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 .
Status of Claims / Response to Amendment
This office action is in response to an amendment filed on May 05, 2026.
Claims 1-10, 12-16, 18-19 and 26-29 were previously pending. Applicant amended claims 1 and 29.
Claims 1-10, 12-16, 18-19 and 26-29 are currently pending, with claim 28 withdrawn.
Claims 1-10, 12-16, 18-19 and 26-27 and 29 are under consideration.
All of the previously presented objection and rejections have been withdrawn as being addressed or obviated by the amendment of the claims, which added new limitations to the claims, that were not considered in the previous rejections.
The previously set forth prior art rejections have been withdrawn in view of the recent claim amendment filed on May 05, 2026, which added new limitations to the claims (i.e., the newly amended method in claim 1 now recites "(f) removing the solid support, thereby removing only the second strand, or only a part thereof comprising the reverse complement of the sequence of interest to obtain the pool of multiple single-stranded oligonucleotides having the sequence of interest"). Thus, the scope of the claims has been changed in a manner that were not considered in the previous rejections.
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
This office action contains new grounds for rejection necessitated by amendment.
Priority
The priority date of the instant claims 1-10, 12-16, 18-29 and 26-27 and 29 is June 12, 2018, filling date of the European Patent Application Number 18177178.3, to which the present application claims priority.
New Grounds of 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 following are new grounds of rejections necessitated by Applicant's amendments. Although the claims were previously rejected as being unpatentable over the same reference(s), Applicant's amendments have necessitated the inclusion of new grounds of rejections in this Office action. It is noted that, to the extent that they apply to the present rejection; Applicant's arguments are addressed in the "Response to Arguments" section following the rejections.
Claims 1-4, 6, 8-10, 13-16, 18-19, 26 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Wang1 (US20130072390 A1-Methods for Synthesizing Pools of Probes; published March 21, 2013; cited as US Patent Documents #A15, on IDS filed 12/10/2020), as evidenced by
Eijk (US7166429B2- Method for generating oligonucleotides, in particular for the detection of amplified restriction fragments obtained using AFLP®; published 2007-01-23);
Pound (Pound et al., Polymerase chain reaction based scaffold preparation for the production of thin, branched DNA origami nanostructures of arbitrary sizes. Nano Lett. 2009 Dec;9(12):4302-5. doi: 10.1021/nl902535q. PMID: 19995086);
Yuce (Yuce et al., Characterization of a dual biotin tag for improved single stranded DNA production. Anal Methods. 2014;6:548–557);
Kao (Kao et al., An Efficient Bead-captured Denaturation Method for Preparing Long Single-stranded DNA. J Chin Chem Soc. 2017;64:1065–1070);
Wilson (Wilson R. Preparation of single-stranded DNA from PCR products with streptavidin magnetic beads. Nucleic Acid Ther. 2011 Dec;21(6):437-40. doi: 10.1089/nat.2011.0322. Epub 2011 Nov 2. Erratum in: Nucleic Acid Ther. 2012 Apr;22(2):137. PMID: 22047177).
A) Wang1 teaches a method for synthesizing pools of DNA probes by amplification for multiplex amplification and analysis of nucleic acid targets (entire document).
Regarding claim 1, Wang 1 teaches a method for producing a pool of multiple single-stranded oligonucleotides having a distinct sequence of interest (FIG. 2; FIG. 8, [0118], lines 11-14; [0133] lines 1-8), wherein the method comprises:
(a) providing a pool of multiple single- or double-stranded nucleic acid precursors each comprising a first strand (FIG. 2; FIG. 8, [0118], lines 11-14),
wherein the first strand comprises the following elements in a 5' to 3' direction:
(i) a first primer binding site (FIG. 2, region 102a; [0098]);
(ii) a first endonuclease recognition site (FIG. 2, region 107a; [0098]);
(iii) the sequence of interest (FIG. 2 ; FIG. 8, 103a,105a, 109, 105b,103b;[0090]);
(iv) a second endonuclease recognition site (FIG.2, 107b; [0098]); and
(v) a second primer binding site (FIG. 2, region 102b);
wherein the first endonuclease recognition site is designed such that, after duplexing, a first endonuclease cleaves the sugar-phosphate backbone of the first strand immediately upstream of the sequence of interest (FIG. 2, 151, 107a; [0098], lines 9-11); and,
wherein the second endonuclease recognition site is designed such that, after duplexing, a second endonuclease cleaves the sugar-phosphate backbone of the first strand immediately downstream of the sequence of interest (FIG. 2, 151, 107b; [0098], lines 9-11);
(b) amplifying the pool of multiple precursors of (a) by an isothermal amplification method (FIG 2, 150; [0098]; ([0041], line 11, isothermal amplification method, for instance, SDA), using a first primer (FIG 2, 111a) capable of hybridizing to the first primer binding site and a second primer (FIG 2, 111b) capable of hybridizing to the second primer binding site,
wherein the second primer comprises an affinity-tag (FIG 8, 111a comprises an affinity tag, 111b does not; [0118], lines 7-8) that is not present on the first primer, to produce amplified double-stranded deoxyribonucleic acid (DNA) precursors (FIG 8, 850) comprising an untagged first strand and a tagged complementary second strand ([0118]lines8-9,24-25; Figure 8, 113; [0086]);
(c) digesting the amplified double-stranded DNA precursor obtained in (b) with the first and the second endonuclease (FIG 2, 152 ; [0098], lines 13-21) to produce amplified double-stranded nucleic acid precursors with cleavages of the sugar-phosphate backbone immediately up- and downstream of the sequence of interest and with an intact sugar-phosphate backbone between the tag up to and including the sequence complementary to the sequence of interest (FIG 2, 121 ; [0098], lines 13-21);
(d) immobilizing the amplified double-stranded nucleic acid precursor on a solid support by affinity capture of the tagged complementary second strand ([0135] lines1-5);
(e) denaturing the amplified double-stranded precursor, thereby releasing the single-stranded oligonucleotide having the sequence of interest ([0135] lines 12-15); and
(f) removing the solid support thereby removing only the second strand, or only a part thereof comprising the reverse complement of the sequence of interest to obtain the pool of multiple single-stranded oligonucleotide having the sequence of interest ([0135] the MIPs (which are not biotinylated) are released from the streptavidin beads and recovered").
Regarding the limitation "amplified double-stranded deoxyribonucleic acid (DNA) precursors " in part (b), it is taught by Wang1 as it is clear that the amplification products disclosed in both FIGs 2 and 8 are DNA products. Wang1 is directed to the preparation of DNA probes via amplification, as stated in the abstract. Accordingly, the amplification products from which the DNA probes are derived are DNA. Therefore, a person of ordinary skill in the art would understand that Wang 1 discloses DNA amplification products, which meets the recited limitation.
Although Wang1 does not explicitly disclose all claimed limitations in a single embodiment, a person of ordinary skill in the art, in view of the teachings of Wang1 and the knowledge in the art, would have found the claimed method to be an obvious variation of known methods.
FIG. 2 of Wang1 teaches most of the claimed limitations. FIG. 2 teaches amplification using two primers (FIG. 2, 111a and 111b; [0091]), to produce an amplified double-stranded nucleic acid precursor (114).
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The primary difference is that FIG. 2 teaches amplification using two tagged primers, thereby producing an amplicon in which both strands are tagged, whereas the claim requires that one primer comprises a tag and the other primer does not comprise the same tag, thereby producing a DNA product comprising one tagged strand and one untagged strand. However, this feature is taught In FIG. 8 of Wang1.
Specifically, in Wang1's FIG. 8 and para. [0118] teach a first strand nucleic acid (FIG. 8, 800) amplified by using a first primer (111b) and a tagged second primer (111a), to produce an amplified double-stranded nucleic acid precursor (FIG. 8, 814) comprising an untagged first strand (FIG. 8, bottom sequence is the same sequence as the starter first strand) and a tagged complementary second strand (FIG. 8, top sequence comprising tag).
Further, the use of affinity selectable reagents such as biotin-streptavidin system to separate an untagged single-stranded DNA of interest from a biotin-tagged complementary strand, is well established in the art of single-stranded DNA synthesis.
Eijk (col 33-35, Example VI), Pound (Figure 1), Yuce (Scheme 1, Abstract), Kao (Fig. 1), and Wilson (FIG. 2) each teach the use of streptavidin beads as solid support to remove biotin-tagged antisense strand from solution, thereby isolating the target sense strand. For example, Example VI of Eijk teaches generating single-stranded oligonucleotides by biotin-streptavidin separation, wherein a precursor comprising a biotin tag on the complementary strand is double restriction digested (Eijk, col 34, lines 50-67) and denatured to separate the untagged strand from the tagged complementary strand (Eijk, col 35, lines 1-20).
Therefore, as evidenced by above, both approaches ꟷ amplicons in which both strands are tagged and amplicons in which only the complementary strand is tagged ꟷ were known in the art for the same purpose of isolating synthesized single-stranded DNA products, and both approaches are taught and suggested by Wang1.
Accordingly, it would have been apparent to a skilled artisan that modifying the FIG.2 embodiment such that only one amplification primer is tagged, thereby producing an amplicon having one tagged strand and one untagged strand, represents an obvious variation of the embodiments disclosed in Wang1 in view of established single-stranded DNA synthesis methods in the art. Wang1 already teaches amplification using one tagged primer and another primer lacking the same tag, as shown in FIG. 8. Given the known function of each element as explained by Wang1 and the general knowledge in the field, the combination of such elements represents an assemblage of known elements according to known methods that yields predictable results. The combination of these elements in the manner claimed does not impart any new or unexpected results beyond the teaching of Wang1.
The person having ordinary skill in the art would have had a reasonable expectation of success in making such modification because the detailed teaching in Wang1 provide a strong technical foundation for their successful integration. The difference between FIG. 2 and 8 in relation to the claimed invention, lies in whether a single primer or both primers binding to the first and second strands of a nucleic acid molecule include the same affinity tag. It is well within the capability of a skilled artisan to use primers with or without affinity tags. Wang1 also teaches in paragraph [0137] that variations of the examples provided are included within the scope of its disclosure, thus implying that alternatives and substitutions are obvious to a skilled artisan.
A person of ordinary skill in the art, motivated by the general desire to enhance the process of oligonucleotide probes synthesis, which will further enable multiplexed target-specific nucleic acid detection at larger scale, as suggested by Wang1([0003]), would have found it obvious to perform routine optimization and make such modification, because affinity-based separation of differently tagged strands in ssDNA synthesis, were well established.
Given that each element performs a known function as per its prior art teaching, their combination to achieve a predictable result would have been obvious, as per MPEP 2143.
Claim 1 has been amended to recite "(f) removing the solid support thereby removing only the second strand, or only a part thereof comprising the reverse complement of the sequence of interest to obtain the pool of multiple single-stranded oligonucleotide having the sequence of interest."
This newly added "thereby" clause is obvious in view of Wang1 because it merely states the intended result of the process taught and suggested by Wang1 and the knowledge in the art as discussed above. Specifically, in affinity separation, the tagged strand will be affinity-bound to the solid support and removed, whereas the untagged strand will remain in solution.
B) Regarding claim 2, Wang1 teaches steps (d) and (e) are reversed, meaning the denaturation takes place prior to immobilizing the nucleic acid amplification products on a solid support (page 11, lines3-5).
Regarding claim 3, Wang1 teaches purifying the single-stranded oligonucleotide (page 16, right col, lines 1-2).
Regarding claim 4, Wang1 teaches denaturing comprises chemical denaturing ([0135] lines 7-10).
Regarding claim 6, Wang 1 teaches the nucleic acid precursor consists of 20 - 200 nucleotides ([0133], lines 2-3, "The length of the oligos was between 110 and 121 bases in length').
Regarding claim 8, Wang 1 teaches the sequence of interest is at least partly complementary to a predetermined genomic sequence ([0133] lines 1-8. "where the genomic homology regions are represented by N20 and vary between MIPs depending on the target."; [0101]).
Regarding claim 9, Wang 1 teaches the produced oligonucleotide is suitable for use in a multiplex oligonucleotide based amplification assay ([0005] lines 1-3).
Regarding claim 10, Wang 1 teaches the nucleic acid precursors are single-stranded (FIG 2; FIG 8).
Regarding claim 13, Wang1 teaches the first and the second endonuclease are two different enzymes (FIG 2. 152).
Regarding claim 14, Wang1 teaches the first endonuclease in (c) cleaves the first DNA strand (FIG 2. 152; [0118], lines 11-14).
Regarding claim 15, Wang1 teaches the amplified double-stranded precursor is purified prior to binding the solid support ([0133] lines 19-21).
Regarding claim 16, Wang1 teaches the tag is biotin and the solid support comprises streptavidin ([0135] lines 1-4).
Regarding claim 18, Wang1 teaches the first primer can selectively anneal only to the first primer binding site and a second primer can selectively anneal to only the second primer binding site ([0133] lines 11-15, the PCR primers have different sequences for binding selectively to distinct sites).
Regarding claim 19, Wang1 teaches the sequence of interest does not comprise the first and the second endonuclease recognition sites or reverse complement thereof (FIG 2. 151, 152; [0098] line 18. "…This cuts the top strand into three pieces…" indicates the sequence of interest does not comprise any endonuclease recognition sites or reverse complement thereof).
Regarding claim 26, Wang1 teaches performing providing step (a), amplifying step (b), digesting step (c), immobilizing step (d), denaturing step (e), and removing step (f) sequentially (FIG. 2; [0098]; [0135]).
Regarding claim 29, Wang1 teaches wherein in (a) the pool of multiple single- or double-stranded nucleic acid precursors comprises at least 3000 unique sequences ([0120]).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Wang1, as applied to claims 1 and 4 above and further in view of Wang2(Wang et al. Characterization of denaturation and renaturation of DNA for DNA hybridization. Environ Health Toxicol. (2014) doi: 10.5620/eht.2014.29.e2014007. PMID: 25234413; PMCID: PMC4168728.)
A) The teachings of the Wang1 are recited above, applied as for base claims 1 and 4 and incorporated here.
Wang1 teaches a method for synthesizing pools of probes by amplification for multiplex amplification and analysis of nucleic acid targets (entire document).
Regarding claim 5, Wang1 teaches chemically denature the amplified DNA products via increasing of pH ([0135] lines 7-10). However, Wang1 does not teach the exact molar concentration of the specific alkaline solution used to increase the pH.
B) Wang2 teaches the characterization of the denaturation of DNA using alkaline solutions of varied concentrations (introduction). Wang2 teaches chemically denaturing DNA by increasing the pH by the addition of sodium hydroxide(NaOH) at a concentration of 1M (Page 6, 1M NAOH shown 100% denaturation capability). Wang2 also suggests (page 6, right-hand col, para 2.): "To ensure and leverage the complete denaturation in the follow-up study for gDNA, the 1 mol/L NaOH can be selected as an effective chemical denaturation method."
C) All limitations in claim 5 are taught by the combination of Wang1 and Wang2.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method for synthesizing pools of probes by amplification with chemical denaturation via increasing pH of Wang1 with the teachings of the use of 1M NaOH for DNA denaturation disclosed by Wang2 because both references are in the overlapping field of molecular biology and DNA denaturation techniques. A person skilled in the art would commonly encounter and consider teachings of denaturation in Wang2, when working on nucleic acid synthesis and analysis of Wang1, as effective denaturation is integral to the method taught by Wang1. The person of ordinary skill would have had a reasonable expectation of success in apply the specific NaOH concentration taught by Wang2 in the method taught by Wang1 because of Wang2's clear teaching that the use of 1M NaOH shows high denaturation capability, and doing so would yield the predictable result of effective denaturation of double stranded DNA. The skilled artisan would have been motivated to do so because using 1M NaOH as an effective chemical denaturation method would ensure complete DNA denaturation, as suggested by Wang2.
Claims 12 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Wang1, as applied to claim 1 above and further in view of Lobato (Lobato et al. Recombinase polymerase amplification: Basics, applications and recent advances. Trends Analyt Chem. (Epub 2017 Oct 26) PMID: 32287544; PMCID: PMC7112910.)
A) The teachings of the Wang1 are recited above, applied as for base claim 1 and incorporated here.
Regarding claims 12 and 27, Wang1 teaches the use of isothermal amplification method, for instance, SDA ([0041], line 11). However, Wang1 does not specifically teach other isothermal amplification methods such as Recombinase Polymerase Amplification (RPA) or Helicase Dependent Amplification (HDA).
B) Lobato provides an overview for Recombinase polymerase amplification and its applications (entire document).
Regarding claims 12 and 27, Lobato teaches the isothermal amplification methods including RPA and SDA (entire document). Lobato specifically teaches the use of both RPA and SDA in DNA amplification applications (page 19, introduction), and when comparing RPA and SDA, RPA does not require initial heating and takes less time to amplify (page 20, Table 1).
Lobato further suggests specific advantages of RPA (page 19, introduction):
"RPA is remarkable due to its simplicity, high sensitivity, selectivity, compatibility with multiplexing, extremely rapid amplification, as well as its operation at a low and constant temperature, without the need for an initial denaturation step or the use of multiple primers. Overall, RPA positions itself very favourably for widespread exploitation in kits and assays for use at the point of-care or point-of-need, as well as in affordable, sensitive, specific, user friendly, rapid, robust, equipment-free and delivered (ASSURED) devices, in low-resource settings."
C) All limitations in claims 12 and 27 are taught by the combination of Wang1 and Lobato.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the isothermal amplification method taught by Wang1 with the teachings of the isothermal amplification method RPA disclosed by Lobato because both references are in the same field of nucleic acid amplification and analysis. The references are related in their use of isothermal amplification methods, a common technique known in the art per the applicant's specification (page 27,line 26-27), thus a skilled artisan would have likely encountered and considered both references in the context of nucleic acid amplification. The person of ordinary skill would have had a reasonable expectation of success in applying RPA in the method taught in Wang1 because Lobato provides detailed information of the application of RPA and insights into the advantages of RPA over SDA. Doing so would have yielded the predictable result of increased operational simplicity and time efficiency. The skilled artisan would have been motivated to use RPA as suggested by Lobato because of several advantages such as not requiring initial heating and faster amplification, which are beneficial in the context of nucleic acid assays such as the probe synthesis methods taught by Wang1.
Response to Arguments: Unexpected results
35 U.S.C. § 103 rejections
The prior 103 rejections have been withdrawn as being obviated by the recent claim amendment filed on May 05, 2026, which added new limitations to the claims, that were not considered in the previous rejections. Therefore, although the claims were previously rejected as being unpatentable over the same reference(s), Applicant's amendments have necessitated the inclusion of new grounds of rejections in this Office action.
In the Remarks filed on May 05, 2026, Applicant presented 3 arguments traversing the prior 103 rejections. It is noted that Applicant's argument regarding lack of motivation in the prior rejection (Argument 2 in Remarks, page 8-9) is rendered moot by the new grounds of rejection set forth in this office action.
To the extent that they apply to the present rejection; Applicant's arguments 1 and 3 are addressed below.
In Argument 1, Applicant argues that the teachings in Wang1 do not teach or suggest all the elements of the present claims, specifically Applicant argues that "Wang1 does not teach or suggest producing "amplified double stranded deoxyribonucleic acid (DNA) precursors comprising an untagged first strand and a tagged complementary second strand ... ," as recited by the present claims. " (Remarks, page 7-8).
This is not found persuasive.
As discussed in the rejection above, a skilled artisan in view of Wang1's teaching and the knowledge in the art, would have found the method in claim 1 obvious. Specifically, Wang1 as evidenced by the prior art representing general knowledge in the field, teaches and suggests the limitation "produce amplified double-stranded deoxyribonucleic acid (DNA) precursors comprising an untagged first strand and a tagged complementary second strand."
First, regarding the matter of "produce amplified double-stranded deoxyribonucleic acid (DNA) precursors," Applicant argues that the amplification products in Wang1 are not DNA because Wang1's primers contain U bases. (Remarks, page 7).
This argument was previously presented by the Applicant, and was found unpersuasive in the Office Action mailed on 02/06/2026 (page 5-7).
Here, it is still not persuasive because again the argument relies on an incorrect assumption that DNA cannot contain U bases.
The fact that there is an enzyme called "uracil DNA glycosylase" is sufficient to rebut the incorrect assumption. Wang1 explicitly teaches this and the fact that U bases can be comprised by DNA is well known in the art:
“[0076] The term “UDG” or “UNG” refers to the enzyme uracil DNA glycosylase. UDG catalyses the release of free uracil from uracil-containing DNA. UDG hydrolyzes uracil from single-stranded or double-stranded DNA. See Lindahl, et al. (1977) J. Biol. Chem., 252, 3286-3294 and Devchand et al., (1993) Nucl. Acids Res., 21, 3437-3443, which are incorporated herein by reference in their entireties. The function of the enzyme in nature is to eliminate uracil bases from DNA by cleaving the N-glycosylic bond and initiating the base-excision repair pathway. UDG specifically recognizes uracil and removes it by hydrolyzing the N—Cl′ glycosylic bond linking the uracil base to the deoxyribose sugar. The loss of the uracil creates an abasic site (also known as an AP site or apurinic/apyrimidinic site) in the DNA. An abasic site is a major form of DNA damage resulting from the hydrolysis of the N-glycosylic bond between a 2-deoxyribose residue and a nitrogenous base. This site can be generated spontaneously or as described above, via UDG catalyzed hydrolysis See Marenstein et al. (2004) DNA Repair 3:527-533. Treatment of the sample DNA molecule or sample nucleic acid with alkaline solutions or enzymes, such as but not limited to apurinic/apyrimidinic endonucleases, for example APE1, will cause controlled breaks in the DNA at the abasic site. See U.S. Pat. No. 6,713,294. High temperature or high pH induced hydrolysis can generate cleavage at abasic sites, although the resulting 3′ termini of the cleavage may not be a substrate for labeling by TdT. An apurinic/apyrimidinic endonuclease can cleave the DNA molecule or nucleic acid at the site of the dU residue yielding fragments possessing a 3′-OH termini, thus allowing for subsequent terminal labeling. “
Therefore, Applicant's argument reflects a misreading of Wang1's teachings and mischaracterization of the common knowledge in the art.
Second, as detailed above an reiterated here: it would have been apparent to a skilled artisan that modifying the FIG.2 embodiment such that only one amplification primer is tagged, thereby producing an amplicon having one tagged strand and one untagged strand, represents an obvious variation of the embodiments disclosed in Wang1 in view of established single-stranded DNA synthesis methods in the art. Wang1 already teaches amplification using one tagged primer and another primer lacking the same tag, as shown in FIG. 8.
Both approaches ꟷ amplicons in which both strands are tagged and amplicons in which only the complementary strand is tagged ꟷ were known in the art for the same purpose of isolating synthesized single-stranded DNA products, and both approaches are taught and suggested by Wang1.
Given the known function of each element as explained by Wang1 and the general knowledge in the field, the combination of such elements represents an assemblage of known elements according to known methods that yields predictable results.
In Argument 2: Applicant argues that "claims 4-5 should be considered independently allowable" for reciting chemical denaturation condition, which yields unexpected results (Remarks, page 10-11).
Specifically, Applicant asserts:
"MPEP 2145 explains that "Office personnel should not require the applicant to show unexpected results over the entire range of properties possessed by a chemical compound or composition. See, e.g., In re Chupp, 816 F.2d 643, 646, 2 USPQ2d 1437, 1439 (Fed. Cir. 1987). Evidence that the compound or composition possesses superior and unexpected properties in one of a spectrum of common properties can be sufficient to rebut a prima facie case of obviousness. Id" (Emphasis added.) Hence, the working examples of the present application supports that the presently claimed method yielded unexpected results, and the present claims should be found non-obvious for this reason as well. "
This argument is not persuasive. Applicant does not explain how the cited case law applies to the present facts. The MPEP guidance and legal decisions cited discuss aspects of an obviousness analysis but the arguments make only generalizations not tied to the facts of the cases.
Applicant appears to have overlooked the core issue, namely that chemical denaturation using alkaline hydroxide within the claimed range was already known in the art, and the disclosure does not provide sufficient evidence demonstrating that the alleged results are unexpected relative to the closest prior art. This issue was discussed in the prior Office Action (Non-Final Office Action - 02/06/2026, pages 10-11) and is reiterated here.
The disclosure (in examples 2 and 3) does not provide evidence to substantiate the assertion that the results are unexpected.
As discussed in the rejections, Wang1 already teaches methods for synthesizing pools of probes by isothermal amplification, comprising chemically denature amplified DNA products via increasing of pH ([0135] lines 7-10). While the specification concludes that its method using RPA and chemical denaturation with NaOH results in higher probe yield compared to using PCR ([0330])); and that chemical denaturation is more efficient than heat denaturation, these comparisons are not the proper basis for determining unexpected results as they do not compare the disclosed method to the closest prior art.
Prior Art
Other prior art also teach single stranded DNA generation from biotin-tagged amplification products using affinity separation followed by alkali denaturation:
Marimuthu et al., Single-stranded DNA (ssDNA) production in DNA aptamer generation. Analyst. 2012 Mar 21;137(6):1307-15. doi: 10.1039/c2an15905h. Epub 2012 Feb 7. PMID: 22314701. (see Fig. 4; page 1310-1311)
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Subject Matter Not Taught/Suggested in Prior Art
Claim 7 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following subject matter is not taught or suggested in the prior art:
Claim 7 recites:
"wherein the pool of nucleic acid precursors comprises 978 different nucleic acid precursors, wherein each one of the nucleic acid precursors has a sequence selected from the group consisting of SEQ ID NO: 1 - SEQ ID NO: 978."
No prior art teach or suggest a specific pool of 978 different nucleic acids, wherein each of the nucleic acid in the pool comprise a sequence selected from the group consisting of SEQ ID NO: 1 - SEQ ID NO: 978.
Conclusion
Claim 7 is objected to; claims 1-6, 8-10, 12-16, 18-19, 26-27 and 29 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIAN NMN YU whose telephone number is (703)756-4694. The examiner can normally be reached Monday - Friday 8:30 am - 5:30 pm.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
Prosecution Insights