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 .
Claim Status/Action Summary
This action is in response to the papers filed on February 25, 2026.
Claims 18 and 20 were canceled in the response. Claims 15-17, 19, and 21-31 are under examination. No other claims are presently pending in the application.
Any objections and rejections not reiterated below are hereby withdrawn.
The 112(b) rejections of record have been withdrawn in view of the amendments to the claims.
The 102 rejections of record have been withdrawn in view of the amendments to independent claim 15.
Priority/Effective Filing Date
The present application is a 371 of PCT/JP2021/047619, filed December 22, 2021 and claims foreign priority to JAPAN 2020-216149, filed on December 25, 2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. However, no certified English language translation of the foreign priority document has been filed in this application. Therefore, the present claims enjoy the benefit of priority to the PCT filing date (December 22, 2021).
Information Disclosure Statement
The listing of references in the specification on pages 2-4 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, they have not been considered.
Drawings
The drawings filed on June 22, 2023 are acceptable.
Claim Interpretation
The specification provides a special definition for the term “cluster”, recited by claim 27 (Specification, paragraph 0052). The specification defines “the accumulated events [within a circle indicating the vicinity of the center of the fluorescence intensity distribution of the detection events on [a scatter plot of detection events of fluorescence emitted from reaction compartments]] are herein referred to as a “cluster”.
Claims 30 and 31 recite “the data is provided for a diagnosis of…[various syndromes or cancers]”. It is noted that the claim does not require any concrete, positively recited step(s) of diagnosing any syndrome or condition. Therefore, these claim phrases are being interpreted as intended uses of the claimed method directed to detecting the presence of or quantitating copy number variation in single cells.
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.
The following 103 rejections are new grounds of rejection necessitated by the amendments to the claims.
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over White et al., “High-throughput microfluidic single-cell RT-qPCR”, PNAS vol. 108, no. 34, pp. 13999-14004 (published August 23, 2011) in view of Tan et al., “A multiplex droplet digital PCR assay for non-invasive prenatal testing of fetal aneuploidies” Analyst, 2019, 144, 2239-2247 (published January 8, 2019).
Regarding claim 15, White et al. teach methods for detecting copy numbers of nucleic acids per single cell in a cell population (White et al., abstract and Figure 3). White et al. teaches amplifying DNA from single cells in reaction compartments containing a PCR system (White et al., Figure 1, see below), and quantifying the copy number of the DNA targets by measuring fluorescence intensities for each reaction compartment during an exponential amplification phase (White et al., figure 3). White et al. further teach the amplicons are quantified using TaqMan probes (i.e. a fluorescent probe method) (White et al., supporting information, page 2).
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White et al. do not teach “the PCR reaction system contains a plurality of [fluorescent] probes… having fluorescence wavelengths that are different… assigned to regions different from each other” (i.e. probes with different emission wavelengths are assigned to different regions) and “each of the regions contains a plurality of targets to which a plurality of [fluorescent probes having identical fluorescent (i.e. emission) wavelengths] are assigned” and “the quantifying… for each of the regions… by collectively measuring an intensity of fluorescence from the plurality of probes…”.
However, Tan et al. teaches multiplexed digital droplet PCR (ddPCR) (i.e. single cell PCR amplifying a DNA sample in a compartment) for non-invasive fetal aneuploidy detection of chromosome 21 and chromosome 18 from cell free DNA isolated from maternal blood comprising 40 primer pairs and two universal probes (i.e. a plurality of probes including fluorophores with identical wavelengths for each of the tested “regions” (i.e. chromosomes)) (Tan et al., Figure 1). Tan et al. further teaches measuring the collective intensity of all of the probes for a given amplicon/region (i.e. chromosome) (Tan et al., Figure 1).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the single cell PCR methods for detecting nucleic acid copy numbers comprising amplifying target nucleic acids and quantifying the copy number of the amplicons by measuring fluorescence intensity during an exponential amplification phase, taught by White et al. with the teachings of Tan et al. comprising multiplex primer and probe sets for non-invasive prenatal diagnosis of aneuploidies in chromosomes 18 and/or 21. The ordinary artisan would have been motivated to modify the single cell qPCR assay taught by White et al. with the primers and probes taught by Tan et al. because both White et al. and Tan et al. teach these similar assays (single cell qPCR and ddPCR) are useful for quantitative detection of nucleic acid abundance in DNA samples derived from single cells.
Regarding claim 16, White et al. teaches stopping a PCR cycle during the exponential phase and measuring the intensity of fluorescence in each of the reaction compartments and quantifying the amplicon from said intensity (White et al., Figure 3).
Regarding claim 17, White et al. teaches the DNA sample is a reverse transcription product of RNA in the single cell (White et al., Figure 1 and 3).
Claims 19, 22, 25-26, and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over White et al. in view of Tan et al. as applied to claims 15-17 above, and further in view of Sato et al., “Direct Assessment of Single-Cell DNA Using Crudely Purified Live Cells: A Proof of Concept for Noninvasive Prenatal Definitive Diagnosis” J Mol Diagn 2020, 22:132-140, Published February 2020.
Regarding claim 19, White et al. in view of Tan et al. teach methods for detecting copy numbers of target nucleic acids from single cells comprising separating the nucleic acids from single cells into separate compartments, amplifying the target DNA by PCR, and quantifying the copy number of the target sequence using a fluorescent probe method comprising a plurality of probes having the same fluorophore binding to a same region, wherein different regions on the target nucleic acid are assigned different fluorophores and the quantitation involves collectively measuring the fluorescence from all of the probes assigned to a particular region having the same fluorophore during an exponential amplification phase (See above).
White et al. in view of Tan et al. do not teach distinguishing reaction compartments wherein the target DNA(s) is/are released from a single cell from reaction compartments wherein only a cell-free nucleic acid is amplified.
However, Sato et al. teach methods for detecting a copy number of a specific nucleic acid per single cell in a cell population comprising amplifying a target DNA sequence from a single cell in reaction compartments and quantifying the copy number of said target sequence (Sato et al., Figure 1) using a Taq-Man copy number assay (Sato et al., page 135).
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Sato et al., Figure 1
Sato et al. further teach the PCR reaction comprises two probes (i.e. a plurality) having fluorophores with different emission wavelengths assigned to different target regions (SRY and RPP30). Sato et al. further teach distinguishing between compartments with both signals, only SRY, only RPP30 (the reference signal), or no signal (Sato et al., figure 1) (i.e. distinguishing droplets with contaminating cfDNA) (Sato et al., page 136, column 1).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have substituted the physical compartmentalization of single cells in chambers of a microfluidic device, taught by White et al. for the equivalent method of compartmentalizing single cells in droplets, taught by Sato et al. The ordinary artisan would have had a reasonable expectation that partitioning the single cells into individual droplets, rather than into chambers of a complex microfluidic device, would have successfully and predictably resulted in isolation/amplification of nucleic acids from said single cells because both White et al. and Sato et al. demonstrate that these two methods for partitioning single cells successfully result in compartments containing single cells that are subsequently lysed within the compartment and nucleic acids released therefrom are successfully amplified by PCR.
Regarding claim 22, Sato et al. teaches the cells are lysed in the reaction compartment containing the single cell, a lysis reagent, and a PCR premix (Sato et al., figure 1).
Regarding claim 25, Sato et al. teaches the reaction compartment is a reaction droplet containing the DNA sample and the PCR reaction system (Sato et al., figure 1).
Regarding claim 26, Sato et al. teaches quantifying SRY and RPP30 abundance using cutoff values predetermined by amplification of control samples using cells in which a copy number of the specific nucleic acid SRY, RPP30 are known (Sato et al., page 134, column 1). Regarding claims 28-29, Tan et al. teaches detecting the presence of chromosome 21 and/or 18 aneuploidies.
Regarding claim 30, Tan et al. teaches providing information (i.e. data) for diagnosing trisomy 21 (Tan et al., Table 1) from samples comprising maternal blood or amniotic fluid.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over White et al. in view of Tan et al. and Sato et al., “Direct Assessment of Single-Cell DNA Using Crudely Purified Live Cells: A Proof of Concept for Noninvasive Prenatal Definitive Diagnosis” J Mol Diagn 2020, 22:132-140, Published February 2020, as applied to claims 15-17, 19, 22, 25-26, and 28-30 above, and further in view of Maeda et al., “High throughput single cell analysis of mitochondrial heteroplasmy in mitochondrial diseases” Scientific Reports 10, 10821 (2020) (Published July 2, 2020) and Belmonte et al., “Digital PCR methods improve detection sensitivity and measurement precision of low abundance mtDNA deletions” Scientific Reports 6, 25186 (2016) (Published April 28, 2016).
Regarding claim 21, the teachings of White et al. in view of Tan et al. and Sato et al. are summarized above.
White et al. in view of Tan et al. and Sato et al. do not teach that the single cell ddPCR reaction system contains fluorescent probes assigned to genomic DNA and mitochondrial DNA.
However, Maeda et al. teach single cell ddPCR with TaqMan probes for several mitochondrial targets (Maeda et al., figure 1B and page 8, paragraphs 2-3). Belmonte et al. teach absolute quantitation of mitochondrial deletions in a population of cells using ddPCR comprising primers and probes for the mitochondrial ND1 and nuclear B2M target sequences (Belmonte et al., Figure 2 and page 3, paragraph 4).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the single cell PCR methods taught by White et al. in view of Tan et al. and Sato et al. with the teachings of Maeda et al. and Belmonte et al. comprising detection of mitochondrial (and nuclear, Belmonte et al.) target sequences in sc-ddPCR and ddPCR, respectively, for the identification of mitochondrial DNA variants associated with various diseases (MELAS, Leigh Syndrome, and LHON) (Maeda et al.) and (MELAS) (Belmonte et al.). The ordinary artisan would have been motivated to have modified the method comprising detection of specific target sequences in single cells by sc-ddPCR, taught by White et al. in view of Tan et al. and Sato et al. with the primers and probes taught by Maeda et al. and Belmonte et al. for detection of nuclear and mitochondrial sequence variants diagnostic for various mitochondrially-inherited genetic disorders because of the teaching of Belmonte et al. that assessment of mtDNA abundance relative to nuclear DNA abundance is an important step for multiplex optimization (Belmonte et al., page 3, paragraph 4).
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over White et al. in view of Tan et al. and Sato et al., “Direct Assessment of Single-Cell DNA Using Crudely Purified Live Cells: A Proof of Concept for Noninvasive Prenatal Definitive Diagnosis” J Mol Diagn 2020, 22:132-140, Published February 2020, as applied to claims 15-17, 19, 22, 25-26, and 28-30 above, and further in view of Kim et al., “Single-Cell RT-PCR in Microfluidic Droplets with Integrated Chemical Lysis”, Analytical Chemistry 2018, 90, 1273-1279.
Regarding claim 23, the teachings of White et al. in view of Tan et al. and Sato et al. are summarized above.
White et al. in view of Tan et al. and Sato et al. do not teach generating the reaction compartment by combining the compartment containing the single cell lysed with a compartment containing a PCR premix.
However, Kim et al. teach methods for detecting copy numbers of specific nucleic acids per single cell in a population comprising amplifying the nucleic acids in a reaction compartment comprising a PCR system and quantifying the corresponding amplicon by measuring an intensity of fluorescence using a TaqMan assay (Kim et al., figure 1).
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Kim et al., Figure 1
Kim et al. further teach lysing the single cell in a compartment and subsequently combining the compartment containing the lysate with a compartment containing a PCR premix (Kim et al., Figure 1 (see step e)).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods taught by White et al. in view of Tan et al. and Sato et al. comprising lysing the single cell in a compartment comprising a lysis reagent and a PCR premix by separating the lysis reagent and PCR premix reagent into two separate droplets that are merged after cell lysis, as taught by Kim et al. The ordinary artisan would have been motivated to have modified the methods as described above by the teachings of Kim et al. that an alkaline lysis step followed by pH neutralization and addition of PCR premix reagents by fusion of a second droplet to the droplet in which the alkaline lysis occurs is important for complete lysis of mammalian cells and for minimizing degradation of target nucleic acid molecules by the alkaline lysis conditions (Kim et al., page 1275, column 2, paragraphs 2-3).
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over White et al. in view of Tan et al. and Sato et al., “Direct Assessment of Single-Cell DNA Using Crudely Purified Live Cells: A Proof of Concept for Noninvasive Prenatal Definitive Diagnosis” J Mol Diagn 2020, 22:132-140, Published February 2020, as applied to claims 15-17, 19, 22, 25-26, and 28-30 above, and further in view of Dodd et al., “Digital Quantitation of Potential Therapeutic Target RNAs” Nucleic Acid Therapeutics Volume 23, Number 3, 2013.
Regarding claim 24, White et al. in view of Tan et al. and Sato et al. do not teach mixing a population of cell nuclei with a PCR premix in bulk prior to generating the reaction compartments.
However, Dodd et al. teaches performing droplet digital PCR to quantify long noncoding RNAs from different subcellular compartments from human cells (Dodd et al., Abstract) comprising purified nuclei and a cytoplasmic fraction (Dodd et al., page 189, column 22, paragraph 4).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods comprising encapsulating whole single cells into droplets (i.e. reaction compartments) comprising a PCR premix in bulk, taught by White et al. in view of Tan et al. and Sato et al. such that single nuclei are encapsulated into droplets (i.e. reaction compartments) comprising a PCR premix in bulk. The ordinary artisan would have been motivated to encapsulate isolated nuclei, rather than whole cells into droplets with PCR premix because of the teaching of Dodd et al. that several long noncoding RNAs (MALAT1, HOTAIR, NEAT1, and SNORD14A) with primary functions in the nucleus, were unequally partitioned across the nucleus and the cytosol (Dodd et al., page 191-192 bridging paragraph-page 192, paragraph 3), and that “a full appreciation for how RNAs function inside of cells and how they can be most efficiently targeted by therapeutics requires an accurate determination of how many RNA molecules are present and where they are functioning within the cell” (Dodd et al., page 193, column 1, paragraph 4).
Claims 28, 29, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over White et al. in view of Tan et al. and Sato et al., “Direct Assessment of Single-Cell DNA Using Crudely Purified Live Cells: A Proof of Concept for Noninvasive Prenatal Definitive Diagnosis” J Mol Diagn 2020, 22:132-140, Published February 2020, as applied to claims 15-17, 19, 22, 25-26, and 28-30 above, and further in view of Gevensleben et al., “Noninvasive Detection of HER2 Amplification with Plasma DNA Digital PCR” Clin Cancer Res; 19(12) June 15, 2013.
Regarding claim 28, the teachings of White et al. in view of Tan et al. and Sato et al. are summarized above.
Regarding claim 31, White et al. in view of Tan et al. and Sato et al. do not teach “generating data that includes … the presence of the single cell having [a copy number variation] wherein the cell population is isolated form a patient and the data is provided for a diagnosis of [a list of alternative cancers].
However, Gevensleben et al. teach methods comprising noninvasive detection of HER2 gene amplification in circulating free plasma DNA using droplet digital PCR (Gevensleben et al., abstract and page 3277, column 2, paragraph 4).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the methods taught by White et al. in view of Tan et al. and Sato et al., comprising detecting copy numbers of RPP30 and/or SRY within single cells by single cell PCR (methods comprising ddPCR or qPCR) for non-invasive diagnosis, for detection of other known genetic abnormalities, such as gene amplification of HER2 in breast cancer, detectable in circulating cell free DNA in patients with breast cancer, as taught by Gevensleben et al. because White et al. in view of Tan et al. and Sato et al. teaches single cell ddPCR is more sensitive than ddPCR (Sato et al., page 133, column 1, paragraph 2) and Gevensleben et al. teaches ddPCR is prone to false negative results due to low tumor DNA abundance relative to non-tumor DNA in plasma (Gevensleben et al., page 3283, column 2, paragraph 1).
The ordinary artisan would have been motivated to detect the ddPCR-detectable targets of Gevensleben et al. (HER2 amplification) for noninvasive detection of breast cancer using the methods taught by White et al. in view of Tan et al. and Sato et al. comprising sc-ddPCR because of the teaching of Gevensleben et al. that very low percentage of tumor DNA in plasma is a source of false-negative results in ddPCR (Gevensleben et al., page 3283, column 2, paragraph 1). The ordinary artisan would therefore have expected the single cell methods taught by Sato et al. to have predictably increased the sensitivity (i.e. decreased the false negative rate) of the method of Gevensleben et al.
Regarding claims 29 and 31, Gevensleben et al. teaches detecting the presence of breast cancer cells with HER2 gene amplification by ddPCR for the diagnosis of breast cancer (Gevensleben et al., Abstract).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over White et al. in view of Tan et al. and Sato et al., “Direct Assessment of Single-Cell DNA Using Crudely Purified Live Cells: A Proof of Concept for Noninvasive Prenatal Definitive Diagnosis” J Mol Diagn 2020, 22:132-140, Published February 2020, as applied to claims 15-17, 19, 22, 25-26, and 28-30 above, and further in view of Hindson et al., “High-Throughput Droplet Digital PCR System for Absolute Quantitation of DNA Copy Number” Analytical Chem. 2011, 83, 8604-8610 (published October 28, 2011).
Regarding claim 27, the teachings of White et al. in view of Tan et al. and Sato et al. are summarized above.
Regarding claim 27, White et al. in view of Tan et al. and Sato et al. do not explicitly teach correcting a PCR amplicon quantity using a quantitative value for a negative cluster.
However, Hindson et al. teach methods for calculating absolute quantities of nucleic acids comprising analyzing data generated by ddPCR wherein amplitude thresholds are applied based upon the observed fluorescence intensity in each channel of a 2D intensity scatterplot relative to a negative cluster of observations (i.e. quantities are corrected using quantities for a negative cluster) (Hindson et al., Figure 1).
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Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the method taught by White et al. in view of Tan et al. and Sato et al. comprising single cell ddPCR with the teachings of Hindson et al. comprising analyzing ddPCR data to calculate the absolute quantity of target nucleic acids within particular Poisson confidence intervals using the amplitude of fluorescence observed for each of the positive, double-positive, and negative clusters. The ordinary artisan would have been motivated to modify the methods of White et al. in view of Tan et al. and Sato et al. with the teachings of Hindson et al. comprising correcting the amplicon quantitation using a result for a negative cluster because of the teaching of Hindson et al. that the dynamic range of said quantitation spans from 1 copy to ~1*105 copies and further Poisson correction further extends the dynamic range of quantitation (Hindson et al., page 8606, column 1, paragraph 1).
Response to arguments
The response asserts that the claims as amended overcome the 102 and 103 rejections of record because the independent claim now includes the limitations “measuring an intensity of fluorescence in each of the plurality of reaction compartments during an exponential amplification phase”, “each of the regions contains a plurality of the targets to which a plurality of probes including fluorescent materials with fluorescence wavelengths identical to each other as assigned, respectively,” and “for each of the regions, the amplicon is quantified by collectively measuring an intensity of fluorescence from the plurality of probes, regardless of a difference between the targets.” The response asserts that Sato, Kim and Uchiyama measure fluorescence after the PCR reaction reaches a plateau and that Tan et al. utilize cfDNA as input rather than intact single cells.
These assertions over the amended claims against the 102 anticipation rejections of record are acknowledged. As amended, the claims have overcome the 102 rejections of record.
The response further asserts “Therefore, since any of White, Sato, Kim, Uchiyama, Tan, Maeda, Dodd and Hindson fails to teach or suggest the features as recited in currently amended claim 15, White, Sato, Kim or Uchiyama whether taken individually or in combination with Tan, Maeda, Dodd and Hindson does not anticipate nor render obvious the claimed invention.”
This assertion of patentability of the amended claims has been reviewed and is not persuasive as detailed in the 103 rejections above necessitated by the new combination of limitations including limitations from now canceled claims 18 and 20 into independent claim 15 as amended.
Conclusion
No claim is 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 ZACHARY MARK TURPIN whose telephone number is (703)756-5917. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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