DETAILED ACTION
Applicant’s response filed 05/08/2026 has been fully considered. The following rejections and/or objections are either reiterated or newly applied.
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 .
Claim Status
Claims 1-6 are currently pending and are herein under examination.
Claims 1-6 are rejected.
Priority
The instant application claims domestic benefit as a continuation of U.S. Application No. 14/684,242 filed 04/10/2015. The claim to domestic benefit is acknowledged. As such, the effective filing date for claims 1-6 is 04/10/2015.
Claim Rejections - 35 USC § 103
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.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Gilbert et al. (“Gilbert”; US 2015/0203907 A1; effective filing date 16 Jan. 2015; previously cited on PTO892 mailed 05/07/2025) in view of Baldwin et al. (“Baldwin”; Genetics in Medicine 10, no. 6 (2008): 415-429; previously cited on PTO892 mailed 05/07/2025).
This rejection is maintained from the previous Office Action.
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 1:
enriching a genomic sample using baits for a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject, wherein the baits for the genomic backbone regions are located approximately 50 kb or more apart, and
Gilbert discloses “a capture library for target enrichment of sequences of interest from a genome DNA sample. The capture library comprises a plurality of capture oligos tiling a plurality of capture regions evenly-spaced along a genome” (enriching a genomic sample using baits) (abstract). Gilbert teaches “This capture library can be used to measure … copy number variation in human pediatric acute lymphocytic leukemia samples, and is also broadly applicable to any CNV application” (plurality of genomic mutation regions) (abstract) [6] [94] [111] (Figure 2).
However, Gilbert does not enrich genomic backbone regions with baits located approximately 50kb or more apart.
Baldwin discloses an array comparative genomic hybridization (aCGH) allowing enhanced detection of clinically relevant genomic imbalances using targeted and whole genome coverage (abstract). For genome-wide coverage, 41,023 probes were established across euchromatic regions of the genome to provide backbone region coverage (pg. 417, col. 1, para. 2-3) (pg. 415, col. 2, para. 4). For the backbone regions, one probe is placed every ~75 kb, designated as vertical black lines in Figure 1 (a plurality of backbone regions located approximately 50 kb or more apart).
Baldwin also teaches, in addition to probes covering genomic backbone regions, probes for targeted coverage “to create additional high density coverage of oligonucleotides in the known clinically relevant regions including the telomeres, centromeres, common microdeletion and microduplication syndromes and selected Mendelian disorders” (pg. 417, col. 1, para. 5) (Complementary Table 2). Figure 1 shows the 75 kb spaced genomic backbone region probes along with the higher density clinically relevant targeted region probes.
the baits for the genomic mutation regions of interest are located 5-10 kb apart;
Gilbert recites “Each two adjacent capture regions of the plurality capture regions are separated by a spacing of about 6 to about 14 kilobases in length” (abstract). MPEP 2144.05.I recites that “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.” In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). Therefore, the range of Gilbert renders prima facie obvious the range of the instant claims because they overlap.
obtaining a plurality of sequence reads from the enriched genomic sample by next-generation sequencing, and the plurality includes sequence reads for the plurality of genomic backbone regions and sequence reads for the plurality of genomic mutation regions of interest.
Gilbert performs target enrichment for sample sequencing libraries comprising total genomic DNA fraction by using the capture library [133] (Figure 4). Next generation sequencing (NGS) is performed after target enrichment to generate sequence reads (obtaining a plurality of sequence reads from the enriched genomic sample by NGS) [61] [137-138]. This includes the capture regions (sequence reads for the plurality of genomic mutation regions of interest) (Figure 2).
However, Gilbert does not teach using NGS to produce sequence reads of genomic backbone regions obtained by probes spaced 50 kb or more apart.
Baldwin discloses enriching genomic backbone regions using probes spaced about every 75 kb (abstract). The combination of Gilbert and Baldwin teach sequencing both the targeted regions and the backbone regions to produce sequence reads.
It would have been prima facie obvious to one of ordinary skill to have modified probe/oligo target enrichment and sequencing regions of interest to detect CNVs in Gilbert by including probes/oligos that enrich genomic backbone regions spaced about every 75 kb to detect CNVs as taught by Baldwin. The motivation for doing so is taught by Baldwin who recites “the genome-wide backbone coverage identified an additional 10 cases (4.7%) of clinically significant abnormalities that would not be detected by current targeted array designs” (pg. 425, col. 2, para. 3). Thus, using probes for both targeted regions and genomic backbone regions would increase a number of CNVs detected, which is advantageous for detecting genomic alterations in disease.
Gilbert teaches further motivation to incorporate genomic backbone region probes by reciting “One concern in selecting an aCGH platform for gene discovery is usually the minimal size of the genomic region having altered copy number that can be reliably detected. This concern also exists in design of capture probes for sequence capture. In design of capture library, both upper and lower resolution limitations should be calculated. Resolution means capture spacing” [120]. Because Baldwin uses both upper and lower limits (i.e. probes for genomic backbone regions and clinically relevant regions) in an aCGH, it would have been prima facie obvious to replicate the probes and probe spacing of Baldwin’s aCGH in Gilbert in order to address the concern of upper and lower resolution limits.
There would have been a reasonable expectation of success to use probes for genomic backbone regions and targeted regions because Gilbert teaches that “Different capture spacing may be defined according to different specific applications such as CGH, pre-natal diagnosis, etc. For example, the minimal size of genomic region having altered copy number may be about 6-12 kb, which is generally provided by microarray platform” [120]. Although mentioning CGH instead of aCGH in the previous quote, one of ordinary skill in the art would have recognized that the capture library of Gilbert could also be defined according to an aCGH application. This is because aCGH uses capture probes that have probe spacing. The probe spacing of Gilbert could be designed after the probe spacing used in aCGH.
Furthermore, there also would have been a reasonable expectation of success because Gilbert recites “the spacing, i.e., distance, between two adjacent capture regions may be various” [123]. This indicates that probe spacing is not limited to a range of 6-14 kb. Thus, a genomic backbone probe spacing of about 75 kb could be used.
Claim 3:
Gilbert teaches that the capture regions are associated with copy number variation used to detect human pediatric acute lymphocytic leukemia samples (abstract).
Claim 4:
Gilbert teaches the capture oligos target human genome DNA sequences [130].
Claim 6:
Gilbert discloses using NGS platforms such as sequencing by synthesis and sequencing by ligation [61].
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Gilbert et al. (“Gilbert”; US 2015/0203907 A1; effective filing date 16 Jan. 2015; previously cited on PTO892 mailed 05/07/2025) in view of Baldwin et al. (“Baldwin”; Genetics in Medicine 10, no. 6 (2008): 415-429; previously cited on PTO892 mailed 05/07/2025), as applied above to claim 1, and in further view of Ashutosh et al. (US 2015/0073724 A1, published; ref. 5 on IDS filed 01/07/2021; previously cited) and McCarroll et al. (“McCarroll”; Nature genetics 40, no. 10 (2008): 1166-1174; previously cited on PTO892 mailed 05/07/2025).
This rejection is maintained from the previous Office Action.
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
The limitations for claim 1 have been taught in the rejection above by Gilbert in view of Baldwin.
Claim 2:
wherein the genomic mutation regions of interest comprise single nucleotide polymorphic sites.
Gilbert detects CNVs (abstract). Baldwin detects common microdeletion/microduplication and Mendelian disorders (Figure 1; Table 1).
However, Gilbert and Baldwin do not target regions that contain SNPs.
Ashutosh discloses a method for identifying a sequence variant in a sample that has been enriched for a particular genomic region [6]. Ashutosh states that the sequence variant can refer to a single nucleotide polymorphism (SNP) [24].
Claim 5:
wherein the enriched genomic sample is obtained using baits designed to target locations in the genome based on known single nucleotide polymorphism (SNP) allelic frequency and estimated properties of the genomic mutation regions of interest in a reference genome.
Gilbert enriches genomic DNA using target capture probes/oligos (abstract).
However, Gilbert and Baldwin do not use probes/oligos to target and enrich regions based on known SNP allelic frequency and estimated properties of genomic mutation regions in a reference genome.
Ashutosh states that an enriched genomic region may be enriched by using hybridization to an oligonucleotide probe [39]. These enriched genomic regions may contain a mutation associated with a cancer [38]. The mutations may be SNPs [24] and have a frequency of at least 1% in a population [16]. The mutations are compared against a reference sequence from a database of known cancer-associated SNPs. One of the SNPs may be from the KRAS gene, which has various mutations that have been catalogued and found at high rates in leukemias, colorectal cancer and lung cancer (designed to target locations in the genome based on known SNP allelic frequency and estimated properties of the genomic regions of interest in the reference genome) [54].
Prima facie case for obviousness:
It would have been prima facie obvious to one of ordinary skill in the art to have modified the method of Gilbert and Baldwin to include capture oligos/probes that target genomic regions based on known SNP allelic frequencies and estimated properties in a reference genome as taught by Ashutosh. This is because Ashutosh states that SNPs can be used to detect, characterize, classify, differentiate, diagnose, or prognose a condition such as leukemia [54] [57].
One of ordinary skill in the art would have had a reasonable expectation of success because these references rely on oligos/probes to target and enrich regions of interest. The combination would have resulted in oligos/probes designed to target regions with SNPs and CNVs.
There also would have been a reasonable expectation of success to generate capture oligos/probes that target both SNPs and CNVs because McCarroll discloses a hybrid genotyping array that simultaneously measures SNPs and CNVs (abstract). Gilbert discloses using hybrid capture microarrays for sequence capture [113-155]. Thus, one of ordinary skill would have recognized that the hybrid capture method of Gilbert could contain oligos/probes that simultaneously capture SNPs and CNVs.
Response to Arguments under 35 USC 103
Applicant's arguments filed 05/08/2026 have been fully considered but they are not persuasive.
Applicant argues that Gilbert discloses even spacing of probes but does not disclose two sets of probes with different spacing schemes, one for genomic backbone regions and one for genomic mutation regions of interest, nor motivation to vary spacing according to region class or function (pg. 4, para. 3 – pg. 5, para. 1). Applicant’s argument is not persuasive because:
Applicant argues against the references individually. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Gilbert in view of Baldwin teach the claimed sets of baits.
Gilbert teaches probes spaced 6-14 kb to capture CNV (baits for the genomic mutation regions of interest are located 5-10 kb apart) (abstract) [6] [94] [111] (FIG. 2). Baldwin discloses probes for genome-wide coverage spaced every ~75 kb across euchromatic regions of a genome to provide backbone region coverage (the baits for the genomic backbone regions are located approximately 50 kb or more apart) (pg. 417, col. 1, para. 2-3) (pg. 415, col. 2, para. 4) (Figure 1). Gilbert in view of Baldwin teach the claimed dual-density bait configuration. The motivation to combine is provided by Baldwin, as discussed in the rejection above.
Applicant argues that Gilbert does not teach that spacing schemes optimized for aCGH should be replicated in sequence-based capture libraries, and that there is no teaching/suggestion for the claimed baits (pg. 5, 1st full para.). Applicant appears to argue that, even though Baldwin discloses targeted and genomic backbone region probes, Baldwin is directed to aCGH and not sequencing (pg. 5, 2nd full para.). Applicant argues that Gilbert in view of Baldwin does not disclose baits for use in sequencing (pg. 5, last para. – pg. 6, para. 1). Applicant’s argument is not persuasive because:
Gilbert teaches target-specific next generation sequencing (NGS) [133]. One type of targeted NGS includes hybrid capture (NGS), which allows selective capture of genomic regions prior to sequencing using microarrays [113] [115]. aCGh is a hybrid capture technique. One of ordinary skill would have recognized that the capture spacing of Gilbert for sequencing could be designed in view of an aCGH, which is a hybrid capture technique. The motivation to combine is provided by Baldwin, as discussed in the paragraph below.
Baldwin recites “the genome-wide backbone coverage identified an additional 10 cases (4.7%) of clinically significant abnormalities that would not be detected by current targeted array designs … Therefore, it may be more efficient and cost-effective to have both targeted and genome-wide coverage in a single assay” (pg. 425, col. 2, para. 3). Thus, one of skill in the art would have been motivated to modify the capture library of Gilbert for detecting target regions (i.e., probes spaced about every 6-14 kb) by including probes for genomic backbone regions as taught by Baldwin because it would detect additional genomic abnormalities that may be overlooked when only using targeted probes. This motivation is in line with the teachings of Gilbert for detecting CNV in pediatric acute lymphocytic leukemia, and Gilbert states that the method is applicable to any CNV application (abstract).
Moreover, although the current rejection under 103 does not rely upon sequencing the probes of an aCGH directly from a microarray, Mamanova et al. (“Mamanova”; Nature methods 7, no. 2 (2010): 111-118; previously cited on PTO892 mailed 02/13/2026) teaches that hybrid capture techniques can be used in sequencing. Figure 1 shows hybrid capture techniques, such as array capture, which are used for target enrichment and subsequent sequencing (Figure 1C caption). Mamanova teaches that hybrid capture arrays have been adapted for use in NGS (pg. 115, col. 1, para. 2-3). Figures 3b and 4 show sequencing directly from hybrid capture arrays. Mamanova recites that an aCGH was adapted to be used in NGS (pg. 115, col. 1, para. 2) (Table 1).
When the above is taken together, one of ordinary skill in the art would recognize that an aCGH probe spacing scheme can be implemented in a sequencing experiment, such as Gilbert, that uses probes. It also shows that the aCGH of Baldwin can be directly sequenced by Gilbert, as taught by Mamanova.
Applicant argues that expanding Gilbert’s probe spacing of 6-14 kb to Baldwin’s probe spacing of ~75 kb would degrade CNV resolution, and thus one of skill would not expect success (pg. 6, para. 2). Applicant’s argument is not persuasive because:
Gilbert in view of Baldwin generates two separate probe sets, one for targeted regions (6-14 kb in Gilbert) and one for genomic backbone regions (~75 kb in Baldwin), rather than converting the 6-14 kb probes into ~75 kb probes. Thus, the 6-14k kb spacing is maintained and the resolution is not degraded. One of ordinary skill would have a reasonable expectation of success to sequence a capture library generated from two sets of probes with different spacing because the captured sequences are isolated then sequenced.
Applicant’s argument regarding degradation of capture performance is not persuasive because Applicant argument does not replace evidence where evidence is needed (pg. 6, para. 1). MPEP 2145.I recites “[a]n assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Applicant’s argument regarding claims 2 and 5 are not persuasive for the same reasons discussed above regarding claim 1 (pg. 6, last two para.).
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Noah A. Auger whose telephone number is (703)756-4518. The examiner can normally be reached M-F 7:30-4:30 EST.
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, Karlheinz Skowronek can be reached at (571) 272-9047. 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.
/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
Prosecution Insights