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 .
Claims 136-155 are pending. Claims 136 and 138-155 are pending, and are being examined on the merits. Claim 137 is withdrawn.
Election/Restrictions
Applicant’s election without traverse of the species for Groups B and C in the reply filed on May 20, 2026 is acknowledged. However, since art was found on both the elected species and the non-elected species for each of Group B and C, all of the species and all of the claims in Groups B and C are considered in this Office Action. The election of species requirement is withdrawn as to Groups B and C.
Applicant’s election without traverse of the Group A species of a “non-terminated nucleotide” in the reply filed on May 20, 2026 is acknowledged.
Claim 137 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 20, 2026.
Information Disclosure Statement
The Information Disclosure Statements submitted December 26, 2023, March 20, 2025 and May 20, 2026 have each been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because the specification includes a nucleic acid sequence, at least, at para. 346.
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Specifically, the nucleic acid sequence at para. 346 is not identified by a SEQ ID NO.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 140 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 140 recites the limitation “said contacting incorporates at least two nucleotides
…”, the meaning of which is unclear. Specifically, claim 140 depends indirectly from claim 136 and directly from claim 139. Claims 136 requires incorporating exactly two nucleotides – the first in step (i) and the second in step (v). Claim 139 identifies characteristics of the nucleotide mixture that is contacted with the nucleic acid strand in the claim 136 (i) incorporation step. Claim 140 then refers back to claim 139, and recites that “said contacting”, presumably in reference to claim 136 (i), “incorporates … two nucleotides”. Since claims 136 (i) recites incorporating only one nucleotide, it is not clear if the second nucleotide in claim 140 is intended to refer to the nucleotide in step 136 (v) or another nucleotide. Further, it is not clear what “ … at least two nucleotides” refers to in embodiments where, e.g., 3 nucleotides are added. That is, the claim 136 method requires incorporating exactly two nucleotides, not more than two. Since the ordinary artisan would not be able to determine the metes and bounds of the claim, it is indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 140 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
As noted above, claim 140 is indefinite. However, there are apparently at least some
embodiments of claim 140 that do not include all of the limitations of claim 136, from which it depends. To the extent that claim 140 is directed to those embodiments, it is in improper dependent form.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 136, 138-140, 142-144 and 147-148 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Turcatti (A new class of cleavable fluorescent nucleotides: synthesis and optimization as reversible terminators for DNA sequencing by synthesis, Nucleic Acids Research, 36(4): 1-13, 2008; with Supplementary Figures).
Regarding independent claim 136 and dependent claims 138, 142-144 and 147-148,
Turcatti teaches …
A method for sequencing, comprising:(i) incorporating a nucleotide, optionally a non-terminated nucleotide, into a growing nucleic acid strand hybridized to a nucleic acid molecule, wherein said nucleotide is coupled to a dye via a cleavable linker; (ii) detecting a signal or change thereof from said dye (p. 6, left col., "Sequencing by synthesis ..." section; Fig. 3);
(iii) cleaving, optionally by reduction of the linker with DTT, said cleavable linker, optionally a disulfide group, to generate a reactive moiety, optionally a thiol, on said nucleotide; (iv) contacting a capping reagent, optionally an irreversible capping agent, optionally a haloactemide, to said reactive moiety to generate a capped moiety (Fig. 3: "[w]hen [the cleavable linker] is a cleavable disulfide linker, removal of dye is achieved by treatment with DTT and capping of the resulting free SH group with iodoacetamide is required);
and (v) incorporating an additional nucleotide adjacent to said nucleotide in said growing nucleic acid strand (p. 6, left col., "Sequencing by synthesis ..." section; Fig. 3).
Regarding dependent claims 139-140, Turcatti additionally teaches contacting said growing nucleic acid strand with a reaction mixture comprising a plurality of nucleotides of a same canonical base type (p. 6, left col., "Sequencing by synthesis ..." section; Fig 3; Supplementary Fig. 4), as recited in claim 139. Regarding claim 140, as noted above it is indefinite. Nevertheless, Turcatti teaches at least some embodiments comprising the step that said contacting incorporates at least two nucleotides of said plurality of nucleotides into said growing nucleic acid strand, wherein said at least two nucleotides are coupled to dyes via cleavable linkers, and wherein said at least two nucleotides comprise said nucleotide (p. 6, left col., "Sequencing by synthesis ..." section; Fig 3; Supplementary Fig. 4).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 141 is rejected under 35 U.S.C. 103 as being unpatentable over Turcatti (A new class of cleavable fluorescent nucleotides: synthesis and optimization as reversible terminators for DNA sequencing by synthesis, Nucleic Acids Research, 36(4): 1-13, 2008; with Supplementary Figures) as applied to claims 136 and 139 above, and further in view of Gordon1 (US Patent App. Pub. No. 2010/0063743 A1).
Regarding dependent claim 141, Gordon teaches that the plurality of nucleotides
comprises a subset of labeled nucleotides and a subset of unlabeled nucleotides (paras. 152, 247). Gordon also teaches that such nucleotide mixtures can be used in sequencing by synthesis methods (paras. 152, 246, 260), and that there are benefits in using mixtures comprising unlabeled nucleotides in that doing so, e.g., improves read lengths and reduces lead and lag (para. 246).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Turcatti method, discussed above, to incorporate the Gordon mixtures of labeled and unlabeled nucleotides. The ordinary artisan would have been motivated to do so to achieve the advantages described in Gordon as to improved read length and reductions in lead and lag. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art.
Claim 145-146 are rejected under 35 U.S.C. 103 as being unpatentable over Turcatti (A new class of cleavable fluorescent nucleotides: synthesis and optimization as reversible terminators for DNA sequencing by synthesis, Nucleic Acids Research, 36(4): 1-13, 2008; with Supplementary Figures) as applied to claim 136 above, and further in view of Glezer (US Patent App. Pub. No. 2021/0189481 A1).
Regarding dependent claims 145-146, Glezer teaches a reversible capping agent,
optionally DPDS (para. 165), and teaches the use of such an agent in sequencing by synthesis methods (Example 2). Further, Turcatti teaches that the cleaved linker requires capping (Fig. 3).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Turcatti method, discussed above, to incorporate the Glezer capping agent. The ordinary artisan would have been motivated to do so to customize the assay as needed through routine optimization. Further, reversible capping agents, such as DPDS, are recognized in the art as being suitable for use in SBS methods, as taught by Glezer. See MPEP 2144.07. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art.
Claims 149-155 are is rejected under 35 U.S.C. 103 as being unpatentable over Turcatti (A new class of cleavable fluorescent nucleotides: synthesis and optimization as reversible terminators for DNA sequencing by synthesis, Nucleic Acids Research, 36(4): 1-13, 2008; with Supplementary Figures) in view of Gordon (US Patent App. Pub. No. 2010/0063743 A1).
Regarding independent claim 149, Turcatti teaches …
A method for sequencing, comprising: (a) incorporating a nucleotide into a growing nucleic acid strand hybridized to a nucleic acid molecule, wherein said nucleotide is coupled to a dye via a cleavable linker; (b) detecting a signal or change thereof from said dye (p. 6, left col., "Sequencing by synthesis ..." section; Fig. 3);
(c) cleaving said cleavable linker to generate a reactive moiety on said nucleotide; (d) contacting said growing nucleic acid strand with a capping reagent and an additional nucleotide, wherein said capping reagent is configured to couple to said reactive moiety to generate a capped moiety (p. 6, left col., "Sequencing by synthesis ..." section; Fig. 3: "[w]hen [the cleavable linker] is a cleavable disulfide linker, removal of dye is achieved by treatment with DTT and capping of the resulting free SH group with iodoacetamide is required).
Turcatti does not teach that a capping reagent and an additional nucleotide are comprised within a mixture. However, Gordon teaches a sequencing by synthesis method where various reagents and nucleotides are comprised within the same reaction volume at the same time, and hence are comprised within a mixture (e.g., para. 138: teaches a SBS embodiment where a solution comprising a cleaving agent scavenger and labeled nucleotides are introduced into the reaction volume, and where “a second nucleotide analogue is incorporated in the presence of said cleaving agent scavenger”).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Turcatti method to incorporate the Gordon reagent and nucleotide mixture. The ordinary artisan would have been motivated to do so to customize the assay as needed through routine optimization, and to achieve the expected advantage of an assay that is more efficient as it requires fewer steps. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art, and because Gordon teaches that various reagents can be comprised within the same reaction mixture and not inhibit the SBS reaction.
Regarding dependent claims 150, Turcatti additionally teaches that the mixture comprises a plurality of nucleotides of a same canonical base type (p. 6, left col., "Sequencing by synthesis ..." section; Fig 3; Supplementary Fig. 4).
Regarding dependent claim 151, Gordon teaches that the plurality of nucleotides
comprises a subset of labeled nucleotides and a subset of unlabeled nucleotides (paras. 152, 247). Gordon also teaches that such nucleotide mixtures can be used in sequencing by synthesis methods (paras. 152, 246, 260), and that there are benefits in using mixtures comprising unlabeled nucleotides in that doing so, e.g., improves read lengths and reduces lead and lag (para. 246).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Turcatti method, discussed above, to incorporate to incorporate the Gordon mixtures of labeled and unlabeled nucleotides. The ordinary artisan would have been motivated to do so to achieve the advantages described in Gordon as to improved read length and reductions in lead and lag. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art.
Regarding dependent claim 152, Turcatti additionally teaches or suggests, although not all in the same embodiment, that the mixture comprises a plurality of nucleotides of at least two canonical nucleotide types, and wherein the at least two canonical nucleotide types are coupled to different detectable moieties comprising different fluorescent dyes (p. 12, left col., para. 4: “four color approach”). Turcatti also teaches that the “four color approach” has the advantages of “being faster … [and] also limits the mis-incorporation rate … [which] increase[s] the sequencing accuracy” (p. 12, left col., para. 4).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Turcatti method, discussed above, to incorporate mixtures comprising at least two canonical nucleotides types coupled to different fluorescent dyes. The ordinary artisan would have been motivated to do so to achieve the advantages described in Turcatti as to improvements in speed and accuracy of the sequencing methods. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art, and because Turcatti explicitly teaches such a modification.
Regarding dependent claim 153, Turcatti teaches that the mixture comprises a plurality of nucleotides of a same canonical base type (p. 6, left col., "Sequencing by synthesis ..." section; Fig 3; Supplementary Fig. 4), while Gordon teaches that said mixture does not comprise a labeled nucleotide, wherein said plurality of nucleotides comprises said additional nucleotide (para. 147).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Turcatti method, discussed above, to incorporate the Gordon mixtures of unlabeled nucleotides. The ordinary artisan would have been motivated to do so to customize the assay as needed through routine optimization. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid assays is well-known in the art.
Regarding dependent claim 154, Turcatti additionally teaches that the nucleotide and the additional nucleotide comprise a same type of canonical nucleobase (p. 6, left col., "Sequencing by synthesis ..." section; Fig 3; Supplementary Fig. 4).
Regarding dependent claim 155, Turcatti additionally teaches that the additional nucleotide comprises a detectable moiety, and further comprising (e) detecting an additional signal from said detectable moiety of said additional nucleotide, and (f) using said signal from (b) and said additional signal from (e) to determine a sequence of said nucleic acid molecule (p. 6, left col., "Sequencing by synthesis ..." section; Fig 3).
Conclusion
Claims 136 and 138-155 are being examined, and are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CAROLYN L GREENE/Primary Examiner, Art Unit 1681
1 Gordon was cited in the Information Disclosure Statement submitted December 26, 2023.
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