DETAILED ACTION
Status of the Application
Claims 1-20 are pending
Claims 1-20 are under examination
The following Office Action is in response to Applicant's communication dated 09/23/2023.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
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.
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.
Brookman-Amissah et al. and Roche
Claim(s) 1-5 and 8-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brookman-Amissah et al. (GEN, Vol. 34, No. 6, 2014) in view of Roche (Human Cot-1 DNA protocol (2021)).
Regarding claim 1, Brookman-Amissah discloses a method of processing genetic material for bioinformatic analysis, the method comprising: receiving a library of genetic material sourced from a sample; (e.g. “prepared sequencing library” [page 3])
adding human Cot-1 DNA to the library to the genetic material to produce an enrichment pool; enriching the genetic material in the enrichment pool to produce enriched genetic material; (e.g. incubate library fragments and Cot-1 DNA [Fig. 2, page 2]).
sequencing the enriched genetic material to produce sequencing data. (e.g. Sequencing is done using Illumina MiSeq®[page 4]).
However, Brookman-Amissah does not disclose the specific ratio of human Cot-1 DNA to genetic material (e.g. between 100:1 and 20:1 of the human Cot-1 DNA to the genetic material).
Roche Human Cot-1 DNA protocol teaches the use of human Cot-1 DNA as a blocking agent to suppress hybridization of repetitive DNA sequences during hybridization-based assays and further teaches the amount and concentration of Cot-1 DNA used depend on amount of target DNA. Roche teaches starting with a 50- to 100-fold excess of COT Human DNA relative to nucleic acid [page 4] and also teaches mixing 100- to 200-fold excess of COT Human DNA relative to nucleic acid [page 5].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply the Cot-DNA amounts and ratios ratio taught by Roche to the sequencing library enrichment method of Brookman-Amissah because both references address the same technical problem, suppression of nonspecific hybridization of repetitive DNA during hybrid-capture and both employ human Cot-1 DNA for the same blocking function. Although Roche does not expressly disclose the specific ratio of human Cot-1 DNA to genetic material recited in claims (e.g. between 20:1 and 100:1), Roche teaches using human Cot-1 DNA in a broad excess range relative to nucleic acid, including 50- to 100- and 100- to 200-fold excess. As set forth in MPEP 2144.05, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. Selecting a particular ratio within or near these disclosed ranges would have been a matter of routine optimization. Hence, it would be obvious to person of ordinary skill in the art to modify method of Brookman-Amissah to add human Cot-1 DNA ratio within the claimed range. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A).
Regarding claim 2, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah and Roche do not disclose human Cot-1 DNA to the library is done at a ratio of 33:1. However, person of ordinary skill in the art would have understood from Roche that the amount of Cot-1 DNA is a result-effective variable that may be selected or optimized base on the type and amount of nucleic present. Selecting a specific ratio such as 33:1 represent a routine optimization or design choice within near ranges taught by Roche to achieve effective suppression of repetitive-sequence hybridization. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Regarding claim 3, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Roche manual further teaches the library of genetic material comprises receiving the library with a mass between 1 and 5 µg [page 4].
Regarding claim 4, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Roche further disclose adding human Cot-1 DNA to the input library comprises adding human Cot-1 DNA at a concentration of more than 8 mg/mL. (e.g. 10 mg/mL [page 6]). Therefore, Roche teaches the additional limitation of claim 4.
Regarding claim 5, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. As discussed above in rejection of claim 1, Brookman-Amissah teaches hybrid-capture sequencing method in which human Cot-1 DNA is added to a sequencing library prior to enrichment, and Roche teaches using human Cot-1 DNA in defined excess ratios relative to nucleic acid. As discussed above in rejection of claim 3, Roche manual further teaches the library of genetic material comprises receiving the library with a mass between 1 and 5 µg [page 4]. As discussed above in rejection of claim 4, Roche teaches concentrating human Cot-1 DNA to 10 mg/mL, which exceeds the concentration recited in claim 5.
Claim 5 combines the previously addressed limitations. Since each of these parameters was independently taught or rendered obvious by the prior art, and such hybridization parameters are routinely selected and adjusted together in hybrid-capture workflow, the combination recited in claim 5 represent predictable optimization of known variable rather than inventive feature.
Regarding claim 8, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah further teaches sequencing enriched libraries on next-generation sequencing platforms, Illumina MiSeq® platform [Fig.3, page 4], which utilizes flow cells to immobilize and sequence nucleic acid fragments. The application of enriched genetic material to one or more flow cells is a standard and well-known step in next generation sequencing workflows. Therefore, Brookman-Amissah teaches the additional limitation of claim 8.
Regarding claim 9, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 8 as discussed fully above and incorporated here. As discussed above, Brookman-Amissah teaches that inclusion of blocking reagents, including Cot-1 DNA, during hybrid capture improves sequencing performance by reducing off-target reads. Brookman-Amissah reports that the use of blocking reagents yields on-target read percentages of approximately 59% and 64%, whereas omission of blocking reagents yields lower on-target read of 35% and 32% respectively [Fig. 1]. These results correspond to relative increases in usable sequencing reads of 50% to 70% when blocking reagents, such as Cot-1 DNA, are used. Therefore, Brookman-Amissah teaches the additional limitation of claim 9.
Regarding claim 10, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah further discloses receiving of the library comprises receiving two or more pooled libraries that have been combined. (e.g. preparing multiple adapter-ligated sequencing libraries bearing unique barcode and expressly state that “The adapter-ligated libraries were then combined for use in subsequent steps. “ prior to target enrichment and sequencing [page 4]). Therefore, Brookman-Amissah teaches the additional limitation of claim 9.
Regarding claim 11, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 10 as discussed fully above and incorporated here. Brookman-Amissah further discloses the method further comprising combining the two or more libraries. (e.g. preparing multiple adapter-ligated sequencing libraries bearing unique barcode and expressly state that “The adapter-ligated libraries were then combined for use in subsequent steps. “ prior to target enrichment and sequencing [page 4]). Therefore, Brookman-Amissah teaches the additional limitation of claim 11.
Regarding claims 12 and 13, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. As discussed above, Brookman-Amissah teaches preparing multiple adapter-ligated libraries bearing unique barcodes and combining libraries prior to target enrichment for multiplexed sequencing. Brookman-Amissah further discloses that blocking strategies are used specifically to support multiplexed hybrid capture, thereby enabling enrichment and sequencing of multiple libraries in a single reaction. Specifying the number of pooled libraries, such as ten or more (claim 12) or ten to fifty (claim 13), reflect routine scaling of a known multiplex technique. As of the application’ s effective filing date, one of ordinary skill in the art would have understood that the number of libraries pooled together depends on experimental designs, barcode availability, sequencing capacity, and design throughput, and that increasing the number of pooled libraries would have been a predictable and routine variation of the known method. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Regarding claim 14, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah further discloses further comprising adding one or more additional blockers to the enrichment pool [page 2]. Therefore, Brookman-Amissah teaches the additional limitation of claim 14.
Regarding claim 15, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah further discloses enriching the genetic material in the enrichment pool comprises amplifying the genetic material prior to sequencing [page 4]. Therefore, Brookman-Amissah teaches the additional limitation of claim 15.
Regarding claim 16, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah further discloses enriching the genetic material in the enrichment pool comprises controlling concentration of the genetic material [page 6]. Therefore, Brookman-Amissah teaches the additional limitation of claim 16.
Brookman-Amissah et al. and Invitrogen
Claim(s) 17 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brookman-Amissah et al. (GEN, Vol. 34, No. 6, 2014) in view of Invitrogen (Human Cot-1 DNA protocol from product disclosed in IDS).
Regarding claim 17, Brookman-Amissah discloses a method of processing genetic material for bioinformatic analysis, the method comprising: receiving a library of genetic material sourced from a sample (e.g. “prepared sequencing library” [page 3]);
adding human Cot-1 DNA to the library to produce an enrichment pool; enriching the genetic material in the enrichment pool to produce enriched genetic material; and sequencing the enriched genetic material to produce sequencing data. [page 4].
However, Brookman-Amissah does not disclose Cot-1 DNA is at least 10 µL of human Cot-1 DNA a concentration of at least 10mg/ml.
Invitrogen manual discloses that human Cot-1 DNA can be concentrated to 10 mg/ml [page 2] and added directly to the hybridization solution. Invitrogen further discloses that the amount of human Cot-1 DNA used depends on the application and the amount of nucleic acid present [page 2], indicating that both concentration and volume of Cot-1 DNA are routinely adjusted to achieve suppression of repetitive-sequence hybridization.
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to apply the human Cot-1 DNA concentration taught by Invitrogen to the hybrid-capture sequencing method of Brookman-Amissah. Once Cot-1 DNA solution having a concentration of 10 mg/ml is used, selecting particular volume, such as at least 10 µL, to provide sufficient amount of blocking DNA would have been the matter of routine experimental design. Selection of solution volume to achieve a desire blocking effect represents a predictable and result-effective variable. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A).
Regarding claim 18, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 17 as discussed fully above and incorporated here. As mentioned above Roche discloses variables such as concentration and volume of Cot-1 DNA are routinely adjusted to achieve suppression of repetitive-sequence hybridization. As of the application’ s effective filing date, one of ordinary skill in the art would have been motivated to further increases concentration of Cot-1 DNA beyond 10 mg/ml, such as 12 mg/ml, in order to enhance blocking performance. Selecting a concentration slightly above a known effective concentration represents routine optimization of a known parameter and would have been predictable to one of ordinary skill in the art. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Brookman-Amissah et al., Roche, and Parla et al.
Claim(s) 6 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brookman-Amissah et al. (GEN, Vol. 34, No. 6, 2014) in view of Roche (Human Cot-1 DNA protocol (2021)) and Parla et al. (Genome Biol. 2011 Sep 29;12(9)).
Regarding claim 6, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah further teaches that the use of blocking reagents results in substantial increases in the percentage of on-target sequencing reads (e.g. 59% and 64%), whereas omission of blocking reagents results lower in on-target reads (e.g. 35% and 32% respectively) [Fig. 1].
Palar further evaluates commercially available exome capture platforms and showed that hybrid-capture exome sequencing routinely achieves on target efficiencies exceeding 70% , with reported intended target and Consensus Coding Sequences (CCDS) coverage frequently of at least 80% [Fig. 1]. Parla shows that such capture efficiencies are obtained using standard hybrid-capture workflows and routine optimization of known parameters.
As of the application’ s effective filing date, person of ordinary skill in the art, in view of Brookman-Amissah’s teaching that blocking reagents increases on-target capture and Parla’s demonstration that exome capture routinely achieves on-target capture efficacies exceeding 70%, would have reasonable expectation of success in achieving at least 70% exome sequence capture through routine optimization of known capture and blocking methods. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Regarding claim 7, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 1 as discussed fully above and incorporated here. Brookman-Amissah teaches that inclusion of blocking reagents shifts sequencing output from off-target capture and toward target specific enrichment, as demonstrated by reduction in off-target sequencing reads when clocking reagents used [Fig.1]
Parla further shows commercially available exome capture platforms routinely achieve on-target capture efficiencies well above 70% [Fig. 1], with corresponding reduction in sequencing reads that do not map to intended exosome targets. Given that increases in on-target capture necessarily corresponds to decreases in off-target capture, a person of ordinary skill in the art would have understood that reducing off-target sequencing reads below a particular threshold, such as less than 30%, represents an expected and predictable result of routine optimization of known hybrid-capture parameters. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, E).
Brookman-Amissah et al., Roche, and Invitrogen
Claim(s) 19 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Brookman-Amissah et al. (GEN, Vol. 34, No. 6, 2014) in view of Invitrogen (Human Cot-1 DNA protocol from product disclosed in IDS) and Roche (Human Cot-1 DNA protocol (2021)).
Regarding claim 19, Brookman-Amissah discloses a method of processing genetic material for bioinformatic analysis, the method comprising: receiving a library of genetic material sourced from a sample (e.g. “prepared sequencing library” [page 3]);
adding human 5 µg of Cot-1 DNA in each 500 ng aliquoted of to produce an enrichment pool [page 2]; enriching the genetic material in the enrichment pool to produce enriched genetic material; and sequencing the enriched genetic material to produce sequencing data. [page 4].
However, Brookman-Amissah does not disclose adding at least 100 µg human Cot-1 DNA to the library to produce an enrichment pool.
Invitrogen and Roche manuals discloses that human Cot-1 DNA is commonly supplied at 1 mg/ml and can be concentrated to 10 mg/ml [Invitrogen, page 2], and further discloses that Cot-1 DNA routinely used in large excess relative to probe or library DNA, including 100- to 200-fold excess [Roche, page 3], depending on application.
As of the application’ s effective filing date, one of ordinary skill in the art would have had a reasonable expectation of success and motivated to apply the human Cot-1 DNA amount taught by Invitrogen/Roche to the hybrid-capture sequencing method of Brookman-Amissah. Person of ordinary skill in the art would have recognized that larger pooled or multiplexed sequencing libraries, which contain high DNA and sequence complexity, would predictably require increased amount of blocking agents, including human Cot-1 DNA, to maintain effective suppression of repetitive sequence during enrichment, Increasing the amount of human Cot-1 DNA in such contexts represent a predictable and routine scaling of a known result-effective variable, consistent with the teachings of Invitrogen/Roche manual and Brookman-Amissah. This reasoning is consistent with KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (see MPEP § 2143, A).
Regarding claim 20, Brookman-Amissah and Roche disclose a method of processing genetic material for bioinformatic analysis of claim 19 as discussed fully above and incorporated here. Roche manual further teaches the library of genetic material comprises receiving the library with a mass between 1 and 5 µg [page 4].
Conclusion
No Claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684