DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 30, 2026 has been entered.
Preliminary Remark
Claims 1-14, 17, 18, 20-22, 26, and 27 are canceled.
Claim Rejections - 35 USC § 112
The rejection of claims 16, 28, and 29 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter, made in the Office Action mailed on November 28, 2025 is withdrawn in view of the Amendment received on March 30, 2026.
The rejection of claim 19 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point out and distinctly claim the subject matter, made in the Office Action mailed on November 28, 2025 is withdrawn in view of the Amendment received on March 30, 2026.
Claim Rejections - 35 USC § 103
The rejection of claims 18, 20-22, and 27 under 35 U.S.C. 103 as being unpatentable over Kainz et al. (BioTechniques, February 2000, vol. 28, no. 2, pages 278-282) in view of Billard et al. (Applied and Environmental Microbiology, February 2012, vol. 78, pages 1063-1068) made in the Office Action mailed on November 28, 2025 is withdrawn in view of the Amendment received on March 30, 2026, canceling the rejected claims (and incorporating them into base claim 1).
Rejection - Maintained
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 rejection of claims 15, 16, 19, 23-25, 28, and 29 under 35 U.S.C. 103 as being unpatentable over Kainz et al. (BioTechniques, February 2000, vol. 28, no. 2, pages 278-282) in view of Billard et al. (Applied and Environmental Microbiology, February 2012, vol. 78, pages 1063-1068) made in the Office Action mailed on November 28, 2025 is maintained for the reasons of record.
Applicants’ arguments presented in the Amendment received on March 30, 2026 have been carefully considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section.
The Rejection:
With regard to claim 15, Kainz et al. teach a method of detecting a target DNA sequence comprising the steps of:
providing (i) a template including the target DNA sequence having a potential sequence (“system for low copy number target amplification, we amplified target sequence of 1 kb or 1.7 kb length … of a phage l genome”, page 278, 3rd column), (ii) a forward primer and a reverse primer bot binding to the template (see Table 1, also “50 mL standard reaction mixture contained the following components: 0.4 mM of each primer …”, page 278, 3rd paragraph); (iii) a DNA polymerase polymerizing a DNA from the forward primer and reverse primer (“[u]sed in this experiment were AmpliTaq DNA polymerase Taq DNA polymerase …”, page 278, 2nd column); (iv) a discrimination-boosting oligonucleotide that is not complementary to the template, to the forward primer and to the revese primer, wherein the discrimination-boosting oligonucleotide is capable of non-specifically reversibly binding to the DNA polymerase and is not an aptamer, and is a double-strand (“the widely used Taq and Tfl DNA polymerases are inhibited by short double-stranded DNA fragments … the presence of these fragments in PCR mixtures is also … to produce hot-start conditions1”, page 278, 2nd column; the double-stranded fragments do not show complementarity to the primers nor the target nucleic acid, see Table 1, also “sequences of the double-stranded DNA fragments used have been designed arbitrarily”, page 278, 3rd column, 2nd paragraph);
performing a polymerase chain reaction (PCR) using the DNA polymerase in the presence of the template, the forward primer, the reverse primer, and the discrimination-boosting oligonucleotide (“PCRs were carried out”, page 279); and
acquiring an amplification reaction and detection outcome (“PCR products were analyzed by 1% agarose gel electrophoresis and ethidium bromide staining”, page 279).
With regard to claim 19, the discrimination boosting-oligonucleotide is a double-stranded oligonucleotide (see above).
With regard to claims 22 and 23, the DNA polymerase is a wild-type thermostable DNA polymerase (Taq DNA polymerase, see above).
With regard to claims 24 and 25, the discrimination-boosting oligonucleotide has a length of 10 to 100; or 15 to 50 bases (see Table 1, double-stranded DNA fragments used and their length being between 15 to 50 bases, which is within 10 to 100 bases).
With regard to claim 27, the discrimination-boosting oligonucleotide has a Tm of 50-85oC (see Table 1).
While Kainz et al. teach that their method of amplification is useful for enhancing the PCR reaction (i.e., hot-start PCR), the artisans do not explicitly teach that their method is adaptable to all possible types target nucleic acids widely assayed in the art of molecular diagnostics.
Consequently, the Kainz et al. do not explicitly teach that the target nucleic acid is for detecting genetic mutations, such as SNPs (claim 1, in-part, claim 21).
Kainz et al. opted to employ a traditional means of detecting the amplified products in the form of gel run. Consequently, the artisans do not explicitly teach that other means of amplification methods, such as real time PCR which produces an amplification curve could be employed for their method, that utilizes a FRET labeled probe (claims 15 (in-part), 16, 18, 28, and 29).
Billard et al. teach a well-known adoption of PCR amplification for the detection of single nucleotide polymorphisms in a sample, wherein the artisans employ a real-time detection/quantification PCR, known as TaqMan® (see Abstract).
Billard et al. teach the well-known mean of target detection which involves the hybridization of a FRET dye pair labeled probe which lies between two flanking primers, wherein the assay is designed to detect a single nucleotide polymorphism of interest (see Fig. 1; also “[w]e developed a sensitive, real-time PCR method for quantifying the underlying DNA polymorphism … Allele-specific real-time PCR assays were conducted … allele-specific primers and then with allele-specific probes”, page 1063, 2nd column; see also page 1064, 1st column, bottom paragraph, “TaqMan Probes were purchased … and were labeled with the 5’ end with a … FAM … and the 3’ end with … non-fluorescent quencher”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Kainz et al. with the teachings of Billard et al., thereby arriving at the invention as claimed for the following reasons.
The Office notes that the basis of the rejection may differ from that of the inventive concept of the instant application, but nevertheless, the invention “as claimed” is deemed obvious from reasons other than the subject-inventive concept.
“The Circuit first erred in holding that courts and patent examiners should look only to the problem the patentee was trying to solve. Under the correct analysis, any need or problem known in the field and addressed by the patent can provide a reason for combining the elements in the manner claimed.” (page 6, Opinion, KSR)
“The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006)
As discussed above, Kainz et al. already teach an amplification method which enhance specificity of a PCR of target nucleic acids in a sample by use of a double-stranded DNA molecules which bind to a thermostable DNA polymerase, wherein the double-stranded DNA molecule comprises a melting temperature that is at or higher than that of the annealing temperature employed in the PCR amplification reaction during amplification:
“Specificity-enhanced hot-start PCR is especially useful because the temperature at which the activity of the polymerase is released is adaptable to the conditions required using the melting temperature of the DNA fragments” (page 278, 2nd column)
“The results indicate that effective hot-start conditions are obtained if the reaction mixtures contain double-stranded DNA fragments with measured melting temperature values between 60oC and 70oC …” (page 282, 1st column)
While Kainz et al. were not explicit in suggesting that their method be employed to other types of diagnostic assays, one of ordinary skill in the art would have been motivated to apply the teachings of Kainz et al. and combine the use of the double-stranded DNA molecule (or discrimination-boosting oligonucleotides) in other PCR employed amplification reactions, such as real-time TaqMan® PCR assay for detecting target nucleic acids which are of interest in the art, such as single nucleotide polymorphisms.
Since the double-stranded DNA molecules of Kainz et al. did interfere with the primers in their amplification reaction, one of ordinary skill in the art would have expected that the probes involved in a TaqMan® PCR amplification reaction (as the aptamer was not target or primer specific) have had a reasonable expectation of success that the probes used in a real-time PCR assay would not have been affected, yielding a predictable outcome.
In KSR, the Supreme Court particularly emphasized “the need for caution in granting a patent based on the combination of elements found in the prior art,” Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are “[t]hree cases decided after Graham [that] illustrate this doctrine.” Id. at 416, 82 USPQ2d at 1395. (1) “In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.”
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Response to Arguments:
Applicants traverse the rejection (page 7, Response).
Applicants contend that Kainz teaches away from simultaneous reaction, citing the statement made by the artisans:
“explicit mechanism of Kainz requires that the inhibitor fragment bind to the DNA polymerase prior to the introduction of other reaction components to prevent low-temperature mis-priming. In particular, Kainz explicitly states: ‘[i]n any case, the fragments should encounter the DNA polymerase before the template and primers are added’” (page 8, Response).
Applicants contend that if the components are reacted simultaneously, as set forth in amended claim 15, the low-temperature hot-start mechanism of Kainz is defeated and therefore, the person of ordinary skill in the art would not be motivated to react Kains’s fragments simultaneously with the primers and template (page 9, Response).
These arguments have been carefully considered but they have not been found persuasive.
Applicants’ position is based on Kainz’s statement that suggested that the discrimination-boosting oligonucleotide (i.e., 0.6 mg of double-stranded DNA fragments), although added separately, should encounter the DNA polymerase before the template and primer were added (see below, from Kainz):
“One unit of DNA polymerase and 0.6 mg of double-stranded DNA fragments [i.e., discrimination-boosting oligonucleotide], if not indicated otherwise, were either combined or added separately to the reaction mixture. In any case, the fragments should encounter the DNA polymerase before the template and primers are added” (Kainz et al.)
Not acquiescing whether this statement would “teach away” from adding the reagents of claim 15(a), separately, the Office contends that claim 15, even as amended does not require that the discrimination boosting oligonucleotides be separately added to the reaction mixture, separated from the DNA polymerase, with templates and primers.
This is because Applicants’ arguments are not commensurate in scope of the presently rejected claims.
Claim 15 has been amended to recite step (a) which provides “a reaction mixture comprising (i) a template including the target DNA sequence having a potential mutation locus … (iii) a DNA polymerase extending the forward primer and the reverse primer along the template … and (iv) a discrimination-boosting oligonucleotide”; and the limitation, “wherein, in the step (b), the discrimination-boosting oligonucleotide is reacted simultaneously with the forward primer, the reverse primer, the template, and the DNA polymerase”.
All that claim 15, step (a) requires is that a mixture be formed with reagents that include: 1) a template including the target DNA sequence; 2) forward and reverse primers2; 3) a DNA polymerase; and 4) discrimination-boosting oligonucleotide.
The claim does not require that the DNA polymerase and discrimination-boosting oligonucleotide be separately provided, but that they are present in a reaction mixture. To this end, the reaction mixture employed by Kainz definitely contains all of the four reagents discussed above.
The latter introduced limitation found in claim 15 that recites that “in the step(b), the discrimination-boosting oligonucleotide is reacted simultaneously with the forward primer, the reverse primer, the template and the DNA polymerase,” does not necessarily require that the discrimination-boosting oligonucleotide is separated from the DNA polymerase when reacted. Even if the DNA polymerase is prior bound to the discrimination-boosting oligonucleotide in the reaction mixture, as Applicants contend, this complex, that is DNA polymerase and the discrimination boosting oligonucleotide is reacted simultaneously with the template DNA and the primers during the PCR reaction. If this were not the case, the amplification would not occur as observed. Therefore, Applicants’ claim as presently recited embraces the scope which Applicants’ allege Kainz teaches away from.
Therefore, Applicants’ argument points (a), (b), and (c) are moot.
With regard to the unpredictability (d), the improvement (e), and Declaration (3) additional data, the Office has considered them carefully.
With regard to the unpredictability and improvement aspect, the Office contends that Kainz actually teaches and provides predictability of using discrimination boosting having a melting temperature above the annealing PCR reaction temperature.
For example, Kainz teaches that effective hot-start conditions are obtained if the reaction mixtures contain double-stranded DNA fragment with measured temperature values between 60oC and 70oC, referring to the discrimination boosting oligonucleotides disclosed in Table 1 (of page 279), with oligonucleotide “G” having a melting temperature of close to 70oC.
Because Kainz teaches a PCR reaction having an annealing temperature of 60oC (“[c]ycling conditions were as follows: 2 min at 93oC, followed by 45 cycles consisting of 50 S at 60oC [i.e., annealing temperature], 1min … at 68oC [extension temperature] …”, 279, bottom paragraph to page 280, 2nd column), there is a predictability of utilizing discrimination-boosting oligonucleotides having a melting temperature that is higher than that of the annealing temperature of a PCR reaction.
With regard to Applicants’ declaration, as discussed above, the claims do not necessarily require that the discrimination boosting oligonucleotides be added separately into the reaction mixture and therefore, is not relevant at this time.
As well, in general, the Office notes that an unpredicted outcome/superiority demonstrated by a Declaration must be commensurate in scope of the claimed invention. A declaration showing a perceived result utilizing a specific conditions and reagents (e.g., SEQ ID NO: 13 for discrimination-boosting oligonucleotide) as being “unexpected” cannot then be applied to a reaction condition not requiring the specific set of reagents involved in the declaration.
For these reasons, the arguments are not found persuasive and the rejection is maintained.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Inquiries
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Young J. Kim whose telephone number is (571) 272-0785. The Examiner can best be reached from 7:30 a.m. to 4:00 p.m (M-F). The Examiner can also be reached via e-mail to Young.Kim@uspto.gov. However, the office cannot guarantee security through the e-mail system nor should official papers be transmitted through this route.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Gary Benzion, can be reached at (571) 272-0782.
Papers related to this application may be submitted to Art Unit 1681 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 CFR 1.6(d)). NOTE: If applicant does submit a paper by FAX, the original copy should be retained by applicant or applicant’s representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED, so as to avoid the processing of duplicate papers in the Office. All official documents must be sent to the Official Tech Center Fax number: (571) 273-8300. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 May 2, 2026
/YJK/
1 A “hot-start” condition is known to produce higher specificity in a PCR reaction by reducing mis-priming of the DNA polymerase to non-specific target nucleic acids, thus within the meaning of the word, “discrimination boosting”.
2 The primers being AS or ARMS primer is not discussed here as these elements have been taught by the supporting references of record.
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