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 .
The claim set dated 6/17/2026 is under consideration.
The amendments and arguments presented in the papers filed 6/17/2026 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 3/10/2026 listed below have been reconsidered as indicated.
a) The amendments to the specification addressing nucleotide sequence disclosure requirements and trade name or mark usage are acknowledged.
The Examiner’s responses to the Remarks regarding issues not listed above are detailed below in this Office action.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Election/Restrictions
Applicant elected without traverse Group I (claims 1-6, 9, 10, 12, 14, 15, 17, 19, 20, 24, 26, 28, 30, 32, 33 and 35) in the reply filed on 12/16/2025.
Claim 37 drawn to a nonelected invention, has been cancelled.
Applicant’s election without traverse of the species: A) a viral nucleic acid; B) n/a; and C) calibrator probe - SEQ ID NO: 1 and indicator probe - SEQ ID NO: 2, in the reply filed on 12/16/2025 is acknowledged.
SEQ ID NOs: 1 and 2 are specific for RRDR. For species A, applicant had an opportunity to elect bacterial amplified nucleic acids, in particular RRDR (claim 10), but elected viral nucleic acids, which do not read on the use of SEQ ID NO: 1 and SEQ ID NO: 2. Thus, in view of the election of a viral nucleic acid, the election of SEQ ID NO: 1 and 2 is not applicable, similar to species “B” being “n/a”.
Claims 10, 12, 24, 26 and 28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/16/2025. The election of a “viral nucleic acid” does not encompass the alternatives of claims 10 and 12. The election of a “viral nucleic acid” does not read on the use SEQ ID NOs: 1 and 2, which target bacterial nucleic acid sequences as encompassed by claims 24, 26 and 28.
Information Disclosure Statement
The listing of references in the specification or the citation of references throughout the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or cited on any submitted IDS, they have not been considered.
Drawings
High resolution copies of the drawings may be accessed via PAIR/Patent Center Retrieval using the Supplemental Content tab.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
The sequence listing filed 6/17/2026 has errors found by the USPTO during validation of the sequence listing. The issues are described in the document “Sequence Listing ins Computer Readable Format is Defective” dated 6/17/2026. For any sequence listing related questions or concerns, Applicant is invited to contact the USPTO Sequence Help desk at 571-272-2510 or SequenceHelpDesk@USPTO.GOV.
Claim Rejections - 35 USC § 112
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.
Claim 32 is rejected 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 which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The following are modified rejections in view of the amendments that have been maintained.
Regarding claim 32, the claim states “at least one additional primers”. It is unclear if the claim implicitly requires both “a primer” and an “additional primer”. It is unclear the modifier “additional” implies that multiple primers are present in the sample or if the claim encompasses a sample having a single primer present.
Response to the traversal of the 112(b) rejections
The Remarks argue the amendments render the rejections moot (p. 11).
The arguments have been fully considered. While the rejections of claims 1, 2, 3, 4, 5, 6, 9, 14, 15, 17, 19, 20, 30, 33 and 35 are overcome by the amendments, claim 32 remains rejected for the reasons provided above.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 4, 6, 9, 14, 15, 17, 19, 20, 30, 32, 33, 35 and 39-41 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Andre (US 2021/0189486 A1).
Regarding claims 1 and 4, Andre teaches “incubating” in a partition a plurality of probe sets corresponding to a plurality of target regions (para. 7), wherein each probe set of the plurality of probe sets comprises (para. 8):
a drop-off probe as an “indicator probe” comprising a drop-off label or “second detectable label” and an oligonucleotide drop-off sequence or “third nucleic acid sequence” that is complementary to a wildtype sequence or “fourth nucleic acid sequence” at a target region corresponding to the respective probe set (para. 9); and
a reference probe as an “calibrator probe” comprising a reference label or “first detectable label” and an oligonucleotide reference sequence or “first nucleic acid sequence” complementary to a wildtype sequence or “second nucleic acid sequence” at an adjacent reference region upstream or downstream to the target region corresponding to the respective probe set (para. 10).
The partition further includes an amplicon as an “amplified target nucleic acid” (para. 11).
Andre further teaches the reference label and a drop-off label of each probe set of the plurality of probe sets are detectable via different detection channels (para. 11).
The incubation is under conditions for hybridization to occur because Andre detects the hybridization (para. 11).
Andre teaches detecting the labels of the probes (para. 11).
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Andre teaches determining a “score value” from the signals of the drop-off probe and the reference probe. A plurality of “score values” are depicted below as a combination of coordinates within a dot plot:
As depicted above, the “score value” for Mutant EGFR “deviates” from WT EGFR as the combined signals from the probes results in the two molecules being shifted relative to one another. Similarly, Mutant KRAS “deviates” in location from WT KRAS and WT NRAS “deviates” from positioning relative to Mutant NRAS.
Andre teaches “determining the absence or the presence of the mutation” by using the detected signals in the plurality of partitions from the hybridization of reference probes and drop-off probes to amplicons.
Andre teaches “control values” or “predetermined threshold values” resulting from the expected combination of signals derived from hybridized probes. For example, WT plot positions may be a “predetermined threshold value” for mutant determination or Mutant plot positions may be a “predetermined threshold values” for wild-type determination. Thus, deviation from these “predetermined threshold values” indicates the absence of a mutation or the presence of the mutation.
Regarding claim 3, as noted above, Andre teaches expected “score values”: 1) detection of a signal from a reference label and a signal from a drop-off label in a probe set indicates a wildtype sequence at the target region corresponding to the probe set; and 2) detection of a signal from a reference label but no signal from a drop-off label in a probe set indicates a mutant sequence at the target region corresponding to the probe set. See para. 11. These “scores” are based on the “absolute value” of signals from two probes when binding to “negative control samples” without the mutation and “positive control samples” with the mutation.
Regarding claim 6, Andre teaches the mutations may be insertion, deletions or single mutations (para. 113, 618).
Regarding claim 9, Andre teaches the nucleic acid target are derived from viruses (para. 226).
Regarding claim 14, Andre teaches the probes have a length of 30-40 nucleotides (para. 178).
Regarding claim 15 and 17, Andre teaches probes may include modified nucleotides, including LNA (para. 178).
Regarding claim 19, Andre teaches the probe labels are fluorescent labels (para. 185).
Regarding claims 20 and 30, Andre teaches the probes are molecular beacons, each having a quencher and a fluorophore (para. 176).
Regarding claim 32, Andre teaches the partition includes “additional” primers and a DNA polymerase (para. 33-35).
Regarding claim 33, Andre teaches amplifying the target nucleic acid using isothermal techniques (para. 117).
Regarding claim 35, Andre teaches real-time detection of probe signals (para. 205) or at an end point (para. 184).
Regarding claim 39, Andre teaches the modified nucleotides are at internal locations in Table 8, e.g. NRAS Drop-off probe and EGFR Dl19 Drop-off.
Regarding claim 40, Andre teaches detecting multiple mutated locations within genes. For example, KRAS may be analyzed for 3 mutations, satisfying the claim element of “fifth” and “sixth” nucleic acid sequences.
Regarding claim 41, Andre teaches the amplification may be LAMP (para. 117).
Response to the traversal of the 102 rejections
The Remarks provide a summary of the standard under section 102 and the prior rejection (p. 11-12).
The examiner’s position, consistent with Office policy as put forth in the MPEP, detailed above.
The Remarks argue as understood by the Office, the method of Andre determines the "absence of a mutation or the presence of the mutation" by essentially determining if two signals are detected or if only one signal is detected. The Remarks further argue the methods of the present claims are toward the use of interacting or competing dual probes specifically tuned to discriminate single-point mutations and references Fig. 2. See p. 12-14.
The arguments have been fully considered but are not persuasive. Andre teaches determining a “score value” from the signals of the drop-off probe and the reference probe are depicted above in Fig. 3 of Andre. The “score value” for Mutant EGFR “deviates” from WT EGFR as the combined signals from the probes results in the two molecules being shifted relative to one another. Similarly, Mutant KRAS “deviates” in location from WT KRAS and WT NRAS “deviates” from positioning relative to Mutant NRAS. Thus, Andre does not simply determine whether or not there is one or two signals, but rather looks at the combined signals represented by the coordinates within the plot area.
It is noted that the features upon which applicant relies (i.e., “interacting or competing dual probes”) are not recited in the rejected claim(s). 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). There is no arguments pointing the particular structure of the claimed probes that are distinct from those of Andre. The arguments are directed towards how mutations are detected based on the gathered data. In regards to that element, there are no arguments pointing out claim features that differ from those of Andre.
Claim 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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 2 and 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andre (US 2021/0189486 A1) in view of Evans (US 2022/0088003 A1).
Regarding claims 2 and 5, Andre teaches “incubating” in a partition a plurality of probe sets corresponding to a plurality of target regions (para. 7), wherein each probe set of the plurality of probe sets comprises (para. 8):
a drop-off probe as an “indicator probe” comprising a drop-off label or “second detectable label” and an oligonucleotide drop-off sequence or “third nucleic acid sequence” that is complementary to a wildtype sequence or “fourth nucleic acid sequence” at a target region corresponding to the respective probe set (para. 9); and
a reference probe as an “calibrator probe” comprising a reference label or “first detectable label” and an oligonucleotide reference sequence or “first nucleic acid sequence” complementary to a wildtype sequence or “second nucleic acid sequence” at an adjacent reference region upstream or downstream to the target region corresponding to the respective probe set (para. 10).
The partition further includes an amplicon as an “amplified target nucleic acid” (para. 11).
Andre further teaches the reference label and a drop-off label of each probe set of the plurality of probe sets are detectable via different detection channels (para. 11).
The incubation is under conditions for hybridization to occur because Andre detects the hybridization (para. 11).
Andre teaches detecting the labels of the probes (para. 11).
Andre teaches determining a “score value” from the signals of the drop-off probe and the reference probe. A plurality of “score values” are depicted above in the reproduction of Fig. 3 in the 102 rejection. As depicted above, the “score value” for Mutant EGFR “deviates” from WT EGFR as the combined signals from the probes results in the two molecules being shifted relative to one another. Similarly, Mutant KRAS “deviates” in location from WT KRAS and WT NRAS “deviates” from positioning relative to Mutant NRAS.
Andre teaches “determining the absence or the presence of the mutation” by using the detected signals in the plurality of partitions from the hybridization of reference probes and drop-off probes to amplicons.
Andre teaches “control values” or “predetermined threshold values” resulting from the expected combination of signals derived from hybridized probes. For example, WT plot positions may be a “predetermined threshold value” for mutant determination or Mutant plot positions may be a “predetermined threshold values” for wild-type determination. Thus, deviation from these “predetermined threshold values” indicates the absence of a mutation or the presence of the mutation.
Andre does not teach the additional elements specific to claims 2 and 5.
However, Evans teaches that z-scores were known and they are calculated using the equation in Table 2 and comparing them to a threshold Table 3.
It would have been prima facie obvious to the ordinary artisan at the time of filing to have modified the method of Andre by using the Z-score and the comparison to determine whether not the mutation is present. The modification has a reasonable expectation of success as it merely requires swapping data analysis methods in order to reach a conclusion about a sample.
Response to the traversal of the 103 rejections
The Remarks provide a summary of the standard under section 103 and the rejections (p. 14).
The examiner’s position, consistent with Office policy as put forth in the MPEP, detailed above.
The Remarks argue the deficiencies of Andre as previously discussed (and summarized by the Examiner above) (p. 14).
The arguments have been fully considered and are not persuasive for the reasons provided above.
The Remarks submit Andre and Evans, either alone or viewed in any combination, fail to suggest a reasonable expectation of success at arriving at the presently claimed methods, and thus a skilled artisan would not have a reason to combine Andre and Evans to arrive at the presently claimed methods, when considering the prior art references as a whole. The Remarks argue while the Office suggests that modification of the method of Andre to arrive at the use of a Z-score to determine the presence or absence of a mutation as presently claimed "merely requires swapping data analysis methods in order to reach a conclusion about a sample", a POSA would understand that making this "swap" is not so simple as the claimed methods determine the presence of a mutation by changes in signal intensity - not simply whether or not the signal is detected or not, like the methods of Andre. See p. 15.
The arguments have been fully considered but are not persuasive. The claimed methods do not require a “signal intensity” be detected, determined and/or observed. The claims broadly encompass detecting “signal”. As depicted in Fig. 3 reproduced above, Andre demonstrates how signals change, including a change in the intensity of the signal as reflected in the shift of positions within the plots.
The Remarks argue assuming that a POSA would look to alternative methods for measuring detectable signals from nucleic acids samples, it is unlikely that they would look to Evans. Evans describes methods of assessing fluorescence in high-throughput chemical screens. The Remarks argue Evans does not describe a method of using a z-score calculation to assess the fluorescence output resulting from any nucleic acid reaction, nor does the reference make any suggestion of that a z- score calculation could be used in such methods. See p. 15.
The arguments have been fully considered but are not persuasive. The Examiner’s position is not that one would look at Evans regarding how “measure” detectable signals, but rather it is the data manipulation and processing of Evans that is relevant in the above rejection. Evans uses Z-scores in analyzing fluorescence signal data, which is analogous to the data gathered by Andre. The question is whether one would have taken the fluorescent data of Andre and considered alternative manner by which to analyze that data. Plus, in para. 64 of Evans gene expression levels using PCR and RNA seq and Z scores in that context. Thus, one would appreciate the nucleic acid data in the form of fluorescence signals may readily be analyzed using Z-scores.
The Remarks argue there is no motivation for a POSA to combine the references to arrive at the present invention, nor would a POSA have any reasonable expectation of successfully doing so (p.
The arguments have been fully considered but are not persuasive. The arguments are largely conclusory, asserting there is no motivation or reasonable expectation of success. As noted above, the question is whether one would have looked at alternative analytical approaches for analyzing fluorescence signal data. Once the data fluorescent signal data is collected, it is reasonable conclude that the data can be analyzed using a variety of approaches.
Conclusion
No claims 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 JOSEPH G DAUNER whose telephone number is (571)270-3574. The examiner can normally be reached 7 am EST to 4:30 EST with second Fridays Off.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at 5712723157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH G. DAUNER/Primary Examiner, Art Unit 1682
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