DETAILED ACTION
The present Office Action is responsive to the Amendment received on December 11, 2025.
Preliminary Remark
Claims 17-23 are new.
Claims 141, 15 and 16 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 July 15, 2025.
Information Disclosure Statement
The IDS received on December 11, 2025 and December 29, 2025 are proper and are being considered by the Examiner.
Claim Objections – Necessitated by Amendment
Claim 19 is objected to because of the following informalities: the word, “Paleococcus” is misspelled. The word should be, “Palaeococcus.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 19 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a Written Description Rejection.
Claim 19 recites that the flap endonuclease being utilized in the method of claim 1 belongs to Genus Palaeococcus.
The Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
Such is the case here. The specification does not provide any evidence of possession of a flap endonuclease from the genus Palaeococcus by way of its sequence, means demonstrative its isolation. The specification appears to simply list various sources from which the endonuclease could be isolated, one of such sources being the genus, Palaeococcus.
The written description requirement ensures that, “an applicant invented the subject matter which is claimed. Further, the written description requirement for a claimed genus may be satisfied through a sufficient description of a representative number of species by 1) reduction to practice; 2) reduction to drawing; or 3) disclosure of relevant identifying characteristics (i.e., structure of other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure) (MPEP 2163 at II(A)(3)(a)(ii)).
Reduction to Practice
The claims and specification simply reiterate each other. There is no additional description made in the specification.
To reiterate, the Federal Circuit reiterated that mere use of the same words in the specification and the claim (an in ipsis verbis test) is not sufficient to establish written description.
Reduction to Drawing
The specification has no drawings to evidence that Applicants were in possession of any endonuclease that has flap cleavage activity isolated from Palaeococcus.
Disclosure of Relevant Identifying Characteristics
While one could argue that a skilled artisan would be able to identify the “representative number of species” of such endonucleases, including from the genus of Palaeococcus, such method would not satisfy the written description for the genus claims when, “the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art” (MPEP 2163(I)(A)). For the claims at issue, such essential or critical feature is the actual enzyme. Applicants have not disclosed a reasonable number of species, let alone, not even a single species within the claimed genus which embraces an endonuclease comprising flap cleavage activity from the genus Palaeococcus.
As stated in University of California v. Eli Lilly and Co. at page 1404:
An adequate written description of a DNA ... "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel, 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
Therefore, for the foregoing reasons, the genus embraced by the claims is not sufficiently described by the number of species disclosed in the specification, and therefore, the specification lacks written description of the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The rejection of claims 1, 3, 8, 9, 11, and 13 under 35 U.S.C. 102(a)(1) as being anticipated by Makino et al. (Journal of Printing Science and Technology, 2017, vol. 56, no. 6, pages 377-382; IDS ref), made in the Office Action mailed on September 25, 2025 is maintained for the reasons of record.
In addition, claim 17 is rejected herein as being necessitated by Amendment (by its addition).
Applicants’ arguments presented in the Amendment received on December 11, 2025 have been considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section.
The Rejection:
With regard to claims 1 and 13, Makino et al. teach a method depicted by the below reproduced figure (from Fig. 6):
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As seen, Makino et al. teach a method of detecting a target nucleic acid (see DNA), comprising:
cleaving a first flap (see the top flap structure) formed by a target nucleic acid, a first nucleic acid and a second nucleic acid (see flap containing first nucleic acid, a second nucleic acid abutting the flapped end of the first nucleic acid, and the target DNA), wherein the flap is cleaved;
cleaving a second flap of a second cleavage structure formed by a third nucleic acid, the cleaved first flap, and the fourth nucleic acid (see the cassette formed from a top strand (third nucleic acid) folded onto the fourth nucleic acid (bottom strand), and the first cleaved flap (annealed to near the FRET dyes), wherein the flap containing “F” dye is cleaved; see also English translation “[w]hen target DNA is present in the microdroplet, invader oligos and allelic probes bind to the target DNA to form a Flap structure. FEN-1 [flap endonuclease] recognizes this structure and cleaves the part of the allele probe [i.e., cleaved first flap generation]. The cleaved fragment [i.e., cleaved first flap] binds to the fluorescent substrate DNA [i.e., third and fourth nucleic acids], forming a flap structure [i.e., second cleavage structure], and the enzyme cleaves the fluorescent substrate DNA again”, section 4.2); and
detecting the presence of the target nucleic acid by detecting the cleaved second flap (see above where cleavage results in signal generation, also “generating a fluorescent signal …”, section 4.2), wherein the cleaving the first flap and second flap is carried out by cleaving with a flap endonuclease (FEN-1, see translation 4.2) and has a sequence identity of 65% or higher with an amino acid sequence of a flap endonuclease of the microbe belonging to the order of Thermococcales (i.e., FEN-1).
With regard to claim 3, the target nucleic acid is DNA (see above).
With regard to claims 8 and 9, the artisans do not teach any reagent concentrations (thus 0 mM).
With regard to claim 11, the artisans teach that the reaction volume is as little as femtoliters (“new digital measurement realizes several tens of femtoliters”, section 4.1, translation).
Therefore, Makino et al. anticipate the invention as claimed.
Response to Arguments:
Applicants traverse the rejection (page 7, bottom paragraph, Response).
Applicants contends that there is “nothing in the cited references that would lead to one skilled in the art to expect the superior S/N ratio values that are obtained with Applicant’s claimed microbes” (page 7, bottom paragraph, Response), alluding to the specification where it is discussed that, “since the cleaving the first flap and the cleaving the second flap are carried out by means of a specific endonuclease, the S/N ratio is enhanced as compared to conventional methods” (page 7, bottom paragraph, Response).
Applicants refer to the data found on specification, in particular, Table 4 wherein S/N ratio demonstrate the unexpectedly superior properties of the claimed invention (page 7, Response).
These arguments have been considered but are not found persuasive because the invention as claimed is not commensurate with that which is discussed in the specification that produces the so-called, “unexpected,” “superior” properties.
And this is not acquiescing to the result of the assay producing results that is “unexpected” or “superior.”
For example, Table 4, lists a specific type of FEN proteins with specific concentrations producing the purportedly superior S/N ratio. For example, the specification, on page 30 clearly demonstrates, the specifically listed FEN proteins are used in a specific condition that involve specific set of buffer concentration, incubation temperatures and incubation times.
These are not what Applicants are claiming. Rather, the claims deliberately employs a generic claim term in the form of, “flap endonuclease”, wherein the flap endonuclease is microbes belonging to the Order of Thermococcales”. As discussed above, FEN-1 and this endonuclease is thermostable thus from the order of thermococcales.
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).
In regard to claim 17, FEN-1 is an enzyme belonging to Thermococcus.
Therefore, Applicants’ arguments are not found persuasive and the rejection is maintained.
Claim Rejections - 35 USC § 103
The rejection of claim 2 under 35 U.S.C. 103 as being unpatentable over Makino et al. (Journal of Printing Science and Technology, 2017, vol. 56, no. 6, pages 377-382; IDS ref) in view of Lyamichev et al. (US 2006/0183207 A1, published August 2006; IDS ref), as applied to claims 4, 5, 6, 7, and 10 above, and further in view of Schomacher et al. (DNA Repair, 2010, vol. 9, pages 438-447), made in the Office Action mailed on September 25, 2025 is withdrawn in view of the Amendment received on December 11, 2025, removing the rejected element from the claim (i.e., Methanothermobacter Thermautotrophicus strain Dela H).
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 4-7, 10, and 122 under 35 U.S.C. 103 as being unpatentable over Makino et al. (Journal of Printing Science and Technology, 2017, vol. 56, no. 6, pages 377-382; IDS ref) in view of Lyamichev et al. (US 2006/0183207 A1, published August 2006; IDS ref), made in the Office Action mailed on September 25, 2025 is maintained for the reasons of record.
Applicants’ arguments presented in the Amendment received on December 11, 2025 have been considered but they have not been found persuasive for the reasons discussed in the, “Response to Arguments” section.
The Rejection:
The teachings of Makino et al. have already been discussed above.
Makino et al. do not explicitly teach that their assay is performed in a reagent having pH between 7.5-9.0 (claim 4), or that the flap assays are performed at a temperature between 55oC-70oC (claim 5), or that the reagent comprises Mg2+ (claim 6), and its concentration between 2.5 mM-20 mM (claim 7), or the concentration of the flap endonuclease (claim 10).
Makino et al., while explicitly teaching that the second cleavage structure is formed by a hairpin structure produced between the third/fourth nucleic acid and the first cleaved flap, the artisans do not explicitly teach that the hairpin structure comprises a linker molecule (between the third and the fourth nucleic acid, claim 12).
Lyamichev et al. teach a FRET cassette which, in combination with a flap from a first flap cleavage structure, results in a detectable signal generation, which is identical to the means disclosed by Makino et al. (see below from Fig. 112):
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As seen, the FRET cassette comprises a hairpin structure formed between a second and a third nucleic acid, a structure identical to Makino et al., as well as operating in the same mechanism by which Makino’s method operates.
When pertaining to the looped structure of this FRET cassette, Lyamichev et al. teach that this region can be made of nucleotides, or a spacer, or a linker (“loop may be nucleic acids … or a non-nucleic acid spacer or linker”, section [0441]).
In addition, Lyamichev et al. explicitly teach that this method employs a reaction comprising a pH of 7.5 (see section [0785], “25 ng of CLEAVASE BN nuclease in 20 mM MOPS (pH 7.5)”) and an incubation temperature of 61oC (“[a]fter 30 minutes at 61oC”, section [0785]).
Lyamichev et al. teach the use of buffer comprising Mg2+ (section [0744]), at 2 to 4 mM (see section [0820]).
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 Makino et al. with the teachings of Lyamichev et al., thereby arriving at the invention as claimed for the following reasons.
As discussed above, Makino et al. and Lyamichev et al. teach a method of utilizing invasive cleavage structure, wherein the first invasive cleavage structure if formed, generating a first, cleaved flap that is employed in generating a second invasive cleavage structure comprising a label, wherein the formation results in the cleavage of the flap in the second invasive cleavage structure.
Makino et al. teach that their method can be applied in miniaturized compartments for quantification purposes, but do not explicitly teach all reaction conditions involving the assay.
However, Lyamichev et al. teach a general reaction conditions governing the assay of Makino et al. in that the reaction requires mono- or di-valent cations, such as Mg2+, incubation temperature, pH conditions, and enzyme amounts (see above).
Lyamichev et al. also evidence that these conditions were well-characterized conditions that can be optimized and are directly linked to result (i.e., result-effective variables):
“[b]uffer conditions should be chosen that will be compatible with both the oligonucleotide/target hybridization and with the activity of the cleavage agent … optimal buffer conditions for nucleic acid modification enzymes … generally included enough mono- and di-valent salts … KCl buffer or Mg-containing buffer”, section [0425])
“Temperature is also an important factor in the hybridization of oligonucleotides … Where it is desired to have a reaction be run at a particular temperature (e.g., because of an enzyme requirement, for convenience, for compatibility with assay or detection …”, section [0437])
Lyamichev et al. also explicitly teach a temperature condition, pH condition, and amount of divalent cations which overlaps with the presently claimed amounts and while the artisans did not explicitly teach the amount of enzyme (i.e., flap endonuclease), one of ordinary skill in the art would have clearly recognized that determination of an amount which can be optimized for the reaction of Makino et al. would have been a result-effective variable.
In In re Antonie (559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding.
Because one of ordinary skill in the art would have recognized that the amount of flap endonuclease used in the cleavage reaction of Makino et al. played in important part in the outcome of the assay, optimizing such a condition would have been clearly recognized as a result-effective variable among other conditions recognized by Lyamichev et al., the determination of which would have involved a routine optimization involving empirical determination, 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.”
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Response to Arguments:
Applicants traverse the rejection.
Applicants contend that, “Makino offers very little guidance on the suitable choice of suitable flap endonucleases” and that there is nothing that would guide one to Applicants’ microbes belonging to the Order of Thermococcales and microbes belonging to the Order of Methanobacteriales as recited in claim 1 (page 8, Response).
Applicants contend that mere disclosure of mthFEN enzyme in Stomacher as a 5’ flap endonuclease is not sufficient to motivate one skilled in the art to use the enzyme in the Makino method (page 8, Response).
The argument directed to the order of Methanobacteriales is moot as claim 1 and its dependents don’t require the use of Flap enzymes belonging to the order of Methanobacteriales. The rejection is maintainable under FEN-1 which belongs to the order of Thermococcales.
The Office also contends that the observance of improved S/N ratio need not be the sole motivation to arrive at the invention as claimed, so long as another motivation exists in the art, but nevertheless arrive at the same, claimed invention.
“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)
In the present situation, one of ordinary skill in the art would have had a reasonable motivation to involve other prior art known Flap endonucleases which behave the same way as that which was observed by Makino and Lyamichev, all of which would have yielded the same predictable outcome, that is, cleaving the flaps which produce the desired detection signal in the method of Makino. And having had such a motivation based on the same predictable outcome, utilizing such enzymes of the same functional characteristics and discovering their optimal condition (e.g., buffer concentration, reagent concentrations, incubation temperatures/times, etc.) for which the detection is made would have been well-within the purview of the ordinarily skilled artisan as doing so would have been optimization of result-effective variables.
The rejection is maintained.
Rejection – New Grounds, Necessitated by Amendment
Claims 2, 17, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Makino et al. (Journal of Printing Science and Technology, 2017, vol. 56, no. 6, pages 377-382; IDS ref) in view of Burkhart et al. (Journal of Bacteriology, July 2017, vol. 199, no. 13, pages 1-8) and Sorge et al. (WO 01/32922 A2, published May 2001).
The teachings of Makino et al. have already been discussed above.
Makino et al. do not explicitly teach that other types of FEN-1 enzymes could be utilized as their cleavage agent.
Burkhart et al. teach FEN-1 enzyme is found in Thermococcus Strain KOD1:
“activity of the archaeal flap endonuclease (Fen1, encoded by TK1281 in Thermococcus kodakarensis [or KOD1] has been well documented …)” (page 2, 2nd paragraph)
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 Makino et al. with the teachings of Burkhart et al. and Sorge et al., thereby arriving at the invention as claimed for the following reasons.
As discussed above, Burkhart et al. teach an enzyme comprising a 5’ flap endonuclease activity isolated from KOD1.
In addition, Sorge et al., who also teach a method of detecting a target nucleic acid in a sample that involve the formation of a 5’ flap cleavage structure, said flap being cleaved by an FEN nuclease (see page 5, lines 9-14).
Sorge et al. define the enzyme, “FEN nuclease” as below:
“As used herein, a ‘FEN nuclease’ refers to an enzyme that cleaves a cleavage structure according to the invention” (page 5, lines 14-15)
Sorge et al. then defines what a cleavage structure is as below:
“As used herein, a ‘cleavage structure’ refers to a polynucleotide structure … comprising at least a duplex nucleic acid having a single stranded region comprising a flap …” (page 6, lines 11-13)
As well, Sorge et al. provides a list where such FEN nucleases could be isolated from:
“a thermostable nucleic acid polymerase or FEN nuclease derived from thermophilic organisms such as P. furiosus, M. jannaschii, A. fulgidus or P. horikoshii are more stable and active at elevated temperatures as compared to a nucleic acid polymerase from E. coli or a mammalian FEN enzyme.” (page 12, lines 9-15)
“FEN nuclease enzyme derived from Archaeglobus fulgidus, Methanococcus jannaschii, Pyrococcus furiosus, human, mouse or Xenopus laevis …” (page 14, lines 25-26)
Therefore, one of ordinary skill in the art would have had a reasonable expectation of success that FEN nucleases from other organisms could also be utilized in the method of Makino et al., so long as said FEN nuclease cleaved the same 5’ flap structure as required in the method of Makino et al.
Indeed, based on the evidence presented by Burkhart et al. teaching that FEN endonuclease from KOD1 cleaves a 5’ flap structure, one of ordinary skill in the art would have concluded that utilizing the FEN endonuclease from KOD1 would have yielded the same predictable outcome of generating the necessary cleavage function in the method of Makino et al.
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.”
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
Claims 18, 21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Makino et al. (Journal of Printing Science and Technology, 2017, vol. 56, no. 6, pages 377-382; IDS ref) in view of GenBank Accession No. CAB49654 (publicly available March 7, 2015) and Sorge et al. (WO 01/32922 A2, published May 2001).
The teachings of Makino et al. have already been discussed above.
Makino et al. do not explicitly teach that other types of FEN-1 enzymes could be utilized as their cleavage agent.
FEN-1 flap endonuclease isolated from P. abyssi strain GE5 has been characterized and publicly available as evidenced by GenBank Acession No. CAB49654.
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 Makino et al. with the FEN-1 flap endonuclease from P. abyssi strain GE5 and Sorge et al., thereby arriving at the invention as claimed for the following reasons.
As discussed above, GenBank Accession No. CAB49654 teach an enzyme comprising a 5’ flap endonuclease activity isolated from P. abyssi, strain GE5, as well as expressly demonstrating that the enzyme also has FEN-1 flap endonuclease function.
In addition, Sorge et al., who also teach a method of detecting a target nucleic acid in a sample that involve the formation of a 5’ flap cleavage structure, said flap being cleaved by an FEN nuclease (see page 5, lines 9-14).
Sorge et al. define the enzyme, “FEN nuclease” as below:
“As used herein, a ‘FEN nuclease’ refers to an enzyme that cleaves a cleavage structure according to the invention” (page 5, lines 14-15)
Sorge et al. then defines what a cleavage structure is as below:
“As used herein, a ‘cleavage structure’ refers to a polynucleotide structure … comprising at least a duplex nucleic acid having a single stranded region comprising a flap …” (page 6, lines 11-13)
As well, Sorge et al. provides a list where such FEN nucleases could be isolated from:
“a thermostable nucleic acid polymerase or FEN nuclease derived from thermophilic organisms such as P. furiosus, M. jannaschii, A. fulgidus or P. horikoshii are more stable and active at elevated temperatures as compared to a nucleic acid polymerase from E. coli or a mammalian FEN enzyme.” (page 12, lines 9-15)
“FEN nuclease enzyme derived from Archaeglobus fulgidus, Methanococcus jannaschii, Pyrococcus furiosus, human, mouse or Xenopus laevis …” (page 14, lines 25-26)
Therefore, one of ordinary skill in the art would have had a reasonable expectation of success that FEN nucleases from other organisms could also be utilized in the method of Makino et al., so long as said FEN nuclease cleaved the same 5’ flap structure as required in the method of Makino et al.
Indeed, based on the evidence presented by GenBank Accession No. CAB49654 teaching FEN-1 endonuclease from P. abyssi, strain GE5, one of ordinary skill in the art would have concluded that utilizing this FEN endonuclease would have yielded the same predictable outcome of generating the necessary cleavage function in the method of Makino et al.
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.”
For these reasons, the invention as claimed is deemed prima facie obvious over the cited references.
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 rejection of claims 1-13 on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of copending Application No. 17/913,679 (reference application), made in the Office Action mailed on September 25, 2025 is maintained for the reasons of record. The reationale for maintaining the rejection is adopted from the above discussion.
As well, claims 2, 17, 18, and 20-23 are rejected (necessitated by Amendment) based on the above-discussed references (Burkhart et al., Journal of Bacteriology, July 2017, vol. 199, no. 13, pages 1-8; GenBank Accession No. CAB49654, publicly available March 7, 2015; and Sorge et al. (WO 01/32922 A2, published May 2001), adopting the same rationale of record.
The Rejection:
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are directed to a method of detecting a target nucleic acid comprising the steps that generate a first cleaved flap structure from a first cleavage structure formed among a target nucleic acid, a first nucleic acid, and a second nucleic acid, wherein the cleaved first flap structure anneals to a second and third nucleic acid to form a second flap cleavage structure, and detecting a signal produced from this second flap cleavage reaction (see claim 1), wherein the flap endonuclease is also recited as having a percent similarity to KOD1, Methanothermobacter thermautotrophicus strain delta H, and Pyrococcus abyssi strain GE5 (see claim 1), with reagent and reaction conditions which overlap with the presently claimed conditions (see dependent claims 3-10), as well as the linker being present between the third and the fourth nucleic acids of the second flap cleavage structure (see claim 11).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
Claim 19 is free of prior art as the prior art does not teach or suggest of any existence or characterization of an endonuclease comprising a flap cleavage activity being isolated from Palaeococcus.
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.
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/YOUNG J KIM/Primary Examiner
Art Unit 1637 February 19, 2026
/YJK/
1 The non-final action mailed on September 25, 2025 contained a typographical error or acknowledging Applicants’ election as pertaining to claims 1-14. However, the totality of the record is clear that Applicants’ election was directed to Group I, claims 1-13 (see Applicants’ Election on July 15, 2025) as well as the substance of the Office Action mailed on September 25, 2025 which does not address claim 14 in any of the rejections.
2 Claim 12 was not shown in the preamble of the rejection by typographical error, but the claim is clearly addressed and rejected on page 6 of the rejection in substance (see first paragraph and fourth paragraph with reference to section [0441] of Lyamichev.