DETAILED ACTION
The present Office Action is responsive to the Amendment received on August 2, 2026.
Preliminary Remark
Claim 9 is canceled.
Claim 18 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 2, 2026.
Information Disclosure Statement
The IDS received on September 16, 2026 is proper and is being considered by the Examiner. The IDS was filed with the statement under 37 CFR 1.97(e)(1).
Drawings
The replacement drawings received on August 2, 2026 are acceptable.
Claim Rejections - 35 USC § 112
The rejection of claims 1-16 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to particularly point out and distinctly claim the subject matter, made in the Office Action mailed on May 1, 2026 is withdrawn in view of the Amendment received on August 2, 2026.
Rejection - Maintained
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.
The rejection of claim 17 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 May 1, 2026 is maintained for the reasons of record.
Applicants’ claim amendment in the Amendment received on August 2, 2026 has been considered but the amendment is deemed insufficient as discussed below.
Applicants state that the trademark Eclipse has been deleted from claim 17. While this is true, Applicants need to delete all trademarks presented in the claim. The Office action merely pointed out Eclipse as an example. The recitation of Iowa Black RQ is another trademarked dye by Integrated DNA Technologies. Applicants must delete all trademarked elements from the claim.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 2, 6-8, and 10-17 under 35 U.S.C. 102(a)(1) as being anticipated by Makarov et al. (US 2014/0038185 A1, published February 2014; IDS ref), made in the Office Action mailed on May 1, 2026 is withdrawn in view of the Amendment received on August 2, 2026.
Specifically, Makarov et al. do not teach that the partial primer comprises a spacer located between the sequence binding to the site other than the target hybridization site of the guide probe and the sequence binding to the detection site of the target nucleic acid.
Claim Rejections - 35 USC § 103
The rejection of claims 3-5 and 9 under 35 U.S.C. 103 as being unpatentable over Makarov et al. (US 2014/0038185 A1, published February 2014; IDS ref) in view of Egholm et al. (US 2003/0064402, published April 3, 2003), made in the Office Action mailed on May 1, 2026 is withdrawn in view of the Amendment received on August 2, 2026. However, the rejection is withdrawn because the limitation of claim 9 has been incorporated into base claim 1. The rationale of the rejection is maintained, and Applicants’ arguments are addressed in the order they were presented in the, “Response to Arguments” section.
Rejection – New Grounds, Necessitated by Amendment
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 1-8 and 10-17 are rejected under 35 U.S.C. 103 as being unpatentable over Makarov et al. (US 2014/0038185 A1, published February 2014; IDS ref) in view of Egholm et al. (US 2003/0064402, published April 3, 2003).
With regard to claims 1 and 8, Makarov et al. teach a method of amplifying a target nucleic acid comprising the below-depicted scheme (reproduced from Fig. 5A):
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As seen, the method involves the mixing of a target nucleic acid isolated from a sample (“sample with a target polynucleotide”, section [0123]) with: i) a guide probe capable of hybridizing with a site other than a detection site of the target nucleic acid (the left-side oligonucleotide, wherein Fb anneals to a region on the target that is not “detection site”); ii) a partial primer including a sequence binding to a site other than a target nucleic acid hybridization site of the guide probe and a sequence binding to the detection site of the target nucleic acid (see right-side oligo with Pc as the sequence binding to the “other” site, and Pa binding to the target detection site); and iii) a specific primer capable of paring with the partial primer to amplify the target nucleic acid (see Fig. 8A, or “combination further comprises a reverse primer, wherein the reverse primer comprises a polynucleotide sequence complementary to a polynucleotide strand comprising a sequence that hybridizes to T1”, section [0010]), and performing a PCR (“the polynucleotide combinations are contemplated for use in PCR”, section [0103]); and determining whether or not an amplification product is present (“target amplification … amplify and detect a small number of cancer-specific mutant alleles …”, section [0116]).
With regard to claim 2, the site of the guide probe that hybridizes with the target nucleic acid is present at a 5’ end and a site of the guide probe that hybridizes with the target primer is present at a 3’ end (this configuration is inherent as the Pa region of the partial primer is extended at its 3’ end).
With regard to claim 5, the guide probe, the partial primer and the specific primer comprise oligonucleotide (i.e., natural bases).
With regard to claims 6 and 7, the guide probe is PNA having the sequence length of 10 to 500, or 20 to 150 (i.e., the first probe comprise PNA, “oligonucleotide … contemplates peptide nucleic acid (PNA) …”, section [0075]; “the first polynucleotide is comprised of … PNA”, section [0094]; “first domain of the first polynucleotide is 5 nucleotides that is complementary to a target polynucleotide region … 6 … 7 … 9 … 10 … second domain of the first polynucleotide comprises 10 or more nucleotides”, section [0085]).
With regard to claim 10, the sequence of the partial primer binding to the target nucleic acid side is a sequence of 3 to 15 nucleotides (“second polynucleotide comprises a first domain containing about 10 nucleotides, this first domain of the second polynucleotide being complementary to a target DNA region that is different from the target region recognized by the first domain of the first polynucleotide …”, section [0086], see also Pa length in section [0015]).
With regard to claim 11, the amplification product produced by the two polynucleotides would necessarily comprise between 50 bp to 1kbp because the regions that anneal to the partial primer (i.e., second probe) having the Pa region with contemplated lengths (as discussed above) along with the reverse primer that anneals on the opposing side with its own complementary would result in an amplification product having 50 bp or greater.
As well, Marakorov et al. teach a primer pair (SEQ ID NO: 18 and 20, Example 9) that generates an amplicon with a length of around 79 bp (see below).
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With regard to claims 12 and 13, the amplification is contemplated to involve SYBR Green (section [0124], “[d]ue to the increased specificity of the polynucleotides described herein, real-time PCR can be performed in the presence of SYBR green dye to achieve a specificity that is equivalent to that achieved using TaqMan …”).
With regard to claims 14 and 15, the artisans also contemplate the use of a FRET probe comprising a reporter and a quencher (see Figure 5A, also, “primer combination with a probe … probe polynucleotide comprises a label at its 5’ end and a quencher at its 3’ end”, section [0030]).
With regard to claims 16 and 17, the artisans teach that the FRET dye pair can be FAM (see section [0148]) and Black Hole Quencher (see section [0148]).
While Markarov et al. teach a guide probe that comprises a portion which is complementary to a region of a target nucleic acid, and a portion that is not complementary to the target nucleic acid, but anneals to a partial primer, the artisans do not teach a linker between the two portions (claim 3), the linker being elements received in claim 4.
Makarov et al. do not teach that the partial primer comprises a spacer of 1 to 100 nucleotides between the sequencing binding site to the guide probe and the sequence binding to the target nucleic acid (claim 9).
Egholm et al. teach a means of providing a linker between a probe having a complementary region to a target nucleic acid and a region that complements to second probe (see reproduced below, Fig. 1A):
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As seen, the probe 26 comprises a central region which is comprised a linker located between the two regions of complementarity discussed above, and probe 28 also comprises central region of the same makeup.
Egholm et al. teach that these probes comprising a linker are selected from beta-alanine (@-Ala-OH, C3), C4, C6, C12, AAEA, etc. (section [0058]).
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 Makarov et al. with the teachings of Egholm et al., thereby arriving at the invention as claimed for the following reasons.
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.”
Similarly, one of ordinary skill in the art would have recognized the same predictable outcome of utilizing a flexible linker between the two portions of the probes (of Makarov et al.) that would have provided the constraints present when forming a hybridization complex as observed in Egholm et a.
Similarly, a single-stranded “spacer” region that connected the two annealing portions of the partial primer (i.e., second polynucleotide of Makarov et al.) would also have yielded the same predicable outcome of allowing the two portions to anneal with relief provided by the single-stranded spacer region of multiple nucleotides as needed. Indeed, this knowledge as already been provided by Makarov et al. in the embodiment provided in Figure 12.
Therefore, the invention as claimed is deemed prima facie obvious over the cited references.
Response to Arguments:
Applicants traverse the rejection.
Applicants, on page 13, argue that the element, “linker” in the instant claim 2 is present only in Egholm while “spacer” in claim 1 is not disclosed or suggested in either Makarov or Egholm (page 13, Response).
This argument is confusing because the words, “linker” and “spacer” without an explicit limiting definition, or structural configuration, are distinguishable by words alone. For example, a linker “spaces” two regions of the oligonucleotide from each other, as well as a spacer “linking” the same two regions of the oligonucleotides. Therefore, by words alone, their recitation does not distinguish the structure taught by Egholm et al.
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In other words, the two “bulges” represented by (30), while referred to as a “linker” by Egholm et al. (section [0058]), can both link and space two regions of the oligonucleotides (12 and 14, respectively) and therefore, meets the limitations of the claim.
Next, Applicants contend that the spacer of the present invention is different from that of Egholm in that the spacer is “a single-stranded oligonucleotide” while the flexible linker of Egholm is “C3, C4, C6, C12, AAEA, and the like” (see page 14, Response).
This argument has been carefully considered but has not been found persuasive because the usage of a linker in the form of alkane chains or other known forms of linker such as nucleotide sequences have been well-known in the art.
For example, primers such as scorpion primers have long been known in the art which employs stretches of non-target complementary nucleotide portions that allow the primer to provide flexibility (see Thelwell et al., NAR, 2000, vol. 28, no. 19, pages 3752-3761, Table 2 and Figure 1).
This is because the rationale for adding the linkers at positions 30 and 22 is expressly discussed by Egholm, wherein the artisans state:
“It has been discovered that a three-way junction can be stabilized by the introduction of a flexible linker between the portion of the smaller probe that interacts with the target nucleic acid and the portion that interacts with the other smaller probe(s)” (section [0009])
Given that the configuration of the junction formed by the probes and target nucleic acid of instant application and that formed by Makarov is identical, one of ordinary skill in the art would have recognized the benefit of adding a flexible linker that provides flexibility at the “bending” points of the probe of Makarov as expressly motivated by Egholm, with means known in the art such as non-nucleotidic of Egholm, as well as those that are nucleotidic as conventionally known in the art, as evidenced by Thelwell et al.
Next, Applicants contend that the guide probe and the partial primer hybridize with the target nucleic acid results in the formation of a gap between the target nucleic acid hybridization site of the guide probe and the target nucleic acid site of the partial primer when hybridizing to each target nucleic acid, while the probe configuration of Makarov does not (page 14-16, Response).
These arguments are not found persuasive because the claimed “gap” is not explicitly required in any of the instant claims.
Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Notwithstanding this, Egholm teaches such a configuration (see below):
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“the first region 18 and the second region 24 of the target nucleic acid 20 are substantially adjacent, i.e., separated by zero or one nucleotides.” (section [0079]).
Therefore, Applicants’ arguments are not deemed persuasive and the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The provisional rejection of claims 1-17 on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 18/551,590 (reference application), made in the Office Action mailed on May 1, 2026 is maintained for the reasons of record.
Applicants, in the Amendment received on September 16, 2026, contend that the conflicting application claims require a clamping probe that is nowhere specified in instant claims (page 18, Response).
This argument is simply flawed as the narrower claims of the conflicting application contains all of the limitations of the instant claims, and as species anticipates a genus, the claims of the conflicting application claims all of the limitations of the instantly claimed method. The instant claim is therefore obvious over the claims of ‘590 application.
The Rejection:
Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
With regard to instant claim 1, claims of the reference application also claims a method comprising the steps of:
mixing a nucleic acid isolated from a sample with: i) a guide probe capable of hybridizing with a site other than a detection site of the target nucleic acid (“amplifying an isolated nucleic acid”; also “in the presence of: i) a guide probe comprising a sequence capable of hybridizing with a region of a target nucleic acid other than a detection region (see claim 1(a)(i)); ii) a partial primer including a sequence binding to a site other than a target nucleic acid hybridization site of the guide probe and a sequence binding to the detection site of the target nucleic acid (“a partial primer comprising a sequence complementary to the sequence not hybridizing with the target nucleic acid in the guide probe and a sequence complementary to the detection region of the target nucleic acid”, see claim 1(a)(ii)); and iii) a specific a specific primer capable of pairing with the partial primer to amplify the target nucleic acid (“a specific primer capable of amplifying the target nucleic acid by pairing with the partial primer”, see claim 1(a)(iv)); and performing PCR; and
determining whether or not an amplification product is present (“determining the presence or absence of an amplicon”, see claim 1(b)).
With regard to instant claim 2, a site of the guide probe that hybridizes with the target nucleic acid is present at a 5’ end and a site of the guide nucleic acid probe that hybridizes with the partial primer is present at a 3’ end (see claim 2).
With regard to instant claim 3, the guide probe further comprises a linker between the site of the guide probe that hybridizes with the target nucleic acid and the site of the guide probe that hybridizes with the partial primer (see claim 3).
With regard to instant claim 4, the claims of the reference application recites the same Markush elements of linkers (see claim 4).
With regard to instant claim 5, the guide, the partial primer, and the specific primer comprise oligonucleotide (see claim 17).
With regard to instant claim 6, the guide probe is PNA with 10 to 500 bases (see claim 6).
With regard to instant claim 7, the guide probe is PNA with 20 to 150 bases (see claim 7).
With regard to instant claim 8, the guide probe is hybridized with an opposite strand to one strand of the target nucleic acid with which the specific primer hybridizes (see claim 8).
With regard to instant claims 9 and 10, claims 9 and 10 of the reference application are verbatim.
With regard to instant claim 11, the amplicon has a length of 50 to 1 kbp (see claim 14).
With regard to instant claim 12, step (b) uses nucleic acid binding dye or probes (see claim 15).
With regard to instant claim 13, the nucleic acid binding dye are identical to those recited in claim 16 of the reference application.
With regard to instant claim 14, the probe capable of binding to the amplification product is selected LNA, PNA and mixtures thereof (see claim 17).
With regard to instant claim 15, both ends of the probe capable of binding to the amplification product is connected to a reporter and a quencher (see claim 18).
With regard to instant claims 16 and 17, the reporter and quenchers (respectively) are identical to claims 19 and 20 (respectively).
While the reference application does not explicitly claim that the amplicons are produced by a PCR, the ordinarily skilled artisan would have recognized that the configuration by which the recited elements are used would have acted as a forward and reverse primers with a detection probe therebetween, similar to a quantitative/real-time PCR assay that produces amplification products.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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.
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 October 9, 2026
/YJK/
