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. Information Disclosure Statement The IDS received on March 28, 2024 is proper and is being considered by the Examiner. Drawings The drawings received on November 28, 2023 are acceptable. 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 appl icant regards as his invention. Claims 5, 8-10, 13, and 14 are 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 5 is indefinite for reciting the term, “approximately” preceding the term, “1,000 base pairs.” Because the term, “approximately” is not specifically defined as covering a definite range, the metes and bounds surrounding what length is covered by the phrase, “approximately 1,000 base pairs” is vague and indefinite. Claim 8 depends from the canceled claim 6. Claims 9 and 10 depend from claim 8 and therefore has the same root issue. For the purpose of prosecution, claim 8 has been assumed to depend from claim 1. Claims 13 and 14 recite acronyms such as, “TERC,” “TALE protein,” and “CTCF protein”. Any recitation of acronym should first be fully defined. 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. Claim s 1, 7 -12, 14-18, 22 , and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Skene et al. (eLife, 2017, pages 1-35) in view of Zascavage et al. ( Electrophoresis, 2019, vol. 40, pages 272-280 ). With regard to claim 1, Skene et al. teach a method of determining the genomic location of at least one biomolecule-genomic DNA interaction, said method comprising the steps of: incubating a composition comprising a collection of cells, wherein the cells comprise biomolecule of interest, under conditions that allow the biomolecule of interest to contact a genomic DNA sequence (“~5 x 10 8 cells … divided into 10 600 m L aliquots”, page 21; the cells comprise the TF complex already in the nuclei of the cells, see Fig. 1); isolating and permeabilizing nuclei from cells in (a) under conditions that allow isolation of genomic DNA bound by the biomolecule of interest (“permeabilized cells or crude nuclei to magnetic beads”, page 15, bottom paragraph, also Fig. 1A wherein permeabilized nuclei are immobilized to magnetic bead and isolated); contacting the biomolecule bound to genomic DNA with a first binding moiety capable of specifically binding to the biomolecule of interest ( see Fig. 1A, “TF-specific antibody”, also “we bind antibodies … to native unfixed nuclei, where epitopes are preserved and accessible”, page 15, bottom paragraph and page 17, 1 st paragraph); contacting the first binding moiety with a second binding moiety capable of binding to the first binding moiety, wherein said second binding moiety is conjugated to an enzyme that allow modification of genomic DNA (“chimeric fusion between Protein A and MNase (pA-MN)”, page 2, 5 th paragraph; the enzyme MNase is activated by calcium and cleaves the genomic DNA on both sides of the bound protein (TF), see “[p]rotein A binds specifically to Immunoglobulin G, which obviates the need for a fusion protein … after calcium-induced MNase cleavage on both sides of the TF”, page 3, 1 st paragraph; the cleavage of the genomic DNA results in modification of the bases of that genomic DNA); incubating the first binding moiety and second binding moiety of (d) under conditions that allow modification of genomic DNA ( see above, also “Unfixed nuclei are (1) immobilized on lectin-coated magnetic beads, (2) successively incubated with antibodies and protein A-MNase (pA-MN) … mixed with Ca ++ on ice to initiate the cleavage reaction”, page 3, 3 rd paragraph); isolating and preparing the genomic DNA for sequencing, (“DNA is then extracted from the supernatant and used directly for sequencing library preparation”, page 3 rd paragraph); and sequencing the genomic DNA under conditions that allow determining the location of the biomolecule-DNA interaction (the sequencing reaction will necessarily contain the region on which TF was bound on the genomic DNA). With regard to claims 7 and 8, the first binding moiety is an antibody and the second binding moiety is protein A ( see above citation). With regard to claims 9-11, the cell is selected from human cells (“human K562 cells”, page 11, 3 rd paragraph). With regard to claims 12 and 14, the biomolecule of interest is protein (TF, transcriptional factor, see above citation). With regard to claim 15, the human cells are from cell-line K562 (“Human K562 cells were cultured …”, page 20, bottom paragraph). With regard to claim 17, method is employed on a batch of cells that are cultured (“[n]uclei from ~5 x 10 8 cells”, page 21, 2 nd paragraph). With regard to claim 18, the artisans specifically state that MNase cleaves only the regions surrounding the TF binding site ( see page 3, 2 nd paragraph) and absent evidence to the contrary, this would be within the requisite distance as required in claim 18(a). With regard to claim 22, the recited step does not require that the high molecular weight genomic DNA is what is sequenced, but that the isolating and preparing the genomic DNA for sequencing “comprises high molecular weight DNA extraction”. Since the DNA purification of Skene et al. results in both high and low molecular weight genomic DNA from each other, the limitation is met despite Skene et al. sequencing the lower molecular weight gDNA molecules. Skene et al. do not teach that the sequencing library is prepared without amplification. Skene et al. do not employ a long read sequencing technology (claim 23). Zascavage et al. teach a nanopore sequencing , which is a long read sequencing technology, wherein the nucleic acid sequence is not prior enriched nor amplified: “Sequencing libraries from native genomic DNA without enrichment …” (page 274, 2 nd column, section 2.3; also “Native DNA libraries were sequenced on … MinION flow cells”, page 274, 2 nd column) It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Skene et al. with the teachings of Zascavage et al. thereby arriving at the invention as claimed for the following reasons. The teachings of Skene et al. have been discussed above and while Skene et al. teach the sequencing of the genomic DNA which had been bound by TF/antibody/MNase complex, the artisans broadly refer to the sequencing means as employing Illumina paired end sequencing that involve an amplification reaction (“KAPA DNA polymerase library preparation … and amplifying for eight or more cycles”, page 22, 3 rd paragraph). And while Skene et al. employed a sequencing means widely known in the art as NGS, one of ordinary skill in the art would have recognized that other prior art known sequencing means would have yielded the same predictable outcome of producing the sequencing information from the isolated gnomic DNA of Skene et al., that is nanopore sequencing technology, MinION. In KSR , the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” The Office notes that claim 23 simply recites that the means of sequencing employed is a long-read sequencing and does not actively require any length of the product being sequenced. Because the MinION sequencing is a nanopore sequencing technology, the technology is considered a long-read sequencing means. Therefore, the invention as claimed is deemed prima facie obvious over the cited references. Claims 2- 5 , 13, 16 , and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Skene et al. (eLife, 2017, pages 1-35) in view of Zascavage et al. (Electrophoresis, 2019, vol. 40, pages 272-280), as applied to claim s 1, 7 -12, 14-18, 22 , and 23 above, and further in view of Schaik et al. (EMBO reports, 2000, vol. 21, e50636, pages 1-17 ; IDS ref ) and Drodz et al. (Nucleic Acids Research, 2012, vol. 40, no. 5, pages 2119-2130) . The teachings of Skene et al. and Zascavage et al. have already been discussed above. Skene et al. do not explicitly teach that other biomolecule/gDNA binding complex could be characterized. Consequently, Skene et al. do not teach that the biomolecule that complexes with the gDNA is RNA, including ncRNA, tRNA, rRNA, snRNA, snoRNA, miRNA, mRNA, and TERC (claim 13), or that the enzyme which modifies the genomic DNA is a DNA methyltransferase, Dam (clams 3) or Hia5 (claim 4) , or that the sequencing of approximately 1,000 bases (claim 5), or that the protein is recombinant protein (claim 16) , or that the permeabilization occurred with digitonin. Schaik et al. teach a modified CUT&RUN assay, similar to Skene et al., with the modification of substituting the pA conjugated enzyme of Schaik et al. with Dam (DNA adenine methyl transferase) (“[f]or pA-DamID, we used a highly similar strategy, except that we replaced the pA-MNase fusion protein [of Skene et al.] by a pA-Dam fusion protein, which is then activated by addition of its methyl donor S-adenosyl-methionine (SAM)”, page 2, 2 nd column) , wherein the resulting structure results in the methylation of neighboring adenines in the bound protein of interest, wherein “pattern of deposited m6 A can then be mapped genome-wide”, page 2, 2 nd column). Schaik et al. teach that human HAP-1 cells were used in applying the pA-DamID, wherein the HAP-1 cells produce H3K27m3 and H3K9me3 ( see page 3, 1 st column). Schaik et al. teach permeabilization process with digitonin ( see page 13, 1 st column, 1 st paragraph). Drodz et al. teach that hia5 is a DNA methyltransferase ( see page 2124, 1 st column, Identification of the base methylated by the Hia5 … ). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Skene et al. and Zascavage et al. with the teachings of Schaik et al. and Drodz et al. , thereby arriving at the invention as claimed for the following reasons. As explicitly disclosed by Schaik et al., one of ordinary skill in the art would have been capable of substituting the enzyme to which the protein/genomic DNA molecule is bound for characterization of the sequence bound thereon ( i.e., GATC) and sequence them according to any prior art available means of sequencing the isolated nucleic acids, such as the one disclosed by Zascavage et al. As well, replacing the methyltransferase of Schaik et al. with other prior art known methyltransferase, such as that of Drodz et al., would have been obvious in that such would have produced methylated bases to which the antibody/pA-methyltransferase complex is bound , yielding no more than a predictable outcome. In addition, because substituting the enzyme of Skene et al. (MNase which digests the bound genomic DNA) with the enzyme of Schaik et al. (Dam) would have resulted in bound genomic DNA which are no longer cut, sequencing the resulting product via nanopores sequencing would have resulted in a long stretch of bases approaching (if not longer than 1kb in length), which the MinION is capable of sequencing. Regarding the application of such a concept to study the binding locations of other biomolecules such as mRNA, or miRNA to their target nucleic acid , for the purpose of characterizing and sequencing such regions would have also yielded the same predictable outcome In KSR , the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” In KSR International Co v. Teleflex Inc , the supreme court stated that, “A person of ordinary skill in the art is also a person of ordinary creativity , not an automation” (82 USPQ2d at 1397) and that “in many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle” and take into account, “the inference and creative steps that a person of ordinary skill in the art would employ” (82 USPQ2d at 1396). Lastly, doing so would have been well-within the purview of the ordinarily skilled artisan and not beyond the ability of the skilled artisan because engineering an antibody/binding cognate to a known/desired target biomolecules have been well-established in the art of molecular diagnostics, as evidenced by Skene et al. as well as Schaik et al. In KSR , the supreme court stated: “When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, 103 likely bars its patentability. For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill .” (page 13, emphasis added). Therefore, the invention as claimed is deemed prima facie obvious over the cited references. Conclusion No claims are allowed. Inquiries Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7: 3 0 a.m. to 4:00 p.m (M- F ). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route. If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782. Papers related to this application may be submitted to Art Unit 16 81 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /YOUNG J KIM/ Primary Examiner Art Unit 1637 DATE \@ "MMMM d, yyyy" February 23, 2026 /YJK/