DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-16, 19, and 20, drawn to a method of analyzing circulating cell-free DNA from a subject, in the reply filed on 08/22/2025 is acknowledged.
Claims 21 and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/22/2025.
Claims Status
Claims 1-16, 19-21 and 23 are pending.
Claims 21 and 23 are withdrawn.
Claims 17-18 and 22 are canceled.
Claims 19-21 and 23 are amended and entered. No new matter is added.
Claims 1-16 and 19-20 are currently under examination
Priority
This application claims priority to International application number PCT/US2021/032526, filed May 14, 2021, which claims priority to U.S. Provisional Application No. 63/024,673, filed on May 14, 2020.
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 applicant regards as his invention.
Claim 20 is 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 20 is indefinite over the limitation “wherein the library comprises multiplexed samples”. It is unclear what is intended to be multiplexed. The specification states, “A nucleic acid library can comprise a nucleic acid derived from a single sample or multiplexed samples” (Pg. 17), “multiplexed sequencing primers” (Pg. 19 and 36-37). Thus, it is unclear if the sample the circulating cell free nucleic acids ligated to at least one adapter derived from is multiplexed or the circulating cell free nucleic acids ligated to at least one adapter are intended to be multiplexed.
Claims 1-3, 6-8 and 20 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted step is a step for analyzing as indicated by the preamble of claim 1. Claims 2-3, 6-8 and 20 depend on claim 1.
Claim Rejections - 35 USC § 102
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 –
(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.
Claims 1-2, 6-7 and 16 are rejected under 35 U.S.C. 102 (a)(1)/(a)(2) as being anticipated by Jung et al. (“Jung”; Patent App. Pub. US 20190093102 A1, Mar. 28, 2019).
Jung discloses “Methods for preparing enriched sequencing libraries from test samples that contain double-stranded deoxyribonucleic acid (dsDNA) are provided.” (Abstract)
Regarding claim 1, Jung teaches a method comprising “a test sample (e.g., a biological test sample) is obtained from a subject” (Para. 39; Figure 2). Jung teaches a method comprising “the test sample or biological test sample comprises a plurality of cell-free nucleic acids” (Para. 39; Figure 2) and “cell-free nucleic acid” or “cfNA” refers to nucleic acid fragments (DNA, RNA) that circulate in a subject's body” (Para. 34). Jung teaches a method comprising “subsequent library preparation” (Para. 39). Thus, Jung teaches a method for analyzing circulating cell-free nucleic acids from a subject comprising (a) obtaining a sample comprising circulating cell-free nucleic acid fragments from the subject; and (b) preparing a library from the sample, wherein the library comprises the circulating cell-free nucleic acid fragments ligated to at least one adapter.
Claims 2, 6-7 and 16 depend on claim 1. Claim 16 depends on claim 2, which depends on claim 1.
Regarding claim 2, Jung teaches a method comprising “(a) obtaining a test sample comprising a plurality of double-stranded deoxyribonucleic acid (dsDNA) fragments; (b) ligating double-strand DNA (dsDNA) adapters to both ends of the dsDNA fragments to generate a plurality of adapter-fragment constructs… (c) amplifying the adapter-fragment constructs to generate a sequencing library” (Para. 6). Jung also teaches a method comprising “the sequencing library is considered to be enriched for adapter-fragment constructs derived from fragments less than about 150 bp in length” (Para. 6) Thus, Jung teaches a method further comprising selecting for adapter-ligated nucleic acids having a subject cell-free nucleic acid fragment that is less than 150 bp.
Regarding claim 6, Jung teaches a method wherein “the sample is a plasma sample” (Para. 39). Thus, Jung teaches a method wherein the sample is a plasma sample.
Regarding claim 7, Jung teaches a method wherein “the test sample comprises a plurality of circulating tumor DNA (ctDNA)” (Para. 39). Thus, Jung teaches a method wherein the circulating cell-free nucleic acid fragments comprise circulating tumor DNA (ctDNA).
Regarding claim 16, Jung teaches a method wherein “the size selection can be achieved using size selection beads, for example, solid phase reversible immobilization (SPRI) beads (AMPure XP size selection beads, New England BioLabs, Ipswich, Mass.), or a gel-electrophoresis based method. (Para. 59). “AMPure XP size selection beads” reads on magnetic beads. Thus, Jung teaches a method wherein the adapter-ligated nucleic acid fragments are size selected via at least one of electrophoresis, magnetic bead-based selection, or in silico during the processing of sequencing data.
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.
Claims 1-5, 9-13 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Jung et al. (“Jung”; Patent App. Pub. US 20190093102 A1, Mar. 28, 2019).
The teachings of Jung are documented above in the rejection of claims 1-2, 6-7 and 16 under 35 U.S.C. 102 (a)(1)/(a)(2). Claims 3-5, 9-13 and 19-20 depend on claim 1. Claim 9 depends on claim 3. Claims 11-13 depend on claim 10, which depends on claim 5, which depends on claim 4, which depends on claim 3, which depends on claim 2, which depends on claim 1. Claim 19 depends on claim 2.
Jung discloses “Methods for preparing enriched sequencing libraries from test samples that contain double-stranded deoxyribonucleic acid (dsDNA) are provided.” (Abstract).
Regarding claim 3, Jung teaches a method comprising “a sequencing library prepared with biased size selection” (Para. 4). Jung teaches a method comprising “a method for preparing an enriched sequencing library, the method comprising: (a) obtaining a test sample comprising a plurality of double-stranded deoxyribonucleic acid (dsDNA) fragments; (b) enriching the sample for dsDNA fragments below a size threshold to generate an enriched sample, wherein the size threshold is less than about 150 bp in length” (Para. 5). “less than about 150 bp in length” reads on greater than 15 bp. Thus, Jung teaches a method further comprising selecting for adapter-ligated nucleic acids having a subject cell-free nucleic acid fragment that is greater than 15 bp.
Regarding claim 4, Jung teaches a method wherein “the sequencing library prepared using the methods of the present invention can be sequenced to obtain a plurality of sequence reads, and the sequence reads analyzed” (Para. 10; Fig. 8). Thus, Jung teaches a method further comprising determining the sequence of the selected subject nucleic acid fragments.
Regarding claim 5, Jung teaches “sequencing of nucleic acid molecules to generate a plurality of sequence reads, and bioinformatic manipulation of the sequence reads to carry out the subject methods” (Para. 77). “sequencing of nucleic acid molecules to generate a plurality of sequence reads, and bioinformatic manipulation of the sequence reads” reads on quantifying copy number alterations. Thus, Jung teaches a method further comprising quantifying copy number alternations (CNAs) in the sequenced subject nucleic acid fragments.
Regarding claim 9, Jung teaches a method wherein “the sequencing library prepared using the methods of the present invention can be sequenced to obtain a plurality of sequence reads, and the sequence reads analyzed to…determine cancer stage or status” (Para. 10). Thus, Jung teaches a method further comprising determining a status of the subject based on the selected subject nucleic acid fragments.
Regarding claim 10-13, Jung teaches “sequencing of nucleic acid molecules to generate a plurality of sequence reads, and bioinformatic manipulation of the sequence reads to carry out the subject methods” (Para. 77). “sequencing of nucleic acid molecules to generate a plurality of sequence reads, and bioinformatic manipulation of the sequence reads” reads on quantifying copy number alterations. Jung teaches a method wherein “the sequencing library prepared using the methods of the present invention can be sequenced to obtain a plurality of sequence reads, and the sequence reads analyzed to detect the presence or absence of cancer, screen for cancer, determine cancer stage or status, monitor cancer progression, and/or determine a cancer classification…In still other embodiments, the sequence reads can be analyzed to monitor disease progression, monitor therapy, and/or monitor cancer growth” (Para. 10). Thus, Jung teaches a method further comprising determining a status of the subject based on CNAs present in the selected subject nucleic acid fragments; wherein the status of the subject is a presence or absence of a cancer; wherein the status of the subject is a progression of a cancer; wherein the status of the subject is a remission of a cancer.
Regarding claim 19, Jung teaches a method wherein “preparing a sequence library that is enriched for shorter nucleic acid fragments (e.g., nucleic acid fragments less than about 150 bp in length).” (Para. 4). Jung teaches a method wherein “dsDNA fragments below a size threshold (e.g., less than about 150 bp, less than about 140 bp, less than about 120 bp, or less than about 100 bp in length)” (Para. 5). Less than 143 bp is comprised within less than about 150 bp, less than about 140 bp, less than about 120 bp, or less than about 100 bp in length. Thus, Jung teaches a method wherein the subject cell free nucleic acid fragments are less than 143 bp.
Regarding claim 20, Jung teaches a method wherein “the test sample may be a biological test sample selected from the group consisting of blood, plasma, serum, urine, saliva, fecal samples, and any combination thereof.” (Para. 39). “any combination thereof” reads on multiplexed sample. Jung teaches a method wherein “the test sample or biological test sample comprises a plurality of cell-free nucleic acids (e.g., cell-free DNA (cfDNA) and/or cell-free RNA (cfRNA)) fragments. In other embodiments, the test sample or biological test sample comprises a plurality of cell-free nucleic acids (e.g., cell-free DNA and RNA) fragments originating from healthy cells and from cancer cells” (Para. 39). “cell-free DNA (cfDNA) and/or cell-free RNA (cfRNA)) fragments” reads on multiplexed sample). “cell-free DNA and RNA) fragments originating from healthy cells and from cancer cells” reads on multiplexed sample. Thus, Jung teaches a method wherein the library comprises multiplexed samples.
Therefore, the invention as recited in claims 1-5, 9-13 and 19-20 are prima facie obvious over the prior art Jung et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to analyze cfNAs from a subject according to the limitations of the instant application claims 1-5, 9-13 and 19-20 based on Jung et al. (Patent App. Pub. No. US 20190093102 A1).
Claims 1-5, 8, 10 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Jung et al. (“Jung”; Patent App. Pub. US 20190093102 A1, Mar. 28, 2019) in view of Sun et al. (“Sun”; Patent App. Pub. (“Sun”; Patent App. Pub. US 20180032666 A1, Feb. 1, 2018).
The teachings of Jung are documented above in the rejection of claims 1-2, 6-7 and 16 under 35 U.S.C. 102 (a)(1)/(a)(2) and claims 1-5, 9-13 and 19-20 under 35 U.S.C. 103. Claims 8 and 14-15 depend on claim 1. Claim 14 depends on claim 10, which depends on claim 5. Claims 15 depends on claim 5. Claim 5 depend on claim 4, which depends on claim 3, which depends on claim 2, which depends on claim 1. Jung does not explicitly teach the limitations of claims 8 and 14-15.
Sun discloses “Technology provided herein relates in part to methods, processes, machines and apparatuses for non-invasive assessment of genomic nucleic acid instability and genomic nucleic acid stability.” (Abstract)
Regarding claim 8, Sun teaches a method wherein “cell-free fetal DNA (CFF-DNA) can be detected in the maternal bloodstream and used for various noninvasive prenatal diagnostics” (Para. 5). Sun teaches a method wherein “analysis of fetal DNA” (Para. 137). Thus, Jung and Sun teach a method wherein the circulating cell-free nucleic acid fragments comprise circulating fetal cell free DNA (fetal cfDNA).
Regarding claim 14, Sun teaches a method wherein “a pregnant subject bearing a fetus having a chromosome aneuploidy” (Para. 134). Thus, Jung and Sun teach a method wherein the status of the subject is pregnant with a fetus exhibiting an aneuploidy.
Regarding claim 15, Sun teaches a method wherein “Genomic nucleic acid from a sample having genomic instability generally includes two (2) or more copy number alterations (CNAs) … Classifying genomic instability sometimes includes determining for a nucleic acid sample from a subject a genomic instability score, measure, assessment or value (e.g., a GIN or distance described herein)” (Para. 38-39). Sun teaches a method wherein “GIN values were expected to be indicative of increasing disruption to normal genomic profiles” (Para. 421). Thus, Jung and Sun teach a method wherein the level of CNAs are quantified using a genomic instability number (GIN).
Jung and Sun are both considered to be analogous to the claimed invention because they are in the same field of measuring or testing processes of cell free nucleic acids used in the analysis of diseases. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of analyzing circulating cell-free nucleic acids from a subject as taught by Jung to incorporate the method wherein the cfDNA is fetal; wherein the status of the subject is pregnant with a fetus exhibiting an aneuploidy; and CNAs are quantified using GIN as taught by Sun and provide a method for analyzing the sequence and levels cfDNAs and determining the status of various subjects. Doing so would allow for a non-invasive assessment of genomic nucleic acid instability and genomic nucleic acid stability.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/317573 (filed May 15, 2023) in view of Jung et al. (“Jung”; Patent App. Pub. US 20190093102 A1, Mar. 28, 2019). Although the claims at issue are not identical, they are not patentably distinct from each other because the instantly claimed invention is made obvious over the claims of copending Application No. 18/317573.
Claim 1 filed on 09/21/203 of copending Application No. 18/317573 is drawn to:
A computer-implemented method, comprising: obtaining nucleic acid from a biological sample that was obtained from a subject; sequencing the nucleic acid from the biological sample or derivatives thereof to obtain thousands to millions of sequence reads; and determining a presence or absence of a copy number variation based on an analysis of the thousands to millions of sequence reads, wherein the analysis comprises determining a plurality of sequence read quantifications corresponding to a plurality of segments.
The teachings of Jung are documented above in the rejection of claims 1-2, 6-7 and 16 under 35 U.S.C. 102 (a)(1)/(a)(2) and claims 1-5, 9-13 and 19-20 under 35 U.S.C. 103.
Therefore, the invention as recited in claim 1 is prima facie obvious over the copending Application No. 18/317573 in view of Jung. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to analyze circulating cfNAs from a s subject according to the limitations recited in claims 1-5 of the instant application based on claim 1 of copending Application No. 18/317573 in view of Jung et al. (“Jung”; Patent App. Pub. US 20190093102 A1).
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682