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 .
Status of the Application
Applicant’s election without traverse of Group I ( claims 1-15) in the reply filed on 03 July 2025 is acknowledged.
Claims 16-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03 July 2025.
Claims 1-15 are under examination.
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 14 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 14 recites the limitation " the method of claim 1, wherein the blocking sequence comprises sequences designed to be reverse complementary to the linker and/or the tag sequence" in the claim.
There is insufficient antecedent basis for the underlined limitation in claim 14 because claim 1 does not recite a tag sequence.
Claim Rejections - 35 USC § 102
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 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.
(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.
Gnerre et al.
Claim(s) 1-13 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gnerre et al. (US20160319345; filed 15 April 2016).
Prior to the effective filing date of the claimed invention, Gnerre et al. teach methods are known comprising attaching Y- shaped adaptors to target DNA fragments, wherein the adaptors comprise a unique molecular identifier(UMI), i.e. index; and amplifying these ligation products prior to sequencing. Furthermore, Gnerre et al. teach adapters comprising read primer sequences (e.g. Entire Gnerre reference and especially para 0022-0024, pg. 2-3; para 0033, pg. 4; Fig. 3A and 3B). Furthermore, Gnerre et al. teach primers for amplification, i.e. hybridization probes(e.g. Entire Gnerre reference and especially para 0096,pg. 8; para 0116, pg. 10-11). Furthermore, Gnerre et al. teach full length, longer and shortened adapters, wherein the adapters are designed to include more or fewer UMI than the full length adapter(e.g. Entire Gnerre reference and especially para 0149-152,pg. 14; Fig. 2C and 2D).
Furthermore, Gnerre et al. teach samples include circulating tumor DNA; fetal cell free DNA; cell samples, and biological fluids samples include, but are not limited to blood, plasma, serum, sweat, tears, sputum, urine(e.g. Entire Gnerre reference and especially para 0185-0188,para 0191, pg. 18-19).
Furthermore, Gnerre et al. teach fragmentation of target nucleic acid by enzymatic means such as restriction digestion or mechanical means, such as shearing. Furthermore, Gnerre et al. teach end repair and A-tailing by single or multiple steps. Furthermore, Gnerre et al. teach fragments from 50-500bp in length (e.g. Entire Gnerre reference and especially para 0192, pg. 19; para 0198-0203, pg. 20). Furthermore, Gnerre et al. teach droplet-based amplification is known in the art (e.g. Entire Gnerre reference and especially ...fragments attached to the beads are PCR amplified within droplets of an oil-water emulsion as in para 0218, pg. 22).
Therefore, Gnerre et al. teach the limitations: method of constructing a capture library comprising the steps of: (1) obtaining fragmented DNAs; (2) connecting the fragmented DNAs with a Y-shaped linker to obtain a pre-library; (3) hybridizing the pre-library and a hybridization probe in the absence of a blocking sequence to obtain a hybridization product; (4) performing a PCR amplification on the hybrid product to obtain the capture library as recited in claim 1.
Furthermore, as Gnerre et al. teach samples include circulating tumor DNA; fetal cell free DNA; cell samples, and biological fluids samples include, but are not limited to blood, plasma, serum, sweat, tears, sputum, urine (e.g. Entire Gnerre reference and especially para 0185-0188,para 0191, pg. 18-19), Gnerre et al. teach claims 2,3 and 5.
Furthermore, as Gnerre et al. teach fragmentation of target nucleic acid by enzymatic means, such as restriction digestion, or mechanical means, such as shearing, followed by end repair and A-tailing by single or multiple steps (e.g. Entire Gnerre reference and especially para 0192, pg. 19; para 0198-0203, pg. 20), Gnerre et al. teach claims 2, 4 and 8-10.
Furthermore, as Gnerre et al. teach fragments from 50-500bp in length (e.g. Entire Gnerre reference and especially para 0192, pg. 19; para 0198-0203, pg. 20), Gnerre et al. teach claims 6 and 7.
Furthermore, Gnerre et al. teach full length, longer and shortened adapters, wherein the adaptors comprise a unique molecular identifier(UMI), i.e. index, wherein the adapters are designed to include more or fewer UMI than the full length adapter; and amplifying these ligation products prior to sequencing. Furthermore, Gnerre et al. teach adapters comprising read primer sequences (e.g. Entire Gnerre reference and especially para 0022-0024, pg. 2-3; para 0033, pg. 4; Fig. 3A and 3B; para 0149-152,pg. 14; Fig. 2C and 2D).
Therefore, Gnerre et al. teach claims 11-13.
Furthermore, as Gnerre et al. teach droplet-based amplification is known in the art (e.g. Entire Gnerre reference and especially ...fragments attached to the beads are PCR amplified within droplets of an oil-water emulsion as in para 0218, pg. 22), Gnerre et al. teach claim 15.
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.
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.
Gnerre et al. and Schmitt et al.
Claim(s) 1-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Gnerre et al. (US20160319345; filed 15 April 2016) in view of Schmitt et al. (WO2013142389).
Prior to the effective filing date of the claimed invention, Gnerre et al. teach methods are known comprising attaching Y- shaped adaptors to target DNA fragments, wherein the adaptors comprise a unique molecular identifier(UMI), i.e. index; and amplifying these ligation products prior to sequencing. Furthermore, Gnerre et al. teach adapters comprising read primer sequences (e.g. Entire Gnerre reference and especially para 0022-0024, pg. 2-3; para 0033, pg. 4; Fig. 3A and 3B). Furthermore, Gnerre et al. teach primers for amplification, i.e. hybridization probes(e.g. Entire Gnerre reference and especially para 0096,pg. 8; para 0116, pg. 10-11). Furthermore, Gnerre et al. teach full length, longer and shortened adapters, wherein the adapters are designed to include more or fewer UMI than the full length adapter(e.g. Entire Gnerre reference and especially para 0149-152,pg. 14; Fig. 2C and 2D).
Furthermore, Gnerre et al. teach samples include circulating tumor DNA; fetal cell free DNA; cell samples, and biological fluids samples include, but are not limited to blood, plasma, serum, sweat, tears, sputum, urine(e.g. Entire Gnerre reference and especially para 0185-0188,para 0191, pg. 18-19).
Furthermore, Gnerre et al. teach fragmentation of target nucleic acid by enzymatic means such as restriction digestion or mechanical means, such as shearing. Furthermore, Gnerre et al. teach end repair and A-tailing by single or multiple steps. Furthermore, Gnerre et al. teach fragments from 50-500bp in length (e.g. Entire Gnerre reference and especially para 0192, pg. 19; para 0198-0203, pg. 20). Furthermore, Gnerre et al. teach droplet-based amplification is known in the art (e.g. Entire Gnerre reference and especially ...fragments attached to the beads are PCR amplified within droplets of an oil-water emulsion as in para 0218, pg. 22).
Regarding the limitation: (3) hybridizing the pre-library and a hybridization probe in the absence of a blocking sequence to obtain a hybridization product as recited in claim 1:
As noted above, Gnerre et al. teach amplifying ligation products prior to sequencing, wherein primers are used for amplification.
Furthermore, Schmitt et al. teach methods are known in the art comprising ligating y-shaped adaptor sequences comprising single molecule identifier(SMI) to a double stranded target molecule; amplifying the adaptor-ligated target molecules by PCR using primers, i.e. hybridization probes, and sequencing the resultant amplicons (e.g. para 0009-0014, p. 3-6; Figure 1 illustrates an overview of Duplex Consensus Sequencing. Sheared double-stranded DNA that has been end-repaired and T-tailed is combined with A-tailed SMI adaptors and ligated according to one embodiment. Because every adaptor contains a unique, double-stranded, complementary n-mer random tag on each end (n-mer = 12 bp according to one embodiment), every DNA fragment becomes labeled with two distinct SMI sequences (arbitrarily designated a and 13 in the single capture event shown). After size-selecting for appropriate length fragments, PCR amplification with primers containing lllumina flow-cell-compatible tails is carried out to generate families of PCR duplicates... as in para 0012; para 0074, pg. 23).
Therefore, as both Gnerre et al. and Schmitt et al. teach methods comprising providing adapter-ligated target nucleic acids for amplification, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the teachings of Gnerre et al. to include using primers to amplify the y-shaped adaptor-ligated target nucleic acid library as taught by Schmitt et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for constructing a library, as required by the claimed invention.
Therefore, the combined teachings of Gnerre et al. and Schmitt et al. teach the limitations: method of constructing a capture library comprising the steps of: (1) obtaining fragmented DNAs; (2) connecting the fragmented DNAs with a Y-shaped linker to obtain a pre-library; (3) hybridizing the pre-library and a hybridization probe in the absence of a blocking sequence to obtain a hybridization product; (4) performing a PCR amplification on the hybrid product to obtain the capture library as recited in claim 1.
Furthermore, as Gnerre et al. teach samples include circulating tumor DNA; fetal cell free DNA; cell samples, and biological fluids samples include, but are not limited to blood, plasma, serum, sweat, tears, sputum, urine (e.g. Entire Gnerre reference and especially para 0185-0188,para 0191, pg. 18-19), the combined teachings of Gnerre et al. and Schmitt et al. teach claims 2,3 and 5.
Furthermore, as Gnerre et al. teach fragmentation of target nucleic acid by enzymatic means, such as restriction digestion, or mechanical means, such as shearing, followed by end repair and A-tailing by single or multiple steps (e.g. Entire Gnerre reference and especially para 0192, pg. 19; para 0198-0203, pg. 20), the combined teachings of Gnerre et al. and Schmitt et al. teach claims 2, 4 and 8-10.
Furthermore, as Gnerre et al. teach fragments from 50-500bp in length (e.g. Entire Gnerre reference and especially para 0192, pg. 19; para 0198-0203, pg. 20), the combined teachings of Gnerre et al. and Schmitt et al. teach claims 6 and 7.
Furthermore, Gnerre et al. teach full length, longer and shortened adapters, wherein the adaptors comprise a unique molecular identifier(UMI), i.e. index, wherein the adapters are designed to include more or fewer UMI than the full length adapter; and amplifying these ligation products prior to sequencing. Furthermore, Gnerre et al. teach adapters comprising read primer sequences (e.g. Entire Gnerre reference and especially para 0022-0024, pg. 2-3; para 0033, pg. 4; Fig. 3A and 3B; para 0149-152,pg. 14; Fig. 2C and 2D).
Therefore, the combined teachings of Gnerre et al. and Schmitt et al. teach claims 11-13.
Furthermore, as Gnerre et al. teach droplet-based amplification is known in the art (e.g. Entire Gnerre reference and especially ...fragments attached to the beads are PCR amplified within droplets of an oil-water emulsion as in para 0218, pg. 22), the combined teachings of Gnerre et al. and Schmitt et al. teach claim 15.
Gnerre et al. and Behlke et al.
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Gnerre et al. (US20160319345; filed 15 April 2016) in view of Behlke et al.(US20140031240).
The teachings of Gnerre et al. as applied in the rejection above are incorporated in this rejection.
As discussed above, Gnerre et al. teach methods are known comprising attaching Y- shaped adaptors to target DNA fragments, wherein the adaptors comprise a unique molecular identifier(UMI), i.e. index; and amplifying these ligation products using primers, i.e. hybridization probes, prior to sequencing.
However, Gnerre et al. do not expressly teach claim 14.
Prior to the effective filing date of the claimed invention, Behlke et al. teach also methods comprising providing adapter ligated target nucleic acids for sequencing. Furthermore, Behlke et al. teach blocking oligonucleotides are known in the art, wherein these “blockers” have complementarity to adaptor attached to target nucleic acid, wherein the adaptors also have barcodes ( e.g. Entire Behlke e reference and especially ... In a second respect, the method includes a blocker having substantial sequence complementarity to the at least one identical terminal adaptor sequence of the library population of template nucleic acids. In a third respect, the method includes as the at least one identical terminal adaptor sequence a barcode domain. In a fourth respect, the method provides a blocker having substantial sequence complementarity to the at least one identical terminal adaptor sequence... as in para 0017, pg.3 ; ... For oligonucleotide blockers having the identical sequence to the terminal adaptors of NGS templates, inclusion of Tm-enhanced oligonucleotides as blockers in the hybrid capture method reduces the level of unwanted contaminating sequences resulting from adaptor-mediated hybrid formation among NGS templates (the "daisy-chain effect"), thereby increasing the overall efficiency of the enrichment process for the desired NGS templates... as in para 0273, pg. 17-18).
Therefore, as both Gnerre et al. and Behlke et al. teach methods comprising providing adapter ligated target nucleic acids for sequencing, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the teachings of Gnerre et al. to include blocking oligonucleotides that hybridize to the adaptor, i.e. linker, as taught by Behlke et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for constructing a library, as required by the claimed invention. Furthermore, Behlke et al. teach the merits of using blocking oligonucleotides ( e.g. ... inclusion of Tm-enhanced oligonucleotides as blockers in the hybrid capture method reduces the level of unwanted contaminating sequences resulting from adaptor-mediated hybrid formation among NGS templates (the "daisy-chain effect"), thereby increasing the overall efficiency of the enrichment process for the desired NGS templates... as in para 0273, pg. 17-18).
Therefore, the combined teachings of Gnerre et al. and Behlke et al. render obvious claim 14.
Gnerre et al., Schmitt et al. and Behlke et al.
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Gnerre et al. and Schmitt et al., as applied to claims 1-13 and 15 above, and further in view of Behlke et al.(US20140031240).
The combined teachings of Gnerre et al. and Schmitt et al. as applied in the rejection above are incorporated in this rejection.
As discussed above, the combined teachings of Gnerre et al. and Schmitt et al. teach methods are known comprising attaching Y- shaped adaptors to target DNA fragments, wherein the adaptors comprise a unique molecular identifier(UMI), i.e. index; and amplifying these ligation products using primers, i.e. hybridization probes, prior to sequencing.
However, the combined teachings of Gnerre et al. and Schmitt et al. do not expressly teach claim 14.
Prior to the effective filing date of the claimed invention, Behlke et al. teach also methods comprising providing adapter ligated target nucleic acids for sequencing. Furthermore, Behlke et al. teach blocking oligonucleotides are known in the art, wherein these “blockers” have complementarity to adaptors attached to target nucleic acid, wherein the adaptors also have barcodes ( e.g. Entire Behlke e reference and especially ... In a second respect, the method includes a blocker having substantial sequence complementarity to the at least one identical terminal adaptor sequence of the library population of template nucleic acids. In a third respect, the method includes as the at least one identical terminal adaptor sequence a barcode domain. In a fourth respect, the method provides a blocker having substantial sequence complementarity to the at least one identical terminal adaptor sequence... as in para 0017, pg.3 ; ... For oligonucleotide blockers having the identical sequence to the terminal adaptors of NGS templates, inclusion of Tm-enhanced oligonucleotides as blockers in the hybrid capture method reduces the level of unwanted contaminating sequences resulting from adaptor-mediated hybrid formation among NGS templates (the "daisy-chain effect"), thereby increasing the overall efficiency of the enrichment process for the desired NGS templates... as in para 0273, pg. 17-18).
Therefore, as Gnerre et al., Schmitt et al. and Behlke et al. all teach methods comprising providing adapter-ligated target nucleic acids for sequencing, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the teachings of Gnerre et al. and Schmitt et al. to include blocking oligonucleotides that hybridize to the adaptor, i.e. linker, as taught by Behlke et al. as a person of ordinary skill in the art would recognize that these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a method for constructing a library, as required by the claimed invention. Furthermore, Behlke et al. teach the merits of using blocking oligonucleotides ( e.g. ... inclusion of Tm-enhanced oligonucleotides as blockers in the hybrid capture method reduces the level of unwanted contaminating sequences resulting from adaptor-mediated hybrid formation among NGS templates (the "daisy-chain effect"), thereby increasing the overall efficiency of the enrichment process for the desired NGS templates... as in para 0273, pg. 17-18).
Therefore, the combined teachings of Gnerre et al., Schmitt et al. and Behlke et al. render obvious claim 14.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHANA S KAUP whose telephone number is (571)272-6897. The examiner can normally be reached on M-F 7am-7pm EST.
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.
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/SAHANA S KAUP/ Primary Examiner, Art Unit 1684