of steps (a) and (b) on the same polynucleotide sequence that was acted upon in the first cycle of the recited method. Step (a) of claim 1 recites "extending an initializing oligonucleotide along the polynucleotide." When step (a) is repeated as required by step (c), a (new) initializing oligonucleotide is extended along the same polynucleotide as was acted upon in the first cycle of the recited method ("the polynucleotide").Labbe Decl., Ex. 9 at 15. By Office Action dated September 30, 2009, the examiner withdrew the claim rejections based on Martinelli (and based on Landegren or Whitely in view of Martinelli):
Patent Owner has provided an unequivocal statement that "repeating" steps (a) and (b) of the claimed method means that the steps are performed on the same nucleic acid sequence in each cycle (response of August 3, 2009, p. 15). In Martinelli, repetition is performed on different portions of the target nucleic acid (col. 4, lines 56-61). Therefore Martinelli does not anticipate the claim and the rejection is withdrawn.Labbe Decl., Ex. 12 at 5. The PTO confirmed that for the reasons detailed in that Office Action, claim 1 is patentable. Labbe Decl., Ex. 13 at 3 (12/22/09 Office Action). An Ex Parte Reexamination Certificate with regard to the '597 patent was issued on March 2, 2010. Labbe Decl., Ex. 3. On March 25, 2010, the Federal Circuit issued its opinion affirming the judgment entered by Judge Alsup in the Applera-AB litigation, as noted above.
II. LEGAL STANDARD
In construing claims, the court must begin with an examination of the claim language itself. The terms used in the claims are generally given their "ordinary and customary meaning." See Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005); see also Renishaw PLC v. Marposs Societa' per Azioni, 158 F.3d 1243, 1248 (Fed. Cir. 1998) ("The claims define the scope of the right to exclude; the claim construction inquiry, therefore, begins and ends in all cases with the actual words of the claim."). This ordinary and customary meaning "is the meaning that the terms would have to a person of ordinary skill in the art in question at the time of the invention. . . ." Phillips, 415 F.3d at 131. A patentee is presumed to have intended the ordinary meaning of a claim term in the absence of an express intent to the contrary. York Products, Inc. v. Central Tractor Farm & Family Ctr., 99 F.3d 1568, 1572 (Fed. Cir. 1996).
Generally speaking, the words in a claim are to be interpreted "in light of the intrinsic evidence of record, including the written description, the drawings, and the prosecution history, if in evidence." Teleflex, Inc. v. Ficosa North Am. Corp., 299 F.3d 1313, 1324-25 (Fed. Cir. 2002) (citations omitted); see also Medrad, Inc. v. MRI Devices Corp., 401 F.3d 1313, 1319 (Fed. Cir. 2005) (court looks at "the ordinary meaning in the context of the written description and the prosecution history"). "Such intrinsic evidence is the most significant source of the legally operative meaning of disputed claim language." Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996).
With regard to the intrinsic evidence, the court's examination begins, first, with the claim language. See id. Specifically, "the context in which a term is used in the asserted claim can be highly instructive." Phillips, 415 F.3d at 1314. As part of that context, the court may also consider the other patent claims, both asserted and unasserted. Id. For example, as claim terms are normally used consistently throughout a patent, the usage of a term in one claim may illuminate the meaning of the same term in other claims. Id. The court may also consider differences between claims as a guide in understanding the meaning of particular claim terms. Id.
Second, the claims "must [also] be read in view of the specification, of which they are a part." Id. at 1315. When the specification reveals a special definition given to a claim term by the patentee that differs from the meaning it would otherwise possess, the inventor's lexicography governs. Id. at 1316. Indeed, the specification is to be viewed as the "best source" for understanding a technical term, informed as needed by the prosecution history. Id. at 1315. As the Federal Circuit stated in Phillips, the specification is "the single best guide to the meaning of a disputed term," and "acts as a dictionary when it expressly defines terms used in the claims or when it defines terms by implication." 415 F. 3d at 1321.
Limitations from the specification, however, such as from the preferred embodiment, cannot be read into the claims absent a clear intention by the patentee to do. Teleflex, 299 F.3d at 1326 ("The claims must be read in view of the specification, but limitations from the specification are not to be read into the claims.") (citations omitted); CCS Fitness, 288 F.3d at 1366 ("a patentee need not describe in the specification every conceivable and possible future embodiment of his invention."); Altiris v. Symantec Corp., 318 F.3d 1363, 1372 (Fed. Cir. 2003) ("resort to the rest of the specification to define a claim term is only appropriate in limited circumstances").
"[T]here is sometimes a fine line between reading a claim in light of the specification, and reading a limitation into the claim from the specification. . . . [A]ttempting to resolve that problem in the context of the particular patent is likely to capture the scope of the actual invention more accurately than either strictly limiting the scope of the claims to the embodiments disclosed in the specification or divorcing the claim language from the specification." Decisioning.com , Inc. v. Federated Dept. Stores, Inc., 527 F.3d 1300, 1308 (Fed. Cir. 2008) (citations omitted). There is therefore "no magic formula or catechism for conducting claim construction," and the court must "read the specification in light of its purposes in order to determine whether the patentee is setting out specific examples of the invention to accomplish those goals, or whether the patentee instead intends for the claims and the embodiments in the specification to be strictly coextensive." Id. (internal citations omitted).
Finally, as part of the intrinsic evidence analysis, the court "should also consider the patent's prosecution history, if it is in evidence." Phillips, 415 F.3d at 1317. The court should take into account, however, that the prosecution history "often lacks the clarity of the specification" and thus is of limited use for claim construction purposes. Id.
In most cases, claims can be resolved based on intrinsic evidence. See Vitronics, 90 F.3d at 1583. Only if an analysis of the intrinsic evidence fails to resolve any ambiguity in the claim language may the court then rely on extrinsic evidence, such as expert and inventor testimony, dictionaries, and learned treatises. See Vitronics, 90 F.3d at 1583 ("In those cases where the public record unambiguously describes the scope of the patented invention, reliance on any extrinsic evidence is improper"). "Within the class of extrinsic evidence, the court has observed that dictionaries and treatises can be useful in claim construction." Phillips, 415 F.3d at 1318. While expert testimony can be useful to a court for a variety of purposes, conclusory assertions by experts are not. Id. The court generally views extrinsic evidence as less reliable than the patent and its prosecution history in determining how to read claim terms, although its consideration is within the court's sound discretion. See id. at 1318-19.
III. DISCUSSION
The parties dispute the construction of nine terms in the '597 patent. The '597 patent contains two independent claims, Claims 1 and 2. Illumina asserts Claim 2 and dependent Claims 4, 5, 9, 10, 14, 15, 16, 17, 18 and 19 in this action. Illumina has previously stipulated that Claim 1 is invalid and does not assert that claim here. However, because dependent claims 9, 10, 14, 15, 16, 17, 18 and 19 are dependent from Claim 1, its construction is necessary.
CGI points out that the most significant terms to be construed are the repeating step of Claim 1 (i.e., step (c)) and "annealing temperatures" and "set"/ "probe set" of Claim 2. CGI contends that it does not infringe because it neither (1) repeats ligation reactions in the manner that the patent teaches nor (2) groups probes into subsets by annealing temperature.
A. Background of the '597 Patent
Judge Alsup articulated a basic overview of DNA and the Sanger method of sequencing DNA in the Applera-AB v. Illumina litigation:
DNA consists of a long polymer of simple units called nucleotides. Each nucleotide in human DNA consists of a deoxyribose sugar linked to both a phosphate group and one of four characteristic nitrogen "bases": adenine (A), cystosine (C), guanine (G), or thymine (T). The deoxyribose sugar has five carbons, numbered 1' to 5', respectively. It is the sequence of these bases that encodes information about the functioning of living organisms. The bases bond with one another, or "hybridize," to create a structure known as a double helix consisting of two intertwined strands of DNA. These two strands are perfectly complementary to one another, such that A bonds with its complement T and C bonds with its complement G. When a single strand of DNA exists in isolation, its sequence is unknown, i.e., the exact lineup of the A, C, G, and T's is unknown. . . .Applera-AB, No. C 07-02845 WHA, doc. no. 232 at 1-3. See '597 patent, 1:18 - 2:64 (Background).
A method used in the prior art for DNA sequencing was known as "Sanger sequencing." In a single DNA strand, adjacent nucleotides are chemically bonded. A dideoxynucleotide, or a ddNTP, is a type of nucleotide that lacks the hydroxyl group of a standard deoxynucleotide, or a dNTP. Hydroxyl is a molecule consisting of an oxygen atom and a hydrogen atom. The lack of this hydroxyl group means that when a ddNTP is added to a sequence of DNA on a strand no further nucleotides, a ddNTP or a dNTP, may be added. The Sanger sequencing method made use of this chemical property. In Sanger sequencing, each base (e.g., A, C, G, and T) was assigned a fluorescent color and the target DNA to be sequenced was bonded with a known DNA sequence. The known DNA sequence was then hybridized by an initializing primer, which added stability to the entire structure. Several strands of the target DNA were then brought into contact with single probe ddNTPs and dNTPs. The result was that several strands of the target DNA would hybridize to the different probes at various points on the DNA strand. Because ddNTPs halt further hybridization on any given single strand of the target DNA, many strands would have varying lengths depending on where the ddNTP hybridized. Some strands that hybridized with the target would be longer (i.e., a ddNTP hybridized at a much later point in the sequence) and some would be shorter (i.e., a ddNTP hybridized at a much earlier point in the sequence). These several strands that hybridized to the target DNA were then collected and placed in a capillary tube to form a group of strands of varying lengths. A magnetic field was then placed on the capillary tube causing the various strands to line up in order of length (e.g., shortest to longest). Each individual strand would then be taken out of the tube and put through a light source which allowed the user to identify the fluorescent light associated with the ddNTP of that sequence. Because the varying strands were lined up according to their length, the user would go through strand by strand to decode each color, and hence base, associated with each nucleotide of the sequence in the correct order, thereby allowing the perfect complement to the target DNA sequence to be determined. In sum, the Sanger sequencing method allowed a target DNA strand to be sequenced by associating fluorescent labels with specific nucleotides that had hybridized with the target DNA sequence. Once the identities of the nucleotides that hybridized were determined, it was simply a matter of taking their complements to determine the sequence of the target DNA strand.
The '597 patent teaches a method of DNA sequencing. As used in the patent, "'ligation' means to form a covalent bond or linkage between the termini of two or more nucleic acids, e.g. oligonucleotides and/or polynucleotides, in a template-driven reaction. The nature of the bond or linkage may vary widely and the ligation may be carried out enzymatically or chemically." '597 patent, 4:28-33 (Definitions). Generally, in ligation reactions, an enzyme can link together two separate strands of DNA that are hybridized adjacent to each other but are not connected in their sugar phosphate backbone. Once the enzyme repairs this break in the DNA ladder, the two pieces are linked together as one strand. Resp. at 3.
As described in the patent, "[t]he invention relates generally to methods for determining the nucleotide sequence of a polynucleotide, and more particularly, to a method of identifying nucleotides in a template by stepwise extension of one or more primers by successive ligations of oligonucleotide blocks." '597 patent, 1:10-14 [Field of the Invention]. The patent states that an objective of the invention is to provide "an alternative approach to presently available DNA sequencing technologies." '597 patent, 2:65-67. The invention provides a method of DNA analysis based on repeated cycles of duplex extension along a single stranded template. '597 patent, 3:3-5.
B. Claim 1
Claim 1 teaches the following method:
1. A method for identifying a sequence of nucleotides in a polynucleotide, the method comprising the steps of:'597 patent, 21:25-24. The parties ask the Court to construe the following terms: "extending an initializing oligonucleotide along the polynucleotide by ligating an oligonucleotide probe thereto to form an extended duplex" (i.e., step (a)); "repeating steps (a) and (b) until the sequence of nucleotides is determined" (i.e., step (c)); "initializing oligonucleotide;" and "oligonucleotide probe."
(a) extending an initializing oligonucleotide along the polynucleotide by ligating an oligonucleotide probe thereto to form an extended duplex;
(b) identifying one or more nucleotides of the polynucleotide; and
(c) repeating steps (a) and (b) until the sequence of nucleotides is determined.
As an initial matter, CGI contends that Illumina is barred by collateral estoppel from relitigating the construction of the terms referring to extending step (a) and repeating step (c). Resp. at 12. Illumina responds that it is not barred from re-arguing claim construction because it relies on statements made during the reexamination which occurred after the Applera-AB litigation. Reply at 2. The law of the regional circuit applies to the doctrine of collateral estoppel, Transocean Offshore Deepwater Drilling, Inc. v. Maersk Contractors USA, Inc., 617 F.3d 1296 (Fed. Cir. 2010). Because the effect of the reexamination history was not presented in the earlier proceeding to Judge Alsup or the Federal Circuit, the issues are not identical, strictly speaking, and Illumina would not appear to be barred by the traditional doctrine of collateral estoppel from doing so now. See Enovsys LLC v. Nextel Communications, Inc., 614 F.3d 1333 (Fed. Cir. 2010) (applying the doctrine of collateral estoppel, or issue preclusion, under California law: (1) the issue sought to be precluded from relitigation is identical to the issue decided in the earlier proceeding; (2) the issue was actually litigated in the former proceeding; (3) the issue was necessarily decided in the former proceeding; and (4) the person against whom collateral estoppel is asserted was a party, or in privity with a party, to the earlier proceeding).
(1) "extending an initializing oligonucleotide along the polynucleotide by
ligating an oligonucleotide probe thereto to form an extended duplex"
+-----------------------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +--------------------------------------------+--------------------------------------------¦ ¦"extending an initializing oligonucleotide ¦ ¦ ¦ ¦"extending an initializing oligonucleotide ¦ ¦along the polynucleotide by ligating an ¦ ¦ ¦ ¦along the polynucleotide by ligating an ¦ ¦oligonucleotide probe thereto to form an ¦ ¦ ¦ ¦oligonucleotide probe thereto to form an ¦ ¦extended duplex" means "Extending an ¦ ¦ ¦ ¦extended duplex" means "ligating an ¦ ¦initializing oligonucleotide along the ¦ ¦ ¦ ¦oligonucleotide probe to an initializing ¦ ¦polynucleotide by ligating an ¦ ¦ ¦oligonucleotide ¦oligonucleotide to form an extended duplex ¦ ¦ ¦and ¦ ¦probe thereto to form an extended duplex, ¦ ¦ ¦and ¦further extending the duplex by ligating a ¦ ¦ ¦new ¦ ¦when step (a) is repeated a new initializing¦ ¦ ¦ ¦oligonucleotide probe to the extended duplex¦ ¦oligonucleotide is extended along the same ¦in ¦ ¦ ¦ ¦ ¦polynucleotide sequence as was acted upon in¦any subsequent cycles" ¦ ¦ ¦ ¦ ¦the first cycle of the recited method" ¦ ¦ +-----------------------------------------------------------------------------------------+
(2) "repeating steps (a) and (b) until the sequence of nucleotides is determined"
+---------------------------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +----------------------------------------+----------------------------------------------------¦ ¦ ¦"repeating steps (a) and (b) until the sequence of ¦ ¦ ¦ ¦ ¦ ¦nucleotides is determined" means "either (1) ¦ ¦ ¦ ¦ ¦ ¦repeatedly extending the extended duplex by ¦ ¦ ¦ ¦ ¦ ¦subsequent cycles of ligation and identifying a ¦ ¦ ¦label ¦ ¦ ¦ ¦ ¦ ¦on or associated with a successfully ligated ¦ ¦ ¦ ¦ ¦ ¦oligonucleotide probe until the sequence of ¦ ¦ ¦ ¦ ¦"repeating steps (a) and (b) until the ¦nucleotides is determined or (2) using parallel ¦ ¦ ¦ ¦ ¦sequence of nucleotides is ¦reactions employing different initializing ¦ ¦ ¦ ¦ ¦determined" means "determining a ¦oligonucleotides, each out of register by one or ¦ ¦ ¦more ¦ ¦nucleotide sequence by repeating steps ¦ ¦ ¦ ¦nucleotides, and identifying a label on or ¦ ¦(a) and (b)" ¦associated ¦ ¦ ¦ ¦ ¦ ¦with a successfully ligated oligonucleotide probe ¦ ¦ ¦until ¦ ¦ ¦ ¦ ¦ ¦the sequence of nucleotides is determined. There is ¦ ¦ ¦no ¦ ¦ ¦ ¦ ¦ ¦need for repetition if the sequence of the ¦ ¦ ¦ ¦ ¦ ¦polynucleotide has been fully determined in the ¦ ¦ ¦first ¦ ¦ ¦ ¦ ¦ ¦cycle" ¦ +---------------------------------------------------------------------------------------------+
The parties agree that the first time "extending" step (a) is practiced, this extending step requires that an initializing oligonucleotide be extended by ligating a probe to it. Resp. at 22-23. The parties dispute what this step requires when it is repeated, referring to "repeating" step (c) of claim 1, which is the central dispute in this litigation. Illumina contends that when step (a) is repeated in a subsequent cycle, it can be repeated by ligating a probe to a "new" initializing oligonucleotide that has either the same sequence as, or a different sequence than, the initializing oligonucleotide that was used in the first cycle. CGI, on the other hand, contends that when step (a) is repeated in a subsequent cycle, the probe has to be ligated either to the previously extended probe that was ligated to the initializing oligonucleotide in the first cycle, or to a "new" initializing oligonucleotide that has a different sequence than the initializing oligonucleotide that was used in the first cycle. CGI points out that Illumina's proposed construction of the "extending" step includes construction of the "repeating" step. The Court considers construction of the "extending" and "repeating" terms simultaneously, as the parties did in presenting oral argument on claim construction.
Illumina's proposed construction
Starting with the construction of the extending term in the Applera-AB litigation, Judge Alsup construed the term "extending an initializing oligonucleotide along the polynucleotide" in claim 1 of the '597 patent to mean that in the first cycle of the method, a probe is ligated to an initializing oligonucleotide, and that the "extending" step (a) is repeated either by (i) ligating a new probe to a new initializing oligonucleotide (i.e., "a brand new initializing oligonucleotide must be laid down along the polynucleotide with each repetition"); or (ii) by further extending by successive ligation, i.e., ligating a second probe to the duplex that was created by ligating a first probe to the initializing oligo in the first cycle (such that "an ever-extending chain of probes is ligated thereto to form an ever-extending duplex"). See Labbe Decl., Ex. 5. Illumina contends that Judge Alsup's repeating option (i) of laying down a "brand new initializing oligonucleotide" includes both (a) repeated use of new copies of the same sequence initializing oligonucleotide that was used in the first cycle and (b) use of new initializing oligonucleotides with different sequences on the same general region of the polynucleotide but staggered to start at a slightly different point, e.g., one nucleotide off from the first initializing oligonucleotide, an embodiment known as re-registration.
With respect to Judge Alsup's repeating option (ii) of successive ligation, or adding an additional probe to the extended duplex, Illumina contends that during reexamination, it narrowed the scope of step (a) to disavow successive ligation in favor of using a new initializing oligonucleotide extended along the same polynucleotide sequence. CGI, however, contends that Illumina's purported disavowal of successive ligation (or Judge Alsup's option (ii)) is not consistent with the Reexamination history or with the entire claim scope of the patent. CGI also points out that at the same time that Illumina made its narrowing statements during reexamination in its August 6, 2009 Supplemental Amendment in response to the Office Action, the cross-appeals from Judge Alsup's judgment were pending before the Federal Circuit, Illumina having filed its original notice of appeal on March 2, 2009, and its amended notice of appeal on April 6, 2009.
With respect to the "repeating" step (c), Judge Alsup determined that the repeating step "is conditional, meaning that there is no need for repetition if the sequence of the polynucleotide has been fully determined in the first cycle." Labbe Decl., Ex. 5 at 2. The Federal Circuit affirmed this construction on appeal. Labbe Decl., Ex. 6. Based on its argument that it disavowed successive ligation during reexamination, Illumina contends that Judge Alsup's construction of the repeating step should be narrowed so that step (c) is not conditional but a required step. Illumina argues that it would be improper to construe the repeating step as conditional after Illumina relied on an unequivocal statement that repetition is a requirement to overcome the prior art.
CGI's proposed construction
Rather than including the repeating step in the extending term, CGI proposes that "extending" be construed without reference to Judge Alsup's repeating option (i) ("possibility [] that a brand new initializing oligonucleotide must be laid down along the polynucleotide with each repetition"). Instead, CGI argues that the extending step should be construed to include successive ligation, as set forth in Judge Alsup's option (ii), to form an extended duplex and further extend the duplex whereby "an ever-extending chain of probes is ligated thereto to form an ever-extending duplex, all beginning with the same initializing oligonucleotide" until the sequence is determined. See Labbe Decl., Ex. 5.
CGI's proposed construction of "repeating" purports to encompass both forms of repeating disclosed by the specification: (1) successive ligation, based on the Examiner's finding that this was an "essential characteristic of the claimed invention, because no embodiment of the invention is disclosed which lacks repeated cycles of extension;" and (2) an optional form of repeating in which parallel reaction mixtures separated into different pots use a new initializing oligonucleotide shifted over by one or more positions on the polynucleotide to allow for the interrogation of other additional locations on the same template, known as re-registration. Resp. at 14 (citing Figure 1 of '597 patent). CGI disputes Illumina's contention that "repeating" should also be construed as using a same sequence new initializing oligonucleotide that is not shifted or re-registered.
With respect to construction of the "extending" and "repeating" steps, the parties dispute whether Illumina disavowed successive ligation during reexamination, whether repeating includes new initializing oligonucleotides with the same sequence as the initializing oligonucleotide used in the first cycle, whether repeating is conditional, and whether repeating uses parallel reactions.
a. Scope of Disavowal During Reexamination
Illumina takes the position that during reexamination of the '597 patent, it provided an unequivocal statement to exclude the form of repeating taught by the Martinelli patent in order to overcome the Examiner's rejection of claim 1. Illumina characterizes the Examiner's rejection of claim 1 by describing the Martinelli patent as disclosing that "the process can be repeated with probes complementary to different portions of the target nucleic acid, which meets the limitations of step 1 of the claim."
By moving to the next portion of the target, a similar experiment can be run. Thus, by moving sequentially along the target, one can determine the site or sites on the target where mutations are found and then proceed to design experiments to identify the exact mutation which occurs at each of the mutation sites.Opening Br. at 13 (quoting Labbe Decl., Ex. 8 (5/28/2009 Office Action)). Illumina now contends that Martinelli's use of the phrase "moving sequentially along the target" discloses successive ligation or the "repeating" step as proposed by CGI. Opening Br. at 16. Illumina argues that to overcome Martinelli, the Examiner required Illumina to narrow claim 1 to require that when step (a) is repeated, rather than "further extending" or "moving sequentially along the target," step (a) was limited to hybridizing a "new" initializing oligonucleotide to the same polynucleotide as was acted upon in the first cycle. Id. (emphasis added). In other words, Illumina argues that it clearly disclaimed a central aspect of the invention called out prominently in the specification. For example, the specification's own description of the field of the invention is "more particularly, to a method of identifying nucleotides in a template by stepwise extension of one or more primers by successive ligations of oligonucleotide blocks," '597 patent, 1:11-14, and its Summary of the Invention states "[t]he invention provides a method of nucleic acid sequence analysis based on repeated cycles of duplex extension along a single stranded template. . . . The extended duplex is then repeatedly extended by subsequent cycles of ligation." Id. at 3:1-11.
During re-examination of the '597 patent, Illumina did narrow "repeating" to extending a "(new) initializing oligonucleotide" along the "same" polynucleotide as was acted upon in the first cycle, distinguishing the claimed invention from the repetition in Martinelli's method, which "does not refer to repeating steps (a) and (b) on the same template sequence." Labbe Decl., Ex. 12 at 5 (9/30/09 Office Action); see Illumina claim construction Slide 23. CGI does not dispute that the '597 patent teaches "repeating" on the same polynucleotide, but disagrees whether Illumina thereby narrowed the scope of "repeating" to exclude successive ligation. CGI has the better argument that Illumina did not make such a broad disavowal.
As CGI points out, Illumina disavowed hybridization on a different target polynucleotide, limiting step (a) to the same polynucleotide to overcome Martinelli, but the reexamination history does not support Illumina's contention that it disavowed extending by successive ligation. Illumina unduly stretches the meaning of its narrowing statement in contending that it disavowed successive ligation and required that a "new" initializing oligonucleotide be used when step (a) is repeated:
As discussed at the interview, the "repeating" step in the claimed method, step (c), requires the repetition of steps (a) and (b) on the same polynucleotide sequence that was acted upon in the first cycle of the recited method. Step (a) of claim 1 recites "extending an initializing oligonucleotide along the polynucleotide." When step (a) is repeated as required by step (c), a (new) initializing oligonucleotide is extended along the same polynucleotide as was acted upon in the first cycle of the recited method ("the polynucleotide").Opening Br. at 14 (quoting Labbe Decl., Ex. 9 (8/6/2009 Amendment)).
The reexamination officer correctly interpreted Illumina's disclaimer as distinguishing Martinelli because the Martinelli method does not repeat the hybridization-ligation methods on the same polynucleotide sequence in each cycle, but rather the "repetition is performed on different portions of the target nucleic acid." Labbe Decl. Ex. 12 at 5 (9/30/09 Office Action) (emphasis added). The reexamination officer acknowledged that Martinelli teaches that "repetition is performed on different portions of the target nucleic acid," which was disclaimed by Illumina by limiting the repeating step to being performed on the "same nucleic acid sequence in each cycle." Labbe Decl. Ex. 12 at 5. As clarified at the further Markman hearing, the parties do not dispute that repeating on the "same" polynucleotide sequence includes anywhere on the polynucleotide that overlaps on the same sequence.
The Martinelli patent informs the construction of the repeating and extending terms because the parties dispute the scope of Illumina's disavowal of the Martinelli patent during reexamination of the '597 patent. Illumina contends that it narrowed "repeating" to be performed on the same sequence of the polynucleotide used in the first cycle, so that it could not repeat the steps on other sequences of the target polynucleotide during subsequent cycles of ligation. Illumina concludes that by disavowing the method of moving along the target polynucleotide to different sequences, it disavowed successive ligation altogether. CGI points out correctly that the reexamination history shows that Illumina only disclaimed "repetition performed on different portions of the target nucleic acid" (9/30/09 Office Action at 5) (emphasis added), which does not amount to disclaiming successive ligation by repeatedly extending the extended duplex by subsequent cycles of ligation.
The reexamination history indicates that Illumina disclaimed extending a new initializing oligonucleotide along different sequences of the target polynucleotide (to overcome the Martinelli prior art), but not successive ligation by further extending the extended duplex. Both Judge Alsup and the reexamination officer found that the successive ligation was a characteristic of the claimed method, and the Federal Circuit affirmed Judge Alsup's construction:
i. Judge Alsup's claim constructionLabbe Decl., Ex. 5.
The better interpretation of this language is that step (a) includes an extension process, whereby, with each repetition, an additional probe is added to what is already there, so that the chain gets longer and longer. Put differently, step (a) includes a scenario where the initializing oligonucleotide is originally attached to the polynucleotide and thereafter an ever-extending chain of probes is ligated thereto to form an ever-extending duplex, all beginning with the same initializing oligonucleotide.
ii. Federal CircuitLaBarre Decl., Ex. O (3/25/10 slip op.) at 14.
Thus, once an extended duplex is formed, it 'is further extended in subsequent cycles.'" ['597 patent], col. 3 ll. 15-16. This description of the invention is echoed throughout the specification, which repeatedly describes regenerating an extendable end on the extended duplex to allow for successive cycles of ligation. [Citations omitted.]
iii. ReexaminationLaBarre Decl., Ex. X (9/30/09 Office Action) at 3 (emphasis added). As CGI points out, the Examiner recognized two possible ways of repeating disclosed by claim 1:
First, 'repeating' refers to 'repeated cycles of duplex extension along a single stranded template' as set forth in the specification (e.g. col. 3, lines 2-19). This is viewed as an essential characteristic of the claimed invention, because no embodiment of the invention is disclosed which lacks repeated cycles of extension.
'Repeating' has several meanings in the context of claim 1. First, "repeating" refers to "repeated cycles of duplex extension along a single stranded template" as set forth in the specification (e.g. col. 3, lines 2-19). This is viewed as an essential characteristic of the claimed invention, because no embodiment of the invention is disclosed which lacks repeated cycles of extension. "Repeating" can also refer to processes wherein the cycling process is performed in multiple "pots" with different initializing oligonucleotides in each pot (Fig. 1). This is an optional feature of the invention, since the method can be performed in a single pot with a single initializing oligonucleotide (col. 5, lines 52-57). Patent Owner's [8/3/2009 response] has clarified that "repeating" requires the repetition of steps (a) and (b) on the same polynucleotide sequence that was acted upon in the first cycle of the method.Id. at 3 (emphasis added). Thus, the Examiner stated that to distinguish Martinelli, the repetition must occur on the same sequence. There was no mention of disavowing successive ligation, and as CGI points out, the Examiner correctly recognized "repeated cycles of duplex extension" to be "an essential characteristic of the claimed invention." Indeed, successive ligation is emphasized throughout the specification, as noted above. Disavowal of successive ligation is further contradicted by the Examiner's statement that Dr. Macevicz' notebook disclosed a method describing successive ligation: "After detection and identification of the label, a new 3' or 5' end is regenerated on the nascent nucleic acid to allow ligation of another labeled oligonucleotide, and the process is repeated until the entire complement of the template nucleic acid has been synthesized." Id. at 4. The reexamination history does not support Illumina's contention that it disclaimed successive ligation.
CGI also points out that Illumina did not discuss with, or attempt to clarify to, the Examiner during Reexamination its argument now that the repeating step uses the same sequence initializing oligonucleotide, in addition to the use of "different initializing oligonucleotides" expressly recognized by the Examiner. LaBarre Decl., Ex. X (9/30/09 Office Action) at 3. Illumina stated in its Amendment that the repeating step uses "a (new) initializing oligonucleotide." Labbe Decl., Ex. 9 at 15. The more common sense meaning of "new" (especially "brand new" as construed by Judge Alsup) suggests different rather than same sequence initializing oligonucleotides, although both meanings are literally correct as a matter of English language. It does not appear from the reexamination history that it occurred to the Examiner that Illumina intended the claim scope of the repeating step to include the use of a same sequence (though physically different copy) initializing oligonucleotide. That interpretation of the "repeating" term is further discussed below.
In addition to citing the reexamination history for disclaimer of claim scope, CGI raised a new theory during the further Markman hearing that Illumina did not disclaim successive ligation during reexamination because Illumina's statements in the reexamination history are not sufficient to give public notice of its disclaimer. Illumina points out that CGI's new theory is inconsistent with its prior argument that "In this Amendment, Illumina disclaimed repetition of the hybridization-ligation-and identification on a different portion of the genome. . . . The Examiner was very clear that Illumina's disclaimer did not disclaim successive ligation." Illumina Resp. at 6 (citing CGI's responsive claim construction brief). Illumina complains that CGI cannot have it both ways by arguing for an ambiguous disclaimer and an express disclaimer. However, parties are entitled to make reasonable arguments in the alternative.
Although the Court accepts CGI's argument that Illumina's clarification of claim scope on reexamination was limited to requiring repetition on the same (or overlapping) sequence, and did not disavow successive ligation, the Court also considers CGI's fallback theory that there is no "clear and unmistakable" disclaimer if a prosecution argument is subject to more than one reasonable interpretation. See SanDisk Corp. v. Memorex Products, Inc., 415 F.3d 1278, 1287 (Fed. Cir. 2005) (finding no disclaimer due to multiple reasonable interpretations of SanDisk's prosecution arguments) and Schwing GmbH v. Putzmeister Aktiengesellschaft, 305 F.3d 1318, 1324 (Fed. Cir. 2002) ("Although prosecution history can be a useful tool for interpreting claim terms, it cannot be used to limit the scope of a claim unless the applicant took a position before the PTO that would lead a competitor to believe that the applicant had disavowed coverage of the relevant subject matter."). In SanDisk, the Federal Circuit noted:
As a basic principle of claim interpretation, prosecution disclaimer promotes the public notice function of the intrinsic evidence and protects the public's reliance on definitive statements made during prosecution. . . . An ambiguous disclaimer, however, does not advance the patent's notice function or justify public reliance, and the court will not use it to limit a claim term's ordinary meaning. There is no "clear and unmistakable" disclaimer if a prosecution argument is subject to more than one reasonable415 F.3d at 1287 (citations and internal quotation marks omitted). Illumina does not dispute that these cases hold that in order for statements to constitute a disavowal, "someone would have to 'believe that the applicant had disavowed coverage,'" that is, the public must have clear, reliable notice of the scope of disclaimer. Illumina Resp. at 7 (quoting Schwing, 305 F.3d at 1324).
interpretation, one of which is consistent with a proffered meaning of the disputed term.
Even assuming in the alternative that Illumina intended to disclaim successive ligation, its purported disclaimer was not "clear and unmistakable." The reexamination history demonstrates that even the Examiner did not understand the disavowal as encompassing successive ligation as Illumina now contends, and neither does the Court. Nor did Illumina make any such argument or otherwise alert the Federal Circuit which was in the process of construing the same term. In particular, the Examiner cited the Summary of the Invention describing the practice of successive ligation where "[t]he extended duplex is then repeatedly extended by subsequent cycles of ligation," and viewed this form of repeating as an essential characteristic of the invention. LaBarre Decl., Ex. X (9/30/09 Office Action) at 3 (citing '597 patent, 3:2-19). The Court finds CGI's argument based on ambiguous disclaimer persuasive and determines, on this alternative ground, that Illumina did not disavow successive ligation during reexamination.
CGI also argued during the Markman hearing that if Illumina had believed that it had changed the claim scope to disavow successive ligation while the appeal in the AB litigation was pending, it should have notified the Federal Circuit of the reexamination decision, which was issued by the PTO only three weeks before the Federal Circuit issued the panel decision. Although there is authority that the Federal Circuit can take judicial notice of the PTO's reexamination proceedings, Old Reliable Wholesale, Inc. v. Cornell Corp., 635 F.3d 539, 548-49 (Fed. Cir. 2011), CGI acknowledges that the Federal Circuit has not adopted a judicial estoppel or similar doctrine to address the situation presented in this case where reexamination proceedings and federal court actions are simultaneously pending and the PTO issues a reexamination certificate before the Federal Circuit issues a decision that the patentee then contends reached different interpretations of the same claim. CGI revised Markman slides 161-63. CGI contends that, for the purposes of this ligitation, Illumina has manufactured a post hoc argument that it disclaimed successive ligation during reexamination. CGI makes a strong argument that if Illumina had actually believed that it had so changed the claim's meaning during reexamination, at the very least it should have notified the Federal Circuit of the reexamination decision, so Illumina should not be permitted now to assert that it made inconsistent arguments to the Federal Circuit and the PTO. The inefficiency, potential waste of judicial resources and unfairness of such a process would seem to go against the basic goal of making litigation just, speedy and inexpensive insofar as practical. Cf. Fed. R. Civ. Proc. 1. Judicial estoppel is invoked "not only to prevent a party from gaining an advantage by taking inconsistent positions, but also because of 'general consideration[s] of the orderly administration of justice and regard for the dignity of judicial proceedings,' and to 'protect against a litigant playing fast and loose with the courts.'" Hamilton v. State Farm Fire & Cas. Co., 270 F.3d 778, 783 (9th Cir. 2001) (quoting Russell v. Rolfs, 893 F.2d 1033, 1037 (9th Cir. 1990)). The Court need not reach the issue of judicial estoppel, however, because it concludes that Illumina did not disavow successive ligation, much less do so clearly.
b. Brand New Initializing Oligonucleotide
In the Applera-AB litigation, Judge Alsup construed the repeating step to include two possibilities: successive ligation (which he found to be the "better" construction) and ligating a "brand new" initializing oligo. Illumina argues that during reexamination, it disavowed successive ligation and narrowed the "repeating" step to using a "new initializing oligonucleotide," which Judge Alsup construed as an alternative to the "better interpretation" of successive ligation: "One possibility is that a brand new initializing oligonucleotide must be laid down along the polynucleotide with each repetition." Labbe Decl., Ex. 5 at 3. Illumina also contends that "repeating" with a "new initializing oligonucleotide" in fact actually encompasses two meanings: (1) new initializing oligonucleotides with different sequences, or re-registration and (2) new initializing oligonucleotides with the same sequence as the initializing oligonucleotide used in the first cycle. Illumina Tutorial Slide 24.
The parties do not dispute that the repeating step can be done by hybridizing new initializing oligonucleotides with different sequences and shifting positions (re-registering) along the polynucleotide relative to the position of the initializing oligonucleotide utilized in the first cycle, which Illumina referred to at the tutorial as re-registration. Illumina Tutorial Slide 35-37. CGI refers to this form of "repeating" in its proposed construction as "(2) using parallel reactions employing different initializing oligonucleotides, each out of register by one or more nucleotides, and identifying a label on or associated with a successfully ligated oligonucleotide probe until the sequence of nucleotides is determined."
The parties dispute, however, whether the "repeating" step allows use of a new initializing oligonucleotide with the same sequence as the initializing oligonucleotide used in the first cycle. Illumina contends that the repeating step also allows repeated use of new copies of the same-sequence initializing oligo, whereas CGI contends that an initializing oligo with the same sequence cannot be repeated unless repeatedly forming an extended duplex through successive ligation.
CGI argues that Illumina is trying to expand claim scope to an undisclosed embodiment of the invention by defining "new initializing oligonucleotide" to include a same-sequence copy of the initializing oligonucleotide. CGI does not point to any part of the specification that requires the "new initializing oligonucleotide" in the repeating step to have a different sequence from the initializing oligonucleotide used in the first cycle. CGI is correct that the specification primarily addresses different initializing oligonucleotides. However, Illumina points out that the specification discloses "repeating" by using an identical copy of the same initializing oligonucleotide, as well as different initializing oligonucleotides: "Different binding regions can be employed with either identical or different initializing oligonucleotides, but for convenience of preparation, it is preferable to provide identical binding regions and different initializing oligonucleotides." '597 patent 5:18-22 (emphasis added). Illumina Markman Slide 38.
CGI argues that in the AB v. Illumina litigation before Judge Alsup and in the briefs filed on appeal in the Federal Circuit, Illumina sought a construction of the repeating step to require "re-registration," i.e., using a different sequence new initializing oligonucleotide, as opposed to a same sequence copy of the initializing oligonucleotide. CGI slides 139-150; LaBarre 2d Decl. Exs. A-H. Illumina responds, however, that it never proposed a construction that would limit "repeating step (a)" to using a different sequence or shifted initializing oligonucleotide. Illumina quotes the following argument from its claim construction brief in the AB litigation:
It cannot be legitimately disputed, however, that step (a) in claim 1 requires exactly what it recites: extending an initializing oligonucleotide by ligating a probe to the end of that initializing oligonucleotide to form an extended duplex. Solexa's [i.e., Illumina's] proposed construction requires that the initializing oligonucleotide utilized when step (a) is repeated (as required by step (c)) be a physically different molecule than the initializing oligonucleotide utilized in the first cycle. But there is no requirement that the initializing oligonucleotide utilized in the second cycle (or those used in subsequent cycles) has to be shifted, or "re-registered," along the polynucleotide relative to the position of the initializing oligonucleotide utilized in the first cycle.Labbe Decl., Ex. A at 9-10 (Solexa's Responsive Trial Brief Regarding Disputed Claim Constructions) (doc. no. 116-1).
Although CGI has consistently taken the position that "repeating" with a new initializing oligonucleotide (as distinguished from repeating by successive ligation) is limited to "re-registration," that is, shifting or staggering, Illumina correctly points out that CGI raised for the first time at the January 13, 2012 hearing its argument that Illumina proposed this limitation in the earlier AB litigation. Illumina has submitted its trial brief on claim construction from the AB litigation which demonstrates that Illumina did not take such an inconsistent position before Judge Alsup that a "brand new" initializing oligo must be limited to "re-registration" using a different sequence initializing oligo. Rather, Illumina argued in the AB litigation that the new initializing oligo must be a "physically different" molecule than the initializing oligo used in the first cycle (by removing the first initializing oligo and replacing it with the second, or new, initializing oligo). Illumina Resp. at 1, 3 (citing Solexa trial brief from AB case). Illumina also stated in its trial brief to Judge Alsup that the new initializing oligo could have the same sequence as the first:
Repeating step (a) exactly as described would of course require the use of a physically different (even if having the same sequence) initializing oligonucleotide.Illumina Resp. at 3 (quoting Solexa trial brief from AB case). These statements by Solexa/Illumina in the AB litigation demonstrate that Illumina did not take the position there that the repeating step could only be performed by re-registration with a different sequence initializing oligo.
But there is no requirement that the initializing oligonucleotide utilized in the second cycle (or those used in subsequent cycles) has to be shifted, or "re-registered," along the polynucleotide relative to the position of the initializing oligonucleotide utilized in the first cycle.
Judge Alsup was not presented with the issue that Illumina raises now, whether a "new" initializing oligonucleotide can copy the same sequence or must have a different sequence. Illumina's trial brief in the AB litigation indicates that there was no apparent dispute between AB and Solexa that claim 1 was not limited to re-registering and that Judge Alsup was not asked to distinguish between same sequence and different sequence initializing oligonucleotides when he construed the repeating step to include a "brand new" initializing oligo:
Although it never actually proposes a construction of any term in claim 1 of the '597 patent in its Trial Brief, AB asks this Court to adopt a construction of the claim that does not limit the scope of the claim to require "resetting" or "re-registering" the initializing oligonucleotide. Solexa agrees, as the terms "resetting" and "reregistering" are not found in claim 1.Labbe Decl., Ex. A at 9.
In further support of its argument that Illumina proposed a construction of repeating that was limited to re-registering, CGI quoted Illumina's experts from the AB litigation. CGI Slides 139-145 (excerpts from Backman and Quackenbush reports and deposition and trial testimony). In its response, Illumina has sufficiently demonstrated that the extrinsic evidence on which CGI relies does not purport to limit use of a "different" initializing oligo to using a different sequence, re-registered initializing oligonucleotide.
i. Backman expert report and testimony
Illumina's expert Backman stated in his rebuttal report that "claim 1 of the '597 patent encompasses the concept of 'reregistering' the initializing oligonucleotide to allow for a shifting (or reregistering) of the interrogation position by one or more nucleotides along the polynucleotide. The repeating of the cycles, as recited in step (c) of claim 1, requires the use of a different initializing oligonucleotide." CGI Markman slide139; LaBarre 2d Decl., Ex. A. To say that a claim "encompasses" a concept does not mean, however, that the claim is limited to it. Backman also testified that "it means that when you go back and repeats steps A and B, you do so using a different initializing oligo." CGI slide 140; LaBarre 2d Decl., Ex. B. Illumina clarifies that Backman made these statements in the response to questions about whether AB's accused SOLiD system would infringe claim 1 if the system didn't use a second, physically different initializing oligo: "if SOLiD only used one [primer, or initializing oligo, cycle], then it would not be doing re-registering and it wouldn't be addressed by this claim." This statement does not amount to an admission that "repeating" is limited to re-registration. Illumina Resp. at 5.
ii. Quackenbush expert report
CGI also cites Illumina's second expert, Quackenbush, who stated, "The repeating of the cycle, as contained in step c of claim 1, requires the use of a different initializing oligonucleotide." CGI slide141; LaBarre 2d Decl., Ex. C. Quackenbush also testified that "step c requires the use of a different initializing oligonucleotide." CGI slide143; LaBarre 2d Decl., Ex. D. Quackenbush's opinion that "repeating" requires use of a "different initializing oligo" does not limit that term to re-registration, as CGI contends.
iii. Backman direct exam
CGI further relies on Backman's testimony at trial, where he testified that Figure 1 of the '597 patent "involves the different initializing oligonucleotide primers [initializing oligos], the ones which bind slightly different positions in each instance." CGI slide 144; LaBarre 2d Decl., Ex. E. He further testified "the next time we go through this elongation process, we're not going to be asking questions about the exactly same positions that we did the first time we went through the process." CGI slide 145; LaBarre 2d Decl., Ex. F. Although Illumina does not directly address these specific excerpts of Backman's trial testimony, Illumina has shown that at other points in the trial and in its briefs it specified that "different" does not require a different sequence, but instead includes repeating step (a) by removing the first initializing oligonucleotide and using a "physically different" initializing oligonucleotide, whether it has the same or different sequence. Illumina Resp. at 5-6. These isolated expert statements from the AB litigation, addressing a specific embodiment of the '597 patent, do not lead to imposing the limitation that CGI advocates.
c. Conditional Repeating Step
Although Judge Alsup determined that the "repeating" step "is conditional, meaning that there is no need for repetition if the sequence of the polynucleotide has been fully determined in the first cycle," Labbe Decl., Ex. 5 at 2, Illumina argues that it would be improper to construe the repeating step as conditional after Illumina relied on an unequivocal statement that repetition is a requirement to overcome the prior art. At reexamination, Illumina stated:
It was discussed that Martinelli did not disclose repeating steps (a) and (b) on the same polynucleotide that was operated on in the first cycle of the claimed method. It was discussed that claim 1 recites a method that is limited to repeating steps (a) and (b) on the same polynucleotide that was operated on in the first cycle of the method. It was agreed that an unequivocal statement by the Applicant that step (c) of claim 1 of the ' 597 patent requires repeating steps (a) and (b) on the same polynucleotide acted upon in the first cycle of the recited method would overcome the rejections based on Martinelli.Labbe Decl., Ex. 9 at 11 (8/6/2009 Suppl. Amendment) (emphasis added).
As CGI points out, Illumina's disclaimer was not related to the conditional aspect of step (c), and does not unconditionally "require" repetition of steps (a) and (b) even if the sequence of the polynucleotide has been fully determined in the first cycle. Rather, as discussed above, its disclaimer distinguished Martinelli as carrying out its method on different, i.e., non-overlapping and noncontiguous, portions of the polynucleotide. Furthermore, the Federal Circuit affirmed Judge Alsup's construction of step (c) as conditional:
The district court construed step (c) as "conditional, meaning that there is no need for repetition if the sequence of the polynucleotide has been fully determined in the first cycle." Solexa argues that this construction is inconsistent with arguments made during the prosecution history. During prosecution, the applicant distinguished the invention from a prior art reference by noting that "the reference does not teach 'repeating steps (a) and (b) until the sequence of nucleotides is determined, as recited in the present claim. Because the prior art method identifies only a single nucleotide, not a sequence of nucleotides, there would be no need for such repetition." Contrary to Solexa's argument, this statement does not require one to repeat steps (a) and (b) even when the polynucleotide has been determined in the first cycle (indeed, it states that the cycle is repeated "until the sequence of nucleotides is determined"). The distinguishing feature of the invention is that it taught a method for identifying a sequence of nucleotides, rather than a method for identifying a single nucleotide. . . . We construe step (c), as the district court did, to have its plain and ordinary meaning. To meet the limitations of claim 1, one must repeat steps (a) and (b) until the sequence of nucleotides is determined. There is no need for repetition once the sequence of the polynucleotide has been fully determined.Labbe Decl., Ex. 6 at 16. Illumina gives no persuasive reason to revisit Judge Alsup's and the Federal Circuit's construction of that term as conditional, "meaning that there is no need for repetition if the sequence of the polynucleotide has been fully determined in the first cycle." Labbe Decl., Ex. 5 at 2.
d. Parallel Reactions
CGI also proposes that "repeating" be construed as "using parallel reactions," but as Illumina persuasively argues, this proposed construction improperly imports limitations from the preferred embodiment disclosed in the patent. Opening Br. at 20-21. See Teleflex, Inc. v. Ficosa North America Corp., 299 F.3d 1313, 1326-27 (Fed. Cir. 2002). During reexamination, the Examiner correctly recognized that the use of parallel reaction mixtures in multiple pots was an optional feature of the invention: "'Repeating' can also refer to processes wherein the cycling process is performed in multiple "pots" with different initializing oligonucleotides in each pot (Fig. 1). This is an optional feature of the invention, since the method can be performed in a single pot with a single initializing oligonucleotide." LaBarre Decl., Ex. X (9/30/09 Office Action) at 3 (citing '597 patent, 5:52-57). The Court therefore declines to adopt this limitation in the construction of the "repeating" term.
Court's Construction
The Court construes the claim term "extending an initializing oligonucleotide along the polynucleotide by ligating an oligonucleotide probe thereto to form an extended duplex" to mean "ligating an oligonucleotide probe to an initializing oligonucleotide to form an extended duplex."
The Court construes the claim term "repeating steps (a) and (b) until the sequence of nucleotides is determined" to mean "either (1) ligating an additional probe to the extended duplex by subsequent cycles of ligation until the sequence of nucleotides is determined or (2) ligating a new probe to a new initializing oligonucleotide, either by extending different sequence initializing oligonucleotides, each out of register by one or more nucleotides, or by extending new initializing oligonucleotides with the same sequence as the initializing oligonucleotide used in the first cycle along the identical polynucleotide sequence as was acted
upon in the first cycle of the recited method, until the sequence of nucleotides is determined. There is no need for repetition if the sequence of the polynucleotide has been fully determined in the first cycle."
(3) "initializing oligonucleotide"
+-----------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +--------------------------------------+--------------------------------------¦ ¦ ¦"initializing oligonucleotide" means¦ ¦ ¦"an ¦ ¦"initializing oligonucleotide" means¦ ¦ ¦"the ¦oligonucleotide that forms a highly ¦ ¦ ¦stable ¦ ¦oligonucleotide to which the ¦ ¦ ¦oligonucleotide ¦duplex with the binding region of the ¦ ¦ ¦ ¦ ¦probe is first ligated" ¦polynucleotide that remains intact ¦ ¦ ¦during any ¦ ¦ ¦ ¦ ¦ ¦washing steps" ¦ +-----------------------------------------------------------------------------+
The parties dispute whether the initializing oligonucleotide must remain intact during all washing steps and must form a highly stable duplex with the binding region.
Illumina's proposed construction
Illumina proposes that in construing the term "initializing oligonucleotide," the Court adopt Judge Alsup's construction of the term "initializing oligonucleotide probe" which appears in the claims of a related Macevicz patent. Judge Alsup held that construction of that term should "take into account that the initializing oligonucleotide probe is the starting point for subsequent ligations," and construed that term to mean "the oligonucleotide to which the first extension oligonucleotide probe is first ligated." Applera, doc. no. 133 at 10.
As CGI points out, Illumina's proposed construction deletes Judge Alsup's construction of the term to mean the oligonucleotide to which the first extension oligonucleotide probe is first ligated. CGI argues that "first extension" implies that there is at least a "second extension" oligonucleotide probe. Although Illumina initially distinguishes Judge Alsup's construction based on the difference between the inventions claimed in the '341 patent and the '597 patent, Illumina waived any objection to including "first extension" in the construction. Reply at 9 n. 31. CGI's proposed construction
CGI contends that surviving washing steps is a critical feature of the initializing oligonucleotide: "After a set of probes is applied, mismatched probes must be washed away before detection (otherwise the mismatched probes would still give off a signal from the label)." Resp. at 26. CGI reasons that if the initializing oligonucleotide does not remain strongly bound to the polynucleotide during the washing steps, the signal would be lost and the method would not work. Id.
As Illumina points out, the specification contains no language that limits "initializing oligonucleotide" to only those oligos that remain bound through any and all washing steps. CGI relies on the following statements in the specification to support its proposed construction which would require the initializing oligonucleotide to survive any washing steps:
Initializing oligonucleotides are selected to form highly stable duplexes with the binding region that remain intact during any washing steps'597 patent, 5:30-49 (emphasis added). As Illumina points out, CGI's proposed construction omits the part of the specification that describes the initializing oligonucleotides as remaining intact during "any washing steps of the extension cycles." Opening Br. at 11. Illumina proposes that if the Court were to adopt CGI's construction, rather than Judge Alsup's prior construction, that "of the extension cycles" be added.
of the extension cycles. This is conveniently achieved by selecting the length(s) of the initializing oligonucleotides to be considerably longer than that, or those, of the oligonucleotide probes and/or by selecting them to be GC-rich. Initializing oligonucleotides may also be cross-linked to the template strand by a variety of techniques, e.g. Summerton et al, U.S. Pat. No. 4,123,610; or they may be comprised of nucleotide analogs that form duplexes of greater stability than their natural counterparts, e.g. peptide nucleic acids, Science, 254:1497-1500 (1991); Hanvey et al, Science, 258: 1481-1485 (1992); and PCT applications PCT/EP92/01219 and PCT/EP92/01220.
Preferably, the length of the initializing oligonucleotide is from about 20 to 30 nucleotides and its composition comprises a sufficient percentage of G's and C's to provide a duplex melting temperature that exceeds those of the oligonucleotide probes being employed by about 10-50o C.
CGI acknowledges that Judge Alsup's construction did not address this "critical feature" of the initializing oligonucleotide to survive the washing steps. Resp. at 27. CGI argues that Judge Alsup's prior construction of the similar "initializing oligonucleotide probe" claim term from the '341 patent does not determine this claim term from the '597 patent, which does not refer to a "probe." To support its proposed construction requiring that the duplex formed with the initializing oligonucleotide "remains intact during any washing steps," CGI also cites Dr. Macevicz's deposition testimony indicating that the washing step would remove the reaction compounds in order to start the next cycle and that "the initializing oligonucleotide would need to remain on the target." Resp. at 26 and LaBarre Decl., Ex. I at 44-45. At oral argument, Illumina conceded that the method includes washing steps, but argued that the highly stable duplex needs to be stable enough only to detect a signal during detection, but not after that point. Even without relying on the extrinsic evidence offered by CGI, the Court determines that the specification language supports CGI's proposed construction, with the additional language that the "highly stable duplexes with the binding region" must remain intact "during any washing steps of the extension cycles."
Illumina also argues that the doctrine of claim differentiation bars CGI's proposed construction requiring that the initializing oligonucleotide form "a highly stable duplex with the binding region." Under the doctrine of claim differentiation, "the presence of a dependent claim that adds a particular limitation raises a presumption that the limitation in question is not found in the independent claim." Liebel-Flarsheim Co. v. Medrad, Inc., 358 F.3d 898, 910 (Fed. Cir. 2004) (citing Wenger Mfg., Inc. v. Coating Mach. Sys., Inc., 239 F.3d 1225, 1233 (Fed.Cir. 2001)). In Liebel-Flarsheim, the Federal Circuit held that the presumption under the doctrine of claim differentiation undermined the alleged infringer's proposed construction where the infringer offered no explanation for why the limitation was found in the dependent claims but not in the corresponding independent claims. "In such a setting, where the limitation that is sought to be "read into" an independent claim already appears in a dependent claim, the doctrine of claim differentiation is at its strongest." Liebel-Flarsheim, 358 F.3d at 910.
Illumina argues that dependent claims 9 and 10 require the polynucleotide to include a binding region, a separate term submitted for claim construction, and that these dependent claims would not have meaning if independent claim 1 were to require a binding region. CGI, however, argues that a binding region is used in every embodiment of the invention, so that any presumption against a limitation is rebutted by the specification. Resp. at 29 (citing Edwards Lifesciences LLC v. Cook Inc., 582 F.3d 1322, 1332 (Fed. Cir. 2009) ("claim differentiation is a rule of thumb that does not trump the clear import of the specification")). CGI cites the embodiment shown in Figure 1 of the '597 patent and an excerpt from the Detailed Description describing that embodiment, 5:16-19, but does not show that the specification describes the preferred embodiment as the invention itself. Cf. Edwards Lifesciences, 582 F.3d at 1330 (finding that "the specification frequently describes an 'intraluminal graft' as 'the present invention' or 'this invention,' indicating an intent to limit the invention to intraluminal devices," and that "the claim language itself" supports the limitation that all of the claimed "graft" devices must be intraluminal).
Edwards Lifesciences held that the claim differentiation doctrine does not trump the language of the specification.
"When different words or phrases are used in separate claims, a difference in meaning is presumed." Nystrom v. TREX Co., 424 F.3d 1136, 1143 (Fed.Cir.2005). "However, simply noting the difference in the use of claim language does not end the matter. Different terms or phrases in separate claims may be construed to cover the same subject matter where the written description and prosecution history indicate that such a reading of the terms or phrases is proper." Id. Although, as Edwards points out, claim 10 of the '458 patent recites a "second graft ... adapted to be intravascularly inserted into a lumen of [a] first graft," the intravascular insertion and the "intraluminal grafts" are not redundant. Instead, an "intraluminal graft" describes the ultimate location of the graft, whereas the intravascular insertion describes the process of moving the graft to that location. In other words, a device could theoretically be "intravascularly inserted" but ultimately reside outside of the vessel, such as inside the heart. Even if the claim construction had rendered the dependent claim redundant, the doctrine of claim differentiation does not require us to give the "graft" devices their broadest possible meaning. We may instead limit "grafts" to "intraluminal" devices, as demanded by the specification. See id.Edwards Lifesciences, 582 F.3d at 1330. CGI does not make as strong a showing that the specification language includes the binding region limitation or describes that embodiment as the invention itself, as was shown in Edwards, and would not overcome the presumption under the claim differentiation doctrine if it applied. Cf Edwards Lifesciences, 582 F.3d at 1330 ("when the preferred embodiment is described in the specification as the invention itself, the claims are not necessarily entitled to a scope broader than that embodiment"). CGI has a stronger argument that claim differentiation is not applicable because claims 9 and 10 include other limitations in addition to binding region, so that those dependent claims would not be rendered completely redundant if the Claim 1 term were to be construed as including a binding region.
CGI contends that claim differentiation only applies where the claims at issue are rendered entirely redundant. Resp. at 29 (citing Enzo Biochem v. Applera Corp., 599 F.3d 1325, 1342 (Fed. Cir. 2010), cert. denied, 131 S. Ct. 3020 (2011)). CGI argues that the presumption under the doctrine of claim differentiation does not apply here because dependent claims 9 and 10 include limitations other than the binding region, such that the binding region is not the only "meaningful difference" between the dependent and independent claims. Id. Dependent claim 9 adds the limitation to claim 1 that "the polynucleotide comprises a binding region and a target polynucleotide" and claim 10 adds not only the binding region limitation but also requires that "the target polynucleotide comprises and unknown sequence" and "in step (a) the initializing oligonucleotide is hybridized to the binding region on the polynucleotide." Labbe Decl., Ex. 3 (3/2/2010 Reexamination Certificate) (emphasis added). The Court agrees with CGI that dependent claim 10 is not rendered superfluous by construing "initializing oligonucleotide" to include a binding region. See Tandon Corp. v. U.S. Intern. Trade Comm'n, 831 F.2d 1017, 1023-24 (Fed. Cir. 1987) (rejecting argument that claim differentiation prevents reading "non-gimballed" limitation from a claim where the limitation related to only one element of that claim which, when viewed as a whole, could still differ in scope from other claims).
The Court agrees with CGI that the doctrine of claim differentiation does not bar construction of the "initializing oligonucleotide" term to include a binding region, and determines that the specification language "remain intact during any washing steps of the extension cycles" must be included in the construction. '597 patent, 5:30-35.
Court's Construction
The Court construes "initializing oligonucleotide" to mean "an oligonucleotide that forms a highly stable duplex with the binding region of the polynucleotide that remains intact during any washing steps of the extension cycles."
(4) "oligonucleotide probe"
+-----------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +-----------------------------------+-----------------------------------------¦ ¦"oligonucleotide probe" means "a ¦"oligonucleotide probe" means "an ¦ ¦nucleic ¦ ¦ ¦ ¦oligonucleotide that contains or is ¦ ¦acid that can bind to the ¦associated ¦ ¦polynucleotide and, ¦ ¦ ¦ ¦with a label and that is ligated to the ¦ ¦when bound to the polynucleotide, ¦initializing ¦ ¦can be ¦ ¦ ¦ ¦oligonucleotide or, in subsequent cycles,¦ ¦ligated to the initializing ¦to the ¦ ¦oligonucleotide" ¦ ¦ ¦ ¦extended duplex" ¦ +-----------------------------------------------------------------------------+
The parties dispute (1) whether the oligonucleotide contains or is associated with a label and (2) whether the oligonucleotide probe can only be ligated to the extended duplex in subsequent cycles.
Illumina's proposed construction
The parties do not dispute that an "oligonucleotide probe" is a nucleic acid that can be ligated to the initializing oligonucleotide, as Illumina proposes. CGI concedes that "not all embodiments in the patent use a label on the oligonucleotide probe." Resp. at 30. CGI contends, however, that Illumina's proposed construction ignores the way the term is used in the patent, because without a label on, or associated with, the probe, it is unclear how the nucleotides would be identified in each cycle. Id.
Illumina does not propose a construction of "oligonucleotide probe" that refers to ligation to the extended duplex in subsequent cycles, or successive ligation, because it contends that it disavowed successive ligation during reexamination. As discussed above, the Court concludes that Illumina did not make such a broad disclaimer of claim scope. Because Illumina's proposed construction construes the term "oligonucleotide probe" as "can be ligated to the initializing oligonucleotide," it does not necessarily limit the term to being ligated only to the initializing oligonucleotide. However, Illumina's proposed construction "oligonucleotide probe" is silent with respect to whether the probe "can be ligated" to an extended duplex when practicing successive ligation.
CGI's proposed construction
a. Label
In support of its proposed construction, CGI contends that the specification emphasizes the need for a label, citing the Summary of the Invention:
The initializing oligonucleotide is extended in an initial extension cycle by ligating an oligonucleotide probe to its end to form an extended duplex. The extended duplex is then repeatedly extended by subsequent cycles of ligation. During each cycle, the identity of one or more nucleotides in the template is determined by a label on, or associated with, a successfully ligated oligonucleotide probe.Resp. at 30 (quoting '597 patent, 3:7-13).
Although Illumina concedes that the specification describes probes in certain embodiments as containing labels used to identify a nucleotide, Illumina contends that the limitations proposed by CGI are contradicted by the specification which describes other embodiments of the invention that use oligonucleotide probes that do not contain labels, in particular, probe (402) which is depicted in Figure 4 exemplifying polymerase extension following ligation:
Identification of nucleotides can be accomplished by polymerase extension following ligation. As exemplified in FIG. 4, for this embodiment, template (20) is attached to solid phase support (10) as described above and initializing oligonucleotide (400) having a 3' hydroxyl is annealed to the template prior to the initial cycle. Oligonucleotide probes (402) ["probe (402)"] are annealed to template (20) and ligated (404) to form extended duplex (406). The 3' monophosphate, which prevents successive ligations of probes in the same cycle, is removed with phosphatase (408) to expose a free 3' hydroxyl (410). Clearly, alternative blocking approaches may also be used. Extended duplex (406) is further extended by a nucleic acid polymerase in the presence of labeled dideoxynucleoside triphosphates (412), thereby permitting the identification of a nucleotide of template (20) by the label of the incorporated dideoxynucleotide. The labeled dideoxynucleotide and a portion of probe (402) are then cleaved (414), for example, by RNase H treatment, to regenerate an extendable end on extended duplex (406). The cycle is then repeated (416).'597 patent, 11:15-38 (emphasis added). Illumina explains that in this embodiment, once probe (402) is ligated to the initializing oligonucleotide (400), a free nucleotide which contains a label ("labeled dideoxynucleoside triphosphates (412)") is added onto the probe (402), and is subsequently removed from the probe after identification. Opening Br. at 23. This embodiment of probe (402) would not require that oligonucleotide probes contain or be associated with a label at all times, but would so require at some point after ligation. See Illumina Markman slides 64-65. CGI responds that in Figure 4, the labeled free nucleotide added onto the probe "associates the label" with the previously added probe. Resp. at 30. In this embodiment, the oligonucleotide probe is "cleaved" to the labeled dideoxynucleotide, i.e., associated with a label, after ligation. '597 patent, 11:35. In this embodiment, however, the label is not added to the oligonucleotide probe until it has been ligated to the initializing oligonucleotide, so that not all probes will be associated with a label, only the successfully ligated ones.
Illumina also points out that the specification discloses "spacer" probes which do not contain a label. '597 patent, 6:30-34 ("in embodiments that rely on polymerase extension for base identification, the probe primarily serves as a spacer, so specific hybridization to the template is not critical, although it is desirable.") (emphasis added). CGI responded at oral argument, however, that when the probe is acting as a spacer, it is added to the labeled base, so that the probe is not floating on its own. As exemplified in Figure 4, the polymerase extension embodiment uses labeled dideoxynucleoside triphosphates (ddntp), "thereby permitting the identification of a nucleotide of template (20) by the label of the incorporated dideoxynucleoside." '597 patent, 11:30-34. CGI argues that while all the embodiments do not use a label on the oligonucleotide probe, all embodiments use either a labeled probe or a probe associated with a label. Resp. at 30. CGI contends that without a label, the probe would serve no function because no nucleotides could be identified. Id. As Illumina conceded during oral argument, if a spacer probe that does not initially have a label is later associated with a probe that has a label, then it would be true in that sense that the first probe is "associated with a label."
CGI has demonstrated that every embodiment described in the specification requires that a successfully ligated oligonucleotide probe either have a label on it or be associated with a label at some point after ligation. The specification thus supports CGI's proposed construction. Edwards Lifesciences, 582 F.3d at 1329-30 ("the only devices described in the specification are intraluminal, supporting an interpretation that is consistent with that description"). CGI also offered Illumina's statement from the Applera-AB litigation that in the claimed invention, an oligonucleotide probe is attached to a "labeled non-extendable chain terminating moiety." CGI Markman revised slide 219. Illumina did not address this argument in its supplemental response, and it lends further support to CGI's proposed construction. However, the Court need not rely on this prior statement to adopt the language proposed by CGI, because the specification adequately supports it: "During each cycle, the identity of one or more nucleotides in the template is determined by a label on, or associated with, a successfully ligated oligonucleotide probe." '597 patent, 3:10-13 (emphasis added).
b. Subsequent Cycles
CGI also contends that an oligonucleotide probe can be ligated not only to the initializing oligonucleotide, but also to the extended duplex formed in the first round of ligation. CGI argues that the specification makes clear that oligonucleotide probes can be added to extend the extended duplex further: "The extended duplex is then repeatedly extended by subsequent cycles of ligation." '597 patent, 3:9-11. CGI argues that the feature of being added to the extended duplex is consistent with Judge Alsup's prior claim construction which recognized that "'step (a) includes an extension process whereby, with each repetition, an additional probe is added to what is already there, so that the chain gets longer and longer.'" Resp. at 31 (quoting LaBarre Decl., Ex. M). In the Applera action, however, Judge Alsup did not construe the term "oligonucleotide probe." Illumina argues that CGI's proposed construction of "oligonucleotide probes" would improperly limit the ligation of probes in "subsequent cycles," or subsequent repeating steps, to sequential ligations to the "extended duplex," or the previously-extended initializing oligonucleotide.
Illumina contends that during reexamination, it disavowed the form of repeating under step (a) in which probes are ligated to an ever-extending duplex. As discussed above, Illumina's statements during reexamination did not constitute such a broad disavowal. Rather, Illumina "agreed that an unequivocal statement by the Applicant that step (c) of claim 1 of the ' 597 patent requires repeating steps (a) and (b) on the same polynucleotide acted upon in the first cycle of the recited method would overcome the rejections based on Martinelli." Labbe Decl., Ex. 9 at 11 (8/6/2009 Suppl. Amendment). Nevertheless, CGI's proposed construction of the term improperly limits ligation of the oligonucleotide probe in subsequent cycles to the previously-extended initializing oligonucleotide and excludes ligation to a new initializing oligonucleotide in subsequent cycles when the method is repeated.
Court's Construction
The Court construes the term "oligonucleotide probe" to mean "a nucleic acid that can bind to the polynucleotide, and, when bound to the polynucleotide, can be ligated to the initializing oligonucleotide or to a previously extended duplex. An oligonucleotide probe that has been successfully ligated either contains, or is associated with, a label.
B. Claim 2
2. A kit for DNA sequence analysis, the kit comprising one or more sets of oligonucleotide probes, wherein
(i) each probe set contains at least 50 different-sequence, single-stranded oligonucleotide probes,
(ii) the oligonucleotide probes of a set have a selected length of up to 12 nucleotides, and
(iii) for at least one said probe set, the different-sequence, single stranded oligonucleotide probes in that set have annealing temperatures whose maximum and minimum values differ from each other by no more than 1° C.
CGI explains that Claim 2 is directed at creating DNA sequencing kits that include sets of probes wherein at least one of the sets is organized by the stability (i.e., binding energy) of the probes: "the oligonucleotide probes may be grouped into mixtures, or subsets, of probes whose perfectly matched duplexes with complementary sequences have similar stability or free energy of binding." '597 patent, 11:40-43. This concept is implemented in both of the Examples given in the specification. Id., columns 14-18. The patent teaches to split up the probes into ninety-six subsets of probes, each subset having a particular annealing temperature between 22-70°C (two subsets for each degree). Id. at 15:66 - 16:9 [Example 1]. CGI contends that the annealing reaction is run at the fixed point annealing temperature for each of the ninety-six groups. Resp. at 31-32.
(5) "set" and "probe set"
+-----------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +--------------------------------------+--------------------------------------¦ ¦Illumina contends that no construction¦"set" and "probe set" mean "a subset¦ ¦is necessary for the terms "set" and ¦of a mixture of all oligonucleotides ¦ ¦"probe set." Should the Court ¦of a selected length that are grouped ¦ ¦determine that construction is ¦according to their free energy of ¦ ¦required, Illumina proposes: "a number¦duplex formation with their perfectly ¦ ¦of probes grouped together" ¦complementary sequences" ¦ +-----------------------------------------------------------------------------+
The terms "set of probes" and "probe set" appear in independent claim 2 and dependent claims 4 and 5. The parties dispute whether to include the phrase "grouped according to their free energy of duplex formation with their perfectly complementary sequences," which refers to grouping the probes according to their relative ability to bind to their complementary sequence at or near the same temperature.
Illumina's proposed construction
Illumina contends that these terms do not need to be construed because they are not defined in the intrinsic record to have meaning other than their ordinary meaning, or if they are construed, to give them their ordinary meaning of "a number of probes grouped together."
CGI concedes that these terms are not highly technical terms, but proposes that the Court construe them to restrict the claim from encompassing prior art and unintended subject matter, in particular, to make clear that Claim 2 cannot encompass a set of all probes of a certain length. Resp. at 36.
CGI's proposed construction
CGI proposes that "set" or "probe set" be defined as probes that are grouped into subsets of probes having similar duplex stability, so as to exclude the possibility that the use of all probes of a given length is claimed by the patent. CGI cites the specification describing the use of "stringency classes" to support its proposed construction:
In order to reduce the number of separate annealing reactions that must be carried out, the oligonucleotide probes may be grouped into mixtures, or subsets, of probes whose perfectly matched duplexes with complementary sequences have similar stability or free energy of binding. Such subsets of oligonucleotide probes having similar duplex stability are referred to herein as "stringency classes" of oligonucleotide probes. The mixtures, or stringency classes, of oligonucleotide probes are then separately combined with the target polynucleotide under conditions such that substantially only oligonucleotide probes complementary to the target polynucleotide form duplexes.'597 patent, 11:39-50 (emphasis added); see CGI Markman slides 262-63. As thus described in the specification, stringency classes are "subsets of oligonucleotide probes having similar duplex stability or free energy of binding." Id. CGI contends that this language from the specification teaches a stringency class technique to assure that only perfectly matched probes will hybridize, but does not teach using a set of all possible probes having the same length.
CGI points to Illumina's statements during patent prosecution distinguishing the Pease prior art, which claims probe matrices that contain "a complete set of all possible sequences of a given length." LaBarre Decl., Ex. FF at 5 (11/16/00 Amendment). CGI contends that Pease teaches use of a set of all X-mer probes on an array, that is, using probes of all possible sequences of a given length. CGI further contends that Illumina distinguished Pease by disclaiming the use of all probes of a given length, telling the Examiner:
Pease et al. was discussed in the response filed May 12, 2000. Briefly, this reference describes preparation of probe matrices which contain either (i) a single sequence, (ii) two different sequences, or (iii) a complete set of all possible sequences of a given length. The first two instancesLaBarre Decl., Ex. FF at 5 (11/16/00 Amendment) at 5 (emphasis added). There, however, Illumina was addressing the use of a single stringency class claimed in the invention, as distinguished from a complete set of all probes of a given length claimed in the Pease prior art. In the amendment, Illumina referred to the benefit of using stringency classes in the invention as follows:
clearly do not show or suggest the probe sets of the invention, each of which contains at least 50 different-sequence oligonucleotides.
The third instance, in which all possible sequences are present, does not suggest a subset of probe oligonucleotides, belonging to a single stringency class, as defined above. Nor is there any suggestion or motivation in the reference to provide subsets of oligonucleotides from a single stringency class. The advantages of using such subsets in the applicants' disclosed sequencing methods, also discussed above, would not be provided by a set of all possible sequences.
The benefits of using sets of probes from the same stringency class are described at page 16, lines 11-22 of the specification. As noted at page 9, first paragraph, the probes are preferably applied to the polynucleotide template as mixtures comprising oligonucleotides of all possible sequences of a given length. Such a mixture can be quite complex; for example, the full set of 8-mers includes over 65,000 oligonucleotides. In such a mixture, individual probes may not be present at concentrations sufficient to drive hybridization at a reasonable rate, particularly for sequences having lower free energy of binding.LaBarre Decl., Ex. FF at 4-5 (11/16/00 Amendment). Illumina then went on to distinguish Pease, which did not teach use of a single stringency class, as claimed in the invention. Id. at 5 ("The third instance, in which all possible sequences are present, does not suggest a subset of probe oligonucleotides, belonging to a single stringency class, as defined above."). While the parties agree that Illumina further amended its claims, see CGI Markman slide 253, the statements by Illumina to overcome the Pease prior art in the 11/16/00 Amendment contemplate use of probes "of all possible sequences of a given length" and use of subsets of such probes from the same stringency class, which was not taught in Pease. LaBarre Decl., Ex. FF at 4-5 (11/16/00 Amendment).
This problem can be addressed by employing groups of stringency classes. As described at page 16, lines 11-21, each set of oligonucleotide probes from a single stringency class may be separately combined with the target polynucleotide under conditions such that substantially only oligonucleotide probes complementary to the target polynucleotide form duplexes. That is, the stringency of the hybridization reaction can be tailored to the free energy of duplex formation of the stringency class being used, so that substantially only perfectly complementary oligonucleotide probes form duplexes. This reduces the possibility of mismatches and errors in sorting or sequencing.
CGI also relies on extrinsic evidence by citing Dr. Macevicz's testimony about how the claim is practiced to support its proposed construction, but there Dr. Macevicz testified specifically about "stringency classes" and was not asked about the more general term "set of probes." Resp. at 37; LaBarre Decl., Ex. I at 52, 139 (Macevicz Depo. Tr.). CGI proposes a construction of "probe sets" to be synonymous with "subset" or "stringency classes," but does not cite any intrinsic evidence that the term "set" or "probe set" (as distinct from the subset of all probes identified in subsection (iii) of Claim 2) was intended to be so limited. As Illumina points out, Claim 2 (iii) itself already requires that the probes have a certain similarity to each other, based on the temperature at which they can hybridize (anneal) to form a stable duplex: "for at least one said probe set, the different-sequence, single stranded oligonucleotide probes in that set have annealing temperatures whose maximum and minimum values differ from each other by no more than 1° C." '597 patent, 21:41-44. See Opening Br. at 28.
The Court declines CGI's proposal to import limitations from the specification dealing with stringency classes into all uses of the term "set" or "probe set" in Claim 2, and adopts Illumina's "plain meaning" construction of the term.
Court's Construction
The Court construes "set" and "probe set" to mean "a number of probes grouped together."
(6) "annealing temperatures"
+-----------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +----------------------------------+------------------------------------------¦ ¦"annealing temperatures" means ¦"annealing temperatures" means "the ¦ ¦"the temperatures at which the ¦temperatures at which particular probes ¦ ¦annealing step can be carried out"¦have about fifty percent maximum annealing¦ ¦ ¦in a standard PCR buffer solution" ¦ +-----------------------------------------------------------------------------+
The parties agree that "annealing temperatures" is a significant term for construction. CGI proposes a construction of "annealing temperature" to define it as a specific temperature, rather than range of temperatures at which the annealing process can take place, as proposed by Illumina.
Illumina's proposed construction
Illumina proposes a construction that reflects that the annealing temperature for an oligonucleotide, at which the annealing step of a process can be carried out, is a range of temperatures, not a specific temperature. As CGI explains,
Annealing occurs when two single strands of DNA containing complementary base sequences come together such that the specific pairing of bases takes place between the complementary strands. Similar to the melting process, the annealing of two strands is a [sic] equilibrium over a temperature range. At high temperatures, fewer strands will anneal together, and at low temperatures many more strands will anneal.Resp. at 32 (citations omitted).
Illumina relies on the portion of the specification which refers to the range of annealing temperatures:
The range of annealing temperatures (22-70° C) is roughly bounded by the temperatures 5-10 degrees below the temperatures at which the least stable and most stable 8-mers, respectively, are expected to have about fifty percent maximum annealing in a standard PCR buffer solution.'597 patent, 16:4-9 (emphasis added). This passage does not, however, refer to the entire range of temperatures at which the probes can anneal, but rather refers to the full range of annealing temperatures by which the stringency classes or subsets are each defined and thereby grouped by specific temperatures within that range: "The 48 stringency conditions are defined by annealing temperatures which range from 22° C. to 70° C., such that each grouping of subsets at the same temperature differ in annealing temperature by 1° C. from that of the subset groupings containing the next highest and next lowest stringency classes." '597 patent, 15:66 - 16:4. The range of annealing temperatures described in this embodiment (22-70° C) covers a range of 48 degrees Celsius, such that each of the 48 stringency groups of probes is defined by particular annealing temperatures that are within 1 degree of each other, covering the range between 22 and 70 degrees Celsius.
CGI does not dispute that the possible annealing temperatures for a given set of probes of the same length cover a wide range of temperatures. CGI contends, however, that the term "annealing temperature" is "best understood as the point at which fifty percent annealing would have taken place," which it adds is also the point where fifty percent melting would have taken place. Resp. at 33 and n.24. CGI contends that Illumina's construction would render the entire claim inoperable because one must be able to compare one probe's annealing temperature to another probe's annealing temperature to determine if they are more than 1 degree apart, as required by the specification. Resp. at 36. CGI further argues that its proposed construction is consistent with the fact that the specification refers to separating the probes into "2 subsets for each of 48 different annealing temperatures" because if "annealing temperature" meant the entire range of temperatures at which a probe can anneal, then grouping the probes into subsets for "each" of 48 different annealing temperatures would be nonsensical. Resp. at 34 (citing '597 patent, 15:55 - 16:9). Illumina responds that one skilled in the art would be familiar with meaningful limits on the range of workable annealing temperatures for a given oligonucleotide, and that there is no support for limiting the range of annealing temperatures to a fixed temperature. Reply at 10.
The Court is persuaded that Illumina's proposed construction of "annealing temperature" as the entire range of temperatures at which the probes can anneal would render the claim inoperable because subsection (iii) of Claim 2 requires the probes in at least one probe set to have "annealing temperatures whose maximum and minimum values differ from each other by no more than 1° C." Thus, the annealing temperature limitation must be sufficiently specific to identify at least one subset of probes whose annealing temperatures are within one degree Celsius of each other. Illumina contends that expert testimony will demonstrate how to compare annealing temperatures to within one degree apart. On its face, however, Illumina's proposed construction would be unworkable generally such that the limitation that the maximum and minimum values cannot differ from each other by more than 1° C would be written out of the claim. The Court must avoid a construction with a nonsensical result. AIA Engineering Ltd. v. Magotteaux Intern. S/A, 657 F.3d 1264, 1276 (Fed. Cir. 2011). "While inoperability in itself does not doom [Illumina's] construction, 'a construction that renders the claimed invention inoperable should be viewed with extreme skepticism.'" Id. at 1278 (quoting Talbert Fuel Sys. Patents Co. v. Unocal Corp., 275 F.3d 1371, 1376 (Fed. Cir.), vacated and remanded on other grounds, 537 U.S. 802 (2002)).
CGI's proposed construction
CGI proposes that the term "annealing temperatures" be defined as "the temperatures at which particular probes have about fifty percent maximum annealing." CGI relies on the specification language which refers to temperatures at which probes "have about fifty percent maximum annealing in a standard PCR buffer solution." Resp. at 33 (quoting '597 patent, 16:4-9). CGI contends that the specification uses the term to mean the fixed midpoint, not the entire range of potential annealing conditions. Referring to Examples 1 and 2 which employ stringency classes (defined as "mixtures, or subsets, of probes whose perfectly matched duplexes with complementary sequences have similar stability or free energy of binding"), CGI contends that the patent teaches a method that separates probes into 96 stringency classes with "2 subsets for each of 48 different annealing temperatures." Resp. at 33-34 (quoting '597 patent, 11:40-43, 15:55-58).
CGI also relies on narrowing statements made by Illumina during prosecution of the '597 patent to overcome the Pease prior art which it distinguished as allowing all probes of a given length without limiting any of the sets to a similar binding energy. At that time, Illumina amended its claims to teach "a subset of probe oligonucleotides, belonging to a single stringency class." Resp. at 35; LaBarre Decl., Ex. FF at 5 (11/16/00 Amendment) ("The third instance, in which all possible sequences are present, does not suggest a subset of probe oligonucleotides, belonging to a single stringency class, as defined above.") (emphasis in bold added). See LaBarre Decl., Ex. FF at 4 ("Claim 20 has been amended to replace the language 'have substantially the same free energy of duplex formation' with 'are from the same stringency class.'").
CGI points out that after the claim was again rejected over prior art, Illumina further amended the claim to the current language of Claim 2 by limiting the claimed probe sets to contain at least one subset whose maximum and minimum annealing temperatures differ from each other by no more than 1° C: "for at least one said probe set, the different-sequence, single stranded oligonucleotide probes in that set have annealing temperatures whose maximum and minimum values differ from each other by no more than 1° C." LaBarre Decl., Ex. GG at 1 (4/5/2001 Amendment). These narrowing statements by Illumina demonstrate that the claimed subset of probes was narrowed in Claim 2 to a subset whose annealing temperatures did not differ by more than 1° C, indicating that the annealing temperature of the probes was determined at least at an approximately fixed temperature point that could be compared to the annealing temperature of the other probes in that subset, not to a wide range of temperatures.
Looking to the specification language, the specification states that annealing temperature is preferably used to define the stringency classes, although other factors also affect stringency classes:
Selection of oligonucleotide probe length and stringency class size depends on several factors, such as length of target sequence and how it is prepared, the extent to which the hybridization reactions can be automated, the degree to which the stringency of the hybridization reaction can be controlled, the presence or absence of oligonucleotide probes with complementary sequences, and the like. . . . Stringency can be controlled, [sic] several varying several parameters, including temperature, salt concentration, concentration of certain organic solvents, such as formamide, and the like. Preferably, temperature is used to define the stringency classes because the activity of the various polymerases or ligases employed limits the degree to which salt concentration or organic solvent concentration can be varied for ensuring specific annealing of the oligonucleotide probes.'597 patent, 11:56 - 12:15. The embodiments in Examples 1 and 2, cited by CGI, define the stringency conditions by annealing temperature:
The 48 stringency conditions are defined by annealing temperatures which range from 22° C to 70° C, such that each grouping of subsets at the same temperature differ in annealing temperature by 1° C, from that of the subset groupings containing the next highest and next lowest stringency classes. The range of annealing temperatures (22-70° C) is roughly bounded by the temperatures 5-10 degrees below the temperatures at which the least stable and most stable 8-mers, respectively, are expected to have about fifty percent maximum annealing in a standard PCR buffer solution.'597 patent, 15:66 - 16:9 (Example 1). See id. 16:65-67 (Example 2) ("As above, the 6-mer probes are prepared in 96 stringency classes of 42 or 43 probes each (2 subsets for each of 48 different annealing temperatures)."). In these embodiments, the stringency classes group the probes by annealing temperatures which range from 22 to 70 degrees Celsius. This particular temperature range stated in the specification is not included as a limitation in Claim 2, but does limit Claim 4 ("The kit of claim 2 wherein said annealing temperatures have a value from 22° C to 70° C.").
Based on the specification, prosecution history and the claim language itself, the Court is persuaded that annealing temperatures refer to a particular temperature, or at least a very narrow range of temperatures, rather than the full range of all temperatures at which the probes can anneal. See '597 patent, 15:55-58 (Example 1) and 16:65-67 (Example 2).
CGI contends that the term "annealing temperature" is best understood as the point at which about fifty percent annealing would take place, based on the specification language referring to the temperatures at which probes are expected to have "about fifty percent maximum annealing in a standard PCR buffer solution." Resp. at 33 n.24. But as Illumina points out, the specification states that the "range of annealing temperatures" is bounded by the temperatures 5-10 degrees below the melting temperatures at which CGI would define the annealing temperature, that is, the temperatures at which the probes are expected to have "about fifty percent maximum annealing." Reply at 10 (citing '597 patent, 16:4-9). Illumina persuasively argues that the specification teaches that to calculate the highest end of the range of annealing temperatures, one practicing the invention would subtract 5-10 degrees from the melting temperature. Opening Br. at 30. Thus, CGI's proposed construction of "annealing temperatures" to be identical to the melting temperature is inconsistent with the specification which defines the range of annealing temperatures to be bounded by temperatures that are five to ten degrees lower than the melting temperatures. Illumina also cites a molecular biology treatise indicating that the melting temperature is not synonymous with the annealing temperature, Labbe Decl, Ex. 20 at 6412 (stating that the annealing temperature "was determined by subtracting 8° from the [melting temperature] of the less stable oligonucleotide"). That treatise further bolsters Illumina's distinction between melting and annealing temperatures, although it is not necessary to rely on this extrinsic evidence.
CGI also relies on the inventor's testimony to support its proposed construction, Resp. at 34-35. The intrinsic evidence provides more support to CGI than Illumina, but does not fully resolve the ambiguity. The Court therefore considers this extrinsic evidence offered by CGI to construe this term. See Vitronics, 90 F.3d at 1583. Dr. Macevicz testified that "all the different oligonucleotides will have different temperatures, so that if you used the full mixture - that is, if you didn't use stringency classes or some other means - you might have incomplete hybridizations or you might have something that hybridizes that you don't want to hybridize because of this difference in binding energies. But if you did it by stringency class, that problem would go away." CGI Markman slide 252. This testimony supports CGI's argument that Claim 2 (iii) requires a specific temperature rather than a broad range, solving the inoperability problem raised by Illumina's proposed construction.
As CGI points out, the specification teaches in both examples that "[a]fter 5-10 minutes incubation at 80° C, the reaction mixtures are brought down to their respective annealing temperatures over a period of 20-30 minutes." Resp. at 34 (citing '597 patent, 16:10-12). The claim language of Claim 2 is also consistent with a construction of "annealing temperature" as a fixed temperature that can be compared to the annealing temperature of the other probes in that probe set. CGI points to the only part of the specification that provides a method for determining the fixed temperature point for annealing, which is somewhat persuasive, but it is not clear that this passage was meant to establish the sole method for doing so. At this point, the Court will not rule out that one skilled in the art would be familiar with other methods to determine the fixed annealing temperature when practicing Claim 2.
The Court determines that as used in the patent, the term "annealing temperatures" refers to particular fixed temperatures at which probes that are grouped in a probe set form a duplex, or anneal, such that, as used in subsection (iii) of Claim 2, the maximum and minimum annealing temperatures of the probes within that set do not differ from each other by more than about 1 degree Celsius.
Court's Construction
The Court construes "annealing temperatures" to mean "particular temperatures at which probes that are grouped in a probe set form a duplex."
C. Dependent Claims 9 and 10
Claim 9 reads as follows:
9. The method of claim 1, wherein the polynucleotide comprises a binding region and a target polynucleotide.
Claim 10 reads as follows:
10. The method of claim 9, wherein the binding region comprises a known sequence and the target polynucleotide comprises an unknown sequence; and wherein in step (a) the initializing oligonucleotide is hybridized to the binding region on the polynucleotide.Labbe Decl., Ex. 3 ('597 patent Ex Parte Reexamination Certificate dated 3/2/2000).
(7) "binding region"
+-----------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +-------------------------------------+---------------------------------------¦ ¦"binding region" means "a region of¦"binding region" means "a known ¦ ¦the polynucleotide to which the ¦sequence of the polynucleotide to which¦ ¦initializing oligonucleotide binds" ¦the initializing oligonucleotide binds"¦ +-----------------------------------------------------------------------------+
The parties agree that the "binding region" is a region of the polynucleotide to which the initializing oligonucleotide binds, but dispute whether the "binding region" must be a known sequence.
Illumina's proposed construction
Illumina cites the specification to show that the singular role of the binding region in the invention is "to bind ("hybridize") to the initializing oligo." Opening Br. at 24. Referring to Figure 1, the specification states as follows:
Binding region (40) has a known sequence, but can vary greatly in length and composition. It must be sufficiently long to accommodate the hybridization of an initializing oligonucleotide. Different binding regions can be employed with either identical or different initializing oligonucleotides, but for convenience of preparation, it is preferable to provide identical binding regions and different initializing oligonucleotides. Thus, all the templates are prepared identically and then separated into aliquots for use with different initializing oligonucleotides. Preferably, the binding region should be long enough to accommodate a set of different initializing oligonucleotides, each hydridizing to the template to produce a different starting point for subsequent ligations. Most preferably, the binding region is between about 20 to 50 nucleotides in length.'597 patent, 5:15-29 [Detailed Description of the Invention]. Illumina acknowledges that in the embodiment depicted in Figure 1, the "binding region" has a known sequence which makes it easier to design an initializing oligonucleotide which will bind to it, but argues that this particular embodiment does not require limiting the binding region to a known sequence. Opening Br. at 24-25.
CGI's proposed construction
CGI relies on the embodiment described in the specification which teaches that the "binding region" has a known sequence. Because the patent only refers to an embodiment, shown in Figure 1, where the binding region has a known sequence, the limitations of this embodiment generally cannot be read into the claims. "Although the specification may aid the court in interpreting the meaning of disputed claim language, particular embodiments and examples appearing in the specification will not generally be read into the claims." Comark Communications, Inc. v. Harris Corp., 156 F.3d 1182, 1187 (Fed. Cir. 1998) (quotation omitted). However, "when the preferred embodiment is described in the specification as the invention itself, the claims are not necessarily entitled to a scope broader than that embodiment." Edwards Lifesciences, 582 F.3d at 1330 (quoting Chimie v. PPG Indus. Inc., 402 F.3d 1371, 1379 (Fed.Cir. 2005)) (quotation marks omitted).
CGI also argues that if the initializing oligonucleotide is "known," as Illumina agrees, then the binding region must also be known if its sole purpose is to bind to the "known" initializing oligonucleotide. Resp. at 38-39. See Opening Br. at 2 ("The sequencing method described and claimed in the '597 patent begins by bringing a short single strand of DNA having a known sequence (an 'initializing oligonucleotide') into contact with a very long single strand of DNA having an unknown sequence (a polynucleotide')"). CGI also argues that there are "no embodiments described in the specification which would allow the binding region to be unknown, and it would be difficult to conceive of a way the method could even work with an unknown binding region. If the binding region is unknown, then the initializing oligonucleotide could not be a known starting point for the reaction." Resp. at 38. In response, Illumina contends that an initializing oligonucleotide can bind to a binding region that does not have a known sequence and points out that CGI's accused process uses a binding region that is arguably unknown. Reply at 9 n.34. However, Illumina does not identify any embodiment of the invention where the binding region is unknown.
In support of its construction, CGI also cites Judge Alsup's claim construction order construing the terms of the parent patent to the '597 patent: "The initializing oligonucleotide then hybridizes with the binding region, a known sequence, and subsequent ligations are done." See Labbe Decl., Ex. 4 at 9. There, however, Judge Alsup was not specifically construing the term "binding region" but instead referring to it in his construction of "initializing oligonucleotide probe," citing an embodiment described in the patent at issue with language similar to the embodiment described in the '597 patent: "Binding region (4) has a known sequence, but can vary greatly in length and composition." Id. at 8 (quoting '341 patent, 5:13-27).
Illumina argues that CGI's proposed construction would violate the doctrine of claim differentiation because claim 10, which itself depends from dependent claim 9, requires that the binding region contain a "known sequence." Under this doctrine, "the presence of a dependent claim that adds a particular limitation gives rise to a presumption that the limitation in question is not present in the independent claim." Enzo, 599 F.3d at 1342 (quoting Phillips, 415 F.3d at 1315) (quotation marks omitted). In Enzo, the patent owner argued that the dependent claim added "a preformed detectable molecular complex" limitation to claim 1, so that the court's construction of the independent claim term "non-radioactive moiety" referring to detection with "a preformed detectable molecular complex" rendered the dependent claim coextensive with the independent claim. Id. The Federal Circuit rejected the claim differentiation argument because the independent claim was broader than the dependent claim:
But the district court's construction imposes no requirement that a preformed detectable molecular complex is actually present in claim 1; rather, it simply requires the "non-radioactive moiety" to be capable of performing a function: " can be detected with a preformed detectable molecular complex." [Citation omitted.] Claim 1, unlike claim 14, is infringed even in the absence of a preformed detectable molecular complex. [Citation omitted.] Because claim 1 is broader than claim 14 under the district court's construction, this case simply does not implicate the doctrine of claim differentiation.
Id.
Here, Illumina argues that CGI's proposed construction of "binding region" to be a known sequence would render the limitation in claim 10 superfluous. "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 the difference between claims is significant." Comark Communications, Inc. v. Harris Corp., 156 F.3d 1182, 1187 (Fed. Cir. 1998). However, CGI correctly points out that claim 10 additionally requires the target polynucleotide to include an unknown sequence and that the initializing oligonucleotide is hybridized to the binding region, so that claim 10 would not be rendered redundant. Resp. at 29. CGI's proposed construction would not, therefore, render claim 10 entirely superfluous by requiring a "known sequence."
CGI contends that a binding region is known in every embodiment of the invention, so that any presumption against the limitation under the doctrine of claim differentiation is rebutted by the specification itself. CGI Markman slide 279 (citing Edwards Lifesciences, 582 F.3d at 1332). In Edwards, the court determined that the claimed "graft" devices required wires, rejecting Edwards' claim differentiation argument that the claimed graft body did not itself include wires, where the claims that recited the graft bodies also recited that the graft bodies were dockable or attachable, and the parties agreed that such an attachment required wires. Edwards Lifesciences, 582 F.3d at 1332. Here, the intrinsic evidence demonstrates that there is no embodiment of the invention where the binding region has an unknown sequence. The Court therefore adopts CGI's proposed construction of "binding region."
Court's Construction
The Court construes "binding region" to mean "a known sequence of the polynucleotide to which the initializing oligonucleotide binds."
(8) "target polynucleotide"
+-----------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +----------------------------------+------------------------------------------¦ ¦"target polynucleotide" means "a¦"target polynucleotide" means "the ¦ ¦polynucleotide having a portion to¦region of the polynucleotide to be ¦ ¦be sequenced" ¦identified that is conjugated to the ¦ ¦ ¦binding region" ¦ +-----------------------------------------------------------------------------+
The parties disagree (1) whether the "target polynucleotide" is a polynucleotide that has a portion to be sequenced or is a region to be identified, and (2) whether "target polynucleotide" should be construed to require conjugation to the binding region. Following oral argument, the Court instructed the parties to meet and confer, but the parties were unable to reach agreement on the construction of this term. Doc. no. 117.
Illumina's proposed construction
To support its proposed construction of "target polynucleotide" to be "sequenced," Illumina argues that one of ordinary skill in the art would have understood the specification to describe "target polynucleotide" as a polynucleotide having a portion to be sequenced. For example, the patent describes the limitations of conventional sequencing techniques in terms of their ability to sequence "long target polynucleotides." '597 patent, 2:13-17. Further, Illumina contends that the purpose and function of the "target polynucleotide" is to be subjected to the claimed sequencing method, as demonstrated by the two examples described in the specification which are each titled "Sequencing a Target Polynucleotide." Id., 14:40-43 ("EXAMPLE 1: Sequencing a Target Polynucleotide Amplified from pUC19 with Four Initializing Oglionucleotides"); 16:30-33 ("EXAMPLE 2: Sequencing a Target Polynucleotide Amplified from pUC 19 with One Initializing Oligonucleotide"). Opening Br. at 26.
CGI does not address Illumina's argument that the patent describes the "target polynucleotide" as a polynucleotide to be sequenced, but refers to the language of claim 1 which contains identifying language in step (b). Claim 1 does not itself contain the term "target polynucleotide," but teaches a method "for identifying a sequence of nucleotides in a polynucleotide," comprising the steps of extending step (a), identifying step (b) and repeating step (c). Because claim 1 refers to identifying a sequence, not identifying a polynucleotide, the claim language and the specification support Illumina's proposed construction over CGI's proposed construction.
Looking to the claims themselves, Illumina points out that the claims do not state that the target polynucleotide must be conjugated to the binding region. Illumina points out that the specification language describing a preferred embodiment in which a target polynucleotide is conjugated to a binding region to form a template does not limit the scope of the term "target polynucleotide" to be "conjugated to the binding region."
CGI's proposed construction
CGI contends that claim 1 contains identifying language, rather than sequencing language. Step (b), for example, requires "identifying one or more nucleotides of the polynucleotide." CGI represents that the parties have agreed to a construction of this identifying step (b) and have not construed it to mean sequencing. Resp. at 39. Illumina makes the more persuasive argument, however, that the patent specification refers to the "target polynucleotide" as a polynucleotide having a portion to be sequenced. For example, the specification describes the Field of the Invention as follows: "The invention relates generally to methods for determining the nucleotide sequence of a polynucleotide . . . ." '597 patent, 1:10-11. Further, the identifying step (b) of claim 1 on which CGI relies refers to "identifying a sequence of nucleotides." CGI's proposed construction of "target polynucleotide" as a region of the polynucleotide "to be identified" leaves out the aspect of identifying a sequence that is taught by the patent.
CGI also proposes that the "target polynucleotide" be construed to be conjugated to the binding region. CGI relies on the specification, which states "Preferably, a target polynucleotide is conjugated to a binding region to form a template." '597 patent, 8:9-10 (emphasis added). CGI also refers to Figure 1 which depicts the binding region attached to the target polynucleotide. The specification describes this embodiment as follows:
The general scheme of one aspect of the invention is shown diagrammatically in FIG. 1. As described more fully below, the invention is not meant to be limited by the particular features of this embodiment. Template (20) comprising a polynucleotide (50) of unknown sequence and binding region (40) is attached to solid phase support (10).Id., 4:46-51 (emphasis added). As the specification clearly states, the limitations of this preferred embodiment are not intended to limit the claims of the invention: "the invention is not meant to be limited by the particular features of this embodiment." CGI's proposed construction would improperly do so. The Court therefore adopts Illumina's proposed construction of "target polynucleotide."
Court's Construction:
The Court construes "target polynucleotide" to mean "a polynucleotide having a portion to be sequenced."
D. Claim 14
Claim 14 states as follows:
The method of claim 1, wherein the oligonucleotide probe comprises a label which results in a spectrally resolvable fluorescent signal.Labbe Decl., Ex. 3 ('597 patent Ex Parte Reexamination Certificate dated 3/2/2000).
(9) "spectrally resolvable fluorescent signal"
+-----------------------------------------------------------------------------------------+ ¦Illumina's proposed construction ¦CGI's proposed construction ¦ +--------------------------------------------+--------------------------------------------¦ ¦"spectrally resolvable fluorescent signal" ¦ ¦ ¦ ¦"spectrally resolvable fluorescent signal" ¦ ¦means "a light signal generated by ¦ ¦ ¦fluorescence which can be distinguished ¦means "a signal that may be distinguished on¦ ¦based on its spectral characteristics (e.g.,¦the basis of its spectral characteristics" ¦ ¦its color)" ¦ ¦ +-----------------------------------------------------------------------------------------+
The parties agree that a "spectrally resolvable fluorescent signal" is a signal that can be distinguished on the basis of its spectral characteristics, but disagree as to whether the signal must be a "fluorescent" light signal, or one involving the emission of fluorescent light.
Illumina's proposed construction
Illumina relies on the claim term itself to propose that the term be construed as a signal "generated by fluorescence." CGI does not address whether it disputes Illumina's proposed definition of "fluorescent" as "generated by fluorescence." Rather, CGI contends that the term should not be limited to the detection of a particular color of light because the specification gives alternatives to detection of fluorescence:
In one preferred kit, fluorescently labeled oligonucleotide probes are provided such that probes corresponding to different terminal nucleotides of the target polynucleotide carry distinct spectrally resolvable fluorescent dyes. As used herein, "spectrally resolvable" means that the dyes may be distinguished on basis of their spectral characteristics, particularly fluorescence emission wavelength, under conditions of operation. Thus, the identity of the one or more terminal nucleotides would be correlated to a distinct color, or perhaps ratio of intensities at different wavelengths.''597 patent, 14:21-31. CGI suggests that Illumina's proposed construction would exclude embodiments proposed by the patent specification by limiting detection of spectral characteristics to only fluorescent wavelengths. CGI does not, however, explain how this specification language would overcome a plain reading of the claim term itself to include "fluorescent."
CGI's proposed construction
CGI contends that its proposed construction would not exclude embodiments proposed by the patent specification. However, CGI's proposed construction would improperly read "fluorescent" out of the claim term itself. At the same time, Illumina correctly recognizes that color is not necessarily the sole way to distinguish the signal by using "e.g." in its construction. The Court therefore adopts Illumina's proposed construction of "spectrally resolvable fluorescent signal."
Court's construction:
The Court construes "spectrally resolvable fluorescent signal" to mean "a light signal generated by fluorescence which can be distinguished based on its spectral characteristics (e.g., its color)."
IT IS SO ORDERED.
______________________
ELIZABETH D. LAPORTE
United States Magistrate Judge