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 1-20 are pending and are being examined on the merits.
Preliminary Amendment
The Preliminary Amendment filed August 16, 2024 is acknowledged.
Information Disclosure Statement
The Information Disclosure Statements submitted August 16, 2024, January 9, 2026, February 13, 2026, March 3, 2026, April 14, 2026, May 8, 2026, June 25, 2026 and July 23, 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 - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing.
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 incorporation by reference paragraph, 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 Objections
Claim 10 is objected to because of the following informalities:
In claim 10, the limitation “to the 5’ end a template …” in ll. 1-2, should be “to the 5’
end of the template …”.
Appropriate correction is required.
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.
Claims 1-13, 17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (WO 2020/106906 A1) in view of Rosenbaum (US Patent App. Pub. No. 2019/0194719 A1) and Alon (Barcoding bias in high-throughput multiplex sequencing of miRNA, Genome Research, 21(9): 1506-1511, 2011).
Regarding independent claim 1 and dependent claims 13 and 17, Wang teaches …
A method comprising: obtaining a template nucleic acid molecule comprising an adaptor
3' of the template nucleic acid molecule (Fig. 20A);
hybridizing a first target specific region of a first bridge probe to a first target sequence of the template nucleic acid molecule, wherein a first anchor probe landing sequence of the first bridge probe is bound to a first bridge binding sequence of an anchor probe (Fig. 20A);
and hybridizing a second target specific region of a second bridge probe to a second target sequence of the template nucleic acid molecule, wherein a second anchor probe landing sequence of the second bridge probe is bound to a second bridge binding sequence of the anchor probe, thereby generating a complex (Fig. 20A).
Regarding the limitations …
annealing a nucleic acid barcode molecule to the adaptor, wherein the nucleic acid barcode molecule comprises a barcode sequence;
extending the adaptor using the nucleic acid barcode molecule as a template, thereby generating an extension product comprising the complement of the barcode sequence;
… Wang teaches annealing a nucleic acid molecule with a predetermined sequence (AD1) to a template nucleic acid, and extending the template sequence against the nucleic acid molecule to generate an extension product with the complement of the predetermined sequence (Fig. 22D). Wang further teaches barcoding various molecules generated in the assay, and further teaches that barcode sequences can be comprised within a number of different molecules (paras. 139-140, 160, 177).
Further, Rosenbaum teaches annealing a nucleic acid molecule with a predetermined sequence (B) to the adapter (P1’) of a template nucleic acid (Top), optionally where the molecule comprises a 3’ terminator (X), optionally where the adaptor (P1’) does not comprise a barcode sequence, and extending the adaptor to generate an extension product comprising the complement of the predetermined sequence (B’). See Figure 4, as follows …
PNG
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288
278
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Finally, Alon compared (adapter) ligation-based barcoding with PCR-based barcoding, and determined that ligation-based barcoding introduces significant bias into the assay. Alon suggests that adapters with different sequences (i.e., due to the different barcodes) ligate to target molecules with different efficiencies. In contrast, PCR-based barcoding involves fewer steps and less bias (p. 1508, Discussion; p, 1509, Methods: PCR-based barcoding; p. 1509, Methods: Ligation-based barcoding).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Wang method to substitute a PCR based barcoding strategy, as taught by Rosenbaum and Alon. The ordinary artisan would have been motivated to do so to achieve the expected advantages taught in Alon as to a more efficient assay with fewer steps, and a more accurate assay with less ligation bias. The ordinary artisan would have had an expectation of success as the design and modification of adapters and barcoding techniques are well-known in the art.
Regarding dependent claim 2, Wang and Rosenbaum additionally teach or suggest that the first target specific region of the first bridge probe hybridizes to the first target sequence of the template nucleic acid molecule of the extension product, and wherein the second target specific region of the second bridge probe hybridizes to the second target sequence of the template nucleic acid molecule of the extension product. Specifically, as noted above, Wang as modified by Rosenbaum suggest an extension product comprising a template nucleic acid. Further, Wang teaches that the first target specific region of the first bridge probe hybridizes to the first target sequence of the template nucleic acid molecule, and that the second target specific region of the second bridge probe hybridizes to the second target sequence of the template nucleic acid molecule (Fig. 20A).
Regarding dependent claim 3, Wang additionally teaches attaching the adaptor to a 3' end the template nucleic acid molecule, thereby generating the template nucleic acid molecule comprising the adaptor (Fig. 20A).
Regarding dependent claim 4, Wang and Rosenbaum additionally teach or suggest that the adaptor comprises a primer binding sequence, and the nucleic acid barcode molecule comprises a primer designed to hybridize with the primer binding sequence of the adaptor. Specifically, as noted above, Wang as modified by Rosenbaum suggest a nucleic acid barcode molecule, while Rosenbaum teaches the molecule comprises a primer which hybridizes to a primer binding sequence of the adaptor (Fig. 4).
Regarding dependent claim 5, Wang and Rosenbaum additionally teach or suggest combining the template nucleic acid molecule and the nucleic acid barcode molecule with one or more primer extension reagents. Specifically, as noted above, Wang as modified by Rosenbaum suggest a nucleic acid barcode molecule, while Rosenbaum teaches combining that molecule with one or more primer extension reagents (Fig. 4; paras. 64-66, 138-139).
Regarding dependent claims 6-9, Wang and Rosenbaum teach or suggest these limitations. Specifically, Wang teaches combining the template nucleic acid in a hybridization mixture comprising the first bridge probe, the second bridge probe, and the anchor probe (Fig. 20A). Rosenbaum teaches performing the extending step prior to additional hybridizing steps (Fig. 4). Wang and Rosenbaum to do not teach the recited order of adding various reaction components to the reaction volume, and do not teach an extending step after hybridizing step. However, Rosenbaum teaches that the order of the various steps can be modified, and that the various embodiments can be re-arranged in a variety of ways (para. 263). Further, the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. MPEP 2144.04(IV)(C).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Wang method, discussed above, to optimize the reaction components and order of the method steps to optimize the method as desired through routine experimentation. The ordinary artisan would have had an expectation of success as the design and modification of adapters and barcoding techniques are well-known in the art.
Regarding dependent claim 10, Wang additionally teaches attaching an adaptor to the 5’ end of a template nucleic acid molecule (para. 7).
Regarding dependent claims 11-12, Wang additionally teaches that the barcode sequence comprises a sample index sequence or a unique molecular identifier sequence (paras. 56, 140, 177).
Regarding dependent claims 19-20, Wang additionally teaches that the template nucleic acid molecule is a double-stranded molecule comprising first and second strands (para. 123), and Rosenbaum teaches that adaptors are attached at 3’ ends of both strands, and optionally, adaptors are attached at 5’ ends of both strands (Fig. 4).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to further modify the modified Wang method, discussed above, to optimize the reaction components to optimize the method as desired through routine experimentation. The ordinary artisan would have had an expectation of success as the design and modification of adapters and barcoding techniques are well-known in the art.
Prior Art
Claims 14-16 and 18 are free of the art. Although Y-shaped adaptors are generally known in the art, there does not appear to be any reason to modify either the Wang adaptor or the Rosenbaum adapter to make it Y-shaped.
Claims 14-16 and 18 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 84-86 and 91 of copending Application No. 17/816,198 (hereinafter, the ‘198 application) in view of Rosenbaum (US Patent App. Pub. No. 2019/0194719 A1) and Alon (Barcoding bias in high-throughput multiplex sequencing of miRNA, Genome Research, 21(9): 1506-1511, 2011).
This is a provisional nonstatutory double patenting rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 84 and 91 of the ‘198 application teach or suggest all of the limitations of instant claims 1-2, except for …
annealing a nucleic acid barcode molecule to the adaptor, wherein the nucleic acid barcode molecule comprises a barcode sequence;
extending the adaptor using the nucleic acid barcode molecule as a template, thereby generating an extension product comprising the complement of the barcode sequence.
However, Rosenbaum teaches annealing a nucleic acid molecule with a predetermined sequence (B) to the adapter (P1’) of a template nucleic acid (Top), optionally where the molecule comprises a 3’ terminator (X), optionally where the adaptor (P1’) does not comprise a barcode sequence, and extending the adaptor to generate an extension product comprising the complement of the predetermined sequence (B’). See Figure 4,
Further, Alon compared (adapter) ligation-based barcoding with PCR-based barcoding, and determined that ligation-based barcoding introduces significant bias into the assay. Alon suggests that adapters with different sequences (i.e., due to the different barcodes) ligate to target molecules with different efficiencies. In contrast, PCR-based barcoding involves fewer steps and less bias (p. 1508, Discussion; p, 1509, Methods: PCR-based barcoding; p. 1509, Methods: Ligation-based barcoding).
Modifying the method of the ‘198 application to incorporate a PCR based barcoding strategy, as taught by Rosenbaum and Alon, would have been prima facie obvious. The ordinary artisan would have been motivated to do so to achieve the expected advantages taught in Alon as to a more efficient assay with fewer steps, and a more accurate assay with less ligation bias. The ordinary artisan would have had an expectation of success as the design and modification of adapters and barcoding techniques are well-known in the art.
In addition, claims 85-86 of the ‘198 application teach or suggest all of the limitations of instant claims 3 and 19-20.
Conclusion
Claims 1-20 are being examined. Claims 1-13, 17 and 19-20 are rejected. Claim 10 is objected to. Claims 14-16 and 18 are objected to, but are otherwise directed to allowable subject matter.
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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/CAROLYN L GREENE/Primary Examiner, Art Unit 1681
