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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Feb. 23, 2026. Claims 1, 3, 5-7 and 9-20 are pending. Claims 19-20 are withdrawn. Claims 1, 3, 5-7 and 9-18 are currently examined.
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.
(Previous Rejection – Withdrawn) Claims 2-8 and 10 were rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
This rejection is withdrawn in view of the amendments filed on Feb. 23, 2026.
(New Rejection) Claims 1, 3, 5-7 and 9-18 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The base claim 1 is amended to recite “(ii) amplifying the SARS-CoV-2 cDNA using tiled primers that bind at spaced intervals along the viral genome, wherein the step of amplifying the SARS-CoV-2 cDNA comprises hybridizing one strand of the sample SARS-CoV-2 cDNA to a single-stranded probe DNA template comprising a pair of SARS-CoV-2 probes, wherein the first probe is positioned at the 3' end of the probe DNA template to function as a forward primer and the second probe is positioned at the 5' end of the probe DNA template to function as a reverse primer, and filling in the sequence between the two probes to generate a circular single-stranded probe DNA template comprising the sample-specific SARS-CoV-2 nucleic acid between the two probe sequences”. This limitation renders to claims indefinite.
The limitation first specifies “amplifying the SARS-CoV-2 cDNA using tiled primers that bind at spaced intervals along the viral genome”, and then goes on to specify “wherein the step of amplifying the SARS-CoV-2 cDNA comprises hybridizing one strand of the sample SARS-CoV-2 cDNA to a single-stranded probe DNA template comprising a pair of SARS-CoV-2 probes”. Here, there is a lack of information relating the “tiled primers” and the “single-stranded probe DNA template comprising a pair of SARS-CoV-2 probes”. E.g., it is not clear if the “tiled primers” used in amplifying the SARS-CoV-2 cDNA are the same as the “first probe” and the “second probe” which are positioned in the “single-stranded probe DNA template” at the 3’- and 5’ ends, and are referred to as forward primer and reverse primer, respectively.
Additionally, the phrase “single-stranded probe DNA template comprising a pair of SARS-CoV-2 probes” is not clear. First, it is not clear what the term “single-stranded probe DNA template” refers to. Does it refer to a single-stranded DNA molecule that comprises the sequences of the “pair of SARS-CoV-2 probes”? If this is the case, then the recited “first probe” and “second probe” do not exist independently, but represent regions in the recited “single-stranded probe DNA template”. And, in this case, the probe sequence positioned at the 5’ end of the “single-stranded probe DNA template”, i.e., the second probe, cannot function as a reverse primer since it lacks a free 3’ end (its 3’ end is in the “single-stranded probe DNA template”) and cannot function as a “reverse primer” to initiate a DNA polymerase reaction.
Additionally, claim 1 recites “(c) performing nucleic acid sequencing on the sample-specific SARS-CoV-2 nucleic acid”. Here, the phrase “the sample-specific SARS-CoV-2 nucleic acid” is not clearly and exclusively defined. Claim 1 appears to be defining this phrase in the step b by the sub-steps b(i) and b(ii). However, the claim does not recite a conjunction word between the b(i) and b(ii) sub-steps, making it unclear if both b(i) and b(ii) are required.
It is noticed that Fig. 2 of the instant application depicts a process that appears to comprise (1) annealing probe to target involving hybridization at both ends of a nucleic acid molecule (“single-stranded probe DNA template”) to the target, and (2) gap filling involving filling in the sequence between the two hybridization sites (“two probe sequences”). This process appears to represent an embodiment of the step b(ii) of claim 1, and reads on an art-known technique called molecular inversion probe (MIP) assay (see Akhras et al. (PLoS ONE, 2007, 2(2): e223), cited in the current art rejection below).
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.
(Previous Rejection – Withdrawn) Claims 1-2 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gohl et al. (BMC Genomics (2020) 21:863; submitted in IDS filed on Mar. 10, 2023), Itokawa et al. (PLoS ONE, 2020, 15(9): e0239403), or Freed et al. (Biol Methods Protoc. 2020 Jul 18; 5(1): bpaa014).
This rejection is withdrawn in view of the amendments filed on Feb. 23, 2026.
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 of this title, 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.
(Previous Rejection – Withdrawn) Claims 3 -7 and 9-18 were rejected under 35 U.S.C. 103 as being unpatentable over Gohl et al. (BMC Genomics (2020) 21:863; submitted in IDS filed on Mar. 10, 2023), Itokawa et al. (PLoS ONE, 2020, 15(9): e0239403), and/or Freed et al. (Biol Methods Protoc. 2020 Jul 18; 5(1): bpaa014), cited in the 102 rejection above.
This rejection is withdrawn in view of the amendments filed on Feb. 23, 2026.
(New Rejection) Claims 1, 3, 5-7 and 9-18 are rejected under 35 U.S.C. 103 as being unpatentable over Gohl et al. (BMC Genomics (2020) 21:863; submitted in IDS filed on Mar. 10, 2023), Itokawa et al. (PLoS ONE, 2020, 15(9): e0239403), and/or Freed et al. (Biol Methods Protoc. 2020 Jul 18; 5(1): bpaa014), as applied in the withdrawn rejections above, in view of Akhras et al. (PLoS ONE, 2007, 2(2): e223).
The base claim 1, as amended, recites:
A method for identifying and/or tracking variants of SARS-CoV-2 comprising:
(a) identifying a sample from a subject as positive for SARS-CoV-2 nucleic acid and/or antibodies to SARS-CoV-2;
(b) generating a sample-specific SARS-CoV-2 nucleic acid from the sample, wherein generating the sample-specific SARS-CoV-2 nucleic acid comprises:
(i) generating a sample specific SARS-CoV-2 cDNA from the sample;
(ii) amplifying the SARS-CoV-2 cDNA using tiled primers that bind at spaced intervals along the viral genome, wherein the step of amplifying the SARS-CoV-2 cDNA comprises hybridizing one strand of the sample SARS-CoV-2 cDNA to a single-stranded probe DNA template comprising a pair of SARS-CoV-2 probes, wherein the first probe is positioned at the 3' end of the probe DNA template to function as a forward primer and the second probe is positioned at the 5' end of the probe DNA template to function as a reverse primer, and filling in the sequence between the two probes to generate a circular single-stranded probe DNA template comprising the sample-specific SARS-CoV-2 nucleic acid between the two probe sequences;
(c) performing nucleic acid sequencing on the sample-specific SARS-CoV-2 nucleic acid; and
(d) determining whether the nucleic acid sequence comprises a SARS-CoV-2 variant sequence.
As indicated in the 112(b) rejection above, claim 1 is considered as encompassing a tiled molecular inversion probe (MIP) assay.
Relevance of Gohl, Itokawa and Freed is set forth in the withdrawn art rejections in the previous Office action. Briefly, each of the references teaches the ARTIC protocol using two pools of tiled primers to produce amplicons from SARS-CoV-2 genome sequence via cDNA of the viral genome, and performing nucleic acid sequencing on the SARS-CoV-2-specific amplicons for the virus nucleic acid detection. However, these references are silent on generating the SARS-CoV-2-specific amplicons by a tiled molecular inversion probe (MIP) assay.
Akhras teaches that the Molecular Inversion Probe (MIP) assay has been previously applied to a large-scale human SNP detection. Here the authors describe the PathogenMip Assay, a complete protocol for probe production and applied approaches to pathogen detection. They have demonstrated the utility of this assay with an initial set of 24 probes targeting the most clinically relevant HPV genotypes associated with cervical cancer progression. Probe construction was based on a novel, cost-effective, ligase-based protocol. The assay was validated by performing pyrosequencing and Microarray chip detection in parallel experiments. HPV plasmids were used to validate sensitivity and selectivity of the assay. In addition, 20 genomic DNA extracts from primary tumors were genotyped with the PathogenMip Assay results and were in 100% agreement with conventional sequencing using an L1-based HPV genotyping protocol. The PathogenMip Assay is a widely accessible protocol for producing and using highly discriminating probes, with experimentally validated results in pathogen genotyping, which could potentially be applied to the detection and characterization of any microbe. See Abstract.
Figure 1 of Akhras, shown below, presents schematic overviews of the molecular inversion probe technology. Figure 1A shows a synthetic oligonucleotide containing following four regions; i) H1 and H2: homology regions comprised of unique continuous 40–50 base pair fragments for target recognition ii) BARCODE: molecular barcode comprised of a 20 base pair DNA tag for target identification iii) U1 and U2: universal primer regions for inverted probe amplification, and iv) R: restriction site for probe linearization. Figure 1B shows that upon target recognition, a DNA polymerase fills the missing gap in between the juxtaposition of the probes’ flanking ends, and through the activity of a DNA ligase the probe is circularized.
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Figure 6 of Akhras, shown below, present a schematic over view of the PathogenMip Assay, and its application in detection and genotyping of HPVs. Figure 6A shows the 24 probes included in the assay are situated at their respective target sites on the approximately 8000 base pairs of double stranded HPV genomic DNA. Figure 6B shows that following enzymatic inversion of reacted probes and universal amplification, the amplicons are used for subsequent appropriate HPV genotype screening. See legend.
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Here, the 24 probes shown in Figure 6A include tiled ones.
According, Akhras teaches an MIP technique, called the PathogenMip assay, and a method of detecting/genotyping HPV using this assy, which is indistinguishable from the process specified in the step (b)(ii) of the instant claim 1. Teachings of Akhras indicate MIP is an art known technique that can be used in the detection/characterization of virus nucleic acid together with nucleic acid sequencing.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to introduce the PathogenMip assay technology disclosed in Akhras into the studies of Gohl, Itokawa and Freed for the detection and/or genome characterization of SARS-CoV-2 based on the teachings of Akhras that the PathogenMip Assay is a widely accessible protocol for producing and using highly discriminating probes, with experimentally validated results in pathogen genotyping, which could potentially be applied to the detection and characterization of any microbe. See discussion above. There is a reasonable expectation of success that a PathogenMip Assay for SARS-CoV-2 can be designed and tested based on the teachings of Akhras and genome information of SAR-CoV-2.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671