CTNF 18/273,517 CTNF 99431 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Status Claims 1-18 are under examination (7/20/2023). Priority Claims 1-18 receive the priority date of 2/18/2021, the filing date of the Republic of Korea Application No. KR10-2021-0021723. Information Disclosure Statement 06-49-06 AIA The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Information Disclosure Statements from 7/20/2023 are considered. Nucleotide and/or Amino Acid Sequence Disclosures Drawings REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; ii) the date of creation; and iii) the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: 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 - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Required response – Applicant must provide: Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers, for specifically Figures 3, 5-7, 11, 18 ; AND/OR A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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. Specification The disclosure is objected to because of the following informalities (see MPEP § 608.01): The use of the terms, “MiSeq” (p. 20 and used throughout the Specification), and “Illumina” (p. 20 and used throughout the Specification), are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Claim Rejections - 35 USC § 112 07-30-01 AIA The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 07-31-01 Claims 10-12 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 10 requires a modified nucleic acid unit comprising “a modified site consisting of an organic material or an inorganic material.” Claim 11 further requires the modified site be selected from a functional group, magnetic material, label, or separate nucleic acid chain. Claim 12 requires a plurality of binding sites configured to simultaneously purify nucleic acids having different lengths, and claim 16 requires designing or designating a position capable of binding to the modified nucleic acid unit with a specific base at a specific position. While the specification generally describes modified nucleic acid units and broadly lists possible categories of modifications, the specification does not describe sufficient representative species or common structural characteristics demonstrating possession of the full claimed genus of modified sites, binding-site arrangements, and designed binding configurations capable of performing the claimed selective purification functions. The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated: To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious" and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398. Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co ., the court stated: A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name," of the claimed subject matter sufficient to distinguish it from other materials. Fiers v. Revel , 984 F.2d at 1171,25 USPQA2d, 1601; In re Smyth , 480 F.2d 1376,1383, 178 USPQ 279,284 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is an unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus...") Regents of the University of California v. Eli Lilly & Co ., 43 USPQ2d 1398. The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is "not a sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence." MPEP § 2163. The MPEP does state that, for a generic claim, the genus can be adequately described in the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. This disclosure of only one or a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem , 323 F.3d at 966, 63 USPQ2d at 115; Noelle v. Lederman , 355 F.3d, 1343, 1350, 69 USPO2d 1508, 1514 (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). Here, claims 10-12 and 16 recite broad functional genera of modified sites, binding-site arrangements, and designed binding positions capable of selectively purifying nucleic acids. For example, claim 10 broadly recites a modified site “consisting of an organic material or an inorganic material”, while claims 11 and 12 further encompass numerous categories of modified sites and binding configurations. However, the specification only generally lists categories of possible modifications and desired purification functions without describing sufficient characteristics demonstrating possession of the full claimed scope. Thus, the disclosure does not reasonably convey to one of ordinary skill in the art that the inventor possessed the claimed genus as of the filing date. The rejected claims comprise a broad functional genus of modified nucleic acid units, modified sites, binding-site arrangements, and designed binding positions defined primarily by their ability to selectively bind and purify nucleic acids. Claim 10 requires a modified nucleic acid unit comprising “a modified site consisting of an organic material or an inorganic material.” Claim 11 further requires the modified site be selected from a functional group, magnetic material, label, or separate nucleic acid chain. Claim 12 requires a plurality of binding sites configured to simultaneously purify nucleic acids having different lengths, and claim 16 requires designing or designating a position capable of binding to the modified nucleic acid unit with a specific base at a specific position. To satisfy the written description requirement, the disclosure must reasonably convey to one of ordinary skill in the art that the inventor had possession of the claimed invention as of the filing date. Vas-Cath Inc. v. Mahurkar , 19USPQ2d 1111, clearly states "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See Vas-Cath at page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is now is claimed." (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of prime editing systems, regardless of the complexity or simplicity of the method of isolation or identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel , 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. , 18USPQ2d 1016. Specifically, for a claimed genus, the specification must provide sufficient distinguishing identifying characteristics, such as representative species, structural features, structure/function correlation, or combinations thereof. However, the specification merely lists broad categories of possible modifications and desired purification functions without describing sufficient representative species or common structural characteristics demonstrating possession of the full claimed scope. Thus, one skilled in the art could not reasonably conclude that the applicant possesses the full genus of modified sites, binding-site arrangements, a designed binding positions recited in claims 10-12 and 16 as of the filing date. The rejected claims comprise a broad genus of modified nucleic acid units, modified sites, binding-site arrangements, and designed binding positions defined primarily by their ability to selectively bind and purify nucleic acids. Claim 10 encompasses modified sites consisting of any organic material or inorganic material, claim 11 further encompasses modified sites selected from functional groups, magnetic materials, labels, and separate nucleic acid chains, claim 12 encompasses binding-site arrangements capable of simultaneously purifying nucleic acids of different lengths, and claim 16 encompasses positions designed to bind a modified nucleic acid unit at a specific base and position. Thus, one must be able to envision the structures and structure/function relationships of the modified sites and binding configurations capable of performing the claimed purification functions across the full scope of the genus. To provide adequate written description and evidence of possession of such a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus, including representative species, structural characteristics, structure/function correlation, or combinations thereof, The Specification states the following at paragraph [0067-69]: In addition, the nucleic acid library may comprise a library composed of degenerate sequences. By doing so, the synthesis cost for storing unit information may be reduced. In step S3, at least one modified nucleic acid unit is introduced during the binding process of the nucleic acid units. The modified nucleic acid unit may be one in which a modified site in the form of an organic material or an inorganic material is introduced into the nucleic acid unit to capture or isolate the desired complementary nucleic acid chain. For example, the modified site may include a functional group, a magnetic material, a label (fluorophore, barcode, and the like), a separate nucleic acid chain, and the like. For example, the introduction of a functional group is one of the chemical modifications, and may be performed by a way of linking a nucleic acid unit with a biomolecule such as biotin, a thiol group, an amine group, a phosphate group, other substances used in click chemistry, or the like to a nucleic acid unit. According to an embodiment, the nucleic acid unit or the modified nucleic acid unit may be composed of one or two or more nucleotides, and preferably may be a trimer capable of encoding one amino acid. In essence, the Specification generally describes modified nucleic acid units and lists broad categories of possible modifications, such as organic materials, inorganic materials, functional groups, magnetic materials, labels and separate nucleic acid chains, but does not provide sufficient representative species or common structural characteristics demonstrating possession of the full claimed genus. Accordingly, the Specification does not reasonably convey to one of ordinary skill in the art that Applicant possessed the full scope of the modified sites, binding-site arrangements, and designed binding positions recited in claims 10-12 and 16 as of the filing date. Even if one accepts that the examples described in the Specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only broad listed categories of possible modifications, representing only a limited subset of the claimed genus. The results are not necessarily predictive of other members of the genus, and it is therefore impossible to extrapolate from the examples described herein those embodiments that would necessarily meet the structural and functional characteristics of the rejected claims. The prior art of record does not cure the deficiency in the Specification. For example, Banyai et. al, (KR20160041046, from IDS 7/20/2023) generally describes de novo synthesis of nucleic acid libraries, oligonucleotide building blocks, and microfluidic assembly of nucleic acids (Abstract). Further, Du Hee et al, (KR 20130018575, from IDS 7/20/2023) generally describes tagging nucleic acid fragments with barcode sequences, identifying tagged fragments, collecting desired fragments, and assembling long nucleic acid molecules (Abstract). However, these references do not describe representative species, common structural characteristics, or structure/function correlation for the broad genus of modified sites consisting of organic or inorganic materials, binding site arrangements for simultaneously purifying nucleic acids having different lengths, or designed binding positions capable of binding a modified nucleic acid unit at a specific base and position as recited in claims 10-12 and 16. Thus, the prior art does not overcome the deficiency of the Specification with regard to the description of a genus of modified nucleic acid units, modified sites, binding-site arrangements, and designed binding positions capable of performing the selective purification functions recited in claims 10-12 and 16. Neither the Specification nor the prior art describe representative species, common structural characteristics or sufficient structure/function correlation for the broad genus of modified sites consisting of organic or inorganic materials, binding-site arrangements capable of simultaneously purifying nucleic acid having different lengths, or designed binding positions capable of binding a modified nucleic acid unit at a specific base and position. If one cannot envision the structures encompassed by such modified sites and binding configurations across the full claimed scope, one cannot reasonably conclude that the Applicant possessed the claimed genus. Therefore, one of ordinary skill in the art would have reasonably concluded that the Applicant was not in possession of the claimed invention of claims 10-12 and 16 as of the filing date. 07-30-02 AIA 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. 07-34-01 Claims 6-9 and 12 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 6 is rejected. Claim 6 recites the limitation "the binding cycle” at line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, is there a difference between “the binding cycle”, here, and “the binding process” of independent claim 1. Claims 7-9 are included in this rejection due to their dependency on claim 6. Claim 12 is rejected. Claim 12 recites the limitation “the difference in binding sites” at lines 4-5. There is insufficient antecedent basis for this limitation in the claim. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 07-07-aia AIA 07-07 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 – 07-08-aia AIA (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. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-103 AIA The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. 07-15 AIA Claim (s) 1-18 are rejected under 35 U.S.C. 102( a)(1) and 102 (a)(2 ) as being anticipated by Harkins Kincaid et al. (WO 2020/206143 A1; published 4/2/2020) . Regarding claims 1-2, Harkins Kincaid teaches methods and compositions for analyzing nucleic acid and in some aspects, the technology relates to methods and compositions for preparing a nucleic acid library from single-stranded nucleic acid fragments (p. 1, lines 20-25). Further, Harkins Kincaid teaches that the previously mentioned method includes compositions comprising a nucleic acid composition comprising single-stranded ribonucleic acid (ssRNA) or single-stranded complementary deoxyribonucleic acid (sscDNA); a first oligonucleotide; and a plurality of first scaffold polynucleotide species each comprising an ssRNA or sscDNA hybridization region and a first oligonucleotide hybridization region (p. 4, lines 20-25). Harkins Kincaid also teaches that provided in some aspects are methods for producing a nucleic acid library, comprising combining (i) a nucleic acid composition comprising single-stranded ribonucleic acid (ssRNA) or singlestranded complementary deoxyribonucleic acid (sscDNA), (ii) a first oligonucleotide, and (iii) a plurality of first scaffold polynucleotide species, where (a) each polynucleotide in the plurality of first scaffold polynucleotide species comprises an ssRNA or sscDNA hybridization region and a first oligonucleotide hybridization region; and (b) the nucleic acid composition, the first oligonucleotide, and the plurality of first scaffold polynucleotide species are combined under conditions in which a molecule of the first scaffold polynucleotide species is hybridized to (i) a first ssRNA or sscDNA terminal region and (ii) a molecule of the first oligonucleotide, thereby forming hybridization products in which an end of the molecule of the first oligonucleotide is adjacent to an end of the first ssRNA or sscDNA terminal region (p. 4, lines 1-15). Additionally, Harkins Kincaid teaches that Fig. 3A shows ssDNA final library product size distribution from 1 ng cell-free DNA generated with (top) and without (bottom) the presence of SSB. Fig. 3B shows an overlap of insert length distribution inferred from sequencing data of the two cfDNA libraries (generated with or without SSB) (p. 5, lines 15-20). Harkins Kincaid also teaches that Fig. 10 shows an example workflow with staged ligation using a P7 scaffold adapter having a 5' App modification and ATP delay, X, blocking modification, 5' App, 5'-adenylated DNA. 5' P, 5' phosphate. 3' OH, 3' hydroxyl. N, any nucleotide (p. 6, lines 5-10). Regarding claim 3, Harkins Kincaid teaches that in some embodiments, a modified nucleotide comprises a first member of a binding pair (e.g., biotin); and a second member of a binding pair (e.g., streptavidin) is conjugated to a solid support or substrate, where a solid support or substrate can be any physically separable solid to which a member of a binding pair can be directly or indirectly attached including, but not limited to, surfaces provided by microarrays and wells, and particles such as beads (e.g., paramagnetic beads, magnetic beads, microbeads, nanobeads), microparticles, and nanoparticles (p. 44, lines 20-30). Regarding claim 4, Harkins Kincaid teaches that sequencing by synthesis generally is performed by iteratively adding (e.g., by covalent addition) a nucleotide to a primer or preexisting nucleic acid strand in a template directed manner, where each iterative addition of a nucleotide is detected and the process is repeated multiple times until a sequence of a nucleic acid strand is obtained (p. 92, lines 10-15). Regarding claim 5, Harkins Kincaid teaches that methods of the present disclosure can be used to reduce sequencing error rates and in some embodiments, prior to an initial denaturing, double-stranded molecules can be labeled with a barcode such that, after subsequent denaturing, single-stranded library preparation, and sequencing, sequences from nucleic acid molecules that were originally paired together can be associated and in some embodiments, after initial ligation of scaffold adapters, a pool of index primers is used to conduct index PCR such that copies are generated of both original sample nucleic acid molecules and nucleic acids from initial PCR first strand synthesis that both comprise the same barcode or UMI (or the complement thereof) (p. 93, lines 20-30). Regarding claim 6, Harkins Kincaid teaches that when an oligonucleotide component of a scaffold adapter includes one or a portion of a sequencing adapter, one or more additional sequencing adapters and/or a remaining portion of the sequencing adapter may be added using a variety of approaches and for example, additional and/or remaining portions of sequencing adapters may be added by any one of ligation, reverse transcription, PCR amplification, and the like where in the case of PCR, an amplification primer pair may be employed that includes a first amplification primer that includes a 3' hybridization region (e.g., for hybridizing to an adapter region of the oligonucleotide) and a 5' region including an additional and/or remaining portion of a sequencing adapter, and a second amplification primer that includes a 3' hybridization region (e.g., for hybridizing to an adapter region of a second oligonucleotide added to the opposite end of an ssNA molecule) and optionally a 5' region including an additional and/or remaining portion of a sequencing adapter (p. 18, lines 30-35). Regarding claims 7-9, Harkins Kincaid teaches that for example, in some embodiments a polymerase or a ligase adds a nucleotide to a primer or to a preexisting nucleic acid strand in a template directed manner and in some embodiments of sequencing by synthesis, different types of nucleotides, nucleotide analogues and/or identifiers are used, and further in some embodiments, reversible terminators and/or removable (e.g., cleavable) identifiers are used, and even further in some embodiments, fluorescent labeled nucleotides and/or nucleotide analogues are used. (p. 92, lines 15-25). Regarding claims 10-14, Harkins Kincaid teaches that unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, single nucleotide polymorphisms (SNPs), and complementary sequences as well as the sequence explicitly indicated and specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues, where the term nucleic acid is used interchangeably with locus, gene, cDNA, and mRNA encoded by a gene and the term also may include, as equivalents, derivatives, variants and analogs of RNA or DNA synthesized from nucleotide analogs, single-stranded ("sense" or "antisense," "plus" strand or "minus" strand, "forward" reading frame or "reverse" reading frame) and double-stranded polynucleotides (p. 57, lines 5-10). Further, Harkins Kincaid teaches that the term "gene" refers to a section of DNA involved in producing a polypeptide chain; and generally includes regions preceding and following the coding region (leader and trailer) involved in the transcription/translation of the gene product and the regulation of the transcription/translation, as well as intervening sequences (introns) between individual coding regions (exons), where a nucleotide or base generally refers to the purine and pyrimidine molecular units of nucleic acid (e.g., adenine (A), thymine (T), guanine (G), and cytosine (C)). For RNA, the base thymine is replaced with uracil and nucleic acid length or size may be expressed as a number of bases (p. 57, lines 15-20). Additionally, Harkins Kincaid teaches that in another example, a method herein may comprise adjusting an amount of isopropanol in an SPRI purification to enrich for a desired fragment length or range of lengths, where the amount of adapter dimers recovered is less than about 5% of the total nucleic acid recovered (p. 36, lines 20-25). Regarding claim 15-16, Harkins Kincaid teaches that nucleic acid may be sequenced using any suitable sequencing platform including a Sanger sequencing platform, a high throughput or massively parallel sequencing (next generation sequencing (NGS)) platform, or the like, such as, for example, a sequencing platform provided by lllumina® (e.g., HiSeq™, MiSeq™ and/or Genome Analyzer™ sequencing systems) (p. 86, lines 10-15). Harkins Kincaid also teaches that in some embodiments, some or all nucleic acids in a sample are enriched and/or amplified (e.g., non-specifically, e.g., by a PCR based method) prior to or during sequencing where in certain embodiments, specific nucleic acid species or subsets in a sample are enriched and/or amplified prior to or during sequencing, and in some embodiments, a species or subset of a pre-selected pool of nucleic acids is sequenced randomly and in some embodiments, nucleic acids in a sample are not enriched and/or amplified prior to or during sequencing (p. 89, lines 5-15). Regarding claims 17-18, Harkins Kincaid teaches that kits may include components for capturing single-stranded DNA and/or single-stranded RNA, where kits for capturing single-stranded DNA may be configured such that a user provides double-stranded or single-stranded DNA and kits for capturing single-stranded RNA may be configured such that a user provides cDNA (either single or double stranded), or provides RNA (e.g., total RNA or rRNA depleted, and further a kit for capturing single-stranded RNA may include rRNA depletion reagents, mRNA enrichment reagents, fragmentation reagents, cDNA synthesis reagents, and/or RNA digestion reagents (p. 117, lines 30-25). Further, Harkins Kincaid teaches that components of a kit may be present in separate containers, or multiple components may be present in a single container. Suitable containers include a single tube (e.g., vial), one or more wells of a plate (e.g., a 96-well plate, a 384-well plate, and the like), and the like (p. 118, lines 1-10). Harkins Kincaid teaches that the previously mentioned method includes compositions comprising a nucleic acid composition comprising single-stranded ribonucleic acid (ssRNA) or single-stranded complementary deoxyribonucleic acid (sscDNA); a first oligonucleotide; and a plurality of first scaffold polynucleotide species each comprising an ssRNA or sscDNA hybridization region and a first oligonucleotide hybridization region (p. 4, lines 20-25). Harkins Kincaid also teaches that provided in some aspects are methods for producing a nucleic acid library, comprising combining (i) a nucleic acid composition comprising single-stranded ribonucleic acid (ssRNA) or singlestranded complementary deoxyribonucleic acid (sscDNA), (ii) a first oligonucleotide, and (iii) a plurality of first scaffold polynucleotide species, where (a) each polynucleotide in the plurality of first scaffold polynucleotide species comprises an ssRNA or sscDNA hybridization region and a first oligonucleotide hybridization region; and (b) the nucleic acid composition, the first oligonucleotide, and the plurality of first scaffold polynucleotide species are combined under conditions in which a molecule of the first scaffold polynucleotide species is hybridized to (i) a first ssRNA or sscDNA terminal region and (ii) a molecule of the first oligonucleotide, thereby forming hybridization products in which an end of the molecule of the first oligonucleotide is adjacent to an end of the first ssRNA or sscDNA terminal region (p. 4, lines 1-15). Additionally, Harkins Kincaid teaches that Fig. 3A shows ssDNA final library product size distribution from 1 ng cell-free DNA generated with (top) and without (bottom) the presence of SSB. Fig. 3B shows an overlap of insert length distribution inferred from sequencing data of the two cfDNA libraries (generated with or without SSB) (p. 5, lines 15-20). Harkins Kincaid also teaches that Fig. 10 shows an example workflow with staged ligation using a P7 scaffold adapter having a 5' App modification and ATP delay, X, blocking modification, 5' App, 5'-adenylated DNA. 5' P, 5' phosphate. 3' OH, 3' hydroxyl. N, any nucleotide (p. 6, lines 5-10). Harkins Kincaid teaches that sequencing by synthesis generally is performed by iteratively adding (e.g., by covalent addition) a nucleotide to a primer or preexisting nucleic acid strand in a template directed manner, where each iterative addition of a nucleotide is detected and the process is repeated multiple times until a sequence of a nucleic acid strand is obtained (p. 92, lines 10-15). Harkins Kincaid teaches that for example, in some embodiments a polymerase or a ligase adds a nucleotide to a primer or to a preexisting nucleic acid strand in a template directed manner and in some embodiments of sequencing by synthesis, different types of nucleotides, nucleotide analogues and/or identifiers are used, and further in some embodiments, reversible terminators and/or removable (e.g., cleavable) identifiers are used, and even further in some embodiments, fluorescent labeled nucleotides and/or nucleotide analogues are used. (p. 92, lines 15-25). Harkins Kincaid teaches that any suitable lysis procedure can be utilized where for example, chemical methods generally employ lysing agents to disrupt cells and extract the nucleic acids from the cells, followed by treatment with chaotropic salts and physical methods such as freeze/thaw followed by grinding, the use of cell presses and the like also are useful and in some instances, a high salt and/or an alkaline lysis procedure may be utilized, and further in some instances, a lysis procedure may include a lysis step with EDTA/Proteinase K, a binding buffer step with high amount of salts (e.g., guanidinium chloride (GuHCI), sodium acetate) and isopropanol, and binding DNA in this solution to silica-based column (p. 60, lines 25-35). Therefore, Harkins Kincaid teaches each and every element of claims 1-18, and thus anticipates claim 1-18. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELIZABETH ROSE LAFAVE whose telephone number is (703)756-4747. The examiner can normally be reached Compressed Bi-Week: M-F 7:30-4:30. 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. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on 571-272-2876. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ELIZABETH ROSE LAFAVE/ Examiner, Art Unit 1684 /HEATHER CALAMITA/ Supervisory Patent Examiner, Art Unit 1684 Application/Control Number: 18/273,517 Page 2 Art Unit: 1684 Application/Control Number: 18/273,517 Page 3 Art Unit: 1684 Application/Control Number: 18/273,517 Page 4 Art Unit: 1684 Application/Control Number: 18/273,517 Page 5 Art Unit: 1684 Application/Control Number: 18/273,517 Page 6 Art Unit: 1684 Application/Control Number: 18/273,517 Page 7 Art Unit: 1684 Application/Control Number: 18/273,517 Page 8 Art Unit: 1684 Application/Control Number: 18/273,517 Page 9 Art Unit: 1684 Application/Control Number: 18/273,517 Page 10 Art Unit: 1684 Application/Control Number: 18/273,517 Page 11 Art Unit: 1684 Application/Control Number: 18/273,517 Page 12 Art Unit: 1684 Application/Control Number: 18/273,517 Page 13 Art Unit: 1684 Application/Control Number: 18/273,517 Page 14 Art Unit: 1684 Application/Control Number: 18/273,517 Page 15 Art Unit: 1684 Application/Control Number: 18/273,517 Page 16 Art Unit: 1684 Application/Control Number: 18/273,517 Page 17 Art Unit: 1684 Application/Control Number: 18/273,517 Page 18 Art Unit: 1684 Application/Control Number: 18/273,517 Page 19 Art Unit: 1684 Application/Control Number: 18/273,517 Page 20 Art Unit: 1684 Application/Control Number: 18/273,517 Page 21 Art Unit: 1684 Application/Control Number: 18/273,517 Page 22 Art Unit: 1684 Application/Control Number: 18/273,517 Page 23 Art Unit: 1684 Application/Control Number: 18/273,517 Page 24 Art Unit: 1684
Prosecution Insights