DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed August 18, 2025. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Claims 1-6, 8-10, 14-15, 23, 25-32, 34, and 36 are currently pending.
Claims 28-31, 34, and 36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on October 20, 2023.
Claim Rejections - 35 USC § 103
3. 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.
4. Claims 1-4, 9-10, 23, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Golato (Scientific Reports 7:13007 pages 1-13 Pub Online 10/11/2017) in view of Lohmann (US 2010/0286290 Pub 11/11/2010), Salathia (US 2016/0053253 Pub 2/25/2016), Bobrow (US 2007/0166810 Pub 7/19/2007), Chandler (US 2013/0149724 Pub 6/13/2013), and Ding (Molecular Therapy vol 22 no 6 pages 1075-1083 June 2014).
Regarding Claim 1 Golato teaches that they developed a cell based assay for measuring base excision repair responses. Golato teaches that the general strategy of the assay involves a 5′-biotinylated, “hairpin” oligonucleotide substrate and the following experimental steps: 1. assembly of the damage-specific DNA hairpin substrate; 2. transfection of the prepared substrate into a target cell population; 3. incubation of the transfected cells for some length of time to permit DNA repair; 4. lysis of the cells and retrieval of the biotinylated DNA from the extract; and 5. quantitative PCR (qPCR) across both the DNA damage (Test) and another defined location within the substrate (Reference). The basic principle is that if the damage (or a repair intermediate) remains, PCR amplification across this site is less efficient than if the damage had been removed and repair completed. This approach assumes the ability of the DNA lesion to block/stall a PCR polymerase. PCR of a control region on the substrate allows one to normalize to the amount of DNA retrieved, since there will likely be differences in capture efficiency from sample to sample. Thus, Test amplification relative to Reference amplification (i.e., ΔCt = CtTest − CtRef) will provide an indication of DNA repair capacity (page 2, Fig 1). The hairpin oligonucleotides are shown in Figures 2A and 3A. In the initial design, the hairpin contained three components (i) a biotinylated Flag oligo, (ii) a damage legion, and (iii) hairpin oligo (Fig 2 inset). Golato further teaches that following lysis they used a streptavidin-bead capture method to recover the hairpin DNA (page 7). Thus Golato teaches a method of analyzing enzymatic activities in cells comprising a) exposing a cell to substrate-oligonucleotide conjugates, the substrate-oligonucleotide conjugates comprising one or more oligonucleotides conjugated to enzyme substrates (the damage lesion), b) performing a nucleic acid amplification on oligonucleotides associated with reacted substrates to produce nucleic acid amplification products; and c) analyzing the nucleic acid amplification products, wherein the substrate-oligonucleotide conjugates are linked to a solid support (during hairpin retrieval the biotinylated hairpins are linked to streptavidin beads), and wherein analyzing the nucleic acid amplification products determines at least one of an amount of and a type of enzymatic activity in the cell, and wherein the enzymatic activity is a DNA repair activity.
Regarding Claims 2 and 3 Golato teaches analysis of three different human cell lines (HEK 293T, HeLa, and LN428) (page 9). Thus Golato teaches a method wherein the cell is a human cell from a population of cultured cells.
Regarding Claim 4 Golato teaches that they developed a cell based assay for measuring base excision repair responses. Golato teaches that the general strategy of the assay involves a 5′-biotinylated, “hairpin” oligonucleotide substrate and the following experimental steps: 1. assembly of the damage-specific DNA hairpin substrate; 2. transfection of the prepared substrate into a target cell population; 3. incubation of the transfected cells for some length of time to permit DNA repair; 4. lysis of the cells and retrieval of the biotinylated DNA from the extract; and 5. quantitative PCR (qPCR) across both the DNA damage (Test) and another defined location within the substrate (Reference) (page 4). Thus Golato teaches subjecting the substrate-oligonucleotide conjugates and the cell to conditions in which enzymes within the single cell can act specifically on an enzyme substrate prior to performing the nucleic acid amplification on the oligonucleotides associated with reacted substrates.
Regarding Claim 9 Golato teaches that they developed a cell based assay for measuring base excision repair responses. Golato teaches that the general strategy of the assay involves a 5′-biotinylated, “hairpin” oligonucleotide substrate and the following experimental steps: 1. assembly of the damage-specific DNA hairpin substrate; 2. transfection of the prepared substrate into a target cell population; 3. incubation of the transfected cells for some length of time to permit DNA repair; 4. lysis of the cells and retrieval of the biotinylated DNA from the extract (page 4). Thus Golato teaches a method wherein exposing the cell to substrate-oligonucleotide conjugates comprises lysing the cell in the presence of the substrate-oligonucleotide conjugates.
Regarding Claim 10 Golato teaches that they developed a cell based assay for measuring base excision repair responses. Golato teaches that the general strategy of the assay involves a 5′-biotinylated, “hairpin” oligonucleotide substrate and the following experimental steps: 1. assembly of the damage-specific DNA hairpin substrate; 2. transfection of the prepared substrate into a target cell population; 3. incubation of the transfected cells for some length of time to permit DNA repair; 4. lysis of the cells and retrieval of the biotinylated DNA from the extract; and 5. quantitative PCR (qPCR) across both the DNA damage (Test) and another defined location within the substrate (Reference) (page 4). Thus Golato teaches a method performing the nucleic acid amplification on the oligonucleotides associated with reacted substrates comprises amplifying DNA by polymerase chain reaction (PCR).
Regarding Claim 23 Golato teaches that they developed a cell based assay for measuring base excision repair responses. Golato teaches that the general strategy of the assay involves a 5′-biotinylated, “hairpin” oligonucleotide substrate and the following experimental steps: 1. assembly of the damage-specific DNA hairpin substrate; 2. transfection of the prepared substrate into a target cell population; 3. incubation of the transfected cells for some length of time to permit DNA repair (page 4). Thus Golato teaches a method wherein the substrate-oligonucleotide conjugate is incubated with the cell under physiological conditions comprising buffer, pH, and temperature conditions that facilitate the enzymatic activity present in the single cell.
Regarding Claim 32 Golato teaches that the hairpin substrate is transected into the target cell population by means of chemical reagents (Fig 1). Golato teaches that PolyPlus INTERFERin was the best transfection reagent (page 7). Thus Golato teaches exposing the cell to an aqueous composition (transfection reagent) comprising the substrate-oligonucleotide conjugates.
Golato does not teach a method wherein the analysis of enzymatic activity is performed on a single cell (clm 1).
However Lohman discloses an enzyme activity assay using rolling circle amplification for verifying that a sample contains the enzyme activity in question (abstract). Lohman teaches introducing into the cell(s) in question a probe structure which is not a substrate for RCR and which can only be amplified by RCR if the probe structure is modified by an enzyme specifically able to modify the probe structure, thereby converting the probe structure into a substrate for subsequent amplification by RCR (para 0044). Lohman teaches that the method is well suited for enzyme detection directly in single cells (para 0045).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato by practicing the method on a single cell as suggested by Lohman. One of skill in the art would have been motivated to analyze a single cell particularly since Lohman teaches that monitoring protein activity on single cells is a strong molecular tool, not only in basic research but also in cancer prognostics/diagnostics (para 0337, 0342).
Neither Golato nor Lohman teach a method wherein the oligonucleotide of the substrate-oligonucleotide conjugate comprises a (i) cell identification sequence associated with a specific cell; (ii) a substrate identification sequence associated with a specific type of enzyme substrate; and (iii) a unique molecular identifier sequence (clm 1).
However Salathia teaches methods for single cell gene expression analysis. Salathia teaches that tags can be added to cDNA molecules. Salathia teaches that the tag can comprise a cell specific identifier sequence and a unique molecular identifier sequence (para 0012, abstract).
Additionally Bobrow teaches a method for detecting enzymatic activity. Bobrow teaches particles having an attached enzymatic substrate, the enzymatic substrate being identifiable by a particle code (para 0004).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato and Lohmann by using a substrate oligonucleotide conjugate, wherein the oligonucleotide comprises (i) cell identification sequence associated with a specific cell; (ii) a substrate identification sequence associated with a specific type of enzyme substrate; and (iii) a unique molecular identifier sequence as suggested by the prior art. As demonstrated by Salathia it was known in the art how to add tag sequences to nucleic acid molecules and in particular cell specific identifier sequences and UMI sequences (para 0012). One of skill in the art would have been motivated to add a cell identification sequence associated with a specific cell for the benefit of being able to keep track of which cells have the enzymatic activity and which cells do not. One of skill in the art would have been motivated to add an enzyme substrate sequence associated with a specific type of enzyme substrate for the benefit of being able to keep track of which enzymes particular cells were tested for. Finally the skilled artisan would have been motivated to use UMIs to uniquely tag each molecule for the benefits of accurate detection and removal of PCR duplicates.
The combined references do not teach a method wherein the step of exposing a single cell to substrate oligonucleotide conjugates occurs within a microfluidic device (clm 1).
However Chandler teaches a method of performing cell transfection within a microfluidic device (abstract, paras 0020, 0112-0113).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, and Bobrow by performing the exposing step within a microfluidic device as suggested by Chandler. One of skill in the art would have been motivated to use a microfluidic device since these devices offer several advantages that were known in the art at including automation, low reagent volumes, low cost, and better control for heating/cooling.
Additionally the combined references do not teach a method wherein the substrate-oligonucleotide conjugates are covalently linked to a solid support (clm 1).
However Ding teaches that gold nanoparticles provide an attractive and applicable scaffold for delivery of nucleic acids into cells. In particular Ding discusses covalent AuNP conjugates (pages 1075-1078).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, Bobrow, and Chandler by using substrate-oligonucleotide conjugates that are covalently linked to AuNPs as suggested by Ding. One of skill in the art would have been motivated to use substrate-oligonucleotide conjugates that are covalently linked to AuNP Ding teaches that covalent attachment of nucleic acids to AuNPs is an effective means of transporting gene-silencing oligonucleotides, where the modification does not inhibit biological activity (page 1075, col 2). Further Ding teaches that cellular uptake of pNA-AuNPs is quite rapid with ?50 cell lines (page 1076, col 1).
5. Claims 5 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Golato (Scientific Reports 7:13007 pages 1-13 Pub Online 10/11/2017) Lohmann (US 2010/0286290 Pub 11/11/2010), Salathia (US 2016/0053253 Pub 2/25/2016) Bobrow (US 2007/0166810 Pub 7/19/2007), Chandler (US 2013/0149724 Pub 6/13/2013), and Ding (Molecular Therapy vol 22 no 6 pages 1075-1083 June 2014) as applied to claim 1 above and in further view of Krusemark (WO 2017/031378 Pub 2/23/2017).
The teachings of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding are presented above.
The combined references do not teach a method further comprising separating reacted and unreacted substrate-oligonucleotide conjugates from the single cell contents prior to performing the nucleic acid amplification on the oligonucleotides associated with reacted substrates (clm 5).
However Krusemark teaches a methods for detecting and quantifying proteomic activity using DNA encoded probes, wherein the proteomic activity may be enzymatic activity (abstract). Krusemark teaches that after allowing a sufficient amount of time to pass (i.e. sample exposure), enzyme activity is quenched and the probes are pooled into a probe population comprising both “reacted” DNA-encoded probes comprising product and “unreacted” DNA-encoded probes comprising substrate. The pool is then subjected to a purifying selection for product probes (page 16 lines 19-25).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding by separating the reacted and unreacted DNA probes prior to amplification of the reacted DNA probes as suggested by Krusemark. In the instant case one of skill would have been motivated to separate the two groups particularly since Krusemark teaches that this type of manipulation greatly facilitates the accuracy of the method (page 17, lines 20-24).
The combined references do not teach a method wherein analyzing the nucleic acid amplification products comprises high throughput sequencing of at least a portion of the nucleic acid amplification products to identify the sequence of the oligonucleotide, and analysis of DNA sequence information to identify at least one of type and quantity of enzymatic activities present in the contents of the single cell (clm 27).
However Krusemark teaches a methods for detecting and quantifying proteomic activity using DNA encoded probes, wherein the proteomic activity may be enzymatic activity (abstract). Krusemark teaches that the DNA encoded probes may be sequenced using high throughput DNA sequencing (page 4 lines 1-2). Krusemark teaches a method wherein the initial (pre-purified) DNA pool is sequenced, and a sample of DNA from the purified population is sequenced to identify the various samples, reagents, etc. within a pool. The results of these sequencing assays are then compared with respect to the abundance of the DNA present within each sample, with a higher relative amount of DNA (i.e. the DNA present within the purified pool selected on the basis of being linked to a product and, thus, having undergone enzymatic activity) indicative of high enzymatic activity (page 17, lines 10-20).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding by using high throughput sequencing as suggested by Krusemark. The claim would have been obvious because the skilled artisan would have recognized the advantages of using high throughput sequencing methods known in the art at the time of the invention.
6. Claims 6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Golato (Scientific Reports 7:13007 pages 1-13 Pub Online 10/11/2017) Lohmann (US 2010/0286290 Pub 11/11/2010), Salathia (US 2016/0053253 Pub 2/25/2016), Bobrow (US 2007/0166810 Pub 7/19/2007), Chandler (US 2013/0149724 Pub 6/13/2013), and Ding (Molecular Therapy vol 22 no 6 pages 1075-1083 June 2014) as applied to claim 1 above and in further view of Vigneault (US 2014/0357500 Pub 12/4/2014).
The teachings of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding are presented above.
The combined references do not teach a method wherein the single cells are isolated with an oligonucleotide-linked solid support within a microfluidic device in a reaction chamber selected from an emulsion droplet, a nano well, and between valves in a microfluidic channel (clm 6). The combined references do not teach a method wherein the emulsion droplet is one of a plurality of aqueous droplets formed within a water-in-oil emulsion (clm 8).
However Vigneault teaches that isolated immune cells can be encapsulated in water in oil emulsion in such way to create individual picoliter compartments containing a single immune cell or less per droplets. Millions of cells can be processed for each patients allowing high throughput in single cell sequencing technology. Micron scale paramagnetic beads harboring oligonucleotides complementary to the VH and VL antibody chains are also introduced during the emulsion process. These beads can carry long degenerate barcodes such that each bead can confer a unique identity code to each of the emulsion they are in. The millions of single immune cells are lysed inside the emulsion and the antibody transcripts are reverse transcribed using the barcoded bead primers, followed by PCR amplification of the VH and VL chains. Each VH and VL chain stemming from a single immune cells can be virtually linked to each other with the same barcode identity (para 0225).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding by putting the single cells and an oligonucleotide linked to a bead in a water in oil emulsion as suggested by Vigneault. One of skill in the art would have been motivated to place a single cell and oligonucleotide linked bead in an emulsion for the benefit of being able to individually screen a large number of single cells for the presence or absence of the enzyme and detect the presence of cell to cell differences.
7. Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Golato (Scientific Reports 7:13007 pages 1-13 Pub Online 10/11/2017) Lohmann (US 2010/0286290 Pub 11/11/2010), Salathia (US 2016/0053253 Pub 2/25/2016), Bobrow (US 2007/0166810 Pub 7/19/2007), Chandler (US 2013/0149724 Pub 6/13/2013), and Ding (Molecular Therapy vol 22 no 6 pages 1075-1083 June 2014) as applied to claim 1 above and in further view of Nautiyal (US 2006/0292585 Pub 12/28/2006).
The teachings of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding are presented above.
The combined references do not teach a method comprising reacting oligonucleotides with an abasic endonuclease followed by phosphorylation, and ligating a single strand DNA adaptor to the oligonucleotide, prior to performing the nucleic acid amplification on the oligonucleotides associated with reacted substrates (clm 14).
However Nautiyal that oligonucleotides can be ligated to adaptors, but it may be necessary to treat them chemically or enzymatically to generate ends suitable for ligation. In one aspect the fragments are treated with an AP endonuclease prior to ligation of adaptors (para 0113). This type of endonuclease recognizes and cuts the backbone immediately 5’ of an abasic site generating a abasic deoxyribose 5-phophate.
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding by reacting oligonucleotides with an abasic endonuclease followed by phosphorylation, and ligating a single strand DNA adaptor to the oligonucleotide. One of skill in the art would have been motivated to add a DNA adaptor to facilitate primer binding for amplification.
8. Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Golato (Scientific Reports 7:13007 pages 1-13 Pub Online 10/11/2017) Lohmann (US 2010/0286290 Pub 11/11/2010), Salathia (US 2016/0053253 Pub 2/25/2016), Bobrow (US 2007/0166810 Pub 7/19/2007), Chandler (US 2013/0149724 Pub 6/13/2013), and Ding (Molecular Therapy vol 22 no 6 pages 1075-1083 June 2014) as applied to claim 1 above and in further view of Kreklau (Nucleic Acids Research 2001 Vol 29 No 12 pages 2558-2566).
The teachings of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding are presented above.
The combined references do not teach a method wherein the enzyme substrate comprises a DNA adduct comprising at least one nucleotide aberration that initiates a DNA repair activity such as direct reversal (clm 15).
However Kreklau teaches an oligonucleotide assay to measure alkylation repair via MGMT. The approach involves cell extracts in a common buffer in which the DNA repair protein is active and the use of oligonucleotide substrates containing DNA lesions specific to each repair protein. So for example when the repair enzyme is MGMT, the oligonucleotide substrate comprises the O6-MeG lesion. If left unrepaired the O6-MeG adducts can mispair with thymine, causing a G:C> A:T transition that is associated with both mutagenesis and carcinogenesis (page 2558, col 1-2, page 2559, col 2).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding by using an enzyme substrate that comprises a DNA adduct comprising at least one nucleotide aberration that initiates a DNA repair activity such as direct reversal as suggested by Kreklau. One of skill in the art would have been motivated to use an enzyme substrate that comprises a DNA adduct comprising at least one nucleotide aberration that initiates a DNA repair activity such as direct reversal for the benefit of being able to measure the enzymatic activity of MGMT which is important because when this enzyme is not working properly it can lead to carcinogenesis.
9. Claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Golato (Scientific Reports 7:13007 pages 1-13 Pub Online 10/11/2017) Lohmann (US 2010/0286290 Pub 11/11/2010), Salathia (US 2016/0053253 Pub 2/25/2016), Bobrow (US 2007/0166810 Pub 7/19/2007), Chandler (US 2013/0149724 Pub 6/13/2013), and Ding (Molecular Therapy vol 22 no 6 pages 1075-1083 June 2014) as applied to claim 1 above and in further view of Liu (US 2019//0338279 Filed 6/5/2019 with priority to PCT/CN2016/108940 Filed 12/7/2016).
The teachings of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding are presented above.
The combined references do not teach a method comprising capturing polyadenylated mRNA from the single cell, and creating a cDNA library from the polyadenylated mRNA (clm 25). The combined references do not teach a method wherein the cDNA library is analyzed to obtain gene expression data specific to the single cell (clm 26).
However Liu teaches a method of parallel sequencing of single-cell DNA and RNA, comprising: lysing a cell with a strong lysis buffer, and then capturing the mRNA containing a polyA by using magnetic beads, and after the separation, performing whole genome amplification for the DNA in the remaining liquid for constructing a whole genomic DNA library, and constructing a cDNA library with the RNA (para 0006). Liu teaches that the cDNA library can be used for gene expression analysis (para 0009).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Golato, Lohmann, Salathia, Bobrow, Chandler, and Ding by capturing polyA mRNA from the single cell, creating a cDNA library from the captured mRNA and then using the library for gene expression analysis as suggested by Liu. One of skill in the art performing gene expression assays would have been motivated to capture polyA mRNA and make a cDNA library from the captured mRNA for the benefit of being able to obtain DNA sequences that code for mRNA molecules and lack sequences that are not expressed such as introns.
Response To Arguments
10. In the response the Applicants traversed the rejections under 35 USC 103 based on the combination of Golato, Lohmann, Salathia, and Bobrow. They argue that the claims as amended require that the substrate-oligonucleotide conjugates are exposed to a single cell, or contents thereof, within a microfluidic device, and that the substrate-oligonucleotide conjugates are covalently linked to a solid support. The Action indicates that Golato describes substrate-oligonucleotide conjugates (biotinylated harpins) linked to a solid support (streptavidin beads) and isolated from cell lysates. However, Golato fails to teach exposing a single cell, or contents thereof, to substrate oligonucleotide conjugates in a microfluidic device, wherein the substrate-oligonucleotide conjugates are covalently linked to a solid support. Lohmann, Salathia, and Bobrow fail to cure the deficiencies of Golato in teaching exposing a single cell, or contents thereof, within a microfluidic device, to the claimed substrate oligonucleotide conjugates covalently linked to a solid support. Additionally the Applicants argue that none of the additionally recited references (Krusemark, Vigneault, Nautiyal, Kreklau, and Liu) cure the deficiencies of Golato, Lohmann, Salathia, and Bobrow in teaching the method of claim 1 as amended herein. Therefore Applicants request withdrawal of these rejections.
These arguments and the amendments have been fully considered. It is noted for the record that new rejections have been made herein to address the claims as amended.
11. 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 extension fee 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 date of this final action.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682