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
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 47, 49-54, 56 and 58-66 are currently pending. Claims 47, 51, 52, 58, 60, 62-64 and 66 have been amended by Applicants’ amendment filed 11-17-2025. Claim 67 has been canceled by Applicants’ amendment filed 11-17-2025. No claims have been added by Applicants’ amendment filed 11-17-2025.
A complete reply to the final rejection must include cancellation of nonelected claims or other appropriate action (37 CFR 1.144) See MPEP § 821.01.
Therefore, claims 47, 49-54, 56 and 58-66 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed March 9, 2023 is a CON of US Patent Application 17/580,992, filed January 21, 2022, which claims priority to US Provisional Patent Application 63/139,818, filed on January 21, 2021.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application 63139818, filed January 1, 2021, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 47 does not have support for; “first standard polypeptides”; “first polypeptide composites”; “second standard polypeptide”; “second standard polypeptide composite”; “attaching anchoring groups in the second standard polypeptide composites”; “attaching the anchoring groups to the sample polypeptides; and/or “known quantity” . Therefore, the priority date for the presently claimed invention is January 21, 2022, the filing date of US Patent Application 17/580,992.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claim 47 of the instant application.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed November 17, 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.
Maintained Objections/Rejections
Notice of Non-Compliant Amendment (37 CFR 1.121)
The amendment to the claims filed on November 17, 2025 does not comply with the requirements of 37 CFR 1.121(c) because the status identifier and text of claim 47 is not submitted with markings to indicate the changes that have been made relative to the immediate prior version of claims filed on August 1, 2025.
Amendments to the claims filed on or after July 30, 2003 comply with 37 CFR 1.121(c), which states:
(c)(2) Claims - When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn—currently amended.”
Specifically, the amendments to the claims filed November 17, 2025 include amendments to claim 47 that are not indicated by underlining the added text and/or a showing of deleted matter by strike-through or use of double brackets. For example, claim 47, line 1 has been amended to recite “forming an array of polypeptides, comprising the steps of.” Additionally, the status identifier “(previously presented)” is improper. There are no markings to indicate that instant claim 47 has been amended relative to the immediate prior version of the claims filed on August 1, 2025.
To be fully responsible, Applicant is required to comply with the Notice of Non-Compliant Amendment (37 CFR 1.121). In the interests of compact prosecution, an action on the merits has been prepared. However, future amendments must comply with 37 CFR 1.121(c) in order to avoid a notice of non-compliant amendment.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 47, 49-54, 56 and 58- 66 are 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.
Claim 47 is indefinite for the recitation of the term “forming an array of polypeptides, comprising the steps of” in claim 47, lines 1-2 because instant claim 47 has been amended from the immediate prior version of claim 47 filed 08-01-2025, which recited (at least) “forming an array of polypeptides, comprising.” Additionally, instant claim 47 does not comprise a proper status identifier and/or the required markings to indicate that claim 47 has been amended. It is unclear whether additional amendments have been made to claim 47 and, thus, the metes and bounds of the claim cannot be determined.
Claim 51 is indefinite for the recitation of the term “coupling the first standard polypeptides or the sample polypeptides to the pull down agent…thereby forming the first polypeptide composites” such as recited in claim 51, lines 1-4 because claim 51 depends from claims 47 and 49, wherein claim 47, lines 6-7 recites that “first polypeptide composites” are provided by “attaching anchoring groups to the sample polypeptides and the first standard polypeptides in the first composition.” Therefore, dependent claim 51 cannot provide “first polypeptide composites” by an entirely different method from the process recited in instant claim 47 and, thus, the metes and bounds of the claim cannot be determined.
Claim 52 is indefinite for the recitation of the term “removing post-translational modifications from the first standard polypeptides or the sample polypeptides” such as recited in claim 52, lines 6-7 because claim 52 depends from claims 47 and 50, wherein claims 47 and 50 do not recite that the first standard polypeptides or the sample polypeptides comprise a post-translational modification and, thus, the metes and bounds of the claim cannot be determined.
Claim 64 is indefinite for the recitation of the terms “the standard polypeptides comprise synthetically created standard polypeptides” such as recited in claim 64, lines 1-2. There is insufficient antecedent basis for the terms “the standard polypeptides” and “standard polypeptides” in the claim because claim 47, lines 6-7 and 10 recite the terms “first standard polypeptides” and “second standard polypeptides.”
Claim 66 is indefinite for the recitation of the terms “the standard polypeptides” and “standard polypeptides” such as recited in claim 66, lines 1-4. There is insufficient antecedent basis for the terms “the standard polypeptides” and “standard polypeptides” in the claim because claim 47, lines 6-7 and 10 recite the terms “first standard polypeptides” and “second standard polypeptides.”
Claim 66 is indefinite for the recitation of the term “standard polypeptides containing a post-translational modification, and standard polypeptides lacking a post-translational modification” such as recited in claim 66, lines 2-4 because it is unclear (i) whether all standard polypeptides contain a post-translational modification and lack a different post-translational modification; or (ii) all standard polypeptides either contain a post-translational modification or lack a different post-translational modification. The instant as-filed Specification does not teach standard polypeptides that contain a post-translational modification and also lack a post-translational modification and, thus, the metes and bounds of the claim cannot be determined.
Claims 49, 50, 53, 54, 56, 58- 63 and 65 are indefinite insofar as the claims ultimately depend from instant claim 47.
Claim Rejections - 35 USC § 112(d)
The rejection of claims 52 is maintained, and claim 51 is newly rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 51 recites (in part): “wherein coupling the first standard polypeptides or the sample polypeptides to the pull down agent comprises coupling the first standard polypeptides or the sample polypeptides to particles, thereby forming the first polypeptide composites” in claim 51, lines 1-4 because claim 51 depends from claims 47 and 50, wherein claim 47 recites that first polypeptide composites are provided by attaching anchoring groups to the sample polypeptides and first standard polypeptides in the first composition (e.g., not by attaching first standard polypeptides or sample polypeptides to a pull down agent). Thus, claim 51 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 52 recites (in part): “and removing post-translational modifications from the first standard polypeptides or the sample polypeptides” in claim 52, lines 6-7 because claim 52 depends from claims 47 and 50, wherein claims 47 and 50 do not recite that the first standard polypeptides or the sample polypeptides comprise post-translational modifications. Thus, claim 52 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 47, 49-54, 56 and 58- 67 is maintained under 35 U.S.C. 103 as being obvious over Mallick et al. (hereinafter “Mallick”) (US Patent Application Publication No. 20210239705, published August 5, 2021; also published as WO2019236749, published December 12, 2019; effective filing date June 6, 2018; of record) as evidenced by Elahipanah et al. (hereinafter “Elahipanah”) (Bioconjugate Chemistry, 2017, 28, 1422-1433; of record); and Sharpless et al. (hereinafter “Sharpless”) (US Patent No. 7375234, issued May 20, 2088; of record); and Grant, Russell (hereinafter “Grant”) LabCorp, 2019, 1-66).
Regarding claim 47, Mallick teaches methods and systems for identifying a protein within a sample, wherein a panel of antibodies are acquired, none of which are specific for a single protein or family of proteins, and wherein the binding properties of the antibodies in the panel are determined; and the protein is iteratively exposed to a panel of antibodies, such that a set of antibodies which bind the protein are determined (interpreting proteins as a plurality of sample polypeptides and a plurality of standard polypeptides; interpreting antibodies in the array as particles or linkers to which the proteins bind to form a mixture of sample polypeptide composites and standard polypeptide composites, claims 47 and 53) (Abstract). Mallick teaches determining that each portion of the one or more proteins having an identified unique spatial address contains the one or more epitopes associated with the one or more observed signals, such that each of the conjugated portions of the one or more proteins is associated with an unique spatial address on the substrate, wherein the one or more proteins can comprise a single protein molecule (interpreted as one and only one sample/standard polypeptide attached to a particle, claim 47) (paragraphs [0004]; and [0006]). Mallick teaches an ordered array of functional groups, or of regions of functional groups forming attachment sites, such that the attachment sites can be created by, for example, photolithography including nanoball lithography, wherein the attachment sites on a substrate can comprise the same functional group (interpreting nanoballs as structured nucleic acid particles; and interpreting the same functional groups as identical anchoring groups, claims 47 and 53) (paragraph [0072], lines 1-3 and 11-12). Mallick teaches that the one or more proteins can comprise one single protein molecule; or bulk proteins, such that the one or more proteins can comprise a plurality of a same protein that is conjugated at a same unique spatial address on the substrate (paragraph [0006]). Mallick teaches that proteins are randomly arranged (interpreted as randomly distributed on the array, claims 49 and 52) (paragraph [0013]). Mallick teaches that the method further comprises determining the identity of the portion of the one or more proteins to a threshold degree of accuracy based on the pattern of binding of the affinity reagents, wherein the portions of one or more proteins are conjugated to the substrate using a photo-activatable linker; and at least a portion of the at least one set of affinity reagents is modified to be conjugated to an identifiable tag such as a fluorescent tag, a nucleic acid barcode, and/or an affinity tag, wherein the spatial addresses can be used to quantify the level of that protein in the sample (interpreting affinity agents as attachment standard polypeptides; interpreting tags as coupling standard polypeptides; exogenous of the biological sample; polypeptide of a known quantity; and attaching sample polypeptide composites, wherein attaching is carried out in the presence of attachment standard polypeptide composites; and encompassing peptides in a composite not known to be in any organism, claims 47 and 55) (paragraphs [0008]; and [0009], lines 1-7). Mallick teaches that the samples can be any biological sample containing protein, wherein the samples can be taken from tissues or cells or from the environment of tissues or cells (interpreted as a biological sample; and sample polypeptides that form sample polypeptide composites, claim 47) (paragraph [0049], lines 1-3). Mallick teaches that a sample can be modified before proteins are extracted, wherein a sample can be treated with a reagent to cross link proteins to each other or to other cellular components, such as nucleic acids, lipids, and carbohydrates; and that a sample can be spiked with an internal standard prior to protein extraction, during protein extraction, or after protein extraction, wherein the sample can be spiked with an amount of protein that is foreign to the sample for use as an internal measurement control, purification control, or other control; and that the protein which is foreign to the sample may not interact with the sample, or it can interact with the sample, for example, to facilitate or improve detection of a protein in the sample (interpreting spiking with an internal standard as coupling standard polypeptide composite; first standard polypeptides having a known quantity; exogenous of the biological sample; and modified proteins encompassing peptides in a composite not known to be in any organism, claims 47 and 55) (paragraphs [0055]; and [0069], lines 1-8), where it is known that an internal standard in analytical chemistry is a chemical substance that is added in a constant amount to samples as evidenced by Grant (pg. 5). Mallick teaches that proteins can be tagged with identifiable tags that allow for the multiplexing of samples, wherein non-limiting examples of protein tags include nucleic acid barcoded base linkers, fluorophores, a peptide tags (e.g., an AviTag, a C-tag, an E-tag, a Rho1D4-tag, an S-tag, a His-tag etc.), a radiolabel, etc. to allow for multiplexing of samples (interpreted as sample polypeptides and first standard polypeptides; coupled to anchor groups; encompassing a first composite and a second composite; not known to any organism; and interpreting the different polypeptides comprising different tags as being distinguishable one from the other, claim 47, 50 and 52) (paragraphs [0065]-[0066]). Mallick teaches that proteins are applied to a functionalized substrate to chemically attach proteins to the substrate, wherein the proteins can attach to the substrate via a biotin attachment, or a nucleic acid attachment; proteins can be applied to an intermediate substance, where the intermediate substance is then attached to the substrate; and proteins can be conjugated to beads which can be captured on a surface (interpreting beads as solid supports and as particles; interpreting the surface as a solid support; interpreting functional groups, nucleic acids, and/or biotin as an anchoring groups; interpreting proteins or intermediate molecules as coupling standard polypeptides; attaching sample polypeptide composites and attachment standard polypeptide composites to a solid support; exogenous to the sample; and anchoring groups of the same species, claims 47 and 53) (paragraph [0070]). Mallick teaches that substrates can refer to any solid surface to which proteins can be covalently or non-covalently attached including particles, beads, slides, surfaces of elements of devices, membranes, flow cells, wells, chambers, microfluidic chambers, be flat or curved or have other shapes (interpreted as particles; anchoring groups; and solid supports, claims 47 and 53) (paragraph [0071], lines 1-10). Mallick teaches that the proteins can be spotted, dropped, pipetted, flowed, washed or otherwise applied to the substrate including a substrate that has been functionalized with a moiety such as an NHS ester (interpreted as forming a polypeptide array; comprising a particle; randomly distributed; and anchor groups, claims 47, 49 and 52) (paragraph [0080], lines 1-4). Mallick teaches protein can be conjugated to a nucleic acid and attached to the substrate, such that using the nucleic acid, a nucleic acid nanoball can be formed, thereby having the protein linked to the nucleic acid nanoball (interpreting particles to comprise a nanoball, wherein a nanoball is a structured nucleic acid, claim 48) (paragraph [0081]). Mallick teaches that the substrate can also contain conjugated protein standards and controls, wherein conjugated protein standards and controls can be peptides or proteins of known sequence which have been conjugated in known locations, such that conjugated protein standards and controls can serve as internal controls in an assay (also interpreting the conjugated protein standards and controls as standard polypeptides including a mixture of a sample/standard polypeptides; interpreted as combining a first and second standard polypeptide composites; and coupling to particles to form standard polypeptide composites, claim 47) (paragraph [0091]). Mallick teaches that the substrate can comprise fluorescent standards, wherein the fluorescent standards can be used to calibrate the intensity of the fluorescent signals, for example from assay to assay, and to correlate the intensity of a fluorescent signal with the number of fluorophores present in an area; as well as, a colorimetric standard, a radiolabeled standard, or a magnetic standard (interpreting the fluorescent standards as comprising attachment standard polypeptides, and coupling standard polypeptides; attaching is carried out in the presence of the plurality of attachment standard polypeptide composites; and composites including comprising peptides not known to be found in any organism, claims 47 and 55) (paragraphs [0092]-[0093]). Mallick teaches that detection moieties can be attached to an affinity agent through a linker, or through an affinity reaction, wherein detection moieties include, but are not limited to, fluorophores, bioluminescent proteins, nucleic acid segments including a constant region and barcode region, or chemical tethers for linking to a nanoparticle such as a magnetic particle; as well as, several different fluorophores with different patterns of excitation or emission, wherein the identities of nucleic acids at each location can be determined by sequencing (interpreting detecting attachment standard polypeptides, coupling standard polypeptides, and attachment standard polypeptides; linkers as anchoring groups; attaching is carried out in the presence of the plurality of attachment standard polypeptide composites; composites; particles include nucleic acids; and measuring efficiency of the coupling step by sequencing, claims 47 and 48) (paragraphs [0110]-[0111]; and [0184]). Mallick teaches multiplexing of affinity reagents labeled with nucleic acid tags can be determined by the length of the nucleic acid barcode, wherein one or more affinity reagents can be chosen to bind amino acid motifs of a given length including 2, 4, 6, 8 or more than 10 amino acids (interpreted as standard composites not more than 50 amino acids, claim 54) (paragraph [0116], lines 23-26; and [0118], lines 1-3). Mallick teaches that a substrate can be loaded with known protein standards at known locations and used to assess the specificity of a plurality of affinity reagents, or a substrate can contain both experimental samples and a panel of controls and standards such that the specificity of each affinity reagent can be calculated from the binding to the controls and standards and then used to identify the experimental samples (interpreted as attaching is carried out in the presence of the plurality of attachment standard polypeptide composites; interpreting controls and standards as coupling standard polypeptides and attachment standard polypeptides; composites; and interpreted as detecting the sample polypeptides; coupling standard polypeptides, and attachment polypeptides; and quantitatively measuring efficiency of the coupling step based on the attachment standard polypeptides detected, claim 47) (paragraph [0117]). Mallick teaches that each single, individual, protein molecule can be conjugated to a uniquely labeled nanobead, which can be labeled by any detectable method, such that each nanobead can comprise a unique combination of several possible fluorophores (paragraph [0203], lines 1-10). Mallick teaches the use of affinity reagents that can bind a single protein or a single protein isoform, wherein affinity reagents can be modified to be detectable, such as by conjugation to a fluorophore, radioactive particle, magnetic particle, colorimetric particle; and that affinity reagents can be screened for their ability to bind a single protein (interpreted as one and only one sample/standard polypeptide attached to a particle; and interpreting the affinity agent as a linker for coupling polypeptides, claims 47 and 62) (paragraphs [0007]; [0097]; and [0113]). Mallick teaches that affinity reagents can also comprise a magnetic component useful for manipulating some or all bound affinity reagents into the same imaging plane, wherein manipulating some or all affinity reagents into the same imaging plane can improve the quality of the imaging data and reduce noise in the system (paragraph [0122]). Mallick teaches that protein quantities can be included in quantitative analytes such as differential quantification between healthy and disease states, longitudinal analysis or biomarker discovery (interpreted as detecting the sample polypeptides; coupling standard polypeptides, and attachment polypeptides; and quantitatively measuring efficiency of the coupling step based on the attachment standard polypeptides detected, claim 47) (paragraph [0165]). Mallick teaches that protein modifications can be identified using the methods of this disclosure including wherein post translational modifications can be identified by iterative cycles of detection using modification specific detection reagents interspersed with enzymatic processing (for example phosphatase treatment); and that affinity reagents specific for different modifications can be used to determine the presence of absence of such modifications on the immobilized proteins, such that the method also allows quantification of the number of instances of each protein with and without a given modification (interpreted as detecting the sample polypeptides; coupling standard polypeptides, and attachment polypeptides; and quantitatively measuring efficiency of the coupling step based on the attachment standard polypeptides detected, claim 47) (paragraph [0167]). Mallick teaches that Figure 13 illustrates the percentage of known human proteins that can be identified given a set of x affinity reagents specific to unique amino acid 3-mers as a function of binding efficiency of each affinity reagent, wherein 98% of human proteins can be identified and quantified with 8000 3-mer affinity reagents and a binding likelihood of 10% (quantitively measuring coupling efficiency) (paragraph [0169]; and Figure 13). Figure 13 is shown below:
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Mallick teaches that the binding data can be used to determine the combination of proteins present at each optically resolvable location (interpreted as detecting; and quantitatively measuring efficiency of the coupling step based on the attachment standard polypeptides detected) (paragraph [0183]). Mallick teaches that the methods can be used to identify any single protein molecule from a pool of protein molecules using less affinity reagents than the number of possible proteins, wherein the method can identify a signature of the unknown protein, and thus the presence and quantity of the unknown protein; and that a panel of less than about 100, 500, 1000, or 4000 affinity reagents can be selected, wherein the panel of affinity reagents is capable of uniquely identifying each of at least about 100, 1000, 100,000, or 5 million different proteins (interpreted as detecting the sample polypeptides; interpreting affinity agents as coupling standard polypeptides; and quantitatively measuring efficiency of the coupling step based on the attachment standard polypeptides detected; and a dynamic range of at least 1 x 103, claims 47 and 50) (paragraph [0201]). Mallick teaches that each single, individual, protein molecule can be conjugated to a uniquely labeled nanobead (interpreting molecules attached to nanobeads as sample polypeptide composites), wherein the nanobeads can be labeled by any detectable method, for example, fluorescence including a unique combination of several possible fluorophores; nanobead can be a DNA cluster or another chemical polymer, such that the protein-nano beads can then be applied to a substrate with immobilized affinity reagents (interpreting attachment to labels and/or affinity reagents as attachment standard polypeptides; and randomly distributed), wherein each is optically resolvable address on the substrate comprises either an individual affinity reagent of known properties, or a plurality of copies of a single affinity reagent species; and the substrate is imaged over time, or continuously, such that the location of each conjugated protein nanobead is determined in each image; and the information is used to determine the likely epitopes comprised by the protein, thus allowing the protein to be identified as described herein (interpreted as detecting the sample polypeptides; coupling standard polypeptides, and attachment polypeptides; and quantitatively measuring efficiency of the coupling step based on the attachment standard polypeptides detected; randomly distributed on the array; and encompassing a dynamic range of 1 x103, claims 47 and 49-52) (paragraph [0203]). Mallick teaches method and systems can be used to identify at least 1000 different proteins with at least 50% accuracy at least 10% more quickly than techniques for protein identification that rely on a mass spectrometer (interpreted as different sample polypeptides in the array; and as measuring efficiency of coupling and attachment, claims 47, 50 and 51) (paragraph [0003]), lines 16-20). Mallick teaches that each single, individual, protein molecule can be conjugated to a uniquely labeled nanobead, wherein the nanobeads can be labeled by any detectable method such as fluorescence (interpreted as one and only one sample/standard polypeptide binds a particle, claim 47) (paragraph [0203], lines 1-5). Mallick teaches that each single, individual, protein molecule can be conjugated to uniquely labeled nanobead that can be detectable by any method (interpreted as one and only one sample/standard polypeptide attached to a particle, claim 47) (paragraph [0203], lines 1-5). Mallick teaches that a sample can be spiked with an amount of a protein which is foreign to the sample including as an internal measurement control, purification control, or other control (interpreting the spiked protein to have a known quantity; adding chemical reagents; sequences that are exogenous to the sample polypeptides; and synthetically created standard polypeptides, 47, 50, 52, 64 and 65) (paragraph [0069], lines 1-8). Mallick teaches that since the human sample should not contain any GFP, the total amount of GFP in the sample can be determined by the amount of GFP spiked into the sample, and since the GFP is known to be in the spiked sample, and since the amount of GFP that was spiked into the sample is known, the GFP can be used as a positive control, such as for either or both of the detection and quantification steps (interpreting the spiked protein to have a known quantity; adding chemical reagents; sequences that are exogenous to the sample polypeptides; and synthetically created standard polypeptides, 47, 50, 52, 64 and 65) (paragraph [0069], lines 16-24). Mallick teaches that a substrate can be loaded with known protein standards at known locations and used to assess the specificity of a plurality of affinity reagents and/or a substrate can contain both experimental samples and a panel of controls and standards such that the specificity of each affinity reagent can be calculated from the binding to the controls and standards and then used to identify the experimental samples (interpreted as encompassing a first standard polypeptide and the second standard polypeptide having a known quantity; sample polypeptides; first and second composites; and bound to an array, claim 47) (paragraph [0117]), lines 6-13). Mallick teaches that the substrate can also contain conjugated protein standards and controls, which can serve as internal controls in an assay including peptides, proteins of known sequence which have been conjugated in known locations, radiolabeled standards, colorimetric standards, magnetic standards, and/or fluorescent standards used to calibrate the intensity of fluorescent signals (interpreted as first standard polypeptides; and second standard polypeptides having a known quantity, claim 47) (paragraphs [0091]-[0093]). Mallick teaches that the methods disclosed herein are also capable of uniquely identifying and quantifying n proteins in a mixture of proteins using m binding reagents, and wherein each protein is identified via a unique profile (interpreted as detecting the sample polypeptides; first and second standard polypeptides, sample polypeptides; having a known amount; and quantitatively measuring, claim 47) (paragraph [0201], lines 19-23). Mallick teaches that once each individual protein molecule on the substrate is identified the number of instances of each protein can be quantified for each fraction (interpreted as a known amount of standard polypeptides; and fractionating, claims 47, 53 and 66) (paragraph [0215], lines 19-21). Mallick teaches applying the samples iteratively across the substrate, following each sample application with a protein detection step utilizing a non-specific protein binding reagent or dye (interpreted as a plurality of standard polypeptides comprising a ladder of standard polypeptides, claim 67) (paragraph [0084]).
Regarding claims 49 and 51, Mallick teaches that a candidate drug compound can be immobilized upon a support and exposed to a protein isolate, wherein the drug candidate can be labeled with a moiety which can be used to pull down the drug candidate and bound proteins, and can be applied to cells or tissue samples (interpreted as coupling to a pull down agent; and coupling polypeptides to particles/drug compounds, claims 49 and 51) (paragraph [0190]). Mallick teaches that detection moieties can be attached to an affinity agent through a linker, or through an affinity reaction (interpreting affinity agents as pull down agents, claims 49 and 51) (paragraphs [0110]-[0111]; and [0184]).
Regarding claims 50, 52, 53 and 58, Mallick teaches that a cellular or tissue sample can be homogenized and the membrane containing fraction can be separated from the non-membrane fraction, wherein the membrane associated fraction can be further separated to purify lipid rafts from other membrane; or the sample can be treated to isolate nuclei, and then the nuclear membranes can be isolated to determine proteins associated with the nuclear membrane (interpreted as prior to (a), treating standard polypeptides; fractionating the sample; and including concentrating polypeptides, claims 50, 52, 53 and 58) (paragraph [0186]).
Regarding claims 54 and 57, Mallick teaches that a sample can be modified before proteins are extracted including that a sample can be treated with a reagent to cross link proteins to each other or to other cellular components such as nucleic acids, lipids, and carbohydrates; or a sample can be spiked with an internal standard prior to protein extraction, during protein extraction or after protein extraction (interpreted as treating sample polypeptides with a modifying agent in the presence of standard polypeptides before step (b); interpreting a sample to comprise a combination of sample and standard polypeptides; and interpreting spiking with an internal standard as combining a sample with standard polypeptides, claims 50, 54 and 57) (paragraph [0055]). Mallick teaches that samples can be treated, such as by sonication, to cleave nucleic acids into fragments (interpreted as treating, fractionating, etc., claim 54 and 57) (paragraph [0184]). Mallick teaches that the substrate can also contain conjugated protein standards and controls, wherein conjugated protein standards and controls can be peptides or proteins of known sequence which have been conjugated in known locations, such that conjugated protein standards and controls can serve as internal controls in an assay (interpreting the conjugated protein standards and controls as standard polypeptides; and coupling standard polypeptides to particles to form standard polypeptide composites, claims 47 and 57) (paragraph [0091]).
Regarding claim 56, Mallick teaches that a protein can be conjugated to a nucleic acid, wherein using the nucleic acid a nucleic acid nanoball can be formed thereby having the protein linked to the nucleic acid nanoball; and that the protein can be conjugated to a nanoball or structured nucleic acid (interpreted as attached polypeptide mixture to structured nucleic acids, claim 56) (paragraphs [0081]-[0082]).
Regarding claim 59, Mallick teaches that proteins can be treated to remove modifications that interfere with epitope binding (interpreted as forming functional groups on the polypeptides, claim 59) (paragraph [0057], lines 1-2).
Regarding claim 60, Mallick teaches that cells are placed in a hypotonic solution and water flows into the cells causing the cells to swell and then more easily rupture (interpreting water as a click reagent, and sample/standard polypeptides forming click reagents, claim 60) (paragraph [0211]), wherein it is known that the click reaction occurs in mild conditions in organic solvents or aqueous media and proceeds in high yield as evidenced by Elahipanah (Abstract). Mallick teaches treating proteins with crosslinkers including, for example, N-5-azido-2-nitrobenzyloxysuccinimide (interpreting water as a click reagent, and sample/standard polypeptides forming click reagents, claim 60) (paragraph [0083], lines 8-10), wherein it is known that cycloaddition reaction using azides and alkynes are known in the art as evidenced by Sharpless (Abstract).
Regarding claim 61, Mallick teaches that proteins are applied to a functionalized substrate to chemically attach proteins to the substrate including via biotin or nucleic acid attachment, wherein the term substrates or solid support refers to any solid surface to which proteins can be covalently or non-covalently attached including particles, beads, slides, surfaces of devices, membranes, flow cells, wells, chambers, etc. (interpreted as one and only one sample/standard polypeptide attached to a particle; and interpreting the affinity agent as a linker for coupling polypeptides; and attaching via a linker, claim 61) (paragraph [0071], lines 2-8).
Regarding claim 62, Mallick teaches that a protein can be conjugated to a nucleic acid, which can form a nucleic acid nanoball, wherein a nucleic acid nanoball or structured nucleic acid particle can be formed with a functionally active terminus (e.g., maleimide, NETS-ester, etc.), such that the protein attached to the nucleic acid is attached to the substrate by way of the nucleic acid nanoball (interpreted as one and only one sample/standard polypeptide attached to a particle; and coupling polypeptides to linkers such as the nanoball particle, claims 47 and 62) (paragraph [0014]). Mallick teaches that substrates can comprise an array of attachment sites; and a substrate can be indirectly functionalized, such as by being PEGylated (interpreted as coupling polypeptides to linkers, claims 47 and 62) (paragraphs [0073], lines 1-2; and [0074], lines 1-4).
Regarding claim 63, Mallick teaches that a substrate or solid support can be functionalized by modification with specific functional groups; and that a substrate or solid support further modified to allow or enhance covalent or non-covalent attachment of oligonucleotides (interpreted as coupling a polypeptide composite mixture to a first and second oligonucleotide oligonucleotides at the plurality of sites, claim 63) (paragraph [0071], lines 16-20). Mallick teaches that a protein can be conjugated to a nanoball or structured nucleic acid particle, wherein the protein attached to the nanoball or structured nucleic acid particle can be attached (e.g., by adsorption or by conjugation) to a substrate, wherein the structured nucleic acid particle can comprise at least two conjugated oligonucleotides (interpreted as coupling a polypeptide composite mixture to a first and second oligonucleotide oligonucleotides at the plurality of sites, claim 63) (paragraph [0082]).
Regarding claims 64 and 65, Mallick teaches that the sample can comprise synthetic proteins; and that proteins can be applied to the substrate from purified protein stocks, or they can be synthesized on the substrate (interpreted as standard polypeptide are artificial or synthetic; and polypeptides exogenous from the sample, claim 64) (paragraphs [0049], lines 1-6; and [0091]). Mallick teaches that a binding protein can be naturally occurring in the same organism as the sample is from, naturally occurring from a different organism as the sample is from, modified from a naturally occurring proteins, or a synthetic protein (interpreted as standard polypeptide are artificial or synthetic; and the standard polypeptides are exogenous to the sample polypeptides, claims 64 and 65) (paragraph [0095], lines 10-15). Mallick teaches that a sample can be spiked with an internal standard prior to protein extraction, during protein extraction, or after protein extraction, wherein the sample can be spiked with an amount of protein that is foreign to the sample for use as an internal measurement control, purification control, or other control; and that the protein which is foreign to the sample may not interact with the sample, or it can interact with the sample, for example, to facilitate or improve detection of a protein in the sample (interpreting spiking with an internal standard as standard polypeptide composite; exogenous of the sample polypeptides; and modifying polypeptides, claims 47, 59 and 65) (paragraphs [0055]; and [0069], lines 1-8).
Regarding claim 66, Mallick teaches that affinity reagents can recognize epitopes present in two or more different proteins, wherein affinity reagents used can be highly specific for a single epitope containing a post-translational modification (interpreted as fractions of standard polypeptides containing a post-translational modification, claim 66) (paragraph [0099]).
“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 identifying proteins as exemplified by Mallick, it would have been prima facie obvious before the effective filing date of the claimed invention to modify the method of identifying a protein within a sample by conjugating a uniquely labeled proteins to a nucleic acid particle including a structured nucleic acid linked to a substrate, wherein the substrate can comprise protein standards and controls as disclosed by Mallick to include affinity reagents including multiple protein-specific affinity reagents as taught by Mallick with a reasonable expectation of success measuring quantity and/or binding efficiency of the proteins present in a sample; and/or in screening groups of affinity agents for their ability to bind a single protein, and/or for overlapping binding characteristics to increase binding specificity for a particular protein.
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 November 17, 2025 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Mallick fails to teach the methods of using and modifying the first standard polypeptides and sample polypeptides as recited within claim 47 (pg. 9, second full paragraph); (b) the Examiner's application of Mallick as teaching first standard polypeptides which are distinguishable from sample polypeptides, wherein the first standard polypeptides have a known quantity is an error (Applicant Remarks, pg. 9, last full paragraph through pg. 10, last full paragraph); (c) there is no teaching of taking that sample, with spiked-in proteins, attaching anchoring groups to provide first polypeptide composites, and then combining second standard polypeptides attached to anchoring groups with the spiked protein sample to provide second polypeptide composites (Applicant Remarks, pg. 10, last partial paragraph; and pg. 11, first partial paragraph); and (d) Mallick does not reach taking composite polypeptides, made up from a combination of standard polypeptides and sample polypeptides linked to anchoring groups and combining that with a second set of standard polypeptides attached to anchoring groups (Applicant Remarks, pg. 11, first full paragraph through pg. 12, first partial paragraph).
Regarding (a), Applicant’s assertion that Mallick fails to teach the methods of using and modifying the first standard polypeptides and sample polypeptides as recited within claim 47, is not found persuasive. The Examiner respectfully notes that instant claim 47 does not recite a method of using and/or a method of modifying the first standard polypeptides and sample polypeptides. Thus, the claims remain rejected.
Regarding (b)-(d), the Examiner's application of Mallick as teaching first standard polypeptides which are distinguishable from sample polypeptides, wherein the first standard polypeptides have a known quantity is an error; it’s unclear how second standard composites can be combined with the first polypeptide composites if the first composites are already anchored to a substrate; and there is no teaching of taking a sample with spiked in proteins, attaching anchoring groups, combining with second standard polypeptides attached to anchoring groups to provide second polypeptide composites, is not found persuasive. 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). As an initial matter, instant claim 47 is very broadly recited, such that instant claim 47 does not recite any specific sample, polypeptides, standards, known quantity, anchoring groups, method of providing, method of combining, method of attaching, etc. Additionally, there is no specific order for the recited steps. Moreover, instant claim 47 does not recite the term “such as by having uniquely identifiable sequences that function like a tag.” In the response to the Office Action mailed May 5, 2025, Applicant did not previously argue that Mallick does not teach adding anchoring groups to the first standard polypeptides and the sample polypeptides. Applicant’s argument was directed to first standard polypeptides which are distinguishable from sample polypeptides, wherein the first standard polypeptides have a known quantity. Furthermore, the step of “combining” can broadly refer to combining the polypeptide composites on a solid support during formation of the array.
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 the term “standard polypeptide” is not specifically defined in the as-filed Specification or in the instant claims, such that “standard polypeptides” can have any structure and/or function. Additionally, uniquely labeling each sample polypeptide and each standard polypeptide provides polypeptides that are wholly distinguishable one from another (e.g., barcode, fluorophore, mass tag, 3-mer peptide, etc.). These unique polypeptides are then bound to a bead, a linker, a 3-mer peptide, an affinity reagent, etc. (e.g., an anchor group), and attached to a solid support. Any of the polypeptides can be quantified and/or can be compared to an internal standard and/or an internal control. Thus, the invention lacks novelty.
Moreover, one of ordinary skill in the art would clearly recognize that uniquely labeled sample polypeptides, first standard polypeptides, and/or second standard can be attached to a solid support by any known method including individually, in groups, in any order, etc. The steps recited in instant claim 47 are obvious to one of ordinary skill in the art, and there does not appear to be any surprising results achieved by the steps as recited in claim 47. Thus, the novelty of the instant invention is unclear.
Please see the Examiner’s response to Applicant’s arguments as provided in the Office Action mailed August 26, 2025. Additionally,
Mallick teaches:
Each single, individual, protein molecule can be conjugated to a uniquely labeled nanobead, where the nanobeads can be labeled by any detectable method, such as fluorescence; and the protein nanobeads can then be applied to a substrate with immobilized affinity reagents (interpreted as attaching anchoring groups to standard and sample polypeptides; a first standard polypeptide having a known quantity such as a fluorophore; attaching the anchoring groups to a solid support; and standard polypeptides are distinguishable from sample polypeptides) (paragraph [0203], lines 1-10).
Once each individual protein molecule on the substrate is identified, the number of instances of each protein can be quantified for each fraction (interpreted as a known quantity of first standard polypeptides; and standard polypeptides are distinguishable from sample polypeptides) (paragraph [0215], lines 19-21; and Figures 1 & 2).
A protein can be conjugated to a nucleic acid; and using the nucleic acid, a nucleic acid nanoball can be formed, wherein a DNA nanoball can be attached (e.g., by absorption or by conjugation) to the substrate (interpreted as attaching anchoring groups to standard and sample polypeptides; and attaching the anchoring groups to a solid support) (paragraph [0081]).
A sample can be spiked with an amount of a protein which is foreign to the sample including as an internal measurement control, purification control, or other control (interpreting the spiked protein to have a known quantity; adding chemical reagents; sequences that are exogenous to the sample polypeptides; and synthetically created standard polypeptides).
A sample can be spiked with an internal standard prior to protein extraction, during protein extraction, or after protein extraction, where it is known that an internal standard in analytical chemistry is a chemical substance that is added in a constant amount to samples as evidenced by Grant (pg. 5) (interpreted as a known quantity of first standard polypeptides; and standard polypeptides are distinguishable from sample polypeptides) (paragraph [0055]).
The substrate can contain conjugated protein standards and controls having known sequence including serving as internal controls in an assay including from purified stocks. The substrate can comprise fluorescent standards used to calibrate the intensity of the fluorescent signals, which can correlate with the number of fluorophores present in an area. The substrate can comprise another standard such as a colorimetric standard, a radiolabeled standard, or a magnetic standard (interpreted as a known quantity of first standard polypeptides; and standard polypeptides are distinguishable from sample polypeptides) (paragraph [0091]).
A substrate can be loaded with known protein standards at known locations including a panel of controls and standards. A substrate can contain both experimental samples and a panel of controls and standards such that the specificity of each affinity reagent can be calculated from the binding to the controls and standards and then used to identify the experimental samples (interpreting affinity reagents as anchor groups; interpreting loading standards and loading samples as combining; interpreting standards as having a known quantity of first standard polypeptides; attaching anchoring groups to standard and sample polypeptides; and standard polypeptides are distinguishable from sample polypeptides) (paragraph [0117]).
Each protein can be individually labeled with a unique spatial address and conjugated to attachment sites, wherein the unique spatial addresses can be used to quantify the level of that protein in the sample (interpreting the proteins to be distinguishable; a known quantity of first standard polypeptide; a first composite; and a second composite) (paragraphs [0088]; and [0090]).
Figure 13 illustrates that 98% of human proteins can be identified and quantified with 8000 3-mer affinity reagents (interpreted as standard polypeptides having a known quantity) (paragraph [0169]; and Figure 13).
Mallick teaches all of the limitations of the claims. Thus, the claims remain rejected.
The rejection of claims 47, 49-54, 56 and 58- 66 is maintained under 35 U.S.C. 103 as being unpatentable over Mallick et al. (hereinafter “Mallick”) (US Patent Application Publication No. 20210239705, published August 5, 2021; also published as WO2019236749, published December 12, 2019; effective filing date June 6, 2018; of record) in view of Bergo et al. (hereinafter “Bergo”) (US Patent No. 11131674, issued September 28, 2021; also published as US20200011877, published January 9, 2020; effective filing date April 25, 2013; of record) as evidenced by Elahipanah et al. (hereinafter “Elahipanah”) (Bioconjugate Chemistry, 2017, 28, 1422-1433; of record); and Sharpless et al. (hereinafter “Sharpless”) (US Patent No. 7375234, issued May 20, 2088; of record); and Grant, Russell (hereinafter “Grant”) LabCorp, 2019, 1-66).
The teachings of Mallick with regard to claims 47, 49-54, 56 and 58- 66 are described supra.
Mallick et al. do not specifically exemplify additional modifying agents (claim 54, in part); and additional click functional groups (claim 60, in part).
Regarding claim 54 (in part) and 60 (in part), Bergo teaches a composite microarray comprising a three-dimensional solid support and a plurality of reactive microbeads or other reactive microparticles positioned on the solid support in spatially distinct and addressable locations, wherein the individual microbeads, which can be bonded to one or several distinct active agents, serve as the microarray reactive sites, such that the three-dimensional solid support additionally comprises a plurality of analytical sites, wherein an analytical site is fluidically coupled to a reactive site and dimensioned to accept one or more analytes, which are released from the active site (interpreted as attaching to a solid support sample polypeptide composites, coupling standard polypeptide composites, and attachment standard polypeptide composites, claim 47) (col 2, lines 66-67; and col 3, lines 1-10). Bergo teaches that analytes, which have been transferred from the reactive sites into the analytical sites, form compact and generally uniform spots on the solid support and are analyzable by one or several analytical methods, such as mass spectrometry, optical spectroscopy or other methods (col 3, lines 10-14). Bergo teaches that the term “active agent” can refer to a substance of chemical constituent that possesses chemical or biological activity and is capable of reacting with a sample, which is contacted with a microarray, wherein non-limiting examples of the active agents are polypeptides, proteins, antibodies, protein-nucleic acid complexes, etc. (interpreted as sample/standard polypeptides, claim 47) (col 6, lines 43-52). Bergo teaches that the term “bead” and “microbead” refer to microparticles that is approximately spherical; as well as, to microparticles that are not spherical such as microrods or microcubes have an irregular shape; and microparticles that have cavities (col 6, lines 62-65; and col 7, lines 1-7). Bergo teaches that Figure 1 is a schematic depiction of an embodiment composite microarray according to the instant specification, wherein the solid support is a microwell array plate 101 comprising multiple microwells 102, which in an embodiment are arranged into multiple sub-arrays 103, such that microbeads 104 positioned inside the microwells 102 function as the microarray reactive sites, wherein the individual microbeads can be retained inside the microwells by various means (interpreted as attaching composites to a solid support, claim 47) (col 8, lines 1-12; and Figure 1). Figure 1 is shown below:
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Bergo teaches that Figure 2 is a schematic depiction of utilizing the composite microarray, wherein microbeads positioned inside individual microwells on a microwell plate 201 serve as the microarray reactive sites 202; and an analytical site 211 is a section of a microwell, which is not occupied by the bead and fluidically coupled to the microarray reactive site, such that in Step 1: a sample, which is contacted with the microwell plate 201, reaches individual reactive sites 202 through openings into the microwells 203 and reacts with active agents conjugated to the microbeads; and in Step 2: one or more analytes are released from the reacted reactive sites 212 into the analytical sites 211 and become localized in distinct spots 221 on the microwell array plate (col 8, lines 13-28). Figure 2 is shown below:
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Bergo teaches that a "linker" can be directly conjugated to its corresponding bead via a protein, wherein the term linker can also encompass a "spacer", such as a molecular unit positioned between the active agent and the surface of the bead, which serves to provide optimal physical separation between the active agent and the bead; or the linker and the spacer can be separate structures (interpreted as anchor groups, claim 47) (col 9, lines 1-10). Bergo teaches that non-limiting examples of linkers include a sequence of Glycine residues (the so-called poly-Gly linker), an amino acid sequence comprising several Serine and Glycine residues (Ser-Gly linker), an amino acid sequence comprising small and/or hydrophilic amino 15 acids, a sequence comprising single or multiple polyethylene glycol groups (the PEG linker), an aminohexanoic acid (the Ahx linker), etc.; a nucleic acid sequence, such as a DNA sequence (interpreted as anchor groups, claim 47) (col 9, lines 10-20). Bergo teaches that the microwell array plates can also incorporate additional features such as microchannels or other microfluidic elements, various electronic components including microelectrodes, optical barcodes, other forms of barcodes, RFID tags, labels, etc. (col 11, lines 22-26). Bergo teaches that Figure 8A illustrates that a microbead can comprise a solid support 801 and a capture agent 802 bound to the solid support either directly or via an optional linker 803, wherein the solid support 801 can be manufactured from any suitable material, e.g. agarose, polyethylene, polystyrene or a composite material with variable dimensions including a 90 micron diameter TANTAGEL™ bead, wherein multiple molecules including 1016 molecules of the capture agent 802 can be bound to the solid support 801, such that the capture agent 802 is a polypeptide, a protein or an antibody capable of binding to a specific target, which is present or can be present in a sample contacted with the microbead (col 34, lines 63-67; and col 35, lines 1-5). Bergo teaches in Figure 9A, that a microbead can comprise: (i) a solid support 901; (ii) a capture agent 902 bound to the solid support either directly or via an optional linker; and (iii) a reporter agent 903 bound to the solid support via a photolabile linker 904 (col 37, lines 26-30; and Figure 9A). Bergo teaches that reacting the microbead composition with a sample containing a specific target can result in some, but not all of the capture agents binding and retaining the target analyte 905 on the bead (Figs. 9B and 9C) (interpreted as comprising a sample polypeptide composite, claim 47) (col 37, lines 58-61; and Figure 9B). Figures 8A, 8B and 9A-C are shown below:
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Bergo teaches that Figure 32 illustrates a microphotograph showing a bead array, in which 3 to 5 fluorescently labeled beads are placed inside a single microwell on a microwell array plate (interpreted as comprising an attachment standard composite and/or a coupling standard polypeptide composite, claim 47) (col 5, lines 23-25; and Figure 32). Bergo teaches a chemical reaction between bead-conjugated peptide and a sample containing the protein kinase capable of phosphorylating the bead-conjugated peptide (interpreted as a modifying agent; phosphorylation; and adding a post-translational modification, claims 52 and 54) (col 28, lines 40-42). Bergo teaches that the microarrays of the instant disclosure are used for other forms of functional characterization of linkers and/or spacers that provide conjugation of an active agent to a bead (interpreted as coupling standard polypeptide), such that the individual linkers and/or spacers can be assayed to determine their efficiency in the reactions involving the release of an active agent from a bead such as, for example, the release reaction can involve photolysis reaction, hydrolysis reaction, enzyme-catalyzed hydrolysis reaction, etc., wherein a bead library containing an analyte conjugated to the beads via linkers of different structure can be fabricated and screened in a bead array format to determine the efficiency of the analyte release reaction, which can include characterization of the reaction kinetics (interpreted as treating with a modifying agents, claims 47 and 54) (col 28, lines 61-67; and col 29, lines 1-8). Bergo teaches in Figure 7B that a microbead can comprise a single active agent or several distinct active agents 712 conjugated to the bead surface 710 (interpreted as a particle attached to one and only one polypeptide, claim 47) (col 29, lines 37-39; and Figure 7B). Figure 7B is shown below:
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Bergo teaches that the reporter agent 903 and the target analyte 905 have similar ionization efficiency when analyzed by mass spectrometry (interpreting a reporter as coupling standard polypeptide; and as mass spectrometry as quantitatively measuring efficiency of coupling step, claim 47g) (col 38, lines 19-21). Bergo teaches that Figure 19A-F illustrate an binding biological cells to microbeads and analyzing the cells by mass spectrometry (interpreted as detecting sample polypeptides, coupling standard polypeptides, and attachment standard polypeptides; and quantitatively measuring efficiency of coupling by MS, claim 47) (col 4, lines 43-46; and Figure 19). Bergo teaches that FIG. 39C illustrates an MS image of the top row of spots within the reacted microarray, which was visualized in the 10,431 m/z mass channel, wherein a strong peak near 10,431 m/z was detected in the mass spectra acquired from every reactive site of the microarray including both the control cells and the cells treated with etoposide, camptothecin or andrographolide; and no peak at this position was detected in the mass spectra acquired from the blank spots, wherein the experimental data confirms that the three dimensional structure of a microwell array plate efficiently retains individual cells in the spatially distinct regions of the microwell plate even if the cells are only loosely bound to the surface of the plate or detach from the surface (interpreting loosely bound as randomly distributed; interpreting mass spectrometry as detecting sample polypeptides, coupling standard polypeptides, and attachment standard polypeptides; and quantitatively measuring efficiency of coupling step, claims 47, 49 and 52) (col 82, lines 60-67; and col 83, lines 1-6; and Figure 39C). Bergo teaches that bead microarrays can include bacterial growth inhibitors such as sodium azide, protease and nuclease inhibitors, DTT or glycerol for storage below -18oC (interpreting sodium azide as a click reagent, claim 60) (col 26, lines 38-41). Bergo teaches hydrating the bead microarray on a microwell array plate such that the individual microwells will contain sufficient amount of water (interpreting water as a click reagent, claim 60) (col 13, lines 50-52).
Bergo teaches that analytical methods based on mass spectrometry such as MALDI TOF MS use an internal standard (interpreted as a first or second polypeptide standard) (col 53, lines 44-47). Bergo teaches that whole cell MALDI TOF MS spectra were acquired from the control (untreated) and treated cell populations (interpreted as sample poly peptides and as a first or second polypeptide standard, claim 47) (col 78, lines 10-11). Bergo teaches the quantitative detection of the analyte or detection of the presence of the analyte; and the ability to acquire fluorescence spectral data from a single bead can also include the ability to perform quantitative measurement, such as to measure the emission signal intensity as a function of the dye concentration on its carrier bead (interpreted as quantifying an amount of polypeptide; and a known quantity, claim 47) (col 19, lines 52-56; and col 27, lines 48-51).
Bergo teaches that individual microbeads 1705 can be encoded using positional encoding, optical encoding or mass tag encoding including mass tags localized inside the topologically segregated bilayer beads (interpreted as first standard polypeptides and second standard polypeptides, claim 47) (col 60, lines 40-43).
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Moreover, it is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of providing a plurality of microbeads or other reactive microparticles positioned on a solid support as exemplified by Bergo, it would have been prima facie obvious before the effective filing date of the claimed invention to modify the method of forming a polypeptide array including by attaching sample proteins and standard proteins to a solid support including polypeptides bound to particles and/or beads as disclosed by Mallick, to include the regularly shaped and/or irregularly shaped particles comprising reactive microbeads on a solid support including microparticles comprising a single active agent as taught by Bergo with a reasonable expectation of success in expanding the types of particles useful for forming a polypeptide array; and/or to facilitate the detection and identification of proteins in a sample by providing multiple different surfaces including flat surfaces comprising active agents or reagents that can be manipulated into the same imaging plane to improve the quality of the imaging data and/or to reduce noise in the system.
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 November 17, 2025 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) Mallick and Bergo do not teach providing a first composition having two different populations of polypeptides, sample polypeptides and first standard polypeptides, wherein the first standard polypeptides have a known quantity, and wherein the first standard polypeptides are distinguishable from the sample polypeptide including binding anchoring groups to sample polypeptides and first standard polypeptides as recited in claim 47 (Applicant Remarks, pg. 12, last partial paragraph through pg. 13, last full paragraph); and (b) even if it had been obvious for one of ordinary skill in the art to substitute the microbeads of Bergo for the nanobeads of Mallick as suggested by the Examiner, the resulting array would only have sample active agents, such as the polypeptides (from Bergo) bound to the array and there would not be any of the claimed first standard polypeptides bound to the array that are distinguishable from the other sample polypeptides (Applicant Remarks, pg. 13, last partial paragraph; and pg. 14, first partial paragraph).
Regarding (a), please see the Examiner’s response to Applicant’s arguments as discussed supra with regard to Mallick; and as provided in the Office Action mailed August 26, 2025. 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 nonobviousness 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).
Regarding (b), please see the Examiner’s response to Applicant’s arguments as discussed supra with regard to Mallick; and as previously discussed in the Office Action mailed August 26, 2025. MPEP 2123(I) states:
“The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”).
Applicant’s assertion that even if it had been obvious for one of ordinary skill in the art to substitute the microbeads of Bergo for the nanobeads of Mallick as suggested by the Examiner, the resulting array would only have sample active agents, such as the polypeptides (from Bergo) bound to the array and there would not be any of the claimed first standard polypeptides bound to the array that are distinguishable from the other sample polypeptides, is not found persuasive. As noted supra, the references are relevant for all they teach; and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art. Applicant’s argument is unclear. It is unclear to the Examiner why there would not be any of the claimed first standard polypeptides bound to the array that are distinguishable from the other sample polypeptides. Mallick clearly teaches sample proteins, protein standards, internal standards, protein controls, labeled proteins, tagged proteins, nanoballs, nanobeads, linkers, barcodes, nucleic acids, affinity reagents, modified solid supports having addressable locations, etc. (see, discussion supra).
Bergo teaches:
An active agent conjugated to a bead, wherein active agents include proteins and polypeptides (interpreted as standard polypeptides and sample polypeptides) (col 6, lines 44-52; and col 8, lines 65-66).
Arrays with addressable locations, linkers, spacers, microbeads, and samples linked to functionalized beads that can be quantitatively detected by mass spectrometry including using internal standards (interpreted as standard polypeptides of known quantity) (col 53, lines 44-47).
Photolabile peptide bead mass tags identifiable by mass spectrometry (interpreted as standards attached to polypeptides) (col 91, lines 14-19).
The individual microbeads 1705 can be encoded using positional encoding, optical encoding or mass tag encoding including mass tags localized inside the topologically segregated bilayer beads (interpreted as standards attached to polypeptides) (col 60, lines 40-43).
A solid support comprising a plurality of analytical sites fluidically coupled to a reactive site, wherein analytes that have been transferred from the reactive sites into the analytical sites, form compact and generally uniform spots on the solid support and are analyzable by one or several analytical methods, such as mass spectrometry or other optical spectroscopy or other methods (interpreted as attaching the anchoring groups to a solid support; and determining the quantity of standard polypeptides by MS or other methods) (col 3, lines 5-15).
Screening for post-translational modifications and obtain sequence information by fragmentation of analytes released from individual beads (col 2, lines 57-59).
Applicant’s argument is unclear to the Examiner. It is unclear why would the combination of Mallick and Bergo would prevent an array of microbeads of Bergo from comprising both sample polypeptides and standard polypeptides. The Examiner contends that the combined references of Mallick and Bergo teach all of the limitations of the claims. Thus, the claims remain rejected for the reasons of record.
The Examiner suggests that Applicant amend claim 47 to include specific limitations such as, for example, directed to specific anchoring groups (e.g., unique 3-mer peptides, etc.), specific standards, specific samples, specific methods of combining, specific methods of attaching, etc. to clarify the novelty of the instant invention.
Conclusion
Claims 47, 49-54, 56 and 58-66 are rejected.
THIS ACTION IS MADE FINAL. 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.
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/AMY M BUNKER/Primary Examiner, Art Unit 1684