3DETAILED 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 .
Priority
The instant application claims the benefit of provisional U.S. Patent Application No. 63/190,079, filed on 05/18/2021.
The priority date of claim 1 and its dependents is determined to be 05/18/2021, the filing date of provisional U.S. Patent Application No. 63/190,079.
Status of Claims
Applicant’s amendments to claims filed 06/18/2026 in response to the Non-Final Rejection mailed 03/20/2026 are acknowledged.
Claims 1, 6, 12, and 14 are amended.
Claims 2, 3, 4, and 5 have been canceled.
Claims 1, 6-9, and 12-21 are pending and under examination.
Response to Remarks filed 06/18/2026
The amendments and arguments presented in the papers filed 06/18/2026 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 03/20/2026 listed below have been reconsidered as indicated.
a) The 35 USC 112(b) indefiniteness rejections of claims 1-9 and 12-21 have been withdrawn in view of the amendments to claims and the cancellation of claims 2-5.
b) The rejection of claims 1-9 and 12-21 under 35 U.S.C. 103 as being unpatentable over Ko (WO 2021/067162) in view of Meltzer (WO 2020/069298) are modified in view of the amendments to the claims and the cancellation of claims.
c) The double patenting rejections of claim 1 over U.S. Patent No. 11,866,782, U.S. Patent Application No. 17/281,157 or U.S. Patent Application No. 18/403,902 are modified in view of the amendments to the claim.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Claim Interpretation
Amended claim 1 recites the limitations (1) “target-specific antibodies linked to DNA index oligonucleotides or target-specific antibodies linked to RNA index oligonucleotides”; (2) “reverse transcribing the released RNA captured by the capture oligonucleotide to produce cDNA, wherein reverse transcribing comprises reverse transcribing the RNA index oligonucleotides to produce index cDNA when the target-specific antibodies are linked to RNA index oligonucleotides”, and (3) “creating a sequencing library comprising
(i) copies of the cDNA and the index cDNA when the target-specific antibodies are linked to RNA index oligonucleotides or (ii) copies of the cDNA and the DNA index oligonucleotides when the target-specific antibodies are linked to DNA index oligonucleotides”. For purposes of examination the claim is interpreted to require either, in the alternative:
Target-specific antibodies linked to DNA index oligonucleotide; reverse transcribing the released RNA captured by the capture oligonucleotide to produce cDNA; and creating a sequencing library comprising copies of the cDNA and the DNA index oligonucleotides.
or
target-specific antibodies linked to RNA index oligonucleotides; reverse transcribing the released RNA captured by the capture oligonucleotide to produce cDNA and reverse transcribing the RNA index oligonucleotides to produce index cDNA; and creating a sequencing library comprising (i) copies of the cDNA and the index cDNA.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 6-9, 12-17, and 20- 21 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Ko et al. (WO 2021067162, published 04/08/2021) in view of Meltzer et al. (WO/2020/069298, on IDS dated 11/02/2022).
This maintained rejection has been modified to address claim amendments filed on 06/18/2026.
Regarding claim 1, Ko teaches methods of analyzing individual extracellular vesicles (EVs) from biological samples.
Ko teaches isolating EVs from a biological sample; labeling the EVs with antibody-DNA conjugates (target-specific antibodies linked to DNA index oligonucleotides); obtaining barcoded beads (template particles); encapsulating the labeled EVs (i.e. bound by the antibody) and barcoded beads in droplets (partitions) (p. 3, lines 7-12). Ko teaches any antibody that targets a specific surface EV protein of interest can be used (target-specific antibodies that bind to EV surface proteins) (p. 12, line 26). Ko further teaches the barcoded beads comprise a hybridization region (p. 5, lines 13-15 and Fig. 1), which reads on a template particle comprising capture oligonucleotides.
Ko teaches a barcode (index oligonucleotide) that is specific to an antibody (Fig. 1B) and can be used to distinguish different antibodies (p. 13, lines 1-2), which reads on index oligonucleotides that contain a barcode sequence that identifies a protein to which the antibody binds.
Ko teaches barcoded beads comprising a UMI region (p. 3, lines 24-25 and Fig. 1), i.e. a barcode unique to each template particle, which after partitioning, reads on capture oligonucleotides of each template particle comprising a partition barcode unique to each template particle.
Ko teaches droplets (partitions) are generated by adding oil to form water in oil partitions (p. 9, lines 21-22). Ko also teaches the barcoded beads (template particles) comprise hybridization regions that include complementary sequence to the sequence of the DNA on the antibody-DNA conjugate (i.e. capturing antibodies on the template particle) (p. 3, lines 24-27 and p. 13, lines 29-30).
Ko does not explicitly teach (1) shearing the mixture to form a plurality of water-in-oil partitions, wherein individual extracellular vesicles are (i) isolated in one of the partitions with a template particle and (ii) bound by at least one of the antibodies.
Meltzer teaches methods of target capture and barcoding in monodisperse droplets, including barcoding of specific nucleic acids, including RNA, contained in the captured targets (Abstract). The methods comprise combining capture template particles with a first fluid comprising target particles (para 6) such as extracellular vesicles (para 7). Meltzer teaches template particles that can capture antibodies and polynucleotides (para 5).
Regarding (1), Meltzer teaches shearing or partitioning such that the capture template particles and associated exosomes are encapsulated in a plurality of monodisperse droplets in the partitioning oil (i.e. water-in-oil partitions) such that each capture template particle and associated exosome are encapsulated in a single monodisperse droplet (para 18).
Thus, Meltzer teaches elements satisfying the requirement of water-in-oil partitions forms by shearing, wherein individual extracellular vesicles are (i) isolated in one of the partitions with a template particle and (ii) bound by at least one of the antibodies.
Ko teaches EVs contain small amounts of nucleic acids (p. 16, lines 10-13) and reverse transcribing after droplet breaking (p. 15, lines 15 and 28-31) but does not teach (2) lysing the extracellular vesicles to release RNA within each partition; capturing released RNA and antibodies on the template particle within each partition and reverse transcribing the released RNA captured by the capture oligonucleotide to produce cDNA.
Regarding (2), Ko teaches the barcoded bead comprises hybridization regions that include complementary sequence to the sequence of the DNA on the antibody-DNA conjugate (i.e. capturing antibodies on the template particle) (p. 3, lines 24-27 and p. 13, lines 29-30). Meltzer teaches lysing the exosomes to release RNA within the partition (para 18) and capturing released mRNA with the Poly-T sequences (“Poly-T capture”) of the capture template particle’s capture element genetic identifier (para 18), thus capturing released RNA on the template particle within each partition. Meltzer further teaches template particles with multiple capture elements, including capture moieties comprising target-specific capture elements for capturing antibodies (Fig. 8). Meltzer further teaches performing reverse transcription to generate cDNA templates of the associated mRNAs (para 18).
Regarding creating a sequencing library and sequencing, both Ko (p. 16, lines 3-5) and Meltzer (para 33-34 ) teach sequencing a sequencing library. However, Ko does not teach creating a sequencing library with the recited components.
Meltzer teaches generating cDNA products from captured mRNAs (para 73) and preparing a sequencing library via PCR amplification (para 73). Meltzer further teaches PCR of target-specific capture elements for sequencing library generation (paras 65 and 67) and further teaches PCR is performed with a universal adaptor-specific sequence to release nucleic acids associated to the plurality of capture template particles from said plurality of capture template particles (para 8), which reads on copies of the DNA index oligonucleotide.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ko and Meltzer to arrive at the instantly claimed invention. The modification would have entailed (1) using the method of Meltzer to shear droplets into partitions such that individual extracellular vesicles are isolated in a partition with a bead and bound by an antibody. The modification would have made use of the Meltzer beads multi-capture elements, while retaining the partition-specific barcode information of Ko to capture the antibodies of Ko bound to extracellular vesicle surface proteins. As a result, beads that were partitioned into individual droplets would further partition antibodies bound to the extracellular vesicles. The modification could additionally have involved using the capture oligonucleotides of Ko to hybridize the target-specific oligonucleotides to the template particle. One of skill in the art would have been motivated to use the method of Ko for partitioning control. Both Ko and Meltzer were motivated to characterize single target particles or extracellular vesicles, and droplet partitioning was well-known at the time of filing. The modification would further have entailed (2) processing the partitioned extracellular vesicles by the method of Meltzer, namely lysing the vesicles while in the partition with a bead comprising capture elements to capture RNA from a single vesicle. One of skill in the art would have been motivated to use the bead of Meltzer in the partition to ensure linking antibody and RNA information associated with a single extracellular vesicle. Ko was motivated to develop methods for sequencing nucleic acids from extracellular vesicles along with protein composition analysis. The partitioning and multiple capture element beads of Meltzer contribute towards this goal. Lastly the modification would have entailed (3) generating the sequencing library by the methods of Meltzer. One would have been motivated to use the methods of Meltzer to generate the sequencing library in order to take advantage of the template capture elements on the beads of Meltzer linking a single bead to sequences of RNA and oligonucleotides linked to antibodies capable of identifying extracellular vesicle surface proteins to identify particular vesicles. One of skill in the art would have recognized that converting the captured RNA to cDNA would allow one to use PCR to generate a sequencing library from RNA (now in DNA form) and DNA index oligos. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 6, Ko teaches identifying EV proteins from sequence reads (p. 3, lines 17-18 and ). Ko also teaches barcoded beads (template particles) comprising a UMI region (p. 3, lines 24-25), i.e. a barcode unique to each template particle and thus each EV. Ko teaches DNA index oligonucleotides with a barcode that is specific to an antibody (Fig. 1B) and can be used to distinguish different antibodies (p. 13, lines 1-2), which reads on index oligonucleotides that contain a barcode sequence that identifies a protein to which the antibody binds, i.e. a protein present in the EVs..
However, Ko does not teach identifying nucleic acids present in the EVs from sequence reads or identifying a protein from the sequencing reads.
Meltzer teaches a template particle may comprise a target-specific capture element genetic identifier that captures mRNA and a template ID element (referred to as “Template specific barcode”) (para 18). Reverse transcription generates cDNA templates of the mRNA along with the template specific barcode (para 18). Meltzer teaches generating cDNA products from captured mRNAs (para 73) and preparing a sequencing library via PCR amplification (para 73). Meltzer further teaches template particles with multiple capture elements, including capture moieties comprising target-specific capture elements for capturing antibodies (Fig. 8). Meltzer further teaches PCR of target-specific capture elements for sequencing library generation (paras 65 and 67) and further teaches PCR is performed with a universal adaptor-specific sequence to release nucleic acids associated to the plurality of capture template particles from said plurality of capture template particles (para 8), which reads on copies of the DNA index oligonucleotide.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ko and Meltzer to arrive at the instantly claimed invention. The modification would have entailed generating a sequencing library from the PCR products of Meltzer from the captured DNA index oligonucleotides of Ko, the bead partition-specific barcodes of Ko and the capture RNA of Meltzer, thus capturing information regarding individual partitions (i.e. EVs) and the surface protein and nucleic acids associated with the EV. One would have been motivated by the ability of partitioning and template particle capture to associate both proteins and nucleic acids with an EV and better characterize EVs, a goal of both Ko and Meltzer. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 7, Ko teaches barcoded beads comprising a UMI region (p. 3, lines 24-25 and Fig. 1), i.e. a barcode unique to each template particle, which after partitioning, reads on capture oligonucleotides of each template particle comprising a partition barcode unique to each template particle.
Meltzer teaches partitioning such that the capture template particles and associated exosomes are encapsulated in a plurality of monodisperse droplets in the partitioning oil (i.e. water-in-oil partitions) such that each capture template particle and associated exosome are encapsulated in a single monodisperse droplet (para 18). Thus Meltzer associates individual partitions with individual extracellular vesicles and individual template particles.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ko and Meltzer to arrive at the instantly claimed invention. The modification would have entailed using the barcoded beads of Ko with the additional capture elements of Meltzer to capture the target-specific antibodies of Ko and the released RNA. The modification would further have entailed using the method of Meltzer to isolate individual barcoded beads and EVs and using PCR product incorporating the barcode to associate the partition barcode with surface proteins and released RNA from an individual EV. Both the antibody-DNA conjugate and mRNA could be captured on a single template particle comprising a unique template particle barcode as described in both Ko and Meltzer. One would have been motivated by the benefits of partitions to isolate a single bead or template particle while capturing multiple elements in order to identify differences between extracellular vesicles. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 8, Ko teaches the method can be used to identify EV subtypes (subclasses) (p. 3, lines 4-5) and enable discovery of EV subtypes (p. 8, lines 28-30). Ko further teaches the use of antibodies (which comprise index oligonucle3otides in the method of Ko) that target specific surface EV proteins (p. 12, line 26). Thus Ko teaches elements that satisfy the requirements of using the index oligonucleotide barcodes to identify an extracellular vesicle subclass of the individual EVs.
Regarding claim 9, Ko teaches the EVs can be microvesicles, exomeres, apoptotic bodies, oncosomes (p. 4, lines 27-28).
Regarding claims 12 and 13, Ko teaches breaking the droplets (partitions) (p. 15, line 15) and performing reverse transcription (p. 15, lines 28-31).
However, Ko does not explicitly teach released RNA.
Meltzer teaches the released RNA can be mRNA (para 18, Fig. 4).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ko and Meltzer to arrive at the instantly claimed invention. The modification would have entailed using the capture elements of the template particle to capture mRNA as taught by Meltzer. One would have been motivated by the added ability to analyze extracellular vesicles in an additional dimension (mRNA expression) that was known to be accurate biomarkers. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 14, Ko teaches obtaining the biological sample from a subject (p. 4, lines 30-31).
Regarding claim 15, Ko teaches the method permits detection and identification of diseased EV subtypes (p. 3, lines 4-5) and can resolve the heterogeneity of EVs, i.e. subclass (p. 5, line 19). Ko further teaches analyzing protein composition from individual extracellular vesicles (EVs) from a biological sample; obtaining sequencing results; and analyzing the sequencing results (which contain surface protein identity) to determine if the subject has a disease (p.5, lines 1-3). Thus Ko teaches elements that satisfy the requirements of assessing pathology using extracellular vesicle subclass of one or more individual EVs in the sample.
Regarding claim 16, Ko teaches quantification of the number of EVs in a sample (p. 12, lines 14-15), which reads on quantifying amounts of individual EVs in the sample of a particular extracellular vesicle subclass.
Regarding claim 17, Ko teaches the method can be used to identify EV subtypes (subclasses) (p. 3, lines 4-5) and enable discovery of EV subtypes (p. 8, lines 28-30). Ko further teaches the use of antibodies (which comprise index oligonucle3otides in the method of Ko) that target specific surface EV proteins (p. 12, line 26). Thus Ko teaches elements that satisfy the requirements of analyzing the proteins identified in the EVs.
Regarding claim 20, Ko teaches the disease type can be cancer (p. 5, lines 7-8 and p. 17, line 27) and that EVs include oncosomes (p. 4, lines 27-28).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ko to arrive at the instantly claimed invention. The modification would have entailed selecting cancer as the disease and oncosomes as the EVs. One would have been motivated by the fact that the EV class of oncosomes is associated with cancer. Kop explicitly states that a benefit of the method of single EV analysis allows insight into cancer and vesicles associated with cancer (p. 16 lines 28-31 to p. 17 lines 1-2 and p. 17, lines 29-31). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 21, Ko teaches breaking the droplets (partitions) (p. 15, line 15) and performing reverse transcription (p. 15, lines 28-31), satisfying the requirement of producing cDNA outside of the partitions.
Meltzer teaches reverse transcription to generate cDNA templates of the associated mRNAs (paras 8 and 70).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ko and Meltzer to arrive at the instantly claimed invention. The modification would have entailed using the method of Ko to break the droplets before performing reverse transcription, thereby producing cDNA outside the partitions, and performing RT on the captured mRNA of Meltzer. One would have been motivated to do so by the added benefit of making a library containing mRNA from an EV. One would also have been motivated by the benefits of performing reverse transcription in bulk rather than in single partitions that require individual portions of the appropriate levels of reagents. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Response to Arguments against Claim Rejection - 35 U.S. C § 103 where relevant
The response asserts that the combination of Ko and Meltzer does not teach or suggest
target-specific antibodies linked to RNA index oligonucleotides. Furthermore, that a person of ordinary skill in the art would not be motivated to employ target-specific antibodies linked to RNA index oligonucleotides. Specifically, the response asserts that because Ko teaches that generating RNA from DNA is beneficial, a person of ordinary skill in the art would not be motivated to omit that step by starting with antibodies linked to RNA (p. 9). The response further asserts that the combination of Ko and Meltzer does not teach or suggest creating a sequencing library comprising copies of the cDNA and the index cDNA when the target-specific antibodies are linked to RNA index oligonucleotides (p. 9)
Applicant's arguments have been fully considered but are not persuasive.
The amended claim requires either target-specific antibodies linked to DNA index oligonucleotides or target-specific antibodies linked to RNA index oligonucleotides. Thus, the claim does not require target-specific antibodies linked to RNA index oligonucleotides. Nor does the claim require creating a sequencing library comprising copies of the cDNA and the index cDNA when the target-specific antibodies are linked to RNA index oligonucleotides.
The response asserts that the combination of Ko and Meltzer does not teach or suggest creating a sequencing library comprising copies of the cDNA and the DNA index oligonucleotides when the target-specific antibodies are linked to DNA index oligonucleotides. Specifically, the response asserts that prior to sequencing, Ko teaches that DNA of DNA-antibody conjugates undergoes in vitro transcription to produce RNA which is then converted to cDNA (p. 10).
The response also asserts that, in view of Ko, a person of ordinary skill in the art would not be motivated to employ target-specific antibodies linked to DNA index oligonucleotides and create a sequencing library comprising copies of the cDNA and the DNA index oligonucleotides. Ko teaches that generating RNA from DNA is beneficial. Specifically, Ko states: "by generating RNA from DNA, it is then possible to remove all the DNAs that include dimers and unnecessary products that can cause crosstalk between droplets" and "thousands of RNA can be made from a single DNA strand, which allows signal amplification that is crucial to profile single EV" (Ko, page 14).
Applicant's arguments have been fully considered but are not persuasive.
In the modified 103 rejection above, the sequencing library is produced by PCR using the method of Meltzer.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ko et al. (WO 2021067162) in view of Meltzer et al. (WO/2020/069298, on IDS dated 11/02/2022) as applied to claims 1,6-9, 12-17, and 20-21 above, and further in view of Kawasaki et al. (US 20210396633A1 published 12/23/2021, filed 10/16/2019 and published as WO 2020080387 on 04/23/2020. Citations are to the US document).
Regarding claims 18 and 19, Ko teaches that any antibody that targets a specific surface EV protein of interest can be used (p. 12, line 26) but does not teach a panel of target-specific antibodies with each antibody on the panel binding to a different protein.
Kawasaki teaches a method for recovering extracellular vesicles from an extracellular vesicle-containing sample (abstract), the method comprising using antibodies as extracellular vesicle membrane-binding substances to bind to extracellular vesicle markers selected from a group of identified EV surface markers (i.e., a panel) including such as CD63, CD9, and Phosphatidylserine (para 56)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ko and Meltzer with Kawasaki to arrive at the instantly claimed invention. The modification would have entailed selecting antibodies targeting different surface proteins from the list of Kawasaki. One would have been motivated by the availability of a list of recognized extracellular vesicle membrane markers to choose from for the purpose of capturing EVs as in Ko and Meltzer. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Response to Arguments against Claim Rejection - 35 U.S. C § 103
The response asserts that Kawasaki, as cited by the Examiner in the present Office Action, does not cure the deficiencies of Ko and Meltzer.
Applicant's arguments have been fully considered but are not persuasive.
Applicant does not present any arguments against Kawasaki. Arguments regarding the use of Ko and Meltzer are presented in the 103 rejection above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The following are new rejections necessitated by amendments
(I). Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 12 and 16 of U.S. Patent No. 11866782 in view of Ko et al. (WO 2021067162) and Meltzer et al. (WO/2020/069298). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims are species claims that anticipate the genus claims of instant application.
Regarding instant claim 1, claims 1, 7, 12 and 16 of the ‘782 patent satisfy the requirements of instant claim 1. Claim 1 of the ‘782 patent requires incubating a plurality of nucleic-acid-labelled, target-specific antibodies with a plurality of target cells to promote binding of the nucleic-acid-labelled, target-specific antibodies to target proteins expressed by the target cells; washing the incubated target cells to remove unbound nucleic-acid-labelled, target-specific antibodies; combining template particles and the washed target cells in a first fluid, wherein each template particle comprises first capture probes comprising capture sequences and second capture probes comprising template-switching oligos (TSOs); adding a second fluid to the first fluid; shearing the fluids to generate a plurality of monodisperse droplets simultaneously that contain a single one of the template particles and a single one of the target cells; the release of mRNA molecules, amplifying and sequencing nucleic acid labels from the nucleic-acid-labelled, target-specific antibodies to identify target proteins expressed by the target cells claim 1 of the ‘782 patent. Claim 7 of the ‘782 patent lysing each of the single target cells contained within the monodisperse droplets to release a plurality of distinct mRNA molecules; capturing the plurality of distinct mRNA molecules with the first capture probes; extending the first capture probes with reverse transcriptase to form nascent first strand cDNAs; amplifying and sequencing the cDNA to quantify the plurality of distinct mRNA molecules. Claim 12 of the ‘782 patent requires the second fluid comprises an oil. Claim 16 of the ‘782 patent requires the template particles further comprise a plurality of capture probes comprising: a capture sequence that hybridizes to one or more of the plurality of distinct mRNA.
Thus claims 1, 7, 12 and 16 of the ‘782 patent teach elements of instant claim 1.
The teachings of Ko and Meltzer as they relate to elements of instant claim 1 not taught by the claims of the ‘782 patent are given previously in this office action and are fully incorporated here.
(II). Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 12,13,15-17, 97, and 101 of copending Application No. 17/281,157 (reference application) in view of Ko et al. (WO 2021067162) and Meltzer et al. (WO/2020/069298).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are species claims that anticipate the genus claims of instant application.
Regarding instant claim 1, copending claim 12 requires combining a plurality of capture template particles with a first fluid to provide a first mixture, wherein the first fluid comprises a plurality of target particles, wherein each capture template particles comprises: a target-specific capture element; And a target-specific capture element genetic identifier comprising a unique barcode sequence; association of the plurality of target particles to the plurality of capture template particles via the target-specific capture element, thereby forming a mixture comprising a portion of the plurality of target particles associated to the capture template particles; combining the second mixture with a second fluid; shearing such that a plurality of the capture template particles are encapsulated in a plurality of monodisperse droplets in the second fluid, thereby providing a plurality of monodisperse droplets comprising reaction buffer, one of the capture template particles, and one of the plurality of target particles associated to said capture template particles. Copending claim 13 requires that the second fluid comprises an oil. Copending claims 14-16 require that the first fluid comprises a biological sample (copending 14), the biological sample is a body fluid (copending 15), and the body fluid comprises target particles selected from the group consisting of -- extracellular vesicles (copending claim 16). Copending claim 97 requires target-specific capture element is attached to a capture moiety linked to the template particle. Copending claim 101 requires that the target-specific capture element genetic identifier comprises a template-type element comprising a barcode sequence corresponding to the target-specific capture element. Thus, copending claims 12,13,15-17, 97, 99, and 101 teach elements of instant claim 1.
The teachings of Ko and Meltzer as they relate to elements of instant claim 1 not taught by the claims of the ‘782 patent are given previously in this office action and are fully incorporated here.
This is a provisional nonstatutory double patenting rejection.
(III). Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 6, and 9-11 of copending Application No. 18/403,902 (reference application) in view of Ko et al. (WO 2021067162).
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are species claims that anticipate the genus claims of instant application.
Regarding instant claim 1, copending claim 1 teaches a method for single cell analysis comprising: incubating a plurality of nucleic-acid-labelled, target-specific antibodies with a plurality of target cells to promote binding of the nucleic-acid-labelled, target-specific antibodies to target proteins expressed by the target cells; combining in a first fluid; adding a second fluid to the first fluid; shearing the fluids to generate a plurality of monodisperse droplets; and amplifying and sequencing nucleic acid labels from the nucleic-acid-labelled, target- specific antibodies to identify target proteins expressed by the target cells. Copending claim 1 further requires the template particles comprise a plurality of capture probes comprising:a universal primer sequence, at least one barcode, and a capture sequence that hybridizes to mRNA present in the target cells and to the nucleic acid of the nucleic- acid-labelled, target-specific antibodies. Copending claim 5 teaches lysing the droplets to release mRNA and quantifying the mRNA, Copending claims 3,6,and 9-11 of the ‘902 application further teach nucleic acid labels with a unique molecular identifier sequence (copending claim 3), and a capture portion comprising a polyA sequence (copending claim 6);reverse transcribing the released RNA (copending claim 9) that the fluids for forming the droplets are aqueous (copending claim 10) and oil (copending claim 11).. Thus, copending claims 1, 3, 5, 6, 9-11 and 17 teach elements of instant claim 1.
The teachings of Ko and Meltzer as they relate to elements of instant claim 1 not taught by the claims of the ‘782 patent are given previously in this office action and are fully incorporated here.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments against Double Patenting
The response traverses the double patenting rejections (I) to (III) on the grounds that the amendments render rejections (I) to (III) moot. Further, the present claims remain subject to further amendment, whereby in such amended form this rejection may be inappropriate (p. 7).
Applicant's traversal have been fully considered but are not persuasive.
Modified double patenting rejections are presented above. No terminal disclaimer has been filed and no argument has been presented against the double patenting rejections since no allowable subject matter has been identified and the claims remain subject to further amendment. Thus, for the reasons stated above, and those already of the record, the rejection is maintained.
Conclusion
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 JESSICA GRAY whose telephone number is (571)272-0116. The examiner can normally be reached Monday-Friday 8-5 with second Fridays off.
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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