DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 34-39 and 42-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,591,647. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘647 claims disclose:
Regarding instant claim 34:
A method of detecting a labeled nucleotide analogue,
The ‘647 claims are directed to a method of determining “the identity of a nucleotide residue in an extension product”. However, the ‘647 claims note that the nucleotides are labeled (claim 1: “at least 4 distinguishable, blocked deoxyribonucleotide triphosphate (dNTP) analogue species, at least 3 of which distinguishable, blocked dNTP analogue species are labeled such that each distinguishable, blocked dNTP analogue species in the sequencing reaction mixture can be distinguished from the other distinguishable, blocked dNTP analogue species”; claim 6 further specifies that all analogue species are labeled). Therefore, the ‘647 claimed method inherently detects labeled nucleotide analogues.
the method comprising: contacting a solid support comprising a primer hybridized to a template DNA molecule with a plurality of labeled nucleotide analogues;
Claim 1: “(a) combining in a sequencing reaction mixture a plurality of identical primed template DNA molecules, a DNA polymerase, at least 4 distinguishable, blocked deoxyribonucleotide triphosphate (dNTP) analogue species, at least 3 of which distinguishable, blocked dNTP analogue species are labeled such that each distinguishable, blocked dNTP analogue species in the sequencing reaction mixture can be distinguished from the other distinguishable, blocked dNTP analogue species”. Claim 12: “wherein the template DNA molecules are immobilized on a solid substrate”.
and binding a labeled nucleotide analogue to a complementary nucleotide of the template DNA molecule;
Claim 1: “thereby incorporating a distinguishable, blocked dNTP analogue species into at least one of said plurality of identical primed template DNA molecules and forming a distinguishable, blocked extension product”.
removing unbound labeled nucleotide analogues;
Claim 1: “(b) after step (a), removing unincorporated distinguishable, blocked dNTP analogues followed by adding to the sequencing reaction mixture at least 4 unlabeled, blocked dNTP analogue species”.
imaging said solid support and detecting the bound labeled nucleotide analogue;
Claim 1: “(c) upon addition of the at least 4 unlabeled, blocked dNTP analogue species during step (b), determining the identity of the distinguishable, blocked dNTP analogue incorporated into the distinguishable, blocked extension product in step (a)”. While the ‘647 claims do not use the word “imaging”, they do stipulate that the primed template molecules are immobilized on a support (claim 12), and that the labels can be a fluorophore (claim 7). The detection of a fluorescent label can be broadly considered “imaging”, as such would be an optical detection, and there is no limiting definition of “imaging” in the instant specification.
and, while imaging, contacting said solid support with a plurality of blocked nucleotide analogues, wherein each blocked nucleotide analogue comprises a blocking moiety.
Claim 1: “(c) upon addition of the at least 4 unlabeled, blocked dNTP analogue species during step (b), determining the identity of the distinguishable, blocked dNTP analogue incorporated into the distinguishable, blocked extension product in step (a)”. In the prosecution of the application of the ‘647 claims, Applicant argued that “detection” and “addition” was simultaneous; see remarks submitted 04/14/2022 (italics provided, underscore in original): “None of the references cited by the office, individually or in combination, teach or suggest simultaneously determining the identity of the incorporated distinguishable, blocked dNTP analogue upon addition of an unlabeled, blocked dNTP analogue species.” Therefore, based on Applicant’s remarks, the language of ‘647 claim 1 implies that “imaging” (i.e. “determining”) and “contacting” (i.e. “addition”) happen at the same time. Hence, “while imaging, contacting”.
Regarding instant claim 35:
wherein the solid support further comprises a second template DNA molecule, wherein a second primer is hybridized to the second template DNA molecule
Claim 1: “a plurality of identical primed template DNA molecules”; claim 12: “wherein the template DNA molecules are immobilized on a solid substrate”.
Regarding instant claim 36:
wherein the labeled nucleotide analogue comprises a first label moiety and a blocking moiety
Claim 1: “at least 4 distinguishable, blocked deoxyribonucleotide triphosphate (dNTP) analogue species, at least 3 of which distinguishable, blocked dNTP analogue species are labeled such that each distinguishable, blocked dNTP analogue species in the sequencing reaction mixture can be distinguished from the other distinguishable, blocked dNTP analogue species”.
Regarding instant claims 37, 38:
wherein the blocking moiety comprises an allyl moiety, a 2-nitrobenzyl moiety, an azido moiety, or a disulfide moiety
Claim 8: “wherein the cleavable blocking moiety of the labeled, 3′-blocked dNTP analogues is linked to the 3′-oxygen of a deoxyribose via an allyl moiety, a 2-nitrobenzyl moiety, an azido moiety, or a disulfide moiety”.
Regarding instant claim 39:
wherein the first label moiety is a fluorophore
Claim 7: “wherein the label molecules are selected from the group consisting of a dye, a chromophore, a combinatorial fluorescence energy transfer label, an electrophore, a fluorophore, a mass label, and a radiolabel”.
Regarding instant claim 42:
wherein the blocked nucleotide analogue does not comprise a label
Claim 1: “adding to the sequencing reaction mixture at least 4 unlabeled, blocked dNTP analogue species”.
Regarding instant claim 43:
wherein the labeled nucleotide analogue is incorporated with a polymerase into the primer to form an extension product
Claim 1: “thereby incorporating a distinguishable, blocked dNTP analogue species into at least one of said plurality of identical primed template DNA molecules and forming a distinguishable, blocked extension product”.
Regarding instant claim 44:
wherein the labeled nucleotide analogue is removed and the blocked nucleotide analogue is incorporated into the primer to form a blocked extension product
Claim 1: “removing unincorporated distinguishable, blocked dNTP analogues followed by adding to the sequencing reaction mixture at least 4 unlabeled, blocked dNTP analogue species, incorporating an unlabeled, blocked dNTP analogue species into at least one of said plurality of identical primed template DNA molecules thereby forming an unlabeled, blocked extension product”.
Regarding instant claim 45:
wherein the blocked nucleotide analogue is incorporated with a polymerase into the second primer to form a blocked extension product
Claim 1: “incorporating an unlabeled, blocked dNTP analogue species into at least one of said plurality of identical primed template DNA molecules thereby forming an unlabeled, blocked extension product”.
Regarding instant claims 46, 47:
the method further comprises removing a blocking moiety linked to a 3'-oxygen atom of the blocked extension product to generate an extendible extension product
Claim 4: “further comprises (d) chemical, enzymatic, or photoactivated cleavage, of a blocking moiety linked to a 3′-oxygen atom of a terminal deoxyribose of the distinguishable, blocked extension products and/or unlabeled, blocked extension products to generate extensible extension products”.
Regarding instant claim 48:
wherein imaging comprises detecting and identifying the labeled nucleotide analogue
As noted in the discussion of claim 34 above, in the case of detecting a fluorescent label, such detection can be considered “imaging”.
Regarding instant claims 49, 50:
further comprising contacting the extendible extension product with a second labeled nucleotide analogue
Claim 3: “iterating steps (a)-(c) one or more times, thereby determining a nucleotide sequence of at least a portion of the template DNA molecule”.
Claims 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,591,647 in view of Ju (PNAS 103(52):19635-19640 (2006), IDS ref). The ‘647 claims have been discussed. These claims did not indicate that the label on the labeled dNTP analogue was attached by a cleavable linker, or that the blocked nucleotide analogue added subsequently to the first analogue was also labeled, but with a different label.
Ju taught a similar method of sequencing in which the label as well as the blocking moiety were attached to the nucleotide analogue by cleavable labels, such that following detection of the incorporated nucleotide analogue, the label as well as the blocking moiety could be cleaved off, allowing incorporation and detection of the next nucleotide analogue (which was also blocked, but had a different label); see figures 2 and 3.
It would have been obvious to modify the method of the ‘647 claims to incorporate the features of instant claims 40 and 41, as Ju had already provided a rationale for these modifications, i.e. to perform repeated cycles of extension, detection, and cleavage so as to obtain a sequence of a nucleic acid molecule.
Claims 34, 42, 44, 46, 48, 49, 51, 52 and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,773,439. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘439 claims disclose:
Regarding instant claim 34:
A method of detecting a labeled nucleotide analogue,
the method comprising: contacting a solid support comprising a primer hybridized to a template DNA molecule with a plurality of labeled nucleotide analogues;
Claim 1: “(a) contacting a solid support comprising a primed template DNA molecule with a deoxyribonucleotide triphosphate (dNTP) analogue species, wherein said dNTP analogue species is complementary to a nucleotide of the primed template DNA molecule, and wherein said dNTP analogue species is associated with a detectable label…(c) imaging said solid support during steps (a) and (b)”; claim 3: “wherein step (b) comprises adding at least four different unlabeled, blocked dNTP analogue species”; claim 7: “wherein step (c) further comprises detecting the detectable label and identifying the dNTP analogue species associated with the detectable label”.
and binding a labeled nucleotide analogue to a complementary nucleotide of the template DNA molecule;
Claim 1: “wherein said dNTP analogue species is complementary to a nucleotide of the primed template DNA molecule”. While the ‘439 claims do not use the word “binding”, it is clear from the principle of the disclosed method for sequencing that incorporation of the labeled nucleotide analog (which inherently involves binding to the complementary nucleotide of the template strand) is what allows for its detection; see e.g. column 2, lines 38-40. As set forth in MPEP 804(II)(B)(1):
“those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970). The court in Vogel recognized “that it is most difficult, if not meaningless, to try to say what is or is not an obvious variation of a claim,” but that one can judge whether or not the invention claimed in an application is an obvious variation of an embodiment disclosed in the patent which provides support for the patent claim. According to the court, one must first “determine how much of the patent disclosure pertains to the invention claimed in the patent” because only “[t]his portion of the specification supports the patent claims and may be considered.” The court pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.”
removing unbound labeled nucleotide analogues;
Claim 2: “wherein after step (a), the method further comprises removing the dNTP analogue species”.
imaging said solid support and detecting the bound labeled nucleotide analogue;
Claim 1: “(c) imaging said solid support during steps (a) and (b)”; claim 7: “wherein step (c) further comprises detecting the detectable label and identifying the dNTP analogue species associated with the detectable label”.
and, while imaging, contacting said solid support with a plurality of blocked nucleotide analogues, wherein each blocked nucleotide analogue comprises a blocking moiety.
Claim 1: “(c) imaging said solid support during steps (a) and (b)”; note step (b): “(b) after step (a), contacting said primed template DNA molecule with a plurality of blocked dNTP analogue species”.
Regarding instant claim 42:
wherein the blocked nucleotide analogue does not comprise a label
Claim 3: “wherein step (b) comprises adding at least four different unlabeled, blocked dNTP analogue species”.
Regarding instant claim 44:
wherein the labeled nucleotide analogue is removed and the blocked nucleotide analogue is incorporated into the primer to form a blocked extension product
Claim 2: “wherein after step (a), the method further comprises removing the dNTP analogue species”; claim 1: “after step (a), contacting said primed template DNA molecule with a plurality of blocked dNTP analogue species, and incorporating with a polymerase at least one of said plurality of blocked dNTP analogue species, thereby forming a blocked extension product”.
Regarding instant claim 46:
the method further comprises removing a blocking moiety linked to a 3'-oxygen atom of the blocked extension product to generate an extendible extension product
Claim 4: “wherein after step (c), the method further comprises (d) removing a blocking moiety linked to a 3′-oxygen atom of the blocked extension product to generate an extendible extension product”.
Regarding instant claim 48:
wherein imaging comprises detecting and identifying the labeled nucleotide analogue
Claim 7: “wherein step (c) further comprises detecting the detectable label and identifying the dNTP analogue species associated with the detectable label”.
Regarding instant claim 49:
further comprising contacting the extendible extension product with a second labeled nucleotide analogue
Claim 10: “comprising iterating steps (a)-(c) one or more times, wherein after step (c) of each iteration, the blocked product is treated to generate an extendible extension product, with the proviso that after the last iteration, treatment of the blocked extension product can be omitted”.
Regarding instant claims 51, 52:
wherein imaging occurs for about 1 minute to about 10 minutes; about 1 minute to about 5 minutes; or about 1 minute to about 3 minutes
wherein imaging occurs for less than 15 minutes
Claim 1: “(c) imaging said solid support during steps (a) and (b), wherein the combined steps (a)-(b) occurs for about 1 minute to about 10 minutes”.
Regarding instant claim 53:
wherein said solid support is glass or plastic
Claim 18: “wherein said solid support is glass or plastic”.
Allowable Subject Matter
Claims 34-53 are allowable over the prior art but rejected for the reasons noted above. While sequencing methods as recited in the claims were known (e.g. Ju, cited above, as well as Guo, PNAS 105(27):9145-9150 (2008), IDS ref, and Turcatti, NAR 36(4):e25, 2008), carrying out imaging during a synchronization step (i.e. a step in which unlabeled, blocked nucleotides were added to fill in any copies of the template which had not been extended by a labeled, blocked nucleotide; see Ju, statement spanning pages 19637-8) was not taught in the prior art. Rather, imaging was invariably performed either before or after such synchronization step. By performing the imaging step during the synchronization step, the claimed methods reduce the time needed for the process, making it more efficient.
Conclusion
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/SAMUEL C WOOLWINE/ Primary Examiner, Art Unit 1681