DETAILED ACTION
Applicant's response, filed 4/30/2026, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 1-21 are rejected.
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 .
Priority
This application claims benefit to provisional application 63/313,906 filed on 02/25/2022. Domestic benefit is acknowledged, thus the effective filing date of all claims in this application is 02/25/2022.
Information Disclosure Statement
The information disclosure statement filed 4/30/2026 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because it was filed after a non-final but before a final action. Applicant either would have had to make the statement in 37 CFR 1.97(e) or pay a fee to have the IDS considered (see MPEP 609.01 and 609.04(b).II). It has been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Sequence Listing
The deficiency in the sequence listing has been rectified by amendment.
Claim Rejections - 35 USC § 102
The rejection under 35 U.S.C. § 102 has been withdrawn in light of the claim amendments and arguments (page 1 ¶ 4).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.
The previous 103 rejections are withdrawn in light of the claim amendments.
Claim(s) 1-8 & 15 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (J Mol Diagn. 2015 Nov;17(6):679–688, hereafter “Zhang”, newly cited) in view of Glezer et al. (US 2022/0042083 A1, published Feb 10, 2022, hereafter “Glezer”, previously cited). This rejection is newly recited and necessitated by claim amendment.
Regarding claim 1, Zhang teaches hybridizing a nucleic acid sample with oligonucleotides (pg 680 left col ¶ 2). The oligonucleotide consists of a common probe and a detector probe that hybridize into a single oligonucleotide; this is equivalent to the targeting region and amplification region (pg 680 left col ¶ 2). The ligation probe then hybridizes to the nucleic acid sample (pg 687 left col ¶ 2) and ligates to the nucleic acid sample based on proximity, forming a chimeric molecule (pg 680 left col ¶ 2).
Zhang is silent as to preparing a library of nucleic acids amplified from the one or more oligonucleotides.
Regarding claim 1, Glezer teaches a method of oligo targeted proximity ligation (specification [spec] paragraph [¶] 6), hybridizing a nucleic acid sample (spec ¶ 6), performing a proximity based ligation between the nucleic acid sample and one or more hybridized oligonucleotides (claim 2), and preparing a library of nucleic acids amplified from the one or more oligonucleotides (spec ¶ 182).
Regarding claim 2, Glezer teaches the one or more oligonucleotides having a targeting region (spec ¶ 111), an alkyl linker (spec ¶ 76), a reverse transcription region (spec ¶ 109), and a reverse transcription primer region (spec ¶ 110).
Regarding claim 3, Glezer teaches that the one or more oligonucleotides can be a 3’ or 5’ biotin, alkyne, azide, or phosphate (spec ¶ 147).
Regarding claim 4, Glezer teaches that preparing the nucleic acid sample comprises isolating cells (spec ¶ 182).
Regarding claim 5, Glezer teaches measuring nucleic acid concentration (spec ¶ 168).
Regarding claim 6, Glezer teaches fragmenting the nucleic acid sample. (spec ¶ 139).
Regarding claim 7, Glezer teaches fragmenting the nucleic acid sample with heat, addition of enzymes such as nuclease, and by physical conditions such as mechanical shearing or addition of metal ions (spec ¶ 139).
Regarding claim 8, Glezer teaches a barcode region comprising one or more barcodes (spec ¶ 86).
Regarding claim 15, Glezer teaches that targeting region of the oligonucleotide is complementary to gene of interest (spec ¶ 277).
Regarding claims 1-8 and 15, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching, suggestion, or motivation in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to prepare a library from amplified RNAs from the ligation process in the text of Glezer, to quantify the abundance of RNA molecules in cells with greater sensitivity (Glezer ¶ 182). There would be a reasonable expectation of success in making this combination to a person of ordinary skill in the art, as both methods are directed to proximity ligation. Although the “padlock probe” method of Glezer ligates a probe to itself, this is the only difference, and this would not prevent an ordinary artisan from applying the pre-and-post ligation ancillary processing steps of Glezer to the method of Zhang. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Zhang by adding the library preparation and ancillary processing steps of Glezer, in order to quantify the abundance of RNA molecules in cells with greater sensitivity.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang and Glezer as applied to claims 1-8 & 15 above and in further view of “Handling Magnetic Beads during NGS Library Preparation” (Eppendorf AG, 2021). This rejection is newly recited and necessitated by claim amendment.
Regarding claim 9, Glezer teaches preparing a library (spec ¶ 182). Glezer is silent as to coupling to a magnetic bead.
“Handling Magnetic Beads during NGS Library Preparation” states that “One of the most critical steps in this process [NGS library preparation] is the handling of the magnetic beads,” and teaches the concept of coupling to a magnetic bead.
Regarding claim 9, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some suggestion in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a suggestion to couple one or more oligonucleotides to a magnetic bead in the text of “Handling Magnetic Beads during NGS Library Preparation.” There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the suggested modification is explained in the text of the Eppendorf fact sheet. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Zhang with the suggested modification of the Eppendorf fact sheet, in order to better conform with best practices in NGS library preparation.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang and Glezer as applied to claims 1-8 & 15 above and in further view of “Ethanol Precipitation of DNA and RNA: How it Works” (Nick Oswald, BiteSizeBio 2021, previously cited). This rejection is newly recited and necessitated by claim amendment.
Regarding claim 10, Glezer teaches preparing a library (spec ¶ 182). Glezer is silent as to a precipitation step.
Oswald states that “Ethanol precipitation is a commonly used technique for concentrating and de-salting nucleic acid (DNA or RNA) preparations in an aqueous solution.”
Regarding claim 10, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some suggestion in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a suggestion to use a precipitation step in the text of Oswald. There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the suggested modification is explained in the text of Oswald. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Zhang with the suggested modification of Oswald, in order to better conform with best practices in NGS library preparation.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang and Glezer as applied to claims 1-8 & 15 above and in further view of Oswald as applied to claim 10 above, and in further view of Christians et al. (US9976181B2, 5/22/2018) (hereafter “Christians”). This rejection is newly recited and necessitated by claim amendment.
Regarding claim 11, Oswald teaches a precipitation step. Oswald and Glezer are silent as to nucleic acid end repair.
Regarding claim 11, Christians teaches a nucleic acid end repair step as part of a precipitation process (spec column 84 line 41). The decision of In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) found that selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.
Regarding claim 11, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some suggestion in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a suggestion to use a nucleic acid end repair step in the text of Christians. There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the suggested modification is explained in the text of Christians. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Zhang with the suggested modification of Christians, in order to better conform with best practices in NGS library preparation.
Claims 12, 16, & 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Glezer as applied to claims 1-8 and 15 above, and in further view of “Oligo Clean & Concentrator kits” (Zymo Research Corporation 2019) (hereafter “Zymo”, previously cited). This rejection is newly recited and necessitated by claim amendment.
Regarding claim 12, Glezer teaches preparing a library (spec ¶ 182), barcode chimeric ligation (claim 2), proteinase digestion of samples (spec ¶ 138), and reverse transcription of a nucleic acid sample (spec ¶ 191).
Regarding claims 12, 16, & 17-18, Glezer is silent as to a clean up and concentration step.
Regarding claim 18, the decision of In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) found that selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results.
Zymo states that “The Oligo Clean & Concentrator kits provide a streamlined method for efficient recovery and clean-up of DNA/RNA fragments and oligonucletides ≥16 nt from labeling (radioactive, biotin, DIG, etc.) and other enzymatic reactions.” Regarding claim 17, Zymo states that “Unincorporated nucleotides, short oligos, dyes, enzymes, and salts are effectively removed by the clean-up procedure.”
Regarding claims 12, 16 & 17-18, an invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some suggestion in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a suggestion to use a clean up and concentration step in the text of Zymo. There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the suggested modification is explained in the text of Zymo. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Zhang with the suggested modification of Zymo, in order to better conform with best practices in NGS library preparation.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Glezer as applied to claims 1-8 and 15 above, and in further view of “basic principles of RT-qPCR” (Thermo Fisher Scientific, 2019) (hereafter “Thermo Fisher”, previously cited), Greulich et al. (“Protocol for using heterologous spike-ins to normalize for technical variation in chromatin immunoprecipitation”, STAR Protocols 2 1-37, 2021) (hereafter “Greulich”, previously cited), and “Accurate Demultiplexing” (Illumina, 2020) (hereafter “Illumina”, previously cited). This rejection is newly recited and necessitated by claim amendment.
Regarding claim 13, Greulich teaches DNA sample bead cleanup (page 15 steps 31-39).
Regarding claim 13, Thermo Fisher teaches DNA sample quantification by qPCR and amplification of DNA.
Regarding claim 13, Illumina teaches dual index addition (¶ 1).
Regarding claim 13, an invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to use a bead elution buffer in a library preparation kit in the text of Greulich. There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the instructions for its use are explained in the text of Greulich (page 15 steps 31-39). There is a teaching to use qPCR and RT primer in the text of Thermo Fisher (Heading: “Primer design and controls for accurate quantitation in RT-qPCR”, ¶ 1). There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the instructions for its use are explained in the text of Thermo Fisher (¶ 1). There is a teaching to use dual index addition in the text of Illumina (¶ 1). There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the instructions for its use are explained in the text of Thermo Fisher. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Zhang with the suggested modifications of Greulich, Thermo Fisher, and Illumina, in order to better conform with best practices in NGS library preparation.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Glezer as applied to claims 1-8 and 15 above, and in further view of Edelman (US2019/0316182 A1, 10/17/2019) (hereafter “Edelman”, previously cited). This rejection is newly recited and necessitated by claim amendment.
Regarding claim 14, Zhang is silent as to the complementarity of one or more oligonucleotides to a PolyA tail.
Edelman teaches that “the target regions of barcoded oligonucleotides may be complementary to poly ( A ) tail regions of messenger RNA molecules” (spec ¶ 192).
Regarding claim 14, An invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some suggestion in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a suggestion to bind a targeting region to polyA tail in the text of Edelman. There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the method of polyA tail binding is explained in the text of Edelman (spec ¶ 154, 185). Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Zhang with Edelman’s method of binding to a polyA tail, in order to overcome biophysical challenges associated with common types of experimental DNA samples (Edelman spec ¶ 13).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Glezer.
With respect to claim 19, regarding printed instructions included as part of a kit, and in accordance with MPEP § 2111.05, while “a claim must be read as a whole, USPTO personnel may not disregard claim limitations comprised of printed matter ... [h]owever, USPTO personnel need not give patentable weight to printed matter absent a new and unobvious functional relationship between the printed matter and the substrate”, citing In re Lowry, 32 F.3d 1579, 1583-84, 32 USPQ2d 1031, 1035 (Fed. Cir. 1994). In MPEP § 2111.05(I)(B), citing In re Ngai, 367 F.3d at 1339, 70 USPQ2d at 1864, it is noted that “in a kit containing a set of chemicals and a printed set of instructions for using the chemicals, the instructions are not related to that particular set of chemicals”. Therefore, in the instant claim, the recited instructions do not distinguish over the prior art as instantly applied.
Regarding claim 19, Glezer provides instructions for proximity based ligation enrichment (spec ¶ 6). Glezer teaches the one or more targeted oligonucleotides (spec ¶ 3-5, claim 2).
Regarding claim 19, an invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to use ligation and oligonucleotides in the text of Glezer because it can help lead to new discoveries and therapeutics (¶ 2) . There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the instructions for its use are explained in the text of Glezer (¶ 3-5). Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Glezer by providing printed instructions, in order to equip people with new tools that could lead to new discoveries (¶ 2).
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Glezer as applied to claim 19 above, and in further view of “basic principles of RT-qPCR” (Thermo Fisher Scientific, 2019) (hereafter “Thermo Fisher”) and Greulich et al. (“Protocol for using heterologous spike-ins to normalize for technical variation in chromatin immunoprecipitation”, STAR Protocols 2 1-37, 2021) (hereafter “Greulich”).
Regarding claim 20, Greulich teaches the use of a bead elution buffer in a kit (3rd table on page 9).
Regarding claim 21, Thermo Fisher teaches the use of qPCR primer and RT primer.
Regarding claims 20-21, an invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date of the invention if some teaching in the prior art would have led that person to combine the prior art teachings to arrive at the claimed invention. There is a teaching to use a bead elution buffer in a library preparation kit in the text of Greulich. There would be a reasonable expectation of success for this combination to a person of ordinary skill in the art, as the instructions for its use are explained in the text of Greulich (page 15 steps 31-39). There is a teaching to use qPCR and RT primer in the text of Thermo Fisher. Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time to modify the method of Glezer with the suggested modifications of Greulich and Thermo Fisher, in order to better conform with best practices in NGS library preparation.
Response to Arguments - 35 USC § 103
Applicant’s arguments, see page 3 ¶ 2, filed 4/30/2026, with respect to the rejection(s) of claims 9-14, 16-21 under 35 USC § 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of Zhang.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GRACELYN M HILL whose telephone number is (571)272-9871. The examiner can normally be reached Monday-Friday 8:30-5pm.
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/G.M.H./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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