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 .
Claims 1-22 are pending and are being examined on the merits.
Information Disclosure Statement
The Information Disclosure Statement submitted April 4, 2024 has been considered, except for NPL No. 24 to Zhou, which was not submitted.
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 11-15 and 21 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.
Indefiniteness rejections
Claim 11 recites the limitation “identifying at least one of the tumor mutations that is likely to persist through a cancer treatment”, the meaning of which is unclear. Specifically, it is not clear how the ordinary artisan is supposed to identify a tumor mutation that is likely to persist through a cancer treatment. The specification does not describe how such a determination is intended to be made, nor is there any particular method or standard known in the art for doing so. Since the claim merely recites a description of a problem to be solved, but the specification does not describe particular structure, material or steps that achieve that result, the ordinary artisan would not be able to determine the metes and bounds of the claim and it is indefinite. MPEP 2173.05(g).
Claims 12-15 depend from claim 11, and consequently incorporate the indefiniteness
issues of claim 11.
Claim 11 also recites, in part, the limitations “prior to the [claim 6] providing step: …
performing the pre-amplification after the cancer treatment …” the meaning of which is unclear. Specifically, in claim 6, the pre-amplification step is performed after the providing step. Thus, it is not clear how, in claim 11, the pre-amplification step can be performed prior to the providing step. Since the ordinary artisan would not be able to determine the metes and bounds of the claim, it is indefinite.
Claims 12-15 depend from claim 11, and consequently incorporate the indefiniteness issues of claim 11.
Lack of antecedent basis rejections
Claim 21 recites the limitation "the pair of primers" in in l. 1. There is insufficient antecedent basis for this limitation in the claim. Claim 6, from which claim 21 depends, does not recite primers or pairs of primers.
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.
Claims 1-2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cani (Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection, Molecular Oncology, 16(10): 1969-1985, 2021).
Regarding independent claim 1, Cani teaches …
A method for cancer genome analysis, the method comprising the steps of: conducting whole genome sequencing on tumor tissue (abstract; section 2.4: circulating tumor cells (CTCs) were whole genome amplified and then sequenced; sections 2.7, 3.2);
identifying truncal rearrangements in tumor sequence produced in the conducting step
(section 3.2: p. 1972, right col., para. 3; section 3.5).
Cani additionally teaches ranking the truncal rearrangements, e.g., in the PIK3CA, c-KIT and CDH1 genes, based on a timeline of tumor progression, e.g., at baseline and at treatment discontinuation; selecting truncal arrangements that occur earliest in said timeline, e.g., at baseline; and producing a readout, e.g., a heatmap, that characterizes the tumor based on the earliest truncal rearrangements (Fig. 2; Table 1; sections 2.3, 3.5, 3.6).
Regarding dependent claim 2, Cani teaches that the readout is produced using digital PCR to detect the selected truncal rearrangements (Fig. 2).
Claims 6-7, 10 and 16-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jackson (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016).
Regarding independent claim 6, Jackson teaches …
A method for variant detection, the method comprising the steps of: providing a sample
comprising one or more target nucleic acids (abstract);
performing pre-amplification to increase abundance of the target nucleic acid in the sample (p. 236, right col., para. 2);
aliquoting the sample into a plurality of subsamples, e.g., droplets (p. 237, right col., para. 3 through p. 238, left col., para. 2);
conducting polymerase chain reaction (PCR) on the subsamples (p. 237, right col., para. 3 through p. 238, left col., para. 2);
and detecting the target nucleic acids (p. 238, left col., para. 3).
Regarding dependent claim 7, Jackson teaches that the pre-amplification is exponential (PCR) amplification (p. 236, right col., para. 2).
Regarding dependent claims 10, 17 and 21, Jackson teaches that the PCR comprises digital PCR with fluorescent hydrolysis probes (Table 1; p. 237, right col., para. 3), as recited in claim 10. Further, regarding claims 17 and 21, Jackson teaches that the PCR comprises multiplex digital PCR, which uses pairs of primers that are capable of amplification of different target nucleic acid sequences (Table 1; Fig. 1; p. 237, right col., para. 3 through p. 238, left col., para. 3).
Regarding dependent claim 16, Jackson teaches that the said conducting step comprises: providing a pair of primers capable of specific amplification of a target nucleic acid; providing a nucleic acid polymerase having a polymerase activity at an elongation temperature; preparing PCR reactions, wherein each PCR reaction comprises a part of the sample, the pair of primers, the nucleic acid polymerase, PCR reagents, and optionally detection reagents; and performing symmetrical exponential amplification (Table 1; Fig. 1; p. 237, right col., para. 3 through p. 238, left col., para. 3).
Regarding dependent claims 18-19, Jackson additionally teaches that a portion of the pre-amplification is used as direct input for the PCR (p. 237, right col., para. 3), as recited in claim 18, and that the portion of the reaction mixture is not subject to any clean-up step and the PCR is performed by adding components of a PCR reagent mixture to the portion of the reaction mixture (p. 237, right col., para. 3), as recited in claim 19.
Regarding dependent claim 20, Jackson additionally teaches determining quantities of the target nucleic acid in the sample using (i) counts of the subsamples in which amplicons are detected and (ii) a measure of the increase in the abundance of the target nucleic acid yielded by the pre-amplification (p. 242, left col., para. 3 through p. 242, right col., para. 1; p. 239, left col., para. 2 through p. 240, right col., para. 1).
Regarding dependent claim 22, Jackson additionally teaches that the target nucleic acid molecule includes a single nucleotide variant (p. 236, right col., para. 4).
Claim Rejections - 35 USC § 103
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.
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.
Claims 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over Cani (Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection, Molecular Oncology, 16(10): 1969-1985, 2021) as applied to claims 1-2 above, and further in view of Jackson (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016).
Regarding dependent claims 3-4, Jackson teaches preamplification of the selected
rearrangements using PCR (i.e., exponential) amplification (p. 236, right col., para. 2).
Prior to the effective filing date of the instant invention, it would have been prima facie obvious to modify the Cani method, discussed above, to incorporate a preamplification step. Cani teaches the need for methods with improved sensitivity. Jackson teaches that preamplification improves the detection sensitivity of low frequency mutants. Thus, the ordinary artisan would have been motivated to incorporate the preamplification step into the Cani method to achieve the expected advantage of a highly sensitive method for monitoring genomic alterations in tumor cells. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Regarding dependent claim 5, Cani teaches that the digital PCR is conducted on blood or
plasma comprising cell-free DNA (Fig. 3; sections 2.3, 3.4).
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Jackson (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016) as applied to claim 6 above, and further in view of Saal (US 2018/0340230 A1).
Regarding dependent claims 7-8, Saal teaches that the pre-amplification is incremental
amplification comprising the steps of providing a pair of primers capable of amplification of a target nucleic acid, wherein the pair of primers comprises a primer-H and a primer-L, wherein the melting temperature of primer-H is at least about 10 °C higher than the melting temperature of primer-L, and wherein primer-L comprises a sequence complementary to an elongation product of primer-H; and thermocycling the sample with an annealing temperature at which primer-H anneals but primer-L does not anneal (abstract; paras. 20-37).
Regarding dependent claim 9, Saal teaches that the performing step is asymmetric
incremental amplification comprising the steps of: providing a set of primers comprising at least one primer specifically capable of amplification of only one strand of the target nucleic acid sequence; preparing PCR reactions each comprising a part of the sample, the set of primers, the nucleic acid polymerase, and PCR reagents; and performing an incremental polymerase reaction (paras. 11, 14-15, 19-37).
Prior to the effective filing date of the instant invention, it would have been prima facie
obvious to modify the Jackson method, discussed above, to incorporate the incremental amplification steps of Saal. Jackson teaches the need for detection methods with improved sensitivity. Saal teaches that the various incremental amplification steps achieve “exceedingly high sensitivity”. Thus, the ordinary artisan would have been motivated to incorporate the incremental amplification steps into the Jackson method to achieve the expected advantage of a highly sensitive method for monitoring genomic alterations in tumor cells. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Claims 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Jackson (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016) as applied to claim 6 above, and further in view of Cani (Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection, Molecular Oncology, 16(10): 1969-1985, 2021).
Regarding dependent claim 11, as noted above, the claim is indefinite. However, Cani
teaches prior to the providing step, sequencing tumor DNA (abstract; section 2.4: circulating tumor cells (CTCs) were whole genome amplified and then sequenced; sections 2.7, 3.2) to identify tumor mutations (section 3.2: p. 1972, right col., para. 3; section 3.5); modeling a timeline of progression of the tumor mutations (Fig. 2; Table 1; sections 2.3, 3.5, 3.6); and performing amplification at the time that the cancer treatment is discontinued, which will result in the increase the abundance of the identified tumor mutation (Fig. 2).
Regarding dependent claims 12-13, Cani teaches that the tumor mutation is a truncal
mutation (section 3.2: p. 1972, right col., para. 3; section 3.5), as recited in claim 12, or that the tumor mutation is a structural variation, specifically a copy number variation1 (p. 1973, right col., para. 3), as recited in claim 13.
Regarding dependent claim 14, Cani teaches that the tumor mutation is a copy number variant with a high copy number relative to other tumor mutations identified in the sequencing step (p. 1972, right col., para 2: “[c]opy number alterations … were calculated … yielding a copy number ratio for each amplicon … [g]enes with a copy number estimate < 0.25 or > 4 were considered to have high-level loss or gain, respectively”).
Prior to the effective filing date of the instant invention, it would have been prima facie
obvious to modify the Jackson method, discussed above, to incorporate the Cani sequencing and progression modeling steps. Jackson teaches the need for improvements in treatment monitoring for cancer. Cani teaches the sequencing and progression modeling steps can be used to identify tumor biomarkers that can be non-invasively tracked over the course of treatment. Thus, the ordinary artisan would have been motivated to incorporate the Cani steps into the Jackson method to achieve the expected advantage of a method that is capable of non-invasively monitoring cancer over the course of treatment. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Regarding dependent claim 15, Jackson additionally teaches that the sample is a liquid
biopsy sample and the target nucleic acids comprise ctDNA (p. 236, right col., para. 2).
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 6-10 and 16-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 11-13, 15-17 and 19-22 of copending Application No. 18/204,688 (hereinafter, the ‘688 application).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 11, as well as the combination of claims 1 and 9, of the ’688 application teach all of the limitations of instant claim 6, albeit in different embodiments.
In addition, claims 12, 13, 19/20, 21, 15, 16, 17 and 22 of the ‘688 application teach or suggest all of the limitations of instant claims 7/16, 8/9, 10, 17/21, 18, 19, 20 and 22, respectively.
Modifying the ‘688 application to create different embodiments comprising the limitations of each of these claims, including using various types and formats of amplification methods with corresponding primers and reaction components, various detection reagents and methods, and detecting various targets, can all be arrived at through routine optimization, and thus are obvious based on the limitations of claims 1, 9, 11-13, 15-17 and 19-22 of the ‘688 application. In addition, the ordinary artisan would have had an expectation of success in making these modifications as optimizing the design of amplification assays and trying different targets is well-known in the art.
Claims 6-7, 10 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46 and 51-53 of copending Application No. 17/361,829 (hereinafter, the ‘829 application).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 40 and 44 of the ’829 application teach all of the limitations of instant claim 6, albeit in different embodiments.
In addition, claims 46 and 51-53 of the ‘829 application teach or suggest all of the limitations of instant claims 10 and 7/16, respectively.
Modifying the ‘829 application to create different embodiments comprising the limitations of each of these claims, including using various types and formats of amplification methods with corresponding primers and reaction components, and various detection reagents and methods, can all be arrived at through routine optimization, and thus are obvious based on the limitations of claims 46 and 51-53 of the ‘829 application. In addition, the ordinary artisan would have had an expectation of success in making these modifications as optimizing the design of amplification assays is well-known in the art.
Claims 6-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,066,707 (hereinafter, the ‘707 patent) in view of Jackson (Multiplex Preamplification of Serum DNA to Facilitate Reliable Detection of Extremely Rare Cancer Mutations in Circulating DNA by Digital PCR, Journal of Molecular Diagnostics, 18(2): 235-243, 2016).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘707 patent teaches or suggests all of the limitations of instant claims 6-10, except for the pre-amplification step in claim 6, which is taught by Jackson (p. 236, right col., para. 2), and the fluorescent hydrolysis probes in claim 10, which are also taught by Jackson.
It would have been prima facie obvious to modify the ‘707 patent with the pre-amplification step of Jackson, as Jackson teaches that preamplification improves the detection sensitivity of low frequency mutants. Thus, the ordinary artisan would have been motivated to incorporate the preamplification step into the ‘707 patent method to achieve the expected advantage of a highly sensitive method for monitoring genomic alterations in tumor cells. It would have been additionally obvious to incorporate the Jackson detection reagents into the ‘707 patent method because fluorescent hydrolysis probes are known in the art as being suitable for detecting amplification products. The ordinary artisan would have had an expectation of success as the design and modification of nucleic acid amplification assays is well-known in the art.
Conclusion
Claims 1-22 are being examined and are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN GREENE whose telephone number is (571)272-3240. The examiner can normally be reached M-Th 7:30-5:30 EST.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
1 The instant specification teaches that Mahmoud (Structural variant calling: the long and short of it, Genome Biology, 20:246, 1-14, 2019), which is incorporated by reference, describes structural variants. Mahmoud, in turn, states that “[s]tructural variants … are large genomic alterations, …[c]opy number variations … are a particular subtype” of structural variants (p. 1, left col., para. 1: Introduction).