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 .
Claims 1-20 are currently pending and under examination.
Priority
The instant application 18/718,992 filed on 6/12/24 is a 371 US national phase of PCT/CN2022/139202 filed 12/15/22 and claims foreign priority to CN202111535111.9 filed on 12/15/21. The priority date is determined to be 12/15/22 in the absence of a copy certified translation of CN202111535111.9.
Receipt is acknowledged of CN202111535111.9 certified copies of papers required by 37 CFR 1.55. Priority Documents were electronically retrieved by USPTO from participating IP office on 6/12/24.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statement filed 6/24/24 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered. FOR citations 2-4 and 6-7 and NPL citations 4-5 are provided in Non-English languages.
Claim Rejections - 35 USC § 112 – Indefiniteness
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 17 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 17 contains the trademark/trade name User enzyme. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the New England Biolabs proprietary mix of Uracil DNA glycosylase and Endonuclease VIII and, accordingly, the identification/description is indefinite.
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, 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.
Claims 1, 7-8, 11-16, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Durkin et al. (2021; WO 2021/110878 A1; FOR citation 1 – WO 2021/110878 A1) in view of Johnson et al. (2019; WO 2019/068797 A1).
(i) Durkin et al. teaches limitations relevant to claims 1, 7-8, 11-16, 18, and 20.
Relevant to claim 1 a) – b), Durkin et al. teaches “In an aspect, the invention provides a method for detecting an integration pattern of human papillomavirus (HPV) in genomic DNA of a subject, said method comprising: (a) fragmenting genomic DNA isolated from a sample of the subject; (b) circularizing the DNA fragments to generate circular DNA; (c) removing non-circularized DNA fragments” (page 4, lines 1-5).
Relevant to claim 1 d) – f), Durkin et al. teaches “(d) linearizing the circular DNA using an RNA-guided DNA endonuclease… (f) sequencing the amplified DNA; (g) mapping the sequenced DNA to human genomic DNA sequence; and (h) optionally mapping the sequenced DNA to the HPV genome” (page 4, lines 6-13).
Relevant to claim 7, Durkin et al. teaches “In particular, a primer pair is used comprising a forward primer capable of hybridizing to a viral DNA sequence in a 3' flanking region of the viral DNA region targeted by the guide RNA or the pool of guide RNAs and a reverse primer capable of hybridizing to a viral DNA sequence in a 5' flanking region of the viral DNA region targeted by the guide RNA or the pool of guide RNAs” (page 14, lines 7-11).
Relevant to claim 8, Durkin et al. Abstract teaches “The present invention relates to a method for detecting an integration pattern of a virus, such as human papilloma virus (HPV) in a host genome.”
Relevant to claims 11-12, Durkin et al. teaches “Selective digestion of non-circularized or linear DNA may be achieved using an appropriate selective DNase as commercially available (e.g. Plasmid-Safe™ ATP-Dependent DNase (Epicentre)” (page 11, lines 17-19).
Relevant to claim 13, Durkin et al. teaches “A second notable observation is the cluster of A-to-G transitions observed within a ~70bp window in the 3'LTR. Similar patterns have been ascribed to ADAR1 hypermutation in a number of viruses [citation], including the close BLV relatives HTLV-2 and simian T-cell leukemia virus type 3 (STLV-3) [citation]. Given the small number of hypermutated proviruses observed, it appears to be a minor source of variation in BLV, although it will be interesting to see it this holds for different retroviruses and at different time points during infection” (page 51, lines 27-33).
Relevant to claim 14, Durkin et al. Example 5 teaches animal host DNA starting amounts exceeding 100 ng.
Relevant to claim 15, Durkin et al. claim 1 teaches “A method for detecting an integration pattern of human papillomavirus (HPV) in genomic DNA of a subject…”
Relevant to claim 16, Durkin et al. teaches “The terms ‘subject’ and ‘host’ and ‘patient’ are used interchangeably and refer to a human or non-human animal that is tested for the presence of integrated viral DNA” (page 10, lines 20-21).
Relevant to claim 18, Durkin et al. Abstract teaches “The present invention relates to a method for detecting an integration pattern of a virus, such as human papilloma virus (HPV) in a host genome.”
Relevant to claim 20, Durkin et al. Example 5 teaches animal host DNA starting amounts within the range of 500 – 2500 ng.
(ii) Durkin et al. is silent to specifics regarding performing rolling circle amplification (claim 1 c)). However, these limitations were known in the prior art and taught by Johnson et al.
Relevant to claim 1 c), Johnson et al. teaches “The present invention comprises detecting a target nucleic acid in a sample… In other embodiments, the sample is a cultured sample, e.g., a culture or culture supernatant containing or suspected to contain an infectious agent or nucleic acids derived from the infectious agent. In some embodiments, the infectious agent is… a virus” (page 9, lines 12-27).
Although Durkin et al. does not explicitly teach the Johnson et al. rolling circle amplification, it would have been prima facie obvious to the skilled artisan. Durkin et al. and Johnson et al. are analogous disclosures in the instant field of nucleic acid detection.
The skilled artisan would have been motivated to combine the analogous art. Johnson et al. “Background of the Invention” teaches “Circular nucleic acid templates have multiple uses in nucleic acid analysis. Linear nucleic acids are converted into a circular form for amplification, e.g., by rolling circle amplification (RCA) and subsequent detection and quantification, see U.S. Pat. No. RE44265. The use of circular templates in sequencing is also known in the art. See U.S. Pat. Nos. 7,302,146 and 8,153,375. These strategies create a circular template comprising both strands of the target nucleic acid. The present invention is a novel efficient method of creating a library of templates suitable for sequencing comprising circular single stranded molecules form each strand of the target nucleic acid. The method allows the creation of templates of virtually unlimited length.”
Thus, the skilled artisan would have been motivated to use the Johnson et al. rolling circle amplification within the Durkin et al. methodology in order to take advantage of a widely-known technique that would efficiently generate double-stranded circular templates of target nucleic acids suitable for sequencing. The skilled artisan would have a reasonable expectation of success based on the disclosures of Durkin et al. in view of Johnson et al., as discussed in the preceding paragraphs.
Claims 2 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Durkin et al. (2021; WO 2021/110878 A1; FOR citation 1 – WO 2021/110878 A1) in view of Johnson et al. (2019; WO 2019/068797 A1), as applied to claims 1, 7-8, 11-16, 18, and 20 above, and further in view of Nair et al. (2021; "Mitigating the Non-Specific Amplification in RCA: Assessment of the Role of Ligation and Exonuclease Digestion in Circular DNA Preparation"; https://doi.org/10.26434/chemrxiv.14577975.v1).
The teachings of Durkin et al. in view of Johnson et al. are applied to instantly rejected claims 2 and 5 as they were previously applied to claims 1, 7-8, 11-16, 18, and 20 as rendering obvious a method for detecting an integration site. Durkin et al. in view of Johnson et al. is silent to specifics regarding linkers. However, these limitations were known in the prior art and taught by Nair et al.
Relevant to claim 2, Nair et al. teaches “A third method of preparing circular DNA involves sticky-end ligation, where the 5’- and 3’-termini are brought in proximity for ligation using ‘sticky-ends’ (complementary overhangs)” (page 2, last paragraph).
Relevant to claim 5, Nair et al. teaches “For sticky-end substrates, precursor oligonucleotides (3a/3b or 4a/4b) were separately 5’-phosphorylated” (page 5, section “2.3.1. 5’-Phosphorylation”).
Although Durkin et al. in view of Johnson et al. does not explicitly teach the Nair et al. linkers, it would have been prima facie obvious to the skilled artisan. Durkin et al., Johnson et al., and Nair et al. are analogous disclosures in the instant field of nucleic acid detection.
The skilled artisan would be motivated to combine the analogous art. Nair et al. teaches “A third method of preparing circular DNA involves sticky-end ligation, where the 5’- and 3’-termini are brought in proximity for ligation using ‘sticky-ends’ (complementary overhangs). Such sticky ends can be generated by enzymatic digestion or deliberate sequence design, followed by ligation [citation]. RCA assays involving sticky-end ligated circular DNAs have been applied for the detection of thrombin and let-7 family miRNA [citations]… The circular DNA prepared by these methods can be purified from unligated oligonucleotide precursors by either exonuclease I and exonuclease III digestion or by denaturing polyacrylamide gel electrophoresis (PAGE) [citation].” (last paragraph of page 2 – continued to page 3).
Thus, the skilled artisan would have been motivated to use the Nair et al. sticky-end linkers within the modified-Durkin et al. methodology in order to generate circular DNA able to be purified from non-target nucleic acids. The skilled artisan would have a reasonable expectation of success based on the disclosures of Durkin et al. in view of Johnson et al., and further in view of Nair et al., as discussed in the preceding paragraphs.
Claims 3-4, 6, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Durkin et al. (2021; WO 2021/110878 A1; FOR citation 1 – WO 2021/110878 A1) in view of Johnson et al. (2019; WO 2019/068797 A1), and Nair et al. (2021; "Mitigating the Non-Specific Amplification in RCA: Assessment of the Role of Ligation and Exonuclease Digestion in Circular DNA Preparation"; https://doi.org/10.26434/chemrxiv.14577975.v1), as applied to claims 2 and 5 above, and further in view of Kamberov et al. (2015; WO 2015/074017 A1).
The teachings of Durkin et al. in view of Johnson et al., and further in view of Nair et al. are applied to instantly rejected claims 3-4, 6, and 17 as they were previously applied to claims 2 and 5 as rendering obvious a method for detecting an integration site. Durkin et al. in view of Johnson et al., and further in view of Nair et al. is silent to specifics regarding stem loops and U base sites. However, these limitations were known in the prior art and taught by Kamberov et al.
Relevant to claim 3, Kamberov et al. teaches “By way of example, the degradable adaptors can be used in the preparation of nucleic acid libraries, e.g., nucleic acid libraries for massively parallel (NextGen) sequencing, where a target nucleic acid sample is ligated to a stem-loop oligonucleotide adaptor that contains one or more cleavable bases, such as deoxyuracil (dU). One can achieve complete degradation or substantially complete degradation of the bulk non-ligated stem-loop oligonucleotide adaptors and any adaptor dimers formed by employing a combination of enzymes in a simultaneous or a sequential fashion to generate abasic sites” (paragraph 0035).
Relevant to claim 4, Kamberov et al. teaches “The process can include the following enzymatic steps sequentially or simultaneously (see, FIG. 1): 1) Creating an abasic site at a cleavable base (e.g., dU) using a glycosylase (e.g., uracil-DNA glycosylase (UDG)). 2) Creating a nick at the abasic site using an apurinic/apyrimidinic (AP) endonuclease (e.g., APE 1)” (paragraph 0036).
Relevant to claim 6, Kamberov et al. paragraph 0019 teaches stem-loop adaptor design parameters that would guide the skilled artisan to optimize linker sequences. The Kamberov et al. stem-loop adaptor design and the instant linker share the same purpose and highly similar structure, and design of linker sequences are routinely modified and optimized in the field. The claimed sequence represents one of a finite number of predictable variations that would have been arrived at through ordinary skill.
Relevant to claim 17, Kamberov et al. teaches “Also contemplated are the nicking agents referred to as the USER™ Enzyme, which specifically nicks target molecules at deoxyuridine, and the USER™ Enzyme 2, which specifically nicks target molecules at both deoxyuridine and 8-oxo-guanine both leaving a 5' phosphate at the nick location (see, U.S. Pat. No. 7,435,572). USER™ Enzyme is a mixture of uracil-DNA glycosylase (UDG) and the DNA glycosylase-lyase Endonuclease VIII. UDG catalyzes the excision of a uracil base, forming an abasic (apyrimidinic) site while leaving the phosphodiester backbone intact. The lyase activity of Endonuclease VIII breaks the phosphodiester backbone at the 3' and 5' sides of the abasic site so that base-free deoxyribose is released” (paragraph 0062).
Although Durkin et al. in view of Johnson et al., and further in view of Nair et al. does not explicitly teach the Kamberov et al. limitations, it would have been prima facie obvious to the skilled artisan. Durkin et al., Johnson et al., Nair et al., and Kamberov et al. are analogous disclosures in the instant field of nucleic acid detection.
The skilled artisan would be motivated to combine the analogous art. Kamberov et al. teaches “Upon attachment of the inert adaptor to the molecule, the attached oligonucleotide becomes active and suitable for providing at least in part one or more sequences employable for amplification, while the nonattached, free adaptor and any adaptor dimers are destroyed. As a result, during polymerase chain reaction the free, non-attached inert adaptor and any adaptor dimers can neither be primed nor used as a PCR primer. This provides novel conditions for modification of DNA molecules with the adaptors, and subsequent amplification. These conditions greatly reduce the background in the assay and allow for the use of nanogram, picogram, femtogram, or attogram quantities of input DNA” (paragraph 0006).
Thus, the skilled artisan would have been motivated to use the Kamberov et al. stem loop specifics within the modified-Durkin et al. methodology in order to reduce assay background and required input of DNA. The skilled artisan would have a reasonable expectation of success based on the disclosures of Durkin et al. in view of Johnson et al., and Nair et al., and further in view of Kamberov et al., as discussed in the preceding paragraphs.
Claims 9-10 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Durkin et al. (2021; WO 2021/110878 A1; FOR citation 1 – WO 2021/110878 A1) in view of Johnson et al. (2019; WO 2019/068797 A1), as applied to claims 1, 7-8, 11-16, 18, and 20 above, and further in view of Kamberov et al. (2015; WO 2015/074017 A1).
The teachings of Durkin et al. in view of Johnson et al. are applied to instantly rejected claims 9-10 and 19 as they were previously applied to claims 1, 7-8, 11-16, 18, and 20 as rendering obvious a method for detecting an integration site. Durkin et al. in view of Johnson et al. is silent to specifics regarding exonucleases. However, these limitations were known in the prior art and taught by Kamberov et al.
Relevant to claims 9-10 and 19, Kamberov et al. paragraph 0063 teaches Lambda exonuclease and exonuclease I digestions.
Although Durkin et al. in view of Johnson et al. does not explicitly teach the Kamberov et al. limitations, it would have been prima facie obvious to the skilled artisan. Durkin et al., Johnson et al., and Kamberov et al. are analogous disclosures in the instant field of nucleic acid detection.
The skilled artisan would be motivated to combine the analogous art. Kamberov et al. teaches “Upon attachment of the inert adaptor to the molecule, the attached oligonucleotide becomes active and suitable for providing at least in part one or more sequences employable for amplification, while the nonattached, free adaptor and any adaptor dimers are destroyed. As a result, during polymerase chain reaction the free, non-attached inert adaptor and any adaptor dimers can neither be primed nor used as a PCR primer. This provides novel conditions for modification of DNA molecules with the adaptors, and subsequent amplification. These conditions greatly reduce the background in the assay and allow for the use of nanogram, picogram, femtogram, or attogram quantities of input DNA” (paragraph 0006).
Kamberov et al. further teaches “Exo I (E. coli) catalyzes the removal of nucleotides from single-stranded DNA in the 3' to 5' direction. For example, Exo I can degrade single-stranded oligonucleotides in a reaction mixture containing double-stranded nucleic acid products... Lambda exonuclease may be used to enzymatically degrade a nucleic acid at a nicked site in a 5' to 3' direction” (paragraph 0063).
Thus, the skilled artisan would have been motivated to use the Kamberov et al. exonucleases within the modified-Durkin et al. methodology in order to degrade undesired nucleic acids and reduce assay background and required input of DNA. The skilled artisan would have a reasonable expectation of success based on the disclosures of Durkin et al. in view of Johnson et al., and further in view of Kamberov et al., as discussed in the preceding paragraphs.Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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