DETAILED ACTION
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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-9) in the reply filed on 4/16/2026 is acknowledged.
Status of the Claims
Claims 8-20 have been withdraw as being directed to a non-elected invention. Claims 1-9 are under examination at this time.
Priority
The disclosure of the prior-filed application, Application No. 63/421345, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Specifically, the prior application does not disclose the claimed method, particularly the use of inversion probes, adapters, and creating a circular molecule. Thus, claims reciting inversion probes, adapters, and creating a circular molecule will only be given a priority date of prior-filed application 63/491652 (3/22/2023), which provides support for the claimed method.
Claim Objections
Claim1 is objected to because of the following informalities: claim 1 should recite “in a reference genome of a virus by aligning the sequence reads to the reference genome of the virus”. Appropriate correction is required.
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 7 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 7 recites that the method of claim 1 further comprises
obtaining a prevalent lineage of the virus for a subject population, wherein the prevalent lineage is determined based on the predicted lineage of the virus in the sample;
updating the molecular inversion probes to capture the target molecule, wherein the target molecule is specific to the prevalent lineage;
updating the adapters based on the updated molecular inversion probe; and
obtaining a set of decision rules that are specific to determine the prevalent lineage, wherein the determining the one or more scores of the consensus sequence is determined using the set of decision rules.
Claim 7 is very unclear and confusing. For example, it is not clear how “a prevalent lineage” of the virus is obtained for a population when claim 1 recites obtaining a sample from a subject (a single subject). Next, it is not clear how the molecular inversion probe is “updated”. What is it updated with and how is an update determined? Likewise, it is not clear how the adapters are “updated”. What are the adaptors updated with and how is an update determined? Last, it is not clear how one obtains a set of decision rules that are specific to the prevalent lineage. Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claim.
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 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.
Claim(s) 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Nicot et al. (J Med Virol., 2022,1–10) and further in view of McElroy et al. (Microbial Informatics and Experimentation 2014, 4:1) and Schlecht et al. (Scientific Reports, July 2017, 7:5252).
The instant claims are directed to a method comprising:
(1) obtaining nucleic acid from a sample that was obtained from a subject;
(2) capturing a target molecule in the nucleic acid using a molecular inversion probe under hybridization conditions;
(3) amplifying the target molecule using polymerase chain reaction (PCR) to obtain a plurality of amplified molecules;
for each molecule in the plurality of amplified molecules,
(4) ligating an adapter to each end of the molecule to create a circular molecule; and
(5) sequencing the circular molecule to obtain sequence reads;
(6) generating, using a computing system, a sequencing file comprising the sequence reads of each molecule in the plurality of amplified molecules and a position of each sequence read in a reference genome of a virus by aligning the sequence read to the reference genome of the virus; and
(7) generating, using the computing system and the sequencing file, a reporting file for the subject, wherein the reporting file comprises a predicted lineage of the virus in the sample,
wherein the generating comprises:
generating a consensus sequence for the target molecule based on sequence reads of each molecule in the plurality of amplified molecules, wherein a nucleotide identity is assigned to a position in the consensus sequence if at least a predetermined number of the sequence reads has the nucleotide identity in the position, and wherein an "N" is assigned to a position in the consensus sequence if less than a predetermined number of the sequence reads has the nucleotide identity in the position;
determining one or more scores of the consensus sequence based on the reference genome of the virus or a library of the virus, wherein the one or more scores are determined based on a distribution of mutations of the virus; and
determining the predicted lineage of the virus in the sample based on the one or more scores of the consensus sequence.
Nicot et al. teaches a target capture real-time sequencing protocol. RNA was extracted from nasopharyngeal samples from patients who were SARS-CoV-2 positive [claim 1, part (1)]. Molecular inversion probes with a 675 bp target insert were used to capture target sequences [claim 1, part (2)]. The next step was simultaneous complementary DNA (cDNA) synthesis and inversion probe hybridization [claim 1, part (3)](see Figure 1, right side). The second step was circularization of the generated cDNA molecules [claim 1, part (4), in part]. The cDNA amplification mixture, polymerase chain reaction (PCR) mix, and barcoded M13 Primer mix were subjected to 26 cycles of 98°C/15 s, 55°C/15 s, and 72°C/90 s. Samples were pooled for library construction. A SMRT bell library was prepared and sequenced with the SMRTbell Express Template Prep 2.0 Kit [claim 1, part (5)] (see section 2.3 and Figure 1 below).
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Regarding circularization, Nicot et al. does not teach the use of adapters. However, Schlecht et al. teaches that one can circularize DNA using adapters for the SMRT system, which was used by Nicot et al. Schlecht et al. states:
[S]ingle molecule real-time (SMRT) technology distinguishes itself from other sequencing platforms in three main aspects: (1) during library preparation, closed circular DNA molecules are created by ligating hairpin adapters, termed SMRTbells, to both ends of double-stranded DNA target molecules, (2) these SMRTbells are bound to a sequencing primer and a DNA polymerase, and subsequently loaded as a complex into tiny sequencing units called zero-mode waveguides (ZMWs), and (3) the small volumes of the ZMWs allow real-time optical detection of fluorescently-labeled phospholinked nucleotides as they are incorporated by the DNA polymerase while a copy of the template is synthesized. Because of the circular nature of the SMRTbell-ligated library and the DNA polymerase’s capacity to generate reads longer than multiple kilobases, sequencing is not limited to one template strand but instead extends to multiple passes across both strands. The information from these multiple passes mitigates the relatively high error rate per single pass and is used to generate a circular consensus sequence (CCS) read with high accuracy.
(emphasis added)
For claim 1, parts (6) and (7), and claim 2, Nicot et al. teaches that bioinformatic analysis was done with SMRT Link software using the HiFiViral SARS-CoV-2 Analysis Application with the default parameters, except for the minimum base coverage, which was changed to 10 reads (ECDC recommendations for SARS-CoV-2 sequencing). Consensus sequences were then analyzed with Pangolin lineages and Nextstrain clades. Finally, a customized python script (v3.8.8) analysis was used to generate a user-friendly report, including the number of mapped reads, median coverage, list of S gene mutations (substitutions, insertions, and deletions), S gene missing positions, and previously found clades and lineages. The presence of S gene mutations indicates the presence of SARS-CoV-2.
Additionally, McElroy et al. teaches a similar method as Nicot et al. where PCR amplified target nucleic acids are sequenced. After sequencing, reads with “Ns”, low quality or duplicates are removed. The reads are then aligned. Following alignment, a number of bioinformatic tools are available for SNV calling, haplotype reconstruction, and downstream analysis (see Figure 1 of McElroy et al.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use known bioinformatic tools, e.g., the tools disclosed by Nicot et al. and McElroy et al., to analyze the sequence reads and to generate sequencing and reporting files to display the obtained information. One would have been motivated to do so and there would have been a reasonable expectation of success given the teachings in the art and given the teachings of Nicot et al. and McElroy et al.
For claim 3, Nicot et al. teaches the claimed method where the virus is SARS-CoV-2. Applying the claimed method to other known viruses such as monkeypox is routine experimentation. One of ordinary skill in the art merely substitutes nucleic acid from a desired virus (e.g., monkeypox) and follow the steps taught by Nicot et al.
For claim 4, the inversion probe taught by Nicot et al. was sufficient to capture the target nucleic acids. Accordingly, using a probe where the two binding sites are 600-700 bp apart is routine experimentation.
Furthermore, according to section 2144.05 of the MPEP, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
For claim 5, it is well within the purview of one of ordinary skill in the art to determine the file output for the sequencing file and the reporting file. Nicot et al. teaches that for the bioinformatic analysis, the reads are reported as a VCF file. Applicant has not demonstrated unexpected or superior results for a BAM and/or VCF file.
For claim 6, Nicot et al. teaches that large-scale, high-throughput WGS of SARS-CoV-2 is essential for rapid surveillance and efficient follow-up of the spread of new variants, particularly immune-escaping variants that might interfere with vaccination or treatment. Thus, the presence of variants (e.g., immune-escaping variants) would indicate a new or different treatment protocol that targets that particular variant.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nicole Kinsey White whose telephone number is (571)272-9943. The examiner can normally be reached M to Th 6:30 am to 6:00 pm.
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/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672
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