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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/20/2026 has been entered.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 2, 7, and 14-17 remain withdrawn. Claims 10-13 have been canceled. Claims 1, 3-6, 8-9, and 18-19 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Claim Objections
Claim 1 was objected to due to minor informalities. In light of Applicant’s amendments to the claims submitted 4/23/2026, this objection has been withdrawn. However, see new grounds of objection below.
35 USC 112(b) Rejections
Claims 11-13 were rejected for various informalities. Applicant has canceled these claims, and so these rejections have been rendered moot.
35 USC 102 Rejections
Claims 1, 5, 12-13, and 18-19 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Deng et al. (WO 2019/226689 A1; cited in Applicant’s IDS). It is noted that in the statement of rejection in the Final Rejection mailed 2/26/2026, Shim was erroneously recited, but this reference is not actually used in the content of the rejection.
In light of Applicant’s amendments to the claims submitted 4/23/2026, the rejections for claims 1, 5, and 18-19 have been withdrawn. Claims 12-13 have been canceled, and so these rejections have been rendered moot.
Claims 1, 3-4, and 8-9 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Deng et al. (WO 2019/226689 A1; cited in Applicant’s IDS), as evidenced by Shim et al. (Biomed Microdevices, 2016).
In light of Applicant’s amendments to the claims submitted 4/23/2026, these rejections have been withdrawn.
35 USC 103 Rejections
Claims 6 and 11 were rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (WO 2019/226689 A1; cited in Applicant’s IDS).
In light of Applicant’s amendments to the claims submitted 4/23/2026, the rejection for claim 6 has been withdrawn. Claim 11 has been canceled, and so this rejection has been rendered moot.
Claim 10 was rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (WO 2019/226689 A1; cited in Applicant’s IDS) in view of Weng et al. (US 2020/0010883 A1).
Claim 10 has been canceled, and so this rejection has been rendered moot.
See also new grounds of rejection below for all currently pending claims and “Response to Applicant’s Arguments” below.
Response to Applicant’s Arguments
It is noted that Applicant’s amendments to claim 1 have incorporated the limitation for previous claim 11 into claim 1, namely the recitation of a primer binding site on the circular strand of the circular adapted nucleic acid. Deng was not noted to teach this limitation under 35 USC 102. This is the basis for the withdrawal of the 35 USC 102 Rejections for all currently pending claims.
Relevant to the amendments to claim 1, Applicant states on page 10 of their Remarks that Deng teaches in para. 156 that the extension reactions of the invention need not have any oligonucleotide primer used. This paragraph is recited in the rejection of claim 11 in the Final Rejection, and is therefore relevant to amended claim 1. However, this teaching of Deng does not apply to all embodiments on the invention, and in fact earlier in the paragraph, it is stated, “The extension reaction may be performed with an oligonucleotide primer.” Thus, both options may be used in the instant invention, and would thus be possible for the ordinary artisan to use. MPEP 2143.01 V states, “‘[a] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine’" (quoting Medichem, S.A. v. Rolabo, S.L., 437 F.3d 1157, 1165, 77 USPQ2d 1865, 1870 (Fed. Cir. 2006).” Thus, while both providing and not providing a primer may have particular advantages and disadvantages in performing the method of Deng, the presence of any disadvantages does not obviate the use of a primer in the overall method.
Specifically regarding the 35 USC 103 Rejections presented in the Final Rejection, Applicant argues that the teachings of para. 156 of Deng are related to single-stranded templates, based on the teachings of para. 74 of the reference (Remarks, pages 15-16). Applicant also argues that Deng teaches away from the claimed invention due to the various points in the reference that teach methods that do not require the use of an oligonucleotide primer.
At several locations throughout the invention, Deng states that in some embodiments, the extension reaction is performed without the use of a primer (e.g. paras. 9, 20, 39, 48, 156, 179, and 217). However, Deng also explicitly recites the use of primers in several instances (e.g. paras. 74, 134, 156, 179, and 217). In order to constitute a teaching away, MPEP 2145 X (D) 1 notes, "Furthermore, "the prior art's mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed.... In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)." Deng does not criticize or discourage the use of primers, particularly as the reference teaches embodiments which use said primers. Thus, the reference cannot be considered to teach away from the claimed invention.
Regarding single and double-stranded targets, though para. 74 of Deng discusses extension with primers in single-stranded polynucleotides, this teaching still generally discloses the use of primers, rendering it relevant to the rejection. Para. 156 of the reference however specifically discusses extension and primer use in the context of double-stranded nucleic acids, and particularly those that are circular (see paras. 154-155 as well, which specifically describe double-stranded nucleic acid molecules). These teachings were combined with additional teachings in the reference, as well as a motivation and a reasonable expectation of success, shown in para. 37 of the Final Rejection. Applicant has not directly addressed the rationale behind the rejection of this claim.
Thus, Applicant’s arguments are not considered sufficient to remove Deng as a reference in regards to prior art rejections. Thus, though new grounds of rejection are provided below due to Applicant’s claim amendments, the relevant teachings of the reference are reiterated.
Claim Objections
Claim 1 is objected to because of the following informalities: in step (c), line 3 reads “template having, wherein the” but the word “having” should be removed. Appropriate correction is required.
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.
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.
Claims 1, 4-6, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (WO 2019/226689 A1; cited in Applicant’s IDS).
Deng teaches an embodiment of their invention in Figure 4B and para. 266. This embodiment involves attaching adapters to double-stranded DNA, circularizing the DNA, nicking a single strand of the DNA, and then amplifying and sequencing the DNA. The nicking can be done via the use of a nickase, and Deng states that the nickases of their invention may be nicking endonucleases (para. 118; instant claim 5). This nickase would act on the adapter sequences, as evidenced by Figure 4B, which states that the adapters have nickase recognition sites. These adapters also have UMI barcode sequences, as shown in Figure 4B (instant claim 4). Deng also states that the nicking site may expose a 3’ free end that can serve as a template for a polymerase (para. 266), and this end is shown as being extended and sequenced in Figure 4B. As the double-stranded circular DNA contains two strands complementary to one another, and the polymerase is shown attaching to both strands at the location of the extendable end in Figure 4B, this polymerase would then perform extension to create a strand at least partially complementary to the circular strand. Furthermore, though para. 266 of Deng is not specific about the length of the nick generated by the nickase, para. 118 states that nicks may be 10 or more nucleotides long, with no upper limit provided. Thus, this embodiment also reads on instant claims 18 and 19.
However, in this embodiment, no teaching is provided regarding primer binding sites. Nevertheless, Deng teaches that the nicking site of the double-stranded adapter is where sequencing can occur. Specifically, an extension reaction can occur from this nicking site to generate a growing strand (para. 9). This extension reaction can occur via the use of an oligonucleotide primer (paras. 74 and 156). Figure 4B also shows an example of extending the gapped strand, where a DNA polymerase can attach to the nicked site (para. 266). As Deng teaches that this extension can occur via the use of a primer, it would be prima facie obvious that the non-nicked strand (i.e. the fully circular strand) would need to contain a binding site for this primer to bind to, in order to guide the DNA polymerase to the correct position to begin extension (Figure 4B shows that the DNA polymerase is capable of such positioning, as it is shown as attached to both strands at the gapped location). This would simply require designing a primer that was similar to, or the same as, part of the sequence of the removed nucleotides on the gapped strand, which would correspond to a portion of the adapter sequence, as the adapter sequence is the nicked sequence in the teachings of Deng described above. Designing or obtaining such a primer would be possible for the ordinary artisan, as this process would be similar to designing or obtaining the initial adapter sequence.
Thus, claims 1, 4-5, and 18-19 are prima facie obvious over Deng.
Regarding claim 6, Deng teaches the methods of claims 1, 4-5, and 18-19, as described above. In para. 159 of Deng, it states that amplification of double-stranded nucleic acids may occur before coupling to the double-stranded adapter, but then this would require the use of a number of adapters that is the same as or more than the number of amplification copies present. Such an amplification is also shown in Figure 4B. However, it would be prima facie obvious to the ordinary artisan that by amplifying the adapter-coupled linear nucleic acids before circularization, this would prevent the need for creating adapters equal to the number of copies of the double-stranded nucleic acids. As the number of copies could easily be in the thousands or tens of thousands, by attaching the adapters before amplification, this would prevent the need for the time and resources required to create such a large number of adapters. This would likely also ensure a more effective circularization reaction, as there would be less unused adapters present in the reaction mixture before circularization, which would lead to more accurate circularization processes, as there would be less interference from the smaller number of unused adapters. There would be a reasonable expectation of success as this change would simply involving changing the order of known procedures (e.g. adapter-attachment and amplification) in the method of Deng, and the same result, namely a circularized double-stranded nucleic acid, would be produced.
Thus, claim 6 is prima facie obvious over Deng.
Claims 1, 3-4, and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (WO 2019/226689 A1; cited in Applicant’s IDS), as evidenced by Shim et al. (Biomed Microdevices, 2016).
Deng teaches methods and systems for processing or analyzing a nucleic acid molecule utilizing adapters, nicking, and circularization (Abstract). Paras. 200-201 and Figure 1D (process 170) show an example method in which a double-stranded nucleic acid is provided, and may be coupled with multiple adapters, where a single adapter contains one or more uracil nucleotides. Two adapters may be provided, one which does contain one or more uracils and one which does not. The adapters may be added via ligation (instant claim 3). The free ends of the two adapters are then ligated together, generating a circular molecule (instant claim 9). Then, the circular molecule may be treated with one or more uracil-specific enzymes which nick uracil residues on the adapter sequence. This results in a double-stranded molecule where one strand is fully circular and the other is gapped. Deng teaches that the adapters used for circularization may comprise one or more barcodes (para. 134; instant claim 4). After circularization, the mixture can be treated with an exonuclease to remove non-circularized polynucleotides (para. 306; instant claim 8).
In para. 201 it is stated that, “Following, the circular nucleic acid molecule may be treated with one or more uracil-specific enzymes (e.g., uracil-specific excision reagent or "USER") to generate a single nucleotide gap (i.e., nick) at the location of the uracil residue.” Here, the language of Deng does not make clear that USER enzymes may cleave multiple uracil residues, even if more than one USER enzyme is provided.
Shim teaches enzymatic reactions related to detaching DNA from particles (Abstract). To capture DNA, a DNA sequence was designed with a four uracil linker (page 2, column 1, para. 3). USER enzyme digestion was eventually performed to remove the entire uracil linker (i.e. more than one uracil residue; see Figure 1a). More than a single USER enzyme was provided (see the concentration illustration of Figure 1b, as well as page 2, column 2, para. 1).
Thus, Shim provides evidence that if more than a single USER enzyme is used, then said USER enzymes can cleave more than a single uracil residue. In the embodiment of Deng detailed above in paras. 200-201, it is explicitly stated that multiple uracil residues may be included on an adapter and that one or more USER enzymes may be used. Thus, this embodiment of Deng encompasses creating gaps of more than one base.
However, in this embodiment, no teaching is provided regarding primer binding sites. Nevertheless, Deng teaches that the nicking site of the double-stranded adapter is where sequencing can occur. Specifically, an extension reaction can occur from this nicking site to generate a growing strand (para. 9). This extension reaction can occur via the use of an oligonucleotide primer (paras. 74 and 156). Figure 4B also shows an example of extending the gapped strand, where a DNA polymerase can attach to the nicked site (para. 266). As Deng teaches that this extension can occur via the use of a primer, it would be prima facie obvious that the non-nicked strand (i.e. the fully circular strand) would need to contain a binding site for this primer to bind to, in order to guide the DNA polymerase to the correct position to begin extension (Figure 4B shows that the DNA polymerase is capable of such positioning, as it is shown as attached to both strands at the gapped location). This would simply require designing a primer that was similar to, or the same as, part of the sequence of the removed nucleotides on the gapped strand, which would correspond to a portion of the adapter sequence, as a portion of the adapter sequence is the nicked sequence in the teachings of Deng described above. Designing or obtaining such a primer would be possible for the ordinary artisan, as this process would be similar to designing or obtaining the initial adapter sequence.
Thus, claims 1, 3-4, and 8-9 are prima facie obvious over Deng.
Conclusion
No claims are currently allowable.
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/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681
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