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 .
Please note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This Office Action is in reply to Applicants’ correspondence of 6/18/2026. Applicants’ remarks and amendments have been fully and carefully considered are found to be partially persuasive (see Remarks under Claim Rejections – 35 USC 103). New grounds of rejection are presented in this Office Action. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action. This Action is NON-FINAL.
Claim Status
Claims 1-4, 7-11, 14-15, 17-19, and 33-35 are pending and being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. For example, see the references listed on page 23-27 of the Specification. These references are not all present on the provided IDS. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112b – Indefiniteness
The rejection of claim 17 under 35 U.S.C. 112(b) is withdrawn in light of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 103
Withdrawn 103 rejections
The rejections as presented in the Office Action of 3/19/2026 are withdrawn in light of Applicants amendments to the claims and arguments presented in the Remarks of 6/18/2026. New grounds of rejection are presented below.
New 103 Rejections
Claims 1, 3-4, 7-8, 14-15, 17-19, and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (Lo et al., WO 2018/137685 A1; cited on IDS of 6/6/2024) in view of Shi (Shi et al., EP 3480310 A1; cited on IDS of 6/6/2024) and Han (Han et al., International Journal of Radiation Oncology, Biology, Physics 9/1/2019).
Regarding claim 1: Lo teaches a method of hybrid capture target enrichment for capturing ctDNA of interest from a human patient sample comprising cell free DNA and wherein the ctDNA corresponds to an oncogenic virus (EBV, HBV, or HPV; paragraphs [0360-0363]). Lo teaches adding a library of nucleic acid hybrid capture probes that are complementary to the ctDNA of interest across the entire oncogenic virus genome and are biotinylated (tagged for capture), allowing the probes to hybridize to the ctDNA, and capturing the hybridized ctDNA using a tag on the probes (paragraph [0360-0361]).
Lo does not teach that the library of probes is complementary to both strands of the double stranded ctDNA of interest, or that the probes complementary to the sense strand of the ctDNA are offset by 40-60% from the probes complementary to the antisense strand. However, using probes that are complementary to both strands of the double stranded DNA of interest that are offset by 40-60% is known in the art, as taught by Shi.
Shi teaches a method of nucleic acid enrichment and capture using sense and antisense probes without an overlapping design that are offset by 50% (Abstract and paragraphs [0005 and 0009]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Lo to include antisense probes that are offset by 50% for the antisense strand, as taught by Shi, in addition to the probes tiled along the entire oncogenic virus genome length for the sense strand. One would be motivated to do so given the assertion by Shi that targeting of both the sense and antisense strands “can improve the capture specificity and increase the number of original copies of the nucleic acid capture from the sample” (paragraphs [0004 and 0015]). One would be motivated to stagger/offset the probes by 40-50% given the assertion by Shi that this “minimizes the interaction between the sense strand probes and the antisense strand probes” (paragraph [0009]). One would have a reasonable expectation of success given that Shi demonstrates that a two-probe design (sense and antisense) demonstrates greater capture yield/efficiency than a one-probe design on DNA in plasma samples (paragraphs [0024-0027]).
Lo in view of Shi does not explicitly teach that the combined methodology captures and detects <1 genome equivalent of the oncogenic virus in the human patient sample. However, capturing and detecting <1 genome equivalent of the oncogenic virus is not a positive process step. Given that that the combined references teach all the limitations of the proposed method of claim 1, it is therefore obvious that the method is capable of the intended use of the claimed methodology.
Lo in view of Shi also do not teach providing a patient sample that has less than 1 genome equivalent (GE) of the oncogenic virus. However, provision and analysis of samples from human patients containing less than 1 GE of oncogenic virus is known in the art, as taught by Han.
Han teaches analyzing clinical samples and performing NGS to detect viral ctDNA (Materials/Methods). Han teaches that some samples contained HPV ctDNA as low as 0.02 HPV GE and EBV ctDNA as low as 0.08 EBV GE (Results).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Lo in view of Shi to analyze samples that contain less than 1 GE of oncogenic virus, as taught by Han. One would be motivated to do so given the teaching by Han that plasma samples from confirmed diagnosed patients with cancer (NPC in the case of HBV and CC in the case of HPV) had levels of oncogenic viral ctDNA at less than 1 GE, indicating the need for methods which detect such low levels of viral ctDNA in plasma samples. One would have a reasonable expectation of success given that Han is also using NGS methodology based on hybrid capture of ctDNA from plasma samples (Materials/Methods), similar to that employed by Lo in view of Shi.
Regarding claims 3 and 4: Lo teaches sequencing the captured ctDNA with next-generation sequencing (paragraph [0363]).
Regarding claim 7: Shi teaches that the probes complementary to the sense strand of the ctDNA are offset by 50% from the probes complementary to the antisense strand (“each sense strand and the corresponding antisense strand probes have a complementary part of half length of probes”, paragraph [0009]).
Regarding claim 8: Shi teaches that the probes are 30-89 bp in length (which significantly overlaps with the claimed range of 50-160 bp in length; paragraph [0010]).
Regarding claim 14 and 15: Lo teaches that the oncogenic virus is HPV (paragraph [0363]).
Regarding claim 17: Lo teaches mapping the location of the ctDNA to the genome (paragraphs [0358 and 0363]).
Regarding claims 18 and 19: Lo teaches that the patient sample is peripheral blood plasma (paragraph [0355]).
Regarding claims 33-35: As discussed in the rejection of claim 1 above, Lo in view of Shi does not explicitly teach that the combined methodology captures and detects ctDNA at levels less than 1%, less than 0.1%, or less than 0.001% in the human patient sample. However, capturing and detecting ctDNA at levels less than 1%, 0.1%, and 0.001% is not a positive process step. Given that that the combined references teach all the limitations of the proposed method of claim 1, from which claims 33-35 depend, it is therefore obvious that the method is capable of the intended use of the claimed methodology.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Lo (Lo et al., WO 2018/137685 A1; cited on IDS of 6/6/2024) in view of Shi (Shi et al., EP 3480310 A1; cited on IDS of 6/6/2024) and Han (Han et al., International Journal of Radiation Oncology, Biology, Physics 9/1/2019) as applied to claims 1, 3-4, 7-8, 14-15, 17-19, and 33-35 above, and further in view of Czar (Czar et al., Trends in Biotechnology 2008; cited on PTO-892 of 1/31/2025).
The teachings of Lo in view of Shi and Han as they apply to claim 1, from which claim 2 depends, are described above. Relevant to the instantly rejected claim, Lo in view of Shi and Han teach enrichment of target ctDNA corresponding to an oncogenic virus from a human patient sample using capture probes targeting both strands of the double-stranded ctDNA of interest, capturing the ctDNA using the probes, and amplifying the captured ctDNA with PCR.
Lo in view of Shi and Han do not teach assembling the captured fragments via polymerase chain reaction (PCR) assembly. However, assembling overlapping reads via PCR assembly to examine a sequence of interest was known in the art, as taught by Czar.
Czar review methods of gene synthesis by methods of assembly of overlapping oligomers (“Assembling oligomers into genes”). This includes the method of PCR assembly, which utilizes the design of oligos with partial overlap against both strands of a target sequence. Hybridization of this partial overlap and subsequent extensions of those products leads to assembly of a target sequence spanning all of the designed overlapping oligos ("Polymerase chain assembly").
It would have been prima facie obvious to one having ordinary skill in the art, as of the effective filing date of the instant application, to have modified the method of Lo in view of Shi and Han to perform a polymerase chain assembly on the captured DNA as described by Czar. One would be motivated to do so given the assertion by Czar that PCR assembly of a target region using sense and antisense overlapping probes tiled across the region would allow for greater depth of coverage for subsequent sequencing reactions of the full target region.
Claims 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Lo (Lo et al., WO 2018/137685 A1; cited on IDS of 6/6/2024) in view of Shi (Shi et al., EP 3480310 A1; cited on IDS of 6/6/2024) and Han (Han et al., International Journal of Radiation Oncology, Biology, Physics 9/1/2019) as applied to claims 1, 3-4, 7-8, 14-15, 17-19, and 33-35 above, and further in view of Clark (Clark et al., The Journal of Molecular Diagnostics 2018).
The teachings of Lo in view of Shi and Han as it applies to claim 8, from which claims 9-11 depend, are described above. Relevant to the instantly rejected claim, Lo in view of Shi and Han teach enrichment of target ctDNA corresponding to an oncogenic virus from a human patient sample using capture probes targeting both strands of the double-stranded ctDNA of interest. Lo in view of Shi and Han teach that the probes are 30-89 base pairs in length.
Lo in view of Shi and Han do not teach that the probes are 120 bp in length. However, use of 120 bp long probes for hybrid capture-based NGS of target ctDNA in blood samples in known in the art, as taught by Clark.
Clark teaches a method of hybrid capture-based NGS for profiling ctDNA from blood (Abstract). Clark teaches using 120-bp 5’-biotinlated ssDNA oligonucleotide baits for target capture (reads on between 80 bp to 160 bp in length, 100 bp and 140 bp in length, and 120 bp in claims 9, 10, and 11, respectively; Materials and Methods - Panel Design, Hybrid Capture, and Sequencing).
It would have been prima facie obvious to one having ordinary skill in the art, as of the effective filing date of the instant application, to have modified the method of Lo in view of Shi and Han to have used the 120-bp probes as taught by Clark. One would be motivated to do so given the sensitivity of detection that Clark demonstrates in blood samples from patients when sequencing ctDNA captured by the 120 bp probes (Figure 5). One would have a reasonable expectation of success given that Clark successfully captures target ctDNA from blood samples and performs next generation sequencing.
Response to Remarks
Applicant’s arguments, see Remarks (pages 4-6), filed 6/18/2026, with respect to the rejection of claim 36 under Lo, Shi, and Damerla, have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. Any arguments pertaining to Damerla are considered moot, as this reference is no longer being used. However, upon further consideration, a new ground of rejection is made in view of Lo in view of Shi and Han (as presented in the 103 rejections above for claim 1, into which claim 36 was incorporated).
Applicant’s arguments regarding the combination of Lo and Shi, presented on pages 4-6 of Remarks of 6/18/2026, have been carefully considered but are not deemed persuasive. In response to applicant's arguments against the references individually (Shi, pages 4-5 of Remarks), 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).
Applicant argues that Shi’s offset probe design is directed to a “fundamentally different purpose and context”. However, Shi’s offset probe design has several benefits, as acknowledged by Applicant, that are applicable to any hybrid capture based method. Applicant acknowledges that Shi’s probe design offers “improv[ed] capture specificity” and “minimize[s] the interaction between the sense strand probes and the antisense strand probes”, both advantages of which those of skill in the art would recognize as desirable when performing hybrid capture. So even while Shi may be performing the hybrid capture on different types of samples/targets, the stated benefits regarding capture efficiency and prevention of sense/antisense interaction remain the same. Applicant argues that the Examiner must demonstrate why one would apply Shi’s probe design to achieve ultra-sensitive detection. Respectfully, this has already been stated in the 103 rejection above and reiterated by Applicant in their Remarks. Improving capture efficiency and minimizing probes interactions are both advantageous designs that would result in a more sensitive method of detection.
Applicant argues a “qualitative different between (a) improving the yield or specificity of a capture method applied to relatively abundant targets, and (b) achieving reliable detection of targets present at less than 1 genome equivalent in a complex clinical sample”. However, Applicant has not provided any evidence of said qualitative difference. Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, Applicant should not merely rely upon counsel’s arguments in place of evidence in the record. The assertion by Shi of improved capture efficiency would be desirable in a method such as that taught by Lo specifically to improve capture efficiency of target viral ctDNA, as asserted above.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAILEY E CASH whose telephone number is (571)272-0971. The examiner can normally be reached Monday-Friday 8:30am-6pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571)272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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