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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on September 10, 2025 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 1, 3, 5-7, 9, 12-19, 21, 22, 31-35, 38, 40, 49, 50 and 55 are currently pending. Claims 1, 13, 15, 19 and 49 have been amended by Applicants’ amendment filed 09-10-2025. No claims have been added or cancelled by Applicants’ amendment filed 09-10-2025.
Applicant's elects Group I with traverse, claims 1-3, 5-7, 9 and 12-19 drawn to drawn to a multiplexible particle system for use with an electronic detector; and the election of Species with traverse as follows:
Species (A): wherein the unique electrical parameter is electrical impedance (claim 2);
Species (B): wherein the particle polymer population are selected to each have an electrical parameter with a mean value and a standard deviation (claim 15);
Species (C): further comprising a tag connected to and/or embedded in at least one polymer particle population (claim 19);
Species (D): wherein the unique electrical parameter having a value based on (a) polymer composition (claim 16);
Species (E): wherein the polymer material is (a) poly-acrylamide (claim 17);
Species (F): wherein the tag is (e) orthogonally reactive (claim 19);
Species (G): species of method of detecting not elected by Applicant (claims 32, 33, 35 and 38);
Species (H): species of target molecule not elected by Applicant (claim 34); and
Species (I): wherein the stimulus is a chemical stimulus (claim 50), in the reply filed on January 26, 2023 was previously acknowledged.
Regarding the identity of the tag recited in Species (F) (instant claim 19), the examiner previously rejoined the species of tag to include an optical tag. The examination of the species together does not represent an undue burden.
Regarding the species of stimulus recited in Species (I) (claim 50), the examiner previously rejoined the species of stimulus to include chemical stimulus, a biological stimulus, a temperature stimulus, a pH stimulus, and an electromagnetic stimulus. The examination of the species together does not represent an undue burden.
Claims 21, 22, 31-35, 38 and 40 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 3, 5-7, 9, 12, 14 and 16-18 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01-26-2023.
The restriction requirement was deemed proper and was made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 1, 13, 15, 19, 49, 50 and 55 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed May 26, 2020 claims the benefit of US Provisional Patent Application 62/861,454, filed June 14, 2019.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed September 10, 2025 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or
objection not specifically addressed below are herein withdrawn.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 13, 15, 19 and 55 is withdrawn under 35 U.S.C. 102(a1)/(a2) as being anticipated by Cowell et al. (hereinafter “Cowell”) (Lab Chip, 2020, 20, 2274; and Electronic Supplementary Material, 2020, 1-7).
Based on the publication date of the Cowell reference, Cowell is not prior art to the instant application.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1, 13, 15, 19, 49, 50 and 55 is maintained 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.
Claims 1, 13, 15, 19, 49, 50 and 55 are indefinite because the claims appear to recite both a product and process in the same claim. The examiner cautions that according to the MPEP 2173.05(p)(II) states that a single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112, second paragraph. PXL Holdings v. Amazon.com, Inc., 430 F.2d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990) (claim directed to an automatic transmission workstand and the method of using it held ambiguous and properly rejected under 35 U.S.C. 112, second paragraph). For example, claim 1 is directed to “a multiplexible particle system for use with an electronic detector to detect a plurality of distinct targets” such as recited in claim 1, lines 1-2, where instant claim 1 recites, for example: “an electronic detector comprising one or more microchannels” in line 3; “wherein each of the plurality of monodisperse polymer particle populations has a unique electrical parameter during flow through a spatially confined electric field for multiplexed detection” in lines 5-8; and “wherein each of the plurality of monodisperse polymer particle populations comprise polyacrylamide hydrogel beads with a uniform average diameter between each of the plurality of monodisperse polymer particle populations, and each of the plurality of monodisperse polymer particle populations have a polyacrylamide concentration different from any other of the plurality of monodisperse polymer particle populations” in lines 16-21; while claim 1 also recites: “a plurality of monodisperse polymer particle populations, each of the plurality of monodisperse polymer particle populations has a unique electrical parameter during flow through the spatially confined electric field for multiplexed detection” in lines 5-8; “wherein the unique electrical parameter has an electrical parameter distribution for each of the plurality of monodisperse polymer particle populations determined by flow through the spatially confined electric field of the electronic detector” in lines 9-12; “the unique electrical parameter that is electrical impedance having the coefficient of variation of less than 15% measured by the electronic detector for each of the plurality of monodisperse polymer particle populations” in lines 21-24; and “wherein the multiplexible particle system is multiplexed, such that the multiplexible particle system detects the plurality of distinct targets using n monodisperse polymer particle populations, wherein a number of distinct targets in the plurality of distinct targets is greater than n” in lines 25-28. Such claims can also be rejected under 35 U.S.C. 101 based on the theory that the claim is directed to neither a “process” nor a “machine,” but rather embraces or overlaps two different statutory classes of invention set forth in 35 U.S.C. 101 which is drafted so as to set forth the statutory classes of invention in the alternative only. Id. at 1551. It is noted that instant claim 1 does not define the product in terms of the process by which it is made (See, MPEP 2173.05(p)); and does not focus on capabilities of the system. Instead, instant claim 1 clearly recites a product, and a process of using the product.
Claim 1 is indefinite for the recitation of the term “the electrical parameter distribution in each of the plurality of monodisperse polymer particle population…to minimize overlap with any other of the plurality of monodisperse polymer particle populations” such as recited in claim 1, lines 12-15 because it is unclear whether the “sufficiently narrow” electrical parameter distribution is between each polymer particle within a plurality of polymer particles, or whether the “sufficiently narrow” electrical parameter distribution is between each of the plurality of polymer particle populations and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “wherein a number of distinct targets in the plurality of distinct targets is greater than n” in lines 27-28 because the as-filed Specification and instant claim 1 do not that “n” represents an integer or a number including a number of monodisperse polymer particle populations. Moreover, claim 1 does not recite that the distinct targets are present in the multiplexable particle system of claim 1. Moreover, claim 1 does not recite the identity of the distinct targets, such that it is unclear what is being counted and/or being compared with the number of monodisperse particle populations (e.g., analytes, cells, proteins, fragments, DNA, etc.) and, thus, the metes and bounds of the claim cannot be determined.
Claim 13 is indefinite for the recitation of the term “the spatially confined electrical field is a microchannel of the electronic detector” in claim 13, lines 1-2 because claim 13 depends from claim 1, wherein claim 1, line 3 recites that the “electronic detector comprises one or more microchannels”, such that the spatially confined electrical field cannot be a microchannel. Moreover, the claims are directed to a multiplexible particle system, such that no electric field is being generated or confined and, thus, the metes and bounds of the claim cannot be determined.
Claim 13 is indefinite for the recitation of the term “detect particle passage” such as recited in claim 13, line 3 because claim 13 depends from claim 1, wherein claim 1 does not recite the presence of a passage and/or the presence of unidentified “particles”. It is unclear whether the “particle” recited in claim 13 is related to the monodisperse polymer particles, the monodisperse polymer particle population, polyacrylamide hydrogel beads, and/or a target particles recited in claim 1 and, thus, the metes and bounds of the claim cannot be determined.
Claim 13 is indefinite for the recitation of the term “resistive pulse sensing” such as recited in claim 13, line 3 because claim 13 depends from claim 1, wherein claim 1 does not recite that the detector comprises a particular sensor, that it is a Coulter detector, that the detector measures current, that the particles pass through a nanopore, etc. such that the detector could use resistive pulse sensing and, thus, the metes and bounds of the claim cannot be determined.
Claim 15 is indefinite for the recitation of the term “to each have an electrical parameter that is an electrical impedance detected by the electronic detector, with a mean value…during use the multiplexable system provides a monodisperse polymer particle population electrically distinguishable error rate that is less than 10%” in claim 15, lines 2-6 because it is unclear what the mean value, standard deviation and/or error rate are describing, and whether the mean value, standard deviation and/or error rate refer to the size difference between each particle, the size difference between particle populations, the difference in measured impedance between particles (or between particle populations); to the electronic detector; to an error rate in detecting, pulse sensing, etc. and, thus, the metes and bounds of the claim cannot be determined.
Claim 19 is indefinite for the recitation of the term “to further increase multiplexing capacity” such as recited in claim 19, lines 3-4 because claim 19 depends from claim 1, wherein claim 1 does not recite that the system has any particular (or increased) multiplexing capacity, such that multiplexing capacity cannot be “further increased” as recited in claim 19 and, thus, the metes and bounds of the claim cannot be determined.
Claim 19 is indefinite for the recitation of the term “by at least one” such as recited in claim 19, line 4 because claim 19 depends from claim 1, wherein claim 1 does not recite any particular multiplexing capacity. Moreover, it is unclear what “by at least one” refers to (e.g., one particle, one target, one-fold, one order of magnitude, etc.); and it is completely unclear what is increased by “at least one” and, thus, the metes and bounds of the claim cannot be determined.
The rejection of claim 49 is maintained as being indefinite for the recitation of the term “the polymer particles” such as recited in claim 49, line 16. There is insufficient antecedent basis for the term “the polymer particles” in the claim because claim 49, lines 4 and 13 recite the terms “a plurality of monodisperse polymer particles” and “a number of polymer particles in each population”.
The rejection of claim 49 is maintained as being indefinite for the recitation of the term “number of polymer particles” such as recited in claim 49, line 13 and 26. There is insufficient antecedent basis for the term “number of polymer particles” in the claim because claim 49, line 4 recites the terms “a plurality of monodisperse polymer particles”.
Claim 49 is indefinite for the recitation of the term “a degraded plurality of polymer particle populations” such as recited in claim 49, lines 20-21. There is insufficient antecedent basis for the term “a degraded plurality of polymer particle populations” in the claim because claim 49, lines 19-20 recites the term “degrading monodisperse polymer particle populations”.
Claim 49 is indefinite for the recitation of the term “the first flowing and the second flowing steps” such as recited in claim 49, lines 28-29. There is insufficient antecedent basis for the term “the first flowing and the second flowing steps” in the claim because claim 49, lines 9 and 22 recite the terms “first flowing” and “second flowing”.
Claim Rejections - 35 USC § 112(a) – New Matter
The rejection of claim 1 is maintained under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
The claim contains subject matter that was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art (hereafter the Artisan), that the inventor(s), at the time the application was filed, had possession of the claimed invention. 37 CFR §1.118 (a) states that "No amendment shall introduce new matter into the disclosure of an application after the filing date of the application". Claim 1 recites in part, “each of the plurality of monodisperse polymer particle populations comprise polyacrylamide hydrogel beads with a uniform average diameter between each of the plurality of monodisperse polymer particle populations” in lines 16-18; and “the plurality of distinct targets using n monodisperse polymer particle populations, wherein a number of distinct targets in the plurality of distinct targets is greater than n” in lines 26-28. Upon review of the instant as-filed Specification, support was not found for the polyacrylamide hydrogel beads with a uniform average diameter; and a plurality of distinct targets using n monodisperse polymer particle populations, wherein a number of distinct targets in the plurality of distinct targets is greater than n as recited in instant claim 1. The instant as-filed Specification, filed May 26, 2020 recites, that “particle populations retain some uniformity with respect to size” (See, as-filed Specification, paragraphs [0003]); “plurality of polymer particle populations may be described as each having an average diameter, and the maximum average diameter difference between any two populations is less than or equal to 30%,20%, 10% or between 0 and 30%” (See, as-filed Specification, paragraphs [0018]); “at least one of the particle populations having an average diameter that is less than 1 mm “(See, as-filed Specification, paragraph [0022]); and “the solid particles may have an average diameter that is greater than an average pore size in the polymer particle” (See, as-filed Specification, paragraphs [0024]); “Monodisperse refers to a relatively uniform population *e.g., the population has a “sufficiently narrow dispersion) in terms of an electrical parameter associated with the population” (See, as-filed Specification, paragraphs [0096]); “we selected magnetic beads with average diameters of 7 mm, 9 mm and 12 mm. Unfortunately, these solid magnetic beads are somewhat heterogeneous in size” (See, as-filed Specification, paragraphs [00172]). No such corresponding teaching regarding polyacrylamide hydrogel beads with a uniform average diameter between each of the plurality of monodisperse polymer particle populations is taught by the instant as-filed Specification.
A claim by claim analysis and for dependent claim 1, and a method step by method step analysis regarding where support can be found in the originally filed specification is respectfully suggested. See MPEP § 2163 particularly § 2163.06.
Claims 1, 13, 15, 19, 49, 50 and 55 will remain rejected until Applicant cancels all new matter.
Response to Arguments
Applicant’s arguments filed September 10, 2025 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) the instant as-filed Specification provides: "An average density for a population reflects that the instant inventions tolerate some variation in uniformity, so long as the ability to distinguish populations remains. This similarly applies to 'average diameter'." Specification at [0098]; and see also Applicant’s response in the priority section (Applicant Remarks, pg. 14, first through third full paragraphs).
Regarding (a), please see the priority discussion supra with regard to the new matter rejection. Additionally, paragraph [0098] teaches:
For example, for solid particles that are embedded in the polymer particle, each of the polymer and the solid particle density contribute to the effective density of the particle. An average density for a population reflects that the instant inventions tolerate some variation in uniformity, so long as the ability to distinguish populations remains. This similarly applies to "average diameter.''
The Examiner contends that the term ‘tolerating some variation in uniformity’ for solid particles embedded in the polymer particle is not the same as teaching that “each of the plurality of monodisperse polymer particle populations comprise polyacrylamide hydrogel beads with a uniform average diameter between each of the plurality polymer particle populations”. Moreover, the as-filed Specification and original claims, filed May 26, 2020 also do not teach “the plurality of distinct targets using n monodisperse polymer particle populations, wherein a number of distinct targets in the plurality of distinct targets is greater than n” in claim 1, lines 26-28. Thus, the claims remain rejected for the reasons of record.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 13 and 19 is maintained 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.
Claim 13 recites (in part): “wherein the spatially confined electrical field is a microchannel of the electronic detector is configured to detect particle passage by resistive pulse sensing” in lines 1-3 because claim 13 depends from instant claim 1, wherein claim 1 does not recite the passage of particles including unidentified “particles”. Moreover, it is unclear whether the “particle” recited in claim 13 is related to the monodisperse polymer particles recited in claims 1 including whether it is part of the monodisperse polymer particle population, a polyacrylamide hydrogel beads, a target particles; that the detector is a Coulter detector, that the detector measures current, that the particles pass through a nanopore, etc. such that the detector could use resistive pulse sensing. Thus, claim 13 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 19 recites (in part): “further comprising a tag connected to and/or embedded in at least one population of the plurality of monodisperse polymer particle populations to further increase multiplexing capacity of the plurality of distinct targets by at least one…chemical moieties that are orthogonally reactive” in lines 1-11 because claim 19 depends from claim 1, wherein claim 1 does not recite increasing multiplexing capacity, such that multiplexing capacity cannot be “further increased” as recited in claim 19; and claim 1 does not recite chemical moieties, the reaction of any chemical moieties, substrates, directionality of reactive groups, etc. Thus, claim 19 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 § 103
The rejection of claims 1, 13, 15, 19, 49, 50 and 55 is maintained under 35 U.S.C. 103 as being unpatentable over Bharadwaj et al. (hereinafter “Bharadwaj”) (US10544413; issued January 28, 2020; effective filing date May 18, 2017; of record) in view of Kim et al. (hereinafter “Kim”) (US Patent Application No. 20160258856, published September 8, 2016) and further in view of Esfandyarpour et al. (US Patent Application No. 20160273032, published September 22, 2016; of record).
Regarding claims 1 (in part), 13, 15, 19, 49 (in part), 50 and 55, Bharadwaj teaches the generation of a plurality of droplets, wherein some droplets include particles such as cells or beads, and other droplets do not include any particles including field-attractable particles, such that a given droplet in a plurality of droplets can comprise one or more particles including biological particles, beads, etc., such that a particle can be a bead (e.g., a gel bead and/or a cell bead); and/or a biological particle (e.g., a cell or cell derivative), wherein a particle, such as a gel bead, can have a molecular barcode coupled thereto (interpreted as a plurality of polymer particle populations; and comprising a tag group that is orthogonally active, claims 1, 19 and 49) (col 1, lines 36-51; and col 2, lines 43-47). Bharadwaj teaches that a given droplet in the first subset of droplets that includes one or more cells and/or other particles can comprise a sufficiently discrepant number or concentration of field attractable particles than a given droplet in the second subset of droplets that does not include any cells and/or other particles such that when the plurality of droplets is subject to an electric or magnetic field, the first subset of droplets and the second subset of droplets are separated from each other, such that singularly occupied droplets can be separated from unoccupied droplets and otherwise multiply occupied droplets (interpreted as a unique electrical parameter distribution with a coefficient of variation of less than 15%; and subjecting the polymer particles to an electric field, claims 1 and 49) (col 2, lines 51-62). Bharadwaj teaches that a microcapsule can comprise a bead, a bead can be porous, non-porous, solid, semi-solid, semi-fluidic, fluidic, and/or a combination thereof, wherein a bead can be dissolvable, disruptable, and/or degradable; and/or the bead can be a gel bead including a hydrogel bead (interpreting dissolvable, disruptable, and/or degradable as degradable particles; hydrogel particles; comprises a degradation parameter; and degradable upon application of a stimulus, claims 1, 49 and 50) (col 18, lines 29-35). Bharadwaj teaches that the bead can contain molecular precursors (e.g., monomers or polymers), which can form a polymer network via polymerization of the precursors, wherein the precursor can be an already polymerized species capable of undergoing further polymerization via, for example, a chemical cross-linkage and/or the precursor can comprise one or more of an acrylamide or a methacrylamide monomer, oligomer, or polymer; and that beads can comprise mixed polymers, co-polymers and/or block co-polymers (interpreted as a hydrogel; and polyacrylamide hydrogels, claims 1 and 49) (col 18, lines 42-49 and 56-57). Bharadwaj teaches that synthetic polymers include polyacrylamide; and the generation of polyacrylamide gel beads (interpreted as polyacrylamide, claims 1 and 53) (col 19, lines 1-5 and 49-52). Bharadwaj teaches optically active agents such as fluorescent dyes can be coupled to beads via free thiol group of the beads and used to quantify the number of free thiols present in a bead and /or track a bead (interpreted as a particle with an optical tag, claim 19) (col 23, lines 22-26). Bharadwaj teaches that any suitable number of molecular tag molecules such as a primer, barcoded oligonucleotide can be associated with a bead such that, upon release from the bead, the molecular tag molecules are present in the partition (interpreting primers, barcodes oligonucleotides, etc. as tags connected to the polymer particle, claim 19) (col 28, lines 14-18). Bharadwaj teaches that species that do not participate in polymerization including the polymerization of gel beads can also be encapsulated in beads during bead generation, such as oligonucleotides, reagents, primers, cofactors, enzymes, nucleic acids, or other species (interpreted as polymer particle populations; and groups that are orthogonally reactive, claims 1, 19 and 49) (col 25, lines 1-21). Bharadwaj teaches that activation of disulfide linkages within a bead can be controlled such that only a small number of disulfide linkages are activated, where control can be exerted by controlling the concentration of reagents used to form disulfide bonds in the bead polymerization (col 23, lines 6-12). Bharadwaj teaches that beads can be provided as a population or a plurality of beads having a relatively monodisperse size distribution, wherein beads have size distributions with a coefficient of variation in their cross-sectional dimensions of less than 50%, less than 40%, less than 30%, less than 20%, and in some cases less than 15%, less than 10%, less than 5%, or less (interpreted as monodisperse polymer particle populations; and encompassing a uniform average diameter between populations, claims 1 and 49) (col 25, lines 31-36). Bharadwaj teaches the bead can have size distributions that have a coefficient of variation in the cross-sectional dimensions of less than 50%, less than 5%, or less (interpreted as a narrow size distribution, claims 1 and 49) (col 37-40). Bharadwaj teaches applying a magnetic field to a channel intersection, each droplet containing field-attractable particles (e.g., paramagnetic particles), each droplet can be attracted (e.g., due to paramagnetic particles) or repelled (e.g., due to diamagnetic particles) to or away, respectively, from the magnetic field, wherein the degree of attraction (or repulsion) can be proportional to a number (and/or a concentration) of field-attractable particles in each droplet, which is the magnetic force acting on a droplet, from the same magnetic field, can be proportional to a number (and/or a concentration) of field-attractable particles in the droplet including singularly occupied droplet (N+) and doubly occupied droplet (N2+) (interpreted as a unique electrical parameter distribution with a coefficient of variation of less than 15%; and subjecting the polymer particles to an electric field, claims 1 and 49) (col 45, lines 33-65). Bharadwaj teaches that in operation, a plurality of discrete droplets, each comprising a first aqueous fluid 310 can flow as emulsions in a second fluid 308, wherein the second fluid 308 is immiscible to the first aqueous fluid 310, such that the droplets being transported along channel segment 302 into intersection 311 can comprise a first subset of droplets 314 that are each occupied with at least a biological particle, a monodisperse bead, and/or a barcode carrying bead and a second subset of droplets 312 that are each unoccupied, such that one or more characteristics is detected by the sensor 320 of a droplet can be indicative of the type of droplet, such as whether the droplet is occupied or unoccupied, or whether the droplet contains a biological particle and/or a barcode carrying bead, wherein the sensor 320 can be an impedance sensor configured to measure bulk impedance when droplets pass by the sensor 320, such that a higher impedance can be measured for occupied droplets than for unoccupied droplets (e.g., due to mass and/or weight distribution of occupied droplet, etc.); or the sensor 320 can be an optical sensor configured to measure optical properties of a droplet, such as to distinguish whether the droplet is occupied or unoccupied as (interpreted as a plurality of monodisperse polymer particle populations; spatially confined; unique electrical parameter; impedance; a sensor as a detector; flow in channels; optical detection; selecting an electrical parameter, electrical impedance; and each population has an impedance signature that can be measured, claims 1, 15, 19 and 49) (col 52, lines 41-47; and col 53, lines 35-53). Bharadwaj teaches the real time, simultaneous processing, detection or identification, such as real time PCR (interpreted as multiplexible particle, claims 1 and 49) (col 14, lines 22-27). Bharadwaj teaches a microfluidic channel for delivering barcode carrying beads to droplets (interpreting barcodes as tags; and groups that are orthogonally reactive, claims 1, 19 and 49) (col 13, lines 34-35). Bharadwaj teaches the application of different pressure pulses, for example, by varying frequency of the pulses and/or changing pressure differential (interpreted as resistive pulse sensing, claim 13) (col 55, lines 1-5). Bharadwaj teaches the sensor 320 can be one or more devices that are configured to provide one or more of optical sensing, thermal sensing, laser imaging, infrared imaging, capacitance sensing, mass sensing, vibration sensing across at least a portion of the electromagnetic spectrum, and magnetic induction sensing (interpreted as resistive pulse sensing, claim 13) (col 56, lines 28-33). Bharadwaj teaches that a microcapsule, in some instances, can comprise a bead, wherein the bead can be porous, non-porous, solid, semi-solid, semi-fluidic, fluidic, and/or a combination thereof; and the bead can be dissolvable, disruptable, and/or degradable; the bead may not be degradable; and/or the bead can be a gel bead including a hydrogel bead (interpreting the bead as a polymer particle population, wherein at least one population has a degradable parameter, claim 49) (col 18, lines 29-35). Bharadwaj et al. the beads can be degradable, disruptable, or dissolvable spontaneously or upon exposure to one or more stimuli (e.g., temperature changes, pH changes, exposure to particular chemical species or phase, exposure to light, reducing agent, etc.), wherein a bead can be dissolvable, such that material components of the beads are solubilized when exposed to a particular chemical species or an environmental change, such as a change temperature or a change in pH or, in some cases, a gel bead can be degraded or dissolved at elevated temperature and/or in basic conditions, such that degradation or dissolution of a bead bound to a species (e.g., a oligonucleotide, e.g., barcoded oligonucleotide) can result in release of the species from the bead (interpreted as a degradation stimulus comprising a chemical stimulus, a temperature stimulus, a pH stimulus, claim 50) (col 25, lines 49-64). Bharadwaj teaches that the polymer or gel can be of a lower density than an oil, or it can be of a density that is roughly similar to that of a buffer, and wherein the polymer or gel can have a tunable pore size (interpreted as comprising a unique amount of polyacrylamide, claim 54) (col 59, lines 55-58). Bharadwaj teaches that that the polymer or gel can include one or more of disulfide cross-linked polyacrylamide, agarose, alginate, polyvinyl alcohol, polystyrene, polyethylene glycol (PEG), PEG-diacrylate, PEG-acrylate, PEG-thiol, PEG-azide, PEG-alkyne or other acrylates, chitosan, collagen, fibrin, gelatin, elastin or any other polymer or gel; and the polymer can comprise poly(acrylamide-co-acrylic acid) crosslinked with disulfide linkages; and that the cell bead can further comprise one or more field-attractable particles such as paramagnetic particles, conductive particles, etc. (interpreted as polyacrylamide hydrogel beads comprising unique amounts of polyacrylamide, claim 1, 49, 53 and 54) (col 59, lines 40-45; and col 60, lines 1-2 and 31-33). Bharadwaj teaches that the stimulus can be a chemical stimulus, wherein a sensor can be configured to sense one or more characteristics of a droplet indicative of whether the droplet is occupied or unoccupied, such that the sensor can be located downstream of junction 510, wherein the sensor can be an impedance sensor (col 64, lines 4-14). Bharadwaj teaches that the magnetite content on each paramagnetic particle can be adjusted to have higher or lower percentage to be more responsive or less responsive to the same magnetic field, wherein field-attractable particles can be diamagnetic particles, ferromagnetic particles, and/or conductive particles, wherein conductive particles are responsive when exposed to electric fields, such that the conductive particle can be adjusted to have higher or lower percentage to be more responsive or less responsive to the same electric fields (interpreting adjustable field-attractable particles in gel beads as a plurality of monodisperse polymer particle populations having unique electrical parameters including electrical parameter distribution with a coefficient of variation of less than 15%; and measuring an electronic signature, claims 1 and 49) (col 31, lines 65-67; and col 32, lines 1-3 and 17-24). Bharadwaj teaches that while referred to as degradation of a bead, in many instances as noted above, that degradation an refer to the disassociation of a bound or entrained species from a bead, both with and without structurally degrading the physical bead itself, such that entrained species can be released from beads through osmotic pressure differences due to, for example, changing chemical environments (col 26, lines 48-55). Bharadwaj teaches that biological particles can be encapsulated within a microcapsule such as a cell bead, that comprises an outer shell or layer or porous matrix in which is entrained one or more individual biological particle or small groups of biological particles; as well as, field attractable particles that are capable of being formed into a gel or other solid or semi-solid matrix upon application of a particular stimulus to the polymer precursor (interpreted as a plurality of monodisperse polymer particle populations having unique electrical parameters including electrical parameter distribution with a coefficient of variation of less than 15%) (col 33, lines 33-45). Bharadwaj teaches that the magnetite content on each paramagnetic particle can be adjusted (e.g., to have higher or lower percentage) to be more responsive or less responsive to the same magnetic field; or the field-attractable particles can be diamagnetic particles or ferromagnetic particles; and in some cases, the field-attractable particles can be conductive particles, wherein a conductive particle can have micrometer or nanometer size (interpretated as encompassing particle impedance <15%, claims 1 and 49) (col 31, lines 65-67; and col 32, lines 1-7). Bharadwaj teaches that in operation 1002, at an upstream location, a sensor detects and/or measures one or more characteristics of a droplet passing though the upstream location, wherein one or more characteristics can be indicative of a size of the droplet, and/or the sensor can be an impedance sensor configured to detect bulk impedance as a droplet or plurality of droplets passes through the upstream location; and that a higher impedance can be measured for larger droplets than for smaller droplets (interpreted as an electronic detector that measures electrical impedance; and an electrical parameter, claims 1, 13, 49 and 55) (col 75, lines 10-17). Bharadwaj teaches that target nucleic acids are amplified including by PCR; partitioning a desired number of biological polymers; and that that each droplet can contain some number of (or concentration of) field-attractable particles and/or a number of biological particles (interpreted as encompassing a number of distinct targets that is greater than the number of monodisperse polymer particle populations, claim 1) (col 17, lines 21-26; col 18, lines 10-13; col 30, lines 15-16; and col 32, lines 50-65). Bharadwaj teaches functionalization of beads for attachment of oligonucleotides can be achieved through a wide range of different approaches including activation of chemical groups within the polymer, incorporation of active or activatable functional groups in the polymer structure, or attachment at the pre-polymer or monomer stage in bead production (interpretated as encompassing particle impedance <15%, claims 1 and 49) (col 20, lines23-27). Bharadwaj teaches that the relative flow rates of the immiscible fluids can be selected (col 28, lines 51-52). Bharadwaj teaches that occupied particles and unoccupied particles can respond differently to a pressure pulse, for example due to varying predetermined particle and fluid characteristics (interpreted as varying characteristics; and pulse sensing, claims 1 and 13) (col 56, lines 57-59). [It is noted in the instant published Specification that the unique electrical parameter is selected by adjusting one or more of: polymer composition; polymer size; polymer density; presence or absence of a solid particle within the polymer; volume fraction of solid particles within the polymer; functional groups in the polymer that affect hydration status; or organic and/or inorganic moieties attached to the polymer particles (See; instant as-filed Specification; paragraph [0029])].
Bharadwaj does not specifically exemplify polymer particle populations having different polyacrylamide concentrations (claim 1, in part); and specifically using the term electrical signature (claim 49, in part).
Regarding claim 1 (in part) and 49 (in part), Kim teaches hydrogel particles and their use in cytometric applications, wherein hydrogel particles are selectively tunable to have at least one optical property substantially similar to at least one other optical property of a target cell, such that the hydrogel particles provided can be used as a calibration reagent for the detection of a target cell in a sample (Abstract). Kim teaches that the hydrogel has at least one optical property, wherein optical properties include side scatter profile (SSC), forward scatter profile (FSC) and fluorescence emission profile (interpreted as an electrical signature, claim 49) (paragraph [0004]). Kim teaches the ability to adjust a range of parameters including hydrogel components and concentration of the same allows for the ability to tune a particle to mimic a wide range of cells (paragraph [0027]). Kim teaches in Figure 2, making monodisperse droplets with diameters from ~5 – 1000 microns in a microfluidic device by polymerizing droplets using any monomeric units and crosslinkers described herein (paragraph [0068]; and Figure 2). Kim teaches that the fluidic droplets can be monodisperse or substantially mono-disperse including having a homogenous distribution of diameters, for instance, such that no more than about 10%, about 5%, about 3%, about 1%, about 0.03%, or about 0.01 % of the droplets have an average diameter greater than about 10%, about 5%, about 3%, about 1%, about 0.03%, or about 0.01% of the average diameter (interpreted as monodisperse hydrogels; uniform average diameter; and different populations of hydrogels having different sizes, claims 1 and 49) (paragraph [0069], lines 1-10). Kim teaches that the average diameters of hydrogel particles in one embodiment, are tailored, for example by varying flow rates of the fluid streams of the first and second fluids within the channels of a microfluidic device, or by varying the volume of the channels of the microfluidic device (interpreted as varying the flow rates; a first flow and a second flow; different populations of hydrogels having different concentrations of polyacrylamide; and different/tailored sizes, claim 1) (paragraph [0069], lines 13-18). Kim teaches that a bead, plurality of beads, biomolecule, or plurality of biomolecules is embedded (encapsulated) within the hydrogel particle, such that an encapsulated bead or biomolecule is employed to mimic one or more intracellular organelles of a target cell, or a cell after it engulfs a particle; and that encapsulating or embedding a bead or biomolecule is accomplished at the time of hydrogel particle formation, for example, beads can be suspended in the appropriate concentration to allow for an average of one bead to be embedded or encapsulated in a single hydrogel particle, wherein the bead suspension can be included, for example, within the aqueous solution of monomer; and that a biomolecule or mixture of biomolecules can be incorporated into the aqueous solution of monomer to encapsulate the biomolecule or biomolecules (paragraph [0085]). Kim teaches that although the invention is mainly described with respect to the modification of optical properties, the invention is not limited thereto; and that hydrogel particles can be fabricated and adjusted to tune the capacitance of the particles, such as to calibrate coulter counters, wherein a hydrogel particle's capacitance is adjusted by altering the amount of hydrogel monomer in the composition (interpreted as varying the concentration of the monomer including acrylamide and polyacrylamide, claim 1) (paragraph [0119]). Kim teaches that after the hydrogel particle is formed, one or more of the particle's surfaces can be functionalized, for example, to mimic one or more optical properties of a target cell or a labeled target cell, wherein the functionalized hydrogel particle can also include an embedded bead or substance such as a biomolecule, as described above (paragraph [0121]). Kim teaches that to make the basic polyacryl-amide gel particle, a central phase of an aqueous monomer solution containing N-acrylamide (1-20% w/v), a cross-linker (N,N'-bisacryl-amide, 0.05-1 % w/v), an accelerator, and ammonium persulfate (1 % w/v) was used, wherein an accelerator, (N,N,N',N'-tetramethylethylenediamine (2% vol %) was added to the oil-phase in order to trigger hydrogel particle polymerization after droplet formation (interpreted as acrylamide monomer at a first concentration, claim 1) (paragraph [0145]). Kim teaches that as depicted in Figure 4, hydrogel particles are tuned in multiple dimensions to match specific cell types unlike polystyrene beads, wherein hydrogel particles were further functionalized with stoichiometrically tuned ratios of specific chemical side-groups and secondary labels allowing the cell type to be precisely matched without suffering from biological noise as fixed cell lines do (FIG 4C) (paragraph [0150]). Kim teaches in Example 7, the percentage of acrylamide:bis-acrylamide in the hydrogel composition was varied between 10 and 40% to tune the refractive index of the hydrogel particles as measured by forward scattering in a flow cytometer as shown in Figure 9 (interpreted as different polyacrylamide concentrations, claim 1) (paragraph [0155]; and Figure 9). Kim teaches hydrogel parameter tuning to match and/or mimic desired cell population metrics, wherein Figure 10 illustrates analytical measurement using flow cytometry, microscopy, cell imaging, and coulter counting (interpreted as counting, claims 1 and 49) (paragraph [0017]; and Figure 10). Kim teaches that the amount of monomer can be varied by the user of the invention, for example to obtain a particular optical property (interpreted as a plurality of polymer particle populations, claims 1 and 49) (paragraph [0035], lines 1-3). As noted in MPEP 2112.01(II), products of identical chemical composition cannot have mutually exclusive properties. Because the particle populations exemplified by Cowell are identical to the particle populations recited in instant claim 1; as well as, comprising the same composition provided in Bharadwaj and Kim, the particle populations taught by Bharadwaj and Kim inherently have an electrical impedance of less than 15%).
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 method of generating and/or sorting microcapsules including degradable hydrogel microcapsules including microcapsules with or without field-attractable particles that can be detected using an impedance sensor as disclosed by Bharadwaj et al. to include the methods of producing hydrogels, wherein hydrogel microparticle parameters can be adjusted including hydrogel components and/or hydrogel concentration as disclosed by Kim with a reasonable expectation of success tuning hydrogel particle parameters including degradability, non-degradability, differential response to a stimulus and/or to mimic a wide range of cells or populations of cells; and/or in embedding or encapsulating biological molecules into a hydrogel microparticle comprising one or more optical properties that can be detected and/or independently modulated by altering the composition of the hydrogel microparticle; and/or to serve as surrogates for cells in cytometric methods such as flow cytometry, microscopy, cell imaging, coulter counting and/or FACS.
The combined references of Bharadwaj and Kim do not specifically exemplify the term electrical signature (instant claim 49, in part).
Regarding claim 49 (in part), Esfandyarpour et al. devices and methods suitable for sequencing, detecting, amplifying, analyzing and performing sample preparation procedures for nucleic acids and other molecules (Abstract). Esfandyarpour et al. teach a device comprising a well-less sensing array with a plurality of sensors in a housing, wherein at least a subset of sensors can be individually addressable and each sensor can be adapted to directly measure an electronic signature associated with a biological species in solution (interpreted as detecting an electronic signature, claim 49) (paragraph [0009]). Esfandyarpour et al. teach that the device can comprise a fluid flow path in fluid communication with the sensing array, wherein the fluid flow path can provide beads to the sensing array in an emulsion, such that the biological species can be a nucleic acid (paragraph [0010]). Esfandyarpour et al. teach that the electronic signature can be an impedance or a change in impedance, wherein the impedance or change in impedance can be associated with a bead adjacent to the sensor, an electrode of the sensor and/or a species in a fluid adjacent to the sensor (interpreted as detecting an electronic impedance signature, claim 49) (paragraph [0014]). Esfandyarpour et al. teach that the method can further comprise directing a solution comprising the biological species to the sensing array and directly measuring an electronic signature associated with the biological species using the sensor (interpreted as detecting an electronic signature, claim 49) (paragraph [0015], lines 10-14).
“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 of the benefits of detecting an electronic signature associated with a biological species as exemplified by Esfandyarpour et al., 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 method of identifying and/or sorting droplets that comprise field-attractable hydrogel particles using an impedance sensor as disclosed by Bharadwaj to include methods of modulating the optical properties of a hydrogel particle, and/or methods of producing tunable hydrogel microparticles having at least one optical property as taught by Kim; as well as, to include the plurality of individually addressable sensors such as impedance sensors adapted to directly measure an electronic signature associated with a biological species as taught by Esfandyarpour et al., with a reasonable expectation of success in identifying, detecting and/or measuring an electronic signature including a impedance signature of individual particles, particle populations and/or biological particles in solution, such that field-attractable particles and/or beads comprising biological species such as cells and/or nucleic acids can be multiplexed, sorted, counted, and/or isolated to increase efficiency of downstream applications such as amplification and/or sequencing.
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 as obvious over the art.
Response to Arguments
Applicant’s arguments filed September 10, 2025 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Bharadwaj and Kim do not teach that the number of monodisperse polymer particle populations is less than the number of distinct targets, as provided in amended claim 1 (Applicant Remarks, pg. 20, last partial paragraph through pg. 21, third full paragraph).
Regarding (a), although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). It is noted that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Per MPEP 2144.05(II)(A): “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” (underline added). In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).” Moreover, MPEP 2112.01(II) states:
"Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty") (underline added).
As noted in MPEP 2112.01(I),
where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Applicant’s assertion that Bharadwaj does not teach that the number of monodisperse polymer particle populations is less than the number of distinct targets, as provided in amended claim 1, is not found persuasive. As noted supra, although the claims are interpreted in light of the specification, limitations from the Specification are not read into the claims. It is noted that:
Instant claim 1 is directed to a multiplexable particle system, and not to a method of using the multiplexable particle system, such that no monodisperse particle populations and/or distinct targets are being detected.
The as-filed Specification, filed May 26, 2020 and the original claims: (i) do not define “n”; (ii) do not teach that “n” represents ‘a number of monodisperse polymer particle populations’, and/or (iii) that a ‘number’ of distinct targets in the plurality of distinct targets is greater than the ‘number’ of monodisperse polymer particle populations as asserted by Applicant.
Instant claim 1 does not recite:
An identity for the “distinct targets” such that each” distinct target” can be counted and compared to a number of particles and/or particle populations.
Any specific number of monodisperse polymer particles.
Any specific number of monodisperse polymer particles populations.
The presence of distinct targets in the multiplexable particle system.
MPEP 2144.05(II)(A) states (in part) that “[G]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.
Furthermore, Bharadwaj teaches that: (i) target nucleic acids are amplified by PCR; (ii) that a desired number of biological polymers can be partitioned into droplets; and (iii) that that each droplet can contain some number of (or concentration of) field-attractable particles and a number of biological particles. Clearly, the number of PCR amplified nucleic acids and/or a desired number of biological particles can/will be greater than the plurality of monodisperse polymer particle populations. The combined references of Bharadwaj and Kim teach all of the limitations of the claims. Thus, the claims remain rejected.
New Objections/Rejections
Specification Objection
The disclosure is objected to because of the following informalities: paragraph [0093] refers to n electrically distinguishable polymer particle populations, and to n different targets that can be detected; however, “n” is not defined in the as-filed Specification.
Appropriate corrections are required.
Claim Objections
Claims 1, 13, 15, 19 and 55 are objected to because of the following informalities: Claim 1 recites the term “multiplexible”, wherein the term “multiplexable” might be more appropriate.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 1, 13, 15 and 19 are rejected under 35 U.S.C. 101 because the claims are directed to neither a “process” nor a “machine,” but rather embraces or overlaps two different statutory classes of invention set forth in 35 U.S.C. 101 which is drafted so as to set forth the statutory classes of invention in the alternative only. Id. at 1551.
In the instant case, claim 1 is directed to “a multiplexible particle system for use with an electronic detector to detect a plurality of distinct targets” such as recited in claim 1, lines 1-2, where instant claim 1 recites, for example: “an electronic detector comprising one or more microchannels” in line 3; “wherein each of the plurality of monodisperse polymer particle populations has a unique electrical parameter during flow through a spatially confined electric field for multiplexed detection” in lines 5-8; and “wherein each of the plurality of monodisperse polymer particle populations comprise polyacrylamide hydrogel beads with a uniform average diameter between each of the plurality of monodisperse polymer particle populations, and each of the plurality of monodisperse polymer particle populations have a polyacrylamide concentration different from any other of the plurality of monodisperse polymer particle populations” in lines 16-21; while claim 1 also recites: “a plurality of monodisperse polymer particle populations, each of the plurality of monodisperse polymer particle populations has a unique electrical parameter during flow through the spatially confined electric field for multiplexed detection” in lines 5-8; “wherein the unique electrical parameter has an electrical parameter distribution for each of the plurality of monodisperse polymer particle populations determined by flow through the spatially confined electric field of the electronic detector” in lines 9-12; “the unique electrical parameter that is electrical impedance having the coefficient of variation of less than 15% measured by the electronic detector for each of the plurality of monodisperse polymer particle populations” in lines 21-24; and “wherein the multiplexible particle system is multiplexed, such that the multiplexible particle system detects the plurality of distinct targets using n monodisperse polymer particle populations, wherein a number of distinct targets in the plurality of distinct targets is greater than n” in lines 25-28 (e.g., reciting a product and a process in the same claim). Claims 1, 13, 15 and 19 depend from instant claim 1.
Thus, instant claims 1, 13, 15 and 19 recite both a product and a process in the same claim and overlaps two statutory classes of 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, 15, 19, 49, 50 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Valera et al. (hereinafter “Valera”) (Lab on a Chip, April 2018, 18, 1461-1470) in view of Bharadwaj et al. (hereinafter “Bharadwaj”) (US Patent Application Publication 20180334670, published November 22, 2018).
Regarding claims 1 (in part), 15, 19 and 49 (in part), Valera teaches a point of care platform that can potentially detect cell and protein biomarkers simultaneously for sepsis stratification including the use of biomarkers for the continuous monitoring of disease progression and patient response to treatment, which could help reduce high sepsis mortality rates (Abstract; and pg. 1461, col 2, last full paragraph). Valera teaches that blood samples from patients suspected of sepsis were obtained; as well as, obtaining pooled normal human plasma (pg. 1453, col 1, last partial paragraph; and col 2, first partial paragraph). Valera teaches in Figure 1, the microfluidic device components including: (a) the PDMS capture chambers were fabricated in sets of 6 independent chambers, where the zoom-in optical images show top views of the pillars; (b) detailed optical image (top view) of the microfluidic channel aligned over the electrodes, wherein the volume of the microfluidic channel was reduced in the space between the electrodes (aperture); (c) detailed optical image of the PCB board used for the electrical measurements; (d) detailed optical image and schematic of the set-up used for the electrical measurements and analysis (pg. 1463, Figure 1). Figure 1 is shown below:
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Valera teaches in Figure 2, a biochip measurement procedures, where in an off-chip procedure: first, plasma was separated from blood after centrifugation, then, the plasma sample (containing the IL-6) was incubated with a solution of beads-Ab1IL-6 (previously conjugated), such that after washing steps, a suspension of Ab2IL-6-biotin was also incubated to obtain the sandwich immunoassay complex; and on-chip procedure: first, the modified-beads were flowed through the entrance counter, wherein the beads with IL-6 (and as consequence with biotin) were specifically captured in the streptavidin + BSA-blocked capture chamber; and the beads with no IL-6 (and as consequence with no biotin) were flowed through the exit counter; followed by performing the counting analysis, and quantifying the IL-6 concentration (interpreted as multiplexed detection; a differential counting device; and beads of different sizes, claims 1, 49 and 55) (pg. 1465; Figure 2). Figure 2 is shown below:
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Valera teaches microfabricated co-planar gold electrodes were fabricated for the electrical counting, wherein thin Au/Ti (~127.5 nm thickness) electrodes (100 µm wide, 150 µm gap) were patterned on Pyrex wafers, wherein the wafers were diced grouping 2 arrays of 3 electrodes each, to function as entrance and exit counter (interpreted as a differential counter, claim 55) (pg. 1464, col 1, first full paragraph). Valera teaches that the microfluidic biochip was designed to count individual micron-sized beads based on Coulter counting principle, wherein a microfluidic channel with a coulter aperture was aligned in between electrodes, such that when applying a potential between the electrodes (and across the aperture), the passage of a bead through the channel perturbs the electrical current within the aperture, creating a distinct impedance pulse.(interpreted as an electronic detector; a microfluidic device; distinct electrical parameter; impedance; and detecting particle passage by resistive pulse sensing, claim 1, 13 and 49) (pg. 1446, col 2, second full paragraph). Valera teaches that the height of the pulses depends on the bead size, whereas its width depends on its speed, such that after the immuno-chemical procedure, two types of modified-beads remain: (1) beads-Ab1IL-6; and (2) beads-Ab1IL-6-IL-6-Ab2IL-6-biotin; and although the electrical system can clearly distinguish between different bead types in heterogeneous beads populations based on their size and morphology (see ESI†), the system cannot differentiate between the beads with and without the proteins; however, when the two types of modified-beads (beads-Ab1IL-6; beads-Ab1IL-6-IL-6-Ab2IL-6-biotin) were flown through the capture chamber, only the beads including IL-6 (and therefore, biotin), were specifically captured by the streptavidin-functionalized posts in the capture chamber (interpreted as an electronic detector comprising monodisperse polymer particle populations; unique electrical potential; impedance; and interpreting biotin as a receptor molecule/target molecule tag, claims 1, 19 and 49) (pg. 1466, col 2, last partial paragraph). Valera teaches the differential counting of beads (interpreted as a differential counting device, claim 55) (ph. 2467, Figure 4, line 1). Valera teaches that two counters of the biochip are both configured to measure the relative impedance change caused by the passage of a modified bead as shown in Figure 4a (interpreted as inherently comprising an electrical impedance coefficient of variation is > 15%; and an error rate < 10%, claims 1 and 15) (pg. 1467, col 1; first full paragraph, lines 1-3).
Regarding claim 13, Valera teaches that the microfluidic biochip was designed to count individual micron-sized beads based on Coulter counting principle, wherein a microfluidic channel with a coulter aperture was aligned in between electrodes, such that when applying a potential between the electrodes (and across the aperture), the passage of a bead through the channel perturbs the electrical current within the aperture, creating a distinct impedance pulse.(interpreted as a microfluidic device; and detecting particle passage by resistive pulse sensing, claim 1, 13 and 49) (pg. 1446, col 2, second full paragraph).
Regarding claim 55, Valera teaches electrical counting: on-chip procedure, wherein the PCB board (containing the entrance and exit counters) was connected to the breakout board to connect the counters to the Lock-In amplifier; and second, a syringe (loaded with the sample prepared as indicated in section 2.9.1.), as well as the streptavidin + BSA-blocked capture chamber, were serially connected to the counters, completing the whole biochip, such that the entire set-up can be seen in Figure 1d (interpreted as a differential counter, claim 55) (pg. 1465, col 1, last full paragraph; and Figure 1d). Valera teaches the differential counting of beads (interpreted as a differential counting device, claim 55) (pg. 2467, Figure 4, line 1).
Valera does not specifically exemplify polyacrylamide hydrogel beads (claims 1 and 49, in part); and applying a degradation stimulus (claim 49, in part); and a stimulus as listed in claim 50, claim 50).
Regarding claims 1 (in part) and 49 (in part), Bharadwaj teaches methods and systems for sorting droplets that can isolate droplets that include biological particles (e.g., a cell) and/or other particles such as gel beads, cell beads, etc. from droplets that do not include biological particles (interpreted as hydrogel beads, claims 1 and 49) (paragraph [0008], lines 1-5). Bharadwaj teaches that droplets can be sorted, such as by (i) introducing field-attractable particles (e.g., magnetic particles) into the droplets and subjecting the droplets to a field (e.g., magnetic field), (ii) subjecting the droplets to a pressure pulse and separating the droplets based on hydrodynamic forces, and/or (iii) directing the droplets to interface physical structures (e.g., having apertures) in a flow path of the droplets and separating the droplets based on mechanical properties (e.g., deformability) of the droplets (interpreted as sorting based on an electrical property, claims 1 and 49) (paragraph [0006]). Bharadwaj teaches that the methods and systems generally operate by generating a plurality of droplets such that each of the plurality of droplets comprise field-attractable particles, wherein a given droplet in the plurality of droplets can include one or more particles (e.g., biological particles, beads, etc.) (interpreted as particles having unique electronic signal, claims 1 and 49) (paragraph [0009], lines 1-6). Bharadwaj teaches that a given cell bead in the first subset of particles can comprise a sufficiently discrepant number or concentration of field-attractable particles than a given particle in the second subset of particles, such that when the plurality of particles is subject to an electric or magnetic field, the first subset of particles and the second subset of particles are separated from each other (interpreted as unique electrical properties, claims 1 and 49) (paragraph [0010]). Bharadwaj teaches that barcoded oligonucleotides can be initially associated with the microcapsule and then released from the microcapsule upon application of a stimulus which allows the oligonucleotides to dissociate or to be released from the microcapsule including a chemical stimulus, light, temperature, etc. (interpreted as the application of a stimulus including chemical or temperature stimulus, claims 49 and 50) (paragraphs [0129]; and [0151]). Bharadwaj teaches that a microcapsule, in some instances, can comprise a bead including a porous, non-porous, solid, semi solid, semi-fluidic, fluidic, and/or a combination thereof. In some instances, a bead can be dissolvable, disruptable, and/or degradable, wherein the bead can be a gel bead including a hydrogel bead formed from molecular precursors, such as a polymeric or monomeric species (interpreted as a hydrogel bead that is degradable, claims 1 and 49) (paragraph [0130]). Bharadwaj teaches the bead can contain molecular precursors (e.g., monomers or polymers), which can form a polymer network via polymerization of the precursors, wherein the precursor can comprise one or more of an acrylamide or a methacrylamide monomer, oligomer, or polymer including polyacrylamide (interpreted as polyacrylamide hydrogel beads, claims 1 and 49) (paragraph [0131]). Bharadwaj teaches that the beads can be of uniform size or heterogenous size, wherein the diameter of the bead can be at least about 1 micrometer, 100 mm, 500 mm, 1 mm or greater; and/or the bead can have a diameter less than 90 mm, 100 mm, 500 mm, 1 mm or less (interpreted as beads of various sizes, claims 1 and 49) (paragraph [0155]). Bharadwaj teaches that it can be desirable to have a different distribution of droplet sizes, the geometric parameters for the plurality of channel segments 1602 can be varied accordingly (paragraph [0400]). Bharadwaj teaches that the polymer or gel can be functionalized to bind to targeted analytes such as nucleic acids, proteins or other analytes (paragraph [0281]).
Regarding claim 50, Bharadwaj teaches that barcoded oligonucleotides can be initially associated with the microcapsule and then released from the microcapsule upon application of a stimulus which allows the oligonucleotides to dissociate or to be released from the microcapsule including a chemical stimulus, light, temperature, etc. (interpreted as the application of a stimulus including chemical or temperature stimulus, claims 49 and 50) (paragraphs [0129]; and [0151]).
“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 of the benefits of producing beads or particles comprising different electric and/or magnetic characteristics as exemplified by Bharadwaj, 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 systems and methods to differentiate between different types of modified microbeads including microbeads that have captured target proteins as disclosed by Valera to include the methods and systems for producing and/or sorting differentially modified field-attractable particles comprising unique magnetic, electronic, and/or mechanic properties including when subjected to an electric or magnetic field as taught by Bharadwaj with a reasonable expectation of success in producing microbeads comprising unique electronic and/or mechanical characteristics for the capture, detection and/or differentiation between microbeads by Coulter counting principles such as impedance; for the selective capture, sorting, and/or quantification of analytes including captured proteins in biological samples; and/or in producing differentially modified microbeads including hydrogel microbeads that can be degraded upon application of a stimulus, such that the microbeads will release encapsulated or attached species such as protein biomarkers, at a desired time.
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 as obvious over the art.
Conclusion
Claims 1, 13, 15, 19, 49, 50 and 55 are rejected.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684