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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 23, 2026 has been entered.
Status of the Claims
It is acknowledged that claim 1 was amended in the response filed July 23, 2026. Claims 1 and 5-18 are pending and herein examined on their merits.
Summary of Response
In the reply filed July 23, 2026, Applicant supplied amendments to the claims and arguments regarding rejections provided in the previous final office action.
New combinations of references are used in this office action to reject the claims. Those arguments which remain pertinent to the art relied upon are addressed in the Response to Arguments over 35 U.S.C. 103 on pages 11-12. Arguments regarding Double Patenting rejections are addressed on page 17.
Priority/Benefit
Claim to the benefit of provisional application 63/402,515 is acknowledged, and the effective filing date of the instant application is considered to be August 31, 2022.
Claim Objections
Claims 1 and 5-18 is objected to because of the following informalities recited in lines 1-2 of claim 1: “detecting a variant estrogen receptor 1 (ESR1) nucleic acid sequences.” The sentence should have agreement in number between the article and the subject. Appropriate correction is required.
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.
Claims 10, 15, and 18 are 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.
Claims 10 and 18 are rejected over the recitation of the “fourth” variant sequence. These recitations lack antecedent basis because the claims on which they depend do not recite “a fourth variant sequence.” It is unclear, for example, whether the fourth sequence variant is required to have a corresponding probe comprising any optical label. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claim 15 is rejected over the recitation of “fragmented” as indefinite. It is unclear if ‘fragmented’ is merely a description of target nucleic acids having a length of less than 100 bp, or if it is intended to provide further structural limitations (e.g. origin, quality). As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Denis (published Dec. 2017; Denis et al. Mol Diagn Ther. 2017 Dec;21(6):587-600) in view of Jeannot (published Feb. 2020; Jeannot et al. Oncogene 2020 February 10 39, 2987–2995; cited in a previous office action but provided in this office action with Supplementary Material).
Regarding claim 1, Denis teaches a method for detecting a variant nucleic acid sequences, the method comprising: obtaining a sample comprising one or more nucleic acid molecules from a subject (pg. 593, col. 1, par. 2); performing a digital polymerase chain reaction (dPCR) and partitioning the sample into reaction partitions and performing dPCR in each partition (pg. 588, col. 1); and detecting a plurality of optical signals from the dPCR reaction (Fig. 3; Table 1).
Denis teaches a probe that comprises a first optical label and specifically binds to amplicons containing a wildtype sequence; a first set of different probes, wherein each probe comprises a second optical label, wherein each different probe of the set specifically binds to amplicons that comprise at least a first, a second, and a third different variant sequence; and a
a probe comprising the first optical label, wherein the probe is specific for the first variant sequence, and wherein the second and third variant sequences are not bound by a probe comprising the first optical label (Fig. 3C – see below). Denis teaches generating two-color plots from the detected optical signals using dedicated channels for the first and second optical labels (Fig. 3C). In this embodiment (a strategy used by RainDance Technologies), Denis does not explicitly teach a third distinct optical label, nor that the first variant is bound both by a probe comprising the second optical label and a probe comprising the third optical label. However, in a second embodiment (a strategy used by Stilla Technologies), Denis does teach the use of a third optical label (Fig. 3D). In the second embodiment, Denis teaches generating a first two-color plot from the detected optical signals using a dedicated channel for the first optical label versus a dedicated channel for the second optical label and generating a second two-color plot from the detected optical signals using the dedicated channel for the second optical label and a dedicated channel for the third optical label, and identifying the presence of variants based on a shift in the deviation from an expected wild-type cluster on the first two-color plot and the second two-color plot (Fig. 3, legend; pg. 588-589: ‘dPCR and Multiplexing’).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine these elements using known methods. In this case, the combination would require only the use of systems having the capacity for at least 3 colors, and routine methods of performing dPCR and producing labeled probes. At the time, 3+ color systems (pg. 589, col. 1) and dPCR assay adaptations for overlapping probes (pg. 588, col.2, last full par.) were known. A person with ordinary skill in the art would have found the results of this combination predictable because there is no change in the respective function of each element.
Regarding claim 1, Denis does not teach that variant nucleic acids comprise ESR1 nucleic acid sequences, nor that the probes bind to amplicons comprising at least three variant ESR1 sequences and a wildtype ESR1 sequence.
Jeannot teaches a multiplex digital PCR system which detects nucleic acids comprising ESR1 variant sequences (Abstract). Jeannot teaches sets probes that bind to amplicons comprising at least a first, a second, and a third ESR1 variant sequence (pg. 2988, ‘Screening of multiple…’ and ‘Detection of polyclonal…’).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Jeannot and Denis. One would have been motivated to do so in order to detect mutations which may be used as predictive biomarkers in cancer (pg. 2988, col. 1). One would have had reasonable expectation of success because both Jeannot and Denis are directed to the detection of cancer-related mutations using dPCR (Denis: Title; Jeannot: Abstract).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Denis (published Dec. 2017; Denis et al. Mol Diagn Ther. 2017 Dec;21(6):587-600) in view of Jeannot (published Feb. 2020; Jeannot et al. Oncogene 2020 February 10 39, 2987–2995; provided as NPL in previous office action), as applied to claim 1 above, and further in view of Andre (published June 24, 2021; Patent Application Publication No. US 2021/0189486).
Denis and Jeannot teach the limitations of claim 1, as discussed above.
Regarding claim 5, Denis and Jeannot do not explicitly teach that the amplicons are further contacted with an unlabeled probe that specifically binds to a wildtype sequence at the genomic location of the first ESR1 variant sequence.
Regarding claim 5, Andre teaches amplicons which are further contacted with an unlabeled probe that specifically binds to a wildtype sequence (a ‘dark probe’; par. 170).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Denis and Jeannot with the teachings of Andre. One would have been motivated to do so in order to increase the stringency of the assay (par. 170, 183).
Claims 6-8 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Denis (published Dec. 2017; Denis et al. Mol Diagn Ther. 2017 Dec;21(6):587-600) in view of Jeannot (published Feb. 2020; Jeannot et al. Oncogene 2020 February 10 39, 2987–2995; provided as NPL in previous office action), as applied to claim 1 above, and further in view of Dustin (published online July 18, 2019; Dustin et al. Cancer. 2019 Nov 1;125(21):3714-3728. doi: 10.1002/cncr.32345. Epub 2019 Jul 18.) and Chuckalovcak (2021 Sept 28. QIAcuity digital PCR assay optimization: Best practices and guidance. QIAGEN. https://qiagen.showpad.com/share/naAotN72LBPGLsbVYwZUv; provided in previous office action).
Denis and Jeannot teach the limitations of claim 1, as discussed above.
Regarding claims 6 and 7, Denis teaches systems capable of analyzing up to 5 optical labels (pg. 589, col. 1), with at least 3 sequence variants bound by probes using the same optical label (Fig. 3C). Jeannot teaches the inclusion of at least 3 sequence variants as targets for probes comprising the same optical label (pg. 2988, ‘Screening of multiple…’ and ‘Detection of polyclonal…’).
Regarding claim 8, Jeannot teaches specifically amplifying two different ESR1 sequences, thereby producing a first amplicon and a second amplicon (Fig. 1A, 1B; Supplementary Materials: 1st par.).
Regarding claims 6 and 7, the combined references do not explicitly teach 5th, 6th, 7th, 8th, 9th, and 10th ESR1 sequence variants.
Dustin teaches more than 10 ESR1 sequence variants found in clinical samples (Figure 1, Table 1).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Denis and Jeannot with the teachings of Dustin. One would have been motivated to do so in order to identify mutations associated with acquired endocrine resistance in cancer (Dustin: pg. 2, 2nd par.). One would have had reasonable expectation of success because Jeannot and Denis demonstrate that many such mutations are detectable by dPCR (Dustin: pg. 8, par. 3; Jeannot: pg. 2988).
Regarding claims 6, 7, and 14, the combined references do not explicitly teach a fourth and a fifth optical label, nor that the 5 total optical labels comprise FAM, HEX, CY5, ROX, and ATTO550.
Chuckalovcak teaches the use of at least five optical labels in digital PCR, including FAM, HEX, CY5, ROX, and ATTO550 (Table on slide 35).
It would be obvious to one with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Denis, Jeannot, and Dustin with the teachings of Chuckalovcak. One would have been motivated to do so in order to increase multiplexing capacity (Denis: pg. 588, col. 2, 2nd par.). One would have had reasonable expectation of success because multiple systems for 5-color dPCR were available (Denis, Table 1; Chuckalovcak, slide 35) and because Chuckalovcak provides specific guidance on the development of appropriate dPCR assays.
Regarding claims 6 and 7, the combined references do not teach a set of probes binding 5th, 6th, 7th sequence variants which comprise a fourth optical label, nor a set of probes binding and 8th, 9th, 10th sequence variants which comprise a fifth optical label. That is, they do not explicitly teach two additional tranches of probes comprised of three different variants each.
However, both Denis and Jeannot teach methods which involve targeting at least three sequence variants using the probes comprising the same optical label (as discussed above). Barring evidence of a new and unexpected result, it would have been obvious to include at least three sequence variants as targets for each set of probes comprising each optical label. For example, one may have been motivated to do so in order to group mutations having different clinical relevance (Jeannot: pg. 2994, col 1, last 2 par.).
Claims 9-13 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Denis (published Dec. 2017; Denis et al. Mol Diagn Ther. 2017 Dec;21(6):587-600) in view of Jeannot (published Feb. 2020; Jeannot et al. Oncogene 2020 February 10 39, 2987–2995; provided as NPL in previous office action), as applied to claim 1 above, further in view of Dustin (published online July 18, 2019; Dustin et al. Cancer. 2019 Nov 1;125(21):3714-3728. doi: 10.1002/cncr.32345. Epub 2019 Jul 18.) and Chuckalovcak (2021 Sept 28. QIAcuity digital PCR assay optimization: Best practices and guidance. QIAGEN), as applied to claims 6 and 7 above, and further in view of Alcaide (published May 2, 2018; Alcaide et al. Methods Mol Biol. 2018;1768:275-301).
Denis, Jeannot, Dustin, and Chuckalovcak teach the limitations of claims 1, 6, and 7, as discussed above.
Regarding claims 10-12, Jeannot teaches a first amplicon which includes the genomic locations of at least amino acids 536, 537, and 538 of ESR1 (‘exon 8’) and a second amplicon which includes amino acid 380 of ESR1 (‘exon 5’; Results, 1st par.). Dustin teaches that Jeannot’s amplicons would therefore detect at least (Dustin, Table 1): L536H, L536P, L536R, L536F, L536V, Y537S, Y537N, Y537C, Y537D, D538G (in amplicon 1); and E380Q (in amplicon 2). Therefore, the combination teaches the limitations of the claim (i.e. a first amplicon comprising at least 9 variant locations, and a second amplicon comprising at least one). Regarding claim 11, Jeannot does not specifically describe a first amplicon including all amino acids from 526 through 538. However, Jeannot does describe amplicons which include genomic locations overlapping with the instant application’s range, and Dustin describes mutations encompassing an even larger range (mutations at amino acids 524, for example). Thus, amplifying that location can be considered obvious, in order to capture >95% of functionally characterized ESR1 activating mutations (Jeannot: pg. 2988, col. 1, last par.; Dustin: Table 1).
Regarding claim 13, Dustin teaches a mutant allele frequency for at least each of the ESR1 variant sequences taught by Jeannot. Thus, the combination teaches a method wherein each of the mutant allele frequencies were known.
Regarding claim 18, Jeannot discloses variant sequences equivalent to SEQ ID NO 3 (D538G), SEQ ID NO 4 (Y537S), SEQ ID NO 5 (E380Q), SEQ ID NO 6 (Y537C), SEQ ID NO 7 (EY537N), and SEQ ID NO 12 (L536R) in the dPCR assay (Results: Detection of polyclonal alterations). Any one of these would be sufficient to meet the limitations of claim 18, which requires that variant sequences comprise any one of SEQ ID NO 3-12.
Regarding claim 9, the combined references do not explicitly teach first and second amplicons having less than 65 bp in length.
Alcaide teaches design of multiplex dPCR assays in which amplicons are optimized to between 60 and 80 bp (pg. 279, 2nd par).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Denis, Jeannot, Dustin, and Chuckalovcak with the teachings of Alcaide. One would have been motivated to do so in order to reduce background noise, especially when using fragmented DNA (pg. 279, 2nd par.). One would have had reasonable expectation of success because Alcaide provides specific guidelines for the development of appropriate primers (pg. 279-280: ‘PCR Primers’).
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Denis (published Dec. 2017; Denis et al. Mol Diagn Ther. 2017 Dec;21(6):587-600) in view of Jeannot (published Feb. 2020; Jeannot et al. Oncogene 2020 February 10 39, 2987–2995; provided as NPL in previous office action), as applied to claim 1 above, and further in view of Poulet et al. (published May 6, 2021; Poulet et al. Front Oncol. 2021 May 6;11:639675; provided in a previous office action).
Denis and Jeannot teach the limitations of claim 1, as discussed above.
Regarding claims 15 and 16, Denis teaches dPCR methods using patient samples comprising circulating cell free DNA (pg. 593, col. 1, par. 2-3; Table 2).
Regarding claim 17, Denis teaches tissue samples, circulating tumor cells, and tissue biopsy samples (pg. 593, col. 1). Denis also teaches FFPE tissue samples and liquid biopsies (pg. 595: col. 1, last par.; col 2, last two par.).
Regarding claim 15, the combined references do not explicitly teach that the sample comprises fragmented target nucleic acids having a length of less than 100 base pairs
However, Poulet teaches that circulating cell free DNA comprises fragmented target nucleic acids having a length of less than 100 base pairs (pg. 5, col. 2: “RESULTS”). Therefore, Denis’s recitation of the use of samples comprising circulating cell free DNA from cancer patients is considered to have met the limitations of the claim.
Response to Arguments
In the reply filed July 23, 2026, Applicant amended the claims and provided arguments against rejections under 35 U.S.C. 103.
Applicant provided arguments against the use of Wang, Madic, Rowlands, and Zhou, which were previously relied upon to teach the limitations of at least claim 1. As those references have not been relied upon in this office action, these arguments are considered moot.
Regarding Jeannot, Poulet, and Chuckalovcak, Applicant argued that the references do not teach each limitation of the independent claim, including:
A first set of variant sequences that share a common second label, only one of which is additionally labeled with a third optical label
Discriminating the one variant sequence from the others by a shift in deviation between two two-color plots
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The combination of Denis and Jeannot is relied upon to teach the limitations of claim 1. A fuller discussion of the relevance of each reference is included in the rejections under 35 U.S.C. 103 above.
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.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of Alcaide et al. (Application No. 18/240,416). Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn toward detecting a plurality of variant nucleic acid sequences (ref claim 1). Both sets of claims require:
partitioning a nucleic acid sample into reaction partitions (ref claim 1),
performing a digital polymerase chain reaction (ref claim 1, 12) using:
a probe that comprises a first optical label and specifically binds to amplicons containing a wildtype sequence (ref claims 12, 23);
a first set of different probes, wherein each probe comprises a second optical label (ref claims 1, 13), wherein each different probe of the set specifically binds to amplicons that comprise at least three different, variant sequences (ref claims 23)
generating a two-color plot from the detected optical signals (ref claims 1, 2, 24, 25), and
identifying the presence of one or more variant sequences based on a deviation from an expected wild-type cluster on the two-color plot (ref claims 1-4, 21, 23, 24)
a third optical label, wherein the probe is specific for the first variant sequence, and a generating step comprising generating a two-color plot, wherein the presence of the first sequence is based on a shift in the deviation from a two-color plot of the first and second optical channels and the two-color plot of the second and third optical channels (ref claims 4, 13, 23-25)
wherein the amplicons include genomic locations of the variant sequences (ref claim 14)
where a mutant allele frequency is known (ref claim 9)
using optical labels comprise FAM, HEX, CY5, ROX, and ATTO550 (ref claim 16)
obtaining samples comprising cell-free DNA (ref claim 17) or wherein the sample is a tissue sample, a circulating tumor cell, a tissue biopsy sample, a formalin-fixed, paraffin-embedded tissue sample (ref claim 11)
The reference application does not claim explicitly require discriminating between a first variant and two other variants using a mixture of optically labelled probes. That is, it does not require that a set of three variants have a shared optical label and an optical label which is specific for the first variant. However, it does recite a similar strategy using probe concentration (claim 4) This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of Alcaide et al. (Application No. 18/644,268) in view of Denis (published Dec. 2017; Denis et al. Mol Diagn Ther. 2017 Dec;21(6):587-600) and Jeannot (published Feb. 2020; Jeannot et al. Oncogene 2020 February 10 39, 2987–2995; provided as NPL in previous office action).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn toward detecting a plurality of variant nucleic acid sequences (ref claim 1). Both sets of claims require:
obtaining a sample comprising nucleic acids from a subject (ref claim 1, 4)
partitioning the sample into reaction partitions and performing a digital polymerase chain reaction (ref claim 8) in each partition using optically-labelled probes (ref claim 9)
wherein the sample is cell free DNA or liquid biopsy (ref claim 4)
The reference application’s claims do not explicitly describe the detection of ESR1 sequences with a wildtype probe comprising a first optical label and a set of at least three variant probes comprising a second optical label, nor generating or detecting the presence of variant sequences from two-color plots. However, the instant application’s claims are consistent with the limitations of the reference’s claims to general detection of sequence variants in a multiplex digital PCR reaction with optically-labelled probes (ref claim 13-15). To one with ordinary skill in the art, the instant application would be an obvious embodiment of the reference’s claims, in order to efficiently detect a number of mutations which may be used as predictive biomarkers in cancer (Jeannot: pg. 2988, col. 1; Denis: ‘1.2 dPCR and Multiplexing’). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-46 of Alcaide et al. (Application No. 19/213,736) in view of Denis (published Dec. 2017; Denis et al. Mol Diagn Ther. 2017 Dec;21(6):587-600) and Jeannot (published Feb. 2020; Jeannot et al. Oncogene 2020 February 10 39, 2987–2995; provided as NPL in previous office action).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn toward detecting a plurality of variant nucleic acid sequences (ref claim 24). Both sets of claims require:
obtaining a sample comprising nucleic acids from a subject (ref claim 24)
partitioning the sample into reaction partitions and performing polymerase chain reaction in each partition using optically-labelled probes (ref claim 29)
wherein the sample is cell-free DNA or a liquid biopsy sample (ref claim 26)
The reference application does not explicitly describe the detection of ESR1 sequences using a wildtype probe comprising a first optical label and a set of at least three variant probes comprising a second optical label. However, reference claim 24 is directed to detection of cancer-related sequence variants, and claims 31 and 33 describes the detection of variants in a multiplex reaction with a plurality of amplicons and detectably labeled probes. Therefore, the embodiment disclosed by the instant application would be obvious to one with ordinary skill in the art, in order to efficiently detect a number of mutations which may be used as predictive biomarkers in cancer (Jeannot: pg. 2988, col. 1; Denis: ‘1.2 dPCR and Multiplexing’). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
In the response filed July 23, 2026, Applicant requested that the provisional double-patenting rejections be held in abeyance until the claims are otherwise in condition for allowance.
The request has been fully considered. MPEP 804(I)(B)(1) states that “[a] complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance.”
Because Applicants did not file a terminal disclaimer or file a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, the rejections are maintained.
Conclusion
No claims are allowed.
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/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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