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 .
Status of The Claims
Claim(s) 10-17 is/are pending and are under examination.
Claim(s) 1-7 and 18-21 is/are withdrawn.
Applicant’s election without traverse of Group II, which includes Claims 10-17 in the reply filed on 05/11/2026 is acknowledged.
Claim(s) 1-7 and 18-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected method for generating nucleic acid library from biological sample, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/11/2026.
Claim Rejections - 35 USC § 112(b)
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 10-17 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 10, the phrase “the first tagged nucleic acid strand” lacks proper antecedent basis. Claim 10 previously recites “one or more nucleic acids” and “first extension products”, but does not clearly identify what structure constitutes “the first tagged nucleic acid strand”.
For purposes of examination only, the Examiner interprets “the first tagged nucleic acid strand” as first extension products comprising the oligonucleotide-tethered dideoxynucleotide at the 3' end. This interpretation is adopted solely for examination and does not resolve the lack of clarity in the claim language.
Claim 10, the phrase ”pre-annealed oligonucleotide” is unclear because the claim does not specify the nucleic acid strand to which the oligonucleotide is pre-annealed to.
Claims 11-17 depend from claim 10 and are therefore similarly rejected.
Claim 15, the phrase “the first nucleic extension products” lacks proper antecedent basis because the parent claim recites “first extension products”, not “the first nucleic extension products”.
Claim 15, the phrase “the second extension products” lacks proper antecedent basis. Although claim 15 recites the structure of splint oligonucleotide comprises second barcode and universal handle, claim 15 does not recite a step of forming second extension products (e.g. polymerase extension using splint oligonucleotide to generate second extension products) nor do the parent claim and dependency chain leading to claim 15.
Claim 16, the phrase “the first nucleic extension products” lacks proper antecedent basis because the parent claim recites “first extension products”, not “the first nucleic extension products”.
Claim 16, the phrase ”pre-annealed oligonucleotide” is unclear because the claim does not specify the nucleic acid strand to which the oligonucleotide is pre-annealed to.
Claim 17 recites the amplifications primers “optionally comprise third and/or fourth barcodes”, but later requires “the combination of the first, second, and third barcode sequences” is unique to the amplification products originating from a single cell or nucleus. It is unclear whether the third barcode is optional or required.
Claim 17, the term “respectively” in the limitation “third and/or fourth barcodes” and “first and/or second adapter sequences” is unclear as to which primer comprise which barcode and adapter.
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.
Claim(s) 10-17 rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-7 of U.S. Patent No. 11739316B2 (the 316’ patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the rejected claims of the present invention would be anticipated and/or rendered obvious by the subject matter in the claims of the reference patent.
Regarding present claim(s) 10, the claim of the 316’ patent discloses method for generating a library of nucleic acids from a sample comprising one or more nucleic acids, optionally wherein the sample comprises a plurality of cells or cell nuclei, comprising: a. annealing a first primer which is at least partially complementary to the one or more nucleic acids, b. contacting the one or more nucleic acids with a first nucleic acid polymerase, at least one nucleotide not tethered to an oligonucleotide, and at least one oligonucleotide-tethered dideoxynucleotide to form a plurality of first extension products comprising the oligonucleotide-tethered dideoxynucleotide at the 3' end; c. providing a pre-annealed oligonucleotide comprising a sequence which is at least partially complementary to the tethered oligonucleotide of the first extension products, and d. contacting the first tagged nucleic acid strand with the pre-annealed oligonucleotide and a ligase to form a ligation product, thereby producing a library of nucleic acids. (e.g. as per claim(s) 1 of the 316’ patent)
Regarding present claim(s) 11, the claim of the 316’ patent discloses the one or more nucleic acids in the sample comprises an oligonucleotide of an oligonucleotide-tethered binding agent (OTBA). (e.g. as per claim(s) 2 of the 316’ patent)
Regarding present claim(s) 12, the claim of the 316’ patent discloses the tethered oligonucleotide of the OTBA comprises a cell marker binding agent index, and wherein binding agent of the OTBA comprises an aptamer or an antibody or a functional fragment thereof (e.g. as per claim(s) 3 of the 316’ patent)
Regarding present claim(s) 13, the claim of the 316’ patent discloses a sample comprising one or more nucleic acids comprises more than one cell or cell nuclei, wherein the cells or cell nuclei may comprise one or more cell markers, wherein the sample is split into two or more first portions before step a, and wherein each first portion comprises a subpopulation of cells or cell nuclei of the original sample. (e.g. as per claim(s) 4 of the 316’ patent)
Regarding present claim(s) 14, the claim of the 316’ patent discloses the first primer comprises a first universal handle sequence and a first barcode, said first barcode being common among the first primers in each first portion, but different from the first barcodes present in first primers in other first portions; and wherein the oligonucleotide of the oligonucleotide-tethered dideoxynucleotide comprises a second universal handle sequence. (e.g. as per claim(s) 5 of the 316’ patent)
Regarding present claim(s) 15, the claim of the 316’ patent discloses before step c: a. combining the first portions after formation of the first nucleic extension products and b. splitting the combined first portions into two or more second portions, wherein the second portions comprise the splint oligonucleotide; wherein the splint oligonucleotide comprises: i. an oligonucleotide sequence that anneals to the second universal handle on the tethered oligonucleotide; ii. a template sequence for a second barcode, wherein the second barcodes of each second portion are common, but are different from the second barcodes of other second portions, and iii. a template sequence for a third universal handle; wherein the second extension products comprise the second barcode and third universal handle. (e.g. as per claim(s) 6 of the 316’ patent)
Claim 15 and 16 of the instant application are parallel alternatives for adding the second barcode and third universal handle. The difference is how those sequences are added. Claim 15 uses a splint oligonucleotide as a template for polymerase extension, while claim 16 uses pre-annealed oligonucleotide for ligation reaction. Claim 6 of the 316’ patent discloses polymerase extension method, but does not disclose ligation reaction. As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to use ligation as an alternative method append the same second barcode and third universal handle to the tethered oligonucleotide. Substituting ligation for polymerase extension represent using well-known alternative method of joining nucleic acid sequences to obtain the same predictable product containing second barcode and third universal handle for downstream split-pool barcoding workflow.
Regarding present claim(s) 17, the claim of the 316’ patent discloses method further comprising: a. combining the second portions; b. splitting the combined second portions into two or more third portions; c. contacting each third portion with amplification primers, wherein the amplification primers are capable of hybridizing to and extending from the first universal handle and the third universal handle, and wherein the amplification primers optionally comprise third and/or fourth barcodes respectively, and first and/or second adapter sequences, respectively, to generate amplification products, wherein the combination of the first, second, and third barcode sequences ( or complements thereof) of the amplification products are unique to the amplification products originating from a single cell or nucleus. (e.g. as per claim(s) 7 of the 316’ patent)
Closest prior arts
The following references were considered as the closest prior arts:
Baccaro et al. (Angew. Chem. Int. Ed., 51: 254-257, disclosed in IDS) was considered for claim 10 because the reference teaches oligonucleotide-modified dNTPs. However, Baccaro does not teach or suggest converting an extendable oligonucleotide-modified dNTPs into a chain terminating oligonucleotide-modified ddNTPs for producing a 3’ terminal handle on a nucleic acid strand. Hence Baccaro does not teach or suggest the claimed formation of the first extension product comprising an oligonucleotide-tethered dideoxynucleotide at 3’ end for subsesquent ligation with pre-annealed oligonucleotide.
Stoeckius et al. (Nat Methods. 2017;14(9):865-868) was considered for claims 11 and 12 because the reference teaches antibody-oligonucleotide conjugates for marker detection (CITE-seq). However, Stoeckius does not disclose claim 10’s method, nor provide motivation to combine CITE-seq with oligonucleotide-tethered dideoxynucleotide extension/termination approach.
Rosenberg et al. (Science 360,176-182(2018)) was considered for claim 13-17 because the reference teaches split-pool barcoding method (SPLiT-seq). However, Rosenberg does not disclose claim 10’s method, nor provide motivation to combine SPLiT-seq with oligonucleotide-tethered dideoxynucleotide extension/termination approach. Additionally, In SPLiT-seq, the barcodes and adapters are added to target nucleic acid sequences through conventional terminal ligation, while the claimed method requires adding oligonucleotide-tethered moiety through ddNTPs during polymerase extension; then adding barcodes to the tethered oligonucleotides. Accordingly, the final products and mechanism of tagging between art and the claimed method are structurally and mechanistically different.
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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