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 .
DETAILED ACTION
In the claims filed July 19, 2024, claims 1-13 are currently pending.
Therefore, claims 1-13 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed July 19, 2024 claims the benefit of US Provisional Patent Application 63514943, filed July 21, 2023.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on October 22, 2024; January 3, 2025 and May 30, 2025 have been considered. Initialed copies of the IDSs accompany this Office Action.
Claim Objections/Rejections
Claim Rejections - 35 USC § 112(b)
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 1-13 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 1 is indefinite for the recitation of the term “the captured cell” such as recited in claim 1, line 3. There is insufficient antecedent basis for the term “the captured cell” in the claim. The Examiner suggests that Applicant amend claim 1 to recite, for example, “capturing the cell to obtain a captured cell.”
Claim 1 is indefinite for the recitation of the term “collecting lysate…sequencing nucleic acid from the lysate” such as recited in claim 1, lines 3-4 because one or more steps appear to be missing from the method. Claim 1 recites that a lysate is collected and then nucleic acids are sequenced; however, no nucleic acids are recited to be obtained, captured, ligated to adaptors, purified, amplified, etc., such that one or more critical steps appear to be missing from the method and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “to identify mtDNA sequences from the cell” such as recited in claim 1, line 5 because instant claim 1 does not identify or recite the type of sample and/or the type of cell, such that the cell of claim 1 may not comprise mtDNA sequences (e.g., erythrocytes, prokaryotic cells, oocytes, etc.) and, thus, the metes and bounds of the claim cannot be determined.
Claim 2 is indefinite for the recitation of the term “the analyzing step” such as recited in claim 2, line 2. There is insufficient antecedent basis for the term “the analyzing step” in the claim because claim 1, line 5 recites the term “analyzing the sequence data.” The Examiner suggests that Applicant amend the claim to recite, for example, “wherein analyzing comprises mapping.”
Claims 2 and 6 are indefinite for the recitation of the terms “the sequence reads” and “sequence reads” such as recited in claim 2, lines 2 and 3. There is insufficient antecedent basis for the terms “the sequence reads” and “sequence reads” in the claim because claim 2, line 1 recites the term “a plurality of sequence reads.” The Examiner suggests that Applicant amend the claim to recite, for example, “mapping the plurality of sequence reads.”
Claim 2 is indefinite for the recitation of the term “mitochondrial genome” such as recited in claim 2, line 3 because claim 2 depends from instant claim 1, wherein claim 1 does not recite the any specific type of sample and/or specific type of cell, such that the cell comprises mtDNA and/or sequence reads that arise from a mitochondrial genome and, thus, the metes and bounds of the claim cannot be determined.
Claims 3, 11 and 12 are indefinite for the recitation of the term “the sequencing step” such as recited in claim 3, line 2. There is insufficient antecedent basis for the term “the sequencing step” in the claim because claim 1, line 4 recites the term “sequencing nucleic acid.” The Examiner suggests that Applicant amend the claim to recite, for example, “wherein prior to sequencing, isolating the DNA.”
Claim 3 is indefinite for the recitation of the term “isolating DNA” such as recited in claim 3, line 2 because claim 3 depends from instant claim 1, wherein claim 1 does not recite the any specific type of sample and/or a specific type of cell, such that it is unclear whether the cell comprises DNA and, thus, the metes and bounds of the claim cannot be determined.
Claim 4 is indefinite for the recitation of the term “the isolation step” such as recited in claim 4, line 1. There is insufficient antecedent basis for the term “the isolation step” in the claim because claim 3, line 2 recites the term “isolating the DNA.”
Claim 5 is indefinite for the recitation of the term “the lysing step” such as recited in claim 5, line 1. There is insufficient antecedent basis for the term “the lysing step” in the claim because claim 1, line 3 recites the term “lysing the captured cell.”
Claim 5 is indefinite for the recitation of the term “a mitochondrial membrane” such as recited in claim 5, line 2 because claim 5 depends from instant claim 1, wherein claim 1 does not recite a particular sample and/or type of cell including a cell that comprises a mitochondrial membrane and, thus, the metes and bounds of the claim cannot be determined.
Claim 6 is indefinite for the recitation of the term “the analyzing step” such as recited in claim 6, line 1. There is insufficient antecedent basis for the term “the analyzing step” in the claim because claim 1, line 5 recites the term “analyzing the sequence data.”
Claim 6 is indefinite for the recitation of the term “mapping sequence reads of the sequence data to a genomic database” such as recited in claim 6, lines 1-2 because claim 6 depends from instant claim 1, wherein claim 1 does not recite the presence of sequence reads, indicate how sequence data comprises sequence reads, and/or the presence of a genomic database and, thus, the metes and bounds of the claim cannot be determined.
Claim 6 is indefinite for the recitation of the term “to identify mitochondrial sequence reads” such as recited in claim 6, line 2 because claim 6 depends from instant claim 1, wherein claim 1 does not recite a particular sample and/or specific type of cell including a cell that comprises mitochondrial sequence reads and, thus, the metes and bounds of the claim cannot be determined.
Claim 7 is indefinite for the recitation of the term “the mapping step” such as recited in claim 7, line 1. There is insufficient antecedent basis for the term “the mapping step” in the claim because claim 6, line 1 recites the term “mapping sequence reads.”
Claim 7 is indefinite for the recitation of the term “Basic Local Alignment Search Tool” such as recited in claim 7, line 1 because it is unclear as to the identity, components, algorithms, computer programs, etc. that encompass a “Basic Local Alignment Search Tool.” Moreover, the trademark/trade name “Basic Local Alignment Search Tool”. Where a trademark or trade name (research designation) is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b). Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. In the present case, the trademark/trade name is used to identify/describe a computer program that compared query DNA, RNA, or protein sequences against a database to find regions of local similarity as evidenced by Lobo (pg. 1, first to third full paragraphs) and, accordingly, the identification/descriptions are indefinite. For the sake of compact prosecution, the term “Basic Local Alignment Search Tool” has been interpreted to refer to any computer database.
Claim 8 is indefinite for the recitation of the term “fraction of the lysate enriched for mtDNA” such as recited in claim 8, line 2 because claim 8 depends from instant claim 1, wherein claim 1 does not recite the identity of a sample or cell that comprises mtDNA, such that a portion of the lysate can be enriched and, thus, the metes and bounds of the claim cannot be determined.
Claims 9-12 are indefinite for the recitation of the terms “genomic DNA”; “mtDNA”; “mtDNA fragments” and/or “mtDNA sequencing library” such as recited in claim 9, lines 1 and 3 because claim 9 depends from instant claims 1 and 8, wherein claims 1 and 8 do not recite the identity of a specific sample or a specific type of cell that comprises DNA, a nucleus, and/or mtDNA, such that nuclear gDNA and/or mtDNA can be collected, enriched, fragmented, used to produce a mtDNA sequencing library, etc. and, thus, the metes and bounds of the claim cannot be determined.
Claim 9 is indefinite for the recitation of the term “the purification or size selection step” such as recited in claim 9, line 2. There is insufficient antecedent basis for the term “the purification or size selection step” in the claim because claim 8, line 1 recites the term “performing a purification or size selection.”
Claim 9 is indefinite for the recitation of the term “in vessels or tubes separate from the fraction of the lysate enriched for mtDNA” such as recited in claim 9, lines 2-3 because claim 9 depends from claims 1 and 8, wherein claims 1 and 8 do not recite the presence of vessels or tubes. Moreover, it is unclear whether the separate vessels or tubes are also separate from the collected lysate recited in claim 1 and, thus, the metes and bounds of the claim cannot be determined.
Claim 12 is indefinite for the recitation of the terms “one more sample tubes” and the sample tubes” such as recited in claim 12, lines 1 and 2. There is insufficient antecedent basis for the terms “one more sample tubes” and “the sample tubes” in the claim because claim 9, line 2 recites the term “vessels or tubes.”
Claim 12 is indefinite for the recitation of the term “freezing and/or storing” such as recited in claim 12, lines 1-2 because claim 12 depends from instant claims 1, 8 and 9, wherein claims 1, 8 and 9 do not recite the presence of tubes, storage containers, and/or any cooling apparatus and, thus, the metes and bounds of the claim cannot be determined.
Claim 12 is indefinite for the recitation of the term “containing the mtDNA sequencing library” such as recited in claim 12, line 2 because claim 12 depends from instant claims 1, 8 and 9, wherein claims 1, 8 and 9 do not recite the presence and/or production of an mtDNA sequencing library and, thus, the metes and bounds of the claim cannot be determined.
Claim 13 is indefinite for the recitation of the term “promote” such as recited in claim 13, line 2 because the term “promote” is a relative term that renders the claim indefinite. The term “promote” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of “promotion” as compared to some other value that qualifies as an “promoting release” of fragmented nucleic acid (e.g., as compared to unfragmented nucleic acid), such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention and, thus, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-12 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 2-7, 9, 11 and 12 recite (for example): “the X step” (e.g., “the analyzing step”) such as recited in claim 2, lines 2 because claims 2-7, 9, 11 and 12 ultimately depend from instant claim 1, wherein claim 1 does not recite “steps”. Instead, claim 1 recites capturing, lysing, collecting, analyzing, sequencing, etc. Thus, claim 2-7, 9, 11 and 12 are improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 2-6 and 8-12 recite (for example): “mitochondrial genome”; “mtDNA”, “DNA”; “gDNA”; “mitochondrial membrane”; “mtDNA fragments”; and “mtDNA sequencing library” such as recited in claim 2, lines 2 because claims 2-6 and 8-12 ultimately depend from instant claim 1, wherein claim 1 does not identify or recite a specific type of sample and/or a specific type of cell, such that the cell comprises mtDNA, mtDNA sequences, DNA, arise from a mitochondrial genome, etc. (e.g., erythrocytes, prokaryotic cells, oocytes, prokaryotic cells, etc.). Thus, claims 2-6 and 8-12 are improper dependent claims for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 recites (in part): “mapping sequence reads of the sequence data to a genomic database” in lines 1-2 because claim 6 depends from instant claim 1, wherein claim 1 does not recite the presence of sequence reads, indicate how sequence data comprises sequence reads, and/or the presence of a genomic database. Thus, claim 6 is an improper dependent claim for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 recites (in part): “collecting nuclear genomic DNA and/or RNA, from the purification or size selection step, in vessels or tubes separate from the fraction of the lysate enriched for mtDNA” in lines 1-2 because claim 9 depends from instant claims 1 and 8, wherein claims 1 and 8 do not recite the presence of vessels and/or tubes separate from the fraction of the lysate enriched for mtDNA. Thus, claim 9 is an improper dependent claim for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 12 recites (in part): “collecting the mtDNA sequencing library in one more sample tubes and freezing and/or storing the sample tubes containing the mtDNA sequencing library” in lines 1-3 because claim 12 depends from instant claims 1, 8 and 9, wherein claims 1, 8 and 9 do not recite the presence or production of an mtDNA sequencing library, one more sample tubes, storage containers and/or any type of cooling apparatus. Thus, claim 12 is an improper dependent claim for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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 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.
Claims 1, 3-5, 8-10 and 13 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Craighead et al. (hereinafter “Craighead”) (US Patent No. 12303899, issued May 20, 2025; effective filing date November 28, 2018) as evidenced by Craighead et al. (hereinafter “Craighead ‘192”) (US Patent No. 9803192, issued October 31, 2017); and Craighead et al. (hereinafter “Craighead ‘552 (US Patent No. 9926552, issued March 27, 2018); and Craighead et al. (hereinafter “Craighead ‘304”) (International Application WO2017/205304, published November 30, 2017); and Craighead et al. (hereinafter “Craighead ‘267”) (International Application WO2017/205267, published November 30, 2017).
Regarding claim 1, Craighead teaches a microfluidic chip for on-chip detection of the presence or absence of a target nucleic acid region in an isolated nucleic acid sample; and an integrated microfluidic cell processing system is disclosed, which includes: a multiplexed microfluidic flow directing system having a plurality of reconfigurable microfluidic layers that form a plurality of reconfigurable microfluidic channels, where the multiplexed microfluidic flow directing system function to assist in directing flow of materials into, passing through, and out of the integrated cell processing system; and at least one microfluidic chip functionally integrated into at least one layer of the multiplexed microfluidic flow directing system, and operates under continuous flow conditions to process one or more cells (interpreted as a microfluidic device comprising channels, claim 1) (col 3, lines 1-3 and 10-24). Craighead teaches an example of a sequence of processes that could be accomplished in this system can include, without limitation, the steps including: Step 1: introduction of a sample such as blood, containing among other things a few rare cells of interest; Step 2: capture and retention of the cells of interest in the device whereby the cells have been identified by physical or chemical properties such as size, mechanical deformability, or biochemical compounds on the surface (interpreted as capturing cells, claim 1); Step 3: washing away of the unwanted components of the sample, e.g., other cells and liquids, and elution into an array of waste containers; Step 4: introduction of reagents to lyse the cells (interpreted as lysing the captured cell, claim 1); Step 5: retention of the genomic DNA or chromatin on internal microstructures in the microfluidics such as an array of micron-scale pillars and collection of the other cellular components into an array of receiving vessels such as a microplate for subsequent analysis or processing (interpreted as collecting the lysate on a microfluidic device comprising micro-features, claim 1); Step 6: analysis or amplification of the genomic DNA retained in the array by processes such as polymerase chain reaction or isothermal amplification processes, both of which can be done for selected genetic components or the entire genome (interpreted as gDNA, claims 1, 9, 10 and 13); and Step 7: release of the DNA, chromatin, modified DNA, or modified chromatin, including by chemical cleaving of the retained biopolymer or by changing the flow rate of the liquid in the microfluidic element to liberate the retained material from the internal microstructures; and wherein collection of the released material in an array of receiving containers for further analysis or processing; and as noted in Step 5, additional on system processes are possible through the use of appropriate buffers or flow conditions to isolate various cellular components (interpreting micro-structures as micro-features; and interpreting buffers as detergent lysis reagents that break a cell membrane, claims 1 and 5) (col 22, lines 1-43). Craighead teaches in Figure 1 that the material to be extracted can be the genomic DNA, chromatin, or cell lysate other than the DNA including by retaining the genomic DNA in the chip all other cell lysate material can be captured in chip output (feature 8 of Figure 1) and a separate step the DNA can be extracted in a subsequent step and separately collected, such as to provide the possibility to collect and analyze the genomic DNA and separately collect the remaining cell lysate, containing proteins, lipids, RNA, mitochondrial DNA and other molecules from the same cell or cells, such that the off-chip analysis (box 9 in Figure 1) can therefore be any of the available and developing methods of biochemical analysis such as mass spectrometry, chromatography, DNA sequencing, RNA sequencing, analysis by nucleic acid hybridization or other analytical methods (interpreted as collecting lysate; sequencing; and identifying mtDNA sequences from the cell, claim 1) (col 15, lines 15-29; and Figure 1). Figure 1 is shown below:
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Craighead teaches that the method further comprises purifying and sequencing the amplified aptamer population (interpreted as sequencing nucleic acid, claim 1) (col 29, lines 14-16). Craighead teaches the rapid detection and identification of any specific gene sequence or gene mutation from one or more selected cells (interpreted as identifying sequences from the cell, claim 1) (col 14, lines 63-64). Craighead teaches that the target nucleic acid region includes a gene, mutation, or nucleotide sequence that is related to or that is a marker for the presence or risk of a disease or abnormal condition of a multicellular organism, wherein a collection of multiple probes includes, without limitation, a panel of probes effective to produce a genetic profile for a disease or abnormal condition in a multicellular organism (e.g., a mammalian subject) (col 16, lines 5-8 and 33-36).
Regarding claim 3 and 4, Craighead teaches that layers 2 shown in Figures 3A, 3B, 4A, and 4B can include elements such as filters, chromatography columns, or media for treatment of samples before or after passage of material through the microfluidic layers such as, for examples, filters up stream of the microfluidic elements can remove unwanted components of the raw sample; and affinity chromatography material or selective binding media down-stream from the microfluidic layers can concentrate or isolate components of interest such as specific types of proteins, antibodies, RNA or DNA (interpreted as isolating the DNA from the lysate using a column, claims 3 and 4) (col 22, lines 43-54; and Figures 3 & 4).
Regarding claim 5, Craighead teaches Step 7: release of the DNA, chromatin, modified DNA, or modified chromatin, including by chemical cleaving of the retained biopolymer or by changing the flow rate of the liquid in the microfluidic element to liberate the retained material from the internal microstructures; and wherein collection of the released material in an array of receiving containers for further analysis or processing; and as noted in Step 5, additional on system processes are possible through the use of appropriate buffers or flow conditions to isolate various cellular components (interpreting a buffer to be a detergent lysing agent, claim 5) (col 22, lines 33-43). Craighead ‘552 (incorporated herein by reference) teaches lysing the entrapped cell using chemical lysis with an ionic surfactant under sufficient hydrodynamic flow to release DNA contained in the cell without causing DNA shearing, thereby causing the released DNA to be immobilized within the micropillar array of the microfluidic device (interpreted as lysing to obtain sequence data; and a lysing agent including a detergent or chaotropic agent, claims 1 and 5) (col 29, claim 1, lines 55-60).
Regarding claims 8 and 9, Craighead teaches various aspects, components, devices, protocols, systems, and embodiments for use in the devices, systems, and methods for on-chip analysis of nucleic acids and in cell processing systems of the present disclosure are further described in, but not limited to, the following: WO2017/205267A1, WO2017/205304A1, US 9,803,192, and US 9,926,552 describe various microfluidic devices or technologies that can be used for capturing one or more selected cells and separating genomic DNA of these cells from other cellular components for analysis, wherein US 9,803,192, and US 9,926,552 herein incorporated by reference utilize microfluidic devices containing micro-structures to capture selected cells by size or affinity binding, such that by lysing the captured cells the genomic DNA can be immobilized in the device and separated from the other components of the lysed cells (interpreted as lysing cells; purification or size selection; and collecting gDNA and/or RNA via purification or size selection in vessels or tubes separate from the fraction of enriched mtDNA, claims 5, 8 and 9) (col 29, lines 38-42 and 56-67; and col 30, lines 1-2), wherein the micro-column affinity chromatography device is suitable for conducting affinity chromatography in multiple microcolumns in parallel and/or in series as evidenced by Craighead ‘192 (Abstract); and wherein the microfluidic channel includes a micropillar array, an inflow channel disposed between the inlet port and the micropillar array including micropillars spatially configured to entrap, by size exclusion, the cell, to immobilize DNA released from the cell, and to maintain the immobilized DNA as evidenced by Craighead ‘552 (Abstract). Craighead teaches in Step 5: the retention of the genomic DNA or chromatin on internal microstructures in the microfluidics such as an array of micron-scale pillars and collection of the other cellular components into an array of receiving vessels such as a microplate for subsequent analysis or processing (interpreted as collecting the lysate on a microfluidic device comprising micro-features, claim 1) (col 22, lines 15-19). Craighead teaches that the integrated microfluidic cell processing system is suitable for collecting one or more liquid sample from an affinity chromatography microcolumn device, including: (i) a liquid flow mechanism for moving a liquid sample into, through, and out of a microcolumn contained in the device; and (ii) a liquid collection apparatus comprising well portions for collecting liquid samples from the micro-columns, where each well portion is aligned with a single corresponding micro-column for collection of the liquid sample therefrom, wherein the well portions can be replaced with a tube or other sort of conduit that is in fluid alignment with a particular micro-column so as to collect a liquid sample (interpreted as vessels or tubes separate from other fractions, claims 8 and 9) (col 27, lines 64-67; and col 28, lines 1-7 and 13-16).
Regarding claim 10, Craighead teaches that the method further comprises purifying and sequencing the amplified aptamer population; and/or performing reverse transcription amplification, purifying, and/or sequencing steps in one or more separate fluidic devices coupled in fluidic communication with the micro-column devices of the present disclosure (interpreted as sequencing nucleic acid from the gDNA, claim 10) (col 29, lines 14-22).
Regarding claims 11 (in part) and 13, Craighead ‘552 (incorporated herein by reference) teaches removing step can involve subjecting the immobilized DNA to enzymatic digestion sufficient to fragment the DNA so that it passes through the micropillar array and into the outflow channel, wherein suitable enzymes and any related buffers for use in this are well known in the art, and are contemplated by the present invention, such that the removing enzymatic digestion step can involve, without limitation, sonicating the microfluidic device and subjecting the immobilized DNA to hydrodynamic force sufficient to pass the DNA through the micropillar array and into the outflow channel of the microfluidic device (interpreted as fragmenting while on the microfluidic device, claims 11 and 13) (col 11, lines 64-67; and col 12, lines 1-7). Craighead ‘552 (incorporated herein by reference) teaches the extraction and isolation (also referred to as purification) of DNA by physical trapping in tapered arrays of micropillars by microfluidic flow, such that long strands of genomic DNA released from the lysed cells become immobilized in the tapered array of micropillars (also referred to as micro-posts) by hydrodynamic flow due to their relatively large size while the rest of the cellular contents are washed away by pressure driven flow, wherein the flow rate can be optimized so that no DNA shearing occurs in the microchannel (interpreted as fragmenting on the microfluidic device, claim 11) (col 4, lines 23-25 and 30-36). Craighead ‘552 (incorporated herein by reference) teaches that the microfluidic device of the present invention can be integrated with existing flow cytometry systems or microfluidic platforms and used in biomedical devices to extract, purify, and analyze DNA fragments in nanofluidic channels (interpreted as fragmenting on the microfluidic device, claim 11) (col 4, lines 62-66).
Regarding claim 12 (in part), Craighead ‘304 (incorporated herein by reference) teaches that to denature double-stranded gDNA tethered on the micropillar array, buffer was flowed through the device and into ten output reservoirs, wherein each output reservoir was pipette mixed with and the solution containing amplified gDNA was collected off-chip into PCR tubes, and all samples were placed in a -20oC freezer until further use (interpreted as freezing and/or storing in tubes, claim 12) (paragraph [0073]). Craighead ‘267 (incorporated herein by reference) teaches processing and analysis of DNA extracted and immobilized in the device and treating the other cellular components, in other aspects, such that the invention also relates to the use of a microfluidic device for separating the cellular components from the genomic DNA such as mitochondrial DNA or RNA (interpreted as collecting an mtDNA library, claim 12) (paragraph [0089]).
Craighead does not specifically exemplify where data comprises sequence read arising from a mitochondrial genome (claim 2); mapping sequence reads (claim 6); mapping using a basic local alignment search tool (claim 7); ligating adaptors and amplifying adaptor-ligated fragments (claim 11, in part); and an mtDNA sequencing library (claim 12, in part).
Craighead meets all the limitations of the claims and, therefore, anticipates the claimed invention.
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 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.
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 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Craighead et al. (hereinafter “Craighead”) (US Patent No. 12303899, issued May 20, 2025; effective filing date November 28, 2018) in view of Mootha et. al. (hereinafter “Mootha”) (International Patent WO2021248034, published December 9, 2021) as evidenced by Craighead et al. (hereinafter “Craighead ‘192”) (US Patent No. 9803192, issued October 31, 2017); and Craighead et al. (hereinafter “Craighead ‘552 (US Patent No. 9926552, issued March 27, 2018); and Craighead et al. (hereinafter “Craighead ‘304”) (International Application WO2017/205304, published November 30, 2017); and Craighead et al. (hereinafter “Craighead ‘267”) (International Application WO2017/205267, published November 30, 2017).
The teachings of Craighead as applied to claims 1, 3-5, 8-10, 11 (in part), 12 (in part), and 13 are described supra.
Craighead does not specifically exemplify where data comprises sequence read arising from a mitochondrial genome (claim 2); mapping sequence reads (claim 6); mapping using a basic local alignment search tool (claim 7); ligating adaptors and amplifying adaptor-ligated fragments (claim 11, in part); and an mtDNA sequencing library (claim 12, in part).
Regarding claims 2, 6 and 7, Mootha teaches methods of segregation dynamics of mitochondrial DNA, and methods of diagnosing, prognosing, and/or monitoring a mitochondrial disease (Abstract). Mootha teaches methods of determining segregation dynamics of mitochondrial DNA (mtDNA) including detecting a cell signature in the cell or cell population and detecting mtDNA heteroplasmy in the cell or cell population, wherein the cell signature and/or mtDNA heteroplasmy indicates at least cell type and/or cell state (interpreted as mtDNA, claims 1 and 11) (paragraph [0007]). Mootha teaches that raw sequencing reads were demultiplexed and aligned to the hg19 reference genome using the CellRanger-ATAC v1.0 software, wherein cells were identified as barcodes that met the following criteria: (1) ≥ l,000 unique fragments mapping to the nuclear genome; (2) ≥ 40% of nuclear fragments overlapping a previously-established chromatin accessibility peak set in the hematopoietic system; and (3) mean mtDNA coverage of ≥ 20x at position 3243 in the mtDNA genome, such that from the output of the CellRanger-ATAC call, we quantified mtDNA using the mgatk package (interpreted as mapping reads to genomic reference data arising from a mitochondrial genome; and interpreting software as mapping using a basic alignment tool, claims 2, 6 and 7) (paragraph [0420]). Mootha teaches methods to profile the RNA content of tens and hundreds of thousands of individual human cells have been recently developed, including from brain tissues, quickly and inexpensively, wherein special microfluidic devices have been developed to encapsulate each cell in an individual drop, associate the RNA of each cell with a 'cell barcode' unique to that cell/drop, measure the expression level of each RNA with sequencing, and then use the cell barcodes to determine which cell each RNA molecule came from (interpreted as microfluidics, claim 1) (paragraph [0235]). Mootha teaches that microfluidics involves micro-scale devices that handle small volumes of fluids, and because microfluidics can accurately and reproducibly control and dispense small fluid volumes, in particular volumes less than 1μl, application of microfluidics provides significant cost-savings, such that the use of microfluidics technology reduces cycle times, shortens time-to-results, and increases throughput, See, e.g., US 20120219947; and PCT/US2014/058637 for disclosure regarding a microfluidic laboratory on a chip (interpreted as microfluidics, claim 1) (paragraph [0238]).
Regarding claim 11 (in part), Mootha teaches that the nucleic acid barcode includes or is linked to sequencing adapters (e.g., universal primer recognition sequences) such that the barcode and sequencing adapter elements are both coupled to the target molecule; and the sequence of the origin specific barcode is amplified, for example using PCR, wherein an origin-specific barcode further comprises a sequencing adaptor (interpreted as ligating adaptors to mtDNA fragments, claim 11) (paragraph [0183], lines 6-10). Mootha teaches that nucleic acid tags can be sequentially ligated to create a sequence reflecting conditions and order of same (interpreted as ligation, claim 11) (paragraph [0277], lines 3-4). Mootha teaches that nanopore technology libraries are generated by end-repair and sequencing adapter ligation (interpreted as adaptor ligation, claim 11) (paragraph [0292], lines 7-8).
Regarding claim 12 (in part), Mootha teaches kits for diagnosing, prognosing, and/or monitoring a mitochondrial disease and/or determining segregation dynamics of mitochondrial DNA (mtDNA) comprising: a collection vessel configured to collect and/or contain a sample comprising a cell or cell population obtained from a body of a subject, wherein the sample is a bodily fluid, a bodily excretion, a bodily secretion, a tissue, a cell or cell population, or a combination thereof; instructions fixed in a tangible medium of expression that provides direction to collect the sample in the collection vessel and determine: (a) segregation dynamics of mtDNA, (b) a diagnosis of a mitochondrial disease, (c) a prognosis of a mitochondrial disease, or (d) a combination thereof, and optionally monitor any one or more of (a)-(d) by a method comprising: detecting mitochondrial DNA (mtDNA) heteroplasmy and cell type and/or cell state in the cell or cell population, wherein the collection vessel comprises a reagent effective to prepare and/or preserve the sample (interpreted as collecting and storing mtDNA in sample tubes containing an mtDNA sequencing library prior to sequencing, claim 12) (paragraphs [0045]; and [0065]).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Moreover, “it is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view the benefits of using microfluidic devices for mtDNA and RNA profiling as exemplified by Mootha, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the microfluidic chip and/or the methods for detecting the presence or absence of a target nucleic acid region in a sample comprising a marker or mutation for a disease or abnormal condition as exemplified by Craighead to include the droplets, barcodes, sequencing libraries and/or methods of sequencing as disclosed by Mootha with a reasonable expectation of success in creating genetic profiles for a disease or condition using RNA, gDNA and/or mtDNA from a single cell and/or from a population of cells; and/or in diagnosing, prognosing, and/or monitoring the progression of a disease including a mitochondrial disease using an integrated microfluidic chip, while identifying the origin of cell each nucleic acid molecule analyzed, wherein the microfluidic technology significantly reduces cost and cycle times, shortens time-to-results, and increases throughput.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
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 1-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
Claims 1-20 of copending Application No. 19/297,313. US19/297,313 recites: a method of extracting or separating nucleic acids from a biological sample; the method comprising: introducing a sample containing a cell into a channel of a microfluidic device; capturing the cell on one or more cell-capture features disposed within the channel; lysing the captured cell to release DNA from the cell; flowing the DNA through the channel to a capture array within the channel; capturing the DNA on the capture array; and washing the DNA into a collection reservoir by flowing a fluid through the channel under conditions that remove the DNA from the capture array thereby collecting, in the collection reservoir, at least one DNA molecule at least 100 kilobase pairs in length that was released from the cell (claim 1).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant Application and the claims of US19/297,313 are directed to methods of lysing cells and capturing DNA on a microfluidic device comprising an array of microfeatures.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 of copending Application No. 19/461,923. US19/461,923 recites: a sequencing library preparation method comprising introducing a sample containing a cell into a microfluidic device; capturing the cell on one or more cell-capture feature of the microfluidic device; lysing the captured cell to release DNA; capturing the DNA at a capture site within the microfluidic device; and attaching adapters to the DNA to yield library DNA in the microfluidic device (claim 1). Further comprising sequencing, the library DNA on a sequencing device to obtain sequence data of the cell from the sample (claim 3).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant Application and the claims of US19/461,923 are directed to methods of lysing cells and capturing DNA on a microfluidic device comprising an array of microfeatures.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-13 are rejected.
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/AMY M BUNKER/
Primary Examiner, Art Unit 1684
Prosecution Insights