DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the species election of binding assay in claim 86, of equilibrium binding assay in claim 87, and of flow cell in claim 95 in the reply filed on 02/17/2026 is acknowledged. Claim 94 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
A first office action on the merits of claims 82-93 & 95-101 is set forth herein and claim 94 is withdrawn from consideration.
Information Disclosure Statement
Only the abstracts of the references in the IDS submitted on 02/23/2023 & 08/11/2025 that are lined through, under the foreign patent documents section, were considered because an English copy of the full documents were not provided.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 88-90 & 92 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 88, the recitation of “subsequent to (c), performing an additional assay on the polypeptide” in lines 1-2 of the claim is unclear. Claim 82, from which claim 88 depends on, recites a step (c) of expressing the polypeptide followed by a step (d) of performing an assay on the polypeptide. Therefore, it is unclear how an additional (second) assay on the polypeptide can be performed subsequent to (after) step (c) but before an assay (original first assay) is performed on the polypeptide in step (d) as recited in claim 82, from which claim 88 depends from.
Claims 89, 90, & 92 are rejected due to their dependence on claim 88.
Claim Rejections - 35 USC § 103
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.
Claim(s) 82-84, 86, 88, 90, 92, 93, & 95-101 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan (Gan, Yamanaka, Kojima, & Nakano; Biotechnol. Prog., Vol. 24, pages 1107-1114, September 2008), as cited in the IDS dated 02/23/2023, in view of Green (United States Patent Application Publication US 2015/0018236 A1), as cited in the IDS dated 02/23/2023.
Regarding claim 82, Gan teaches a method for coupling protein to its coding DNA on magnetic microbeads comprising biotinylated reverse primers (immobilized oligonucleotides) linked to beads (solid surface) (providing a solid surface comprising a plurality of immobilized oligonucleotides) and nucleic acid templates that encode for proteins (library of nucleic acids encoding a plurality of polypeptides), amplifying the nucleic acid templates (library of nucleic acids encoding polypeptides) with the bead linked reverse primer (immobilized oligonucleotides) (generating a process nucleic acid molecule suing an immobilized oligonucleotide and a nucleic acid molecule wherein the process nucleic acid encodes a polypeptide and is immobilized on the solid surface), then expressing proteins in an emulsion creating a bead-DNA-protein complex (expressing the polypeptide from the processed nucleic acid molecule), labeling the bead-DNA-protein complexes with a fluorescent labeled antibody and then assaying through flow cytometry (performing an assay on the polypeptide to identify one or more properties of the polypeptide), followed by an additional round of screening comprising selection and sequencing of samples (performing an assay on the polypeptide and sequencing performed on the same bead system instrument) (abstract lines 1-16; pg. 1108 column 1 1st full paragraph lines 1-21; pg. 1108 column 2 1st full paragraph lines 1-14; pg. 1109 paragraph bridging column 1 & 2 lines 1-4; pg. 1109 column 2 1st full paragraph lines 1-17; pg. 1110 column 2 1st full paragraph lines 1-18; pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 1). Gan also teaches that the proteins are directly linked on the ends of the nucleic acid templates linked to beads (processed nucleic acid) and thus both genes and proteins are displayed in a gene protein complex (linking properties of polypeptide to processed nucleic acid) (pg. 1108 column 1 1st full paragraph lines 3-9).
Gan does not teach that the process nucleic acid molecule is specifically sequence to identify a processed nucleic acid molecule sequence.
Green teaches a method for screening and identifying polypeptides that provide a biological response in a living cell comprising the use of an emulsion system comprising obtained a population of nucleic acid molecules comprising sequences that encode different polypeptides (nucleic acid molecules encoding a plurality of polypeptides), incubating the encoding nucleic acid molecules (processing nucleic acid molecule) under conditions that permit expression of polypeptides (expressing the polypeptide from processed nucleic acid molecule), and testing cells for biological response to polypeptides and isolating encoding nucleic acid molecules associated with polypeptides to analyze the biologically active polypeptide in which candidate polypeptides remain associated with their coding nucleic acid sequences (processed nucleic acid molecules) through beads and emulsion system so that active polypeptides can be identified by sequencing of the coding nucleic acid sequences (sequencing processed nucleic acid molecules to identify a processed nucleic acid molecule sequence and linking one or more properties of the polypeptide to the process nucleic acid molecule sequence) (paragraph [0008] lines 1-14; paragraph [0011] lines 1-18; paragraph [0111] lines 1-9). Green also teaches that this method provides the ability to effectively screen a vast diversity of sequences and a highly efficient method to identify polypeptides (paragraph [0008] lines 1-4; paragraph [0111] lines 21-27).
Gan and Green are considered to be analogous to the claimed invention because they are all in the same field of analysis and identification of polypeptides through nucleic acid libraries. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of coupling protein to its coding DNA on magnetic microbeads comprising labeling and assaying bead-DNA-protein complexes through flow cytometry, followed by an additional round of screening comprising selection and sequencing of samples in Gan to incorporate the specific sequencing of coding nucleic acid sequences (processed nucleic acid molecules) to identify polypeptides and link one or more properties of a polypeptide to the processed nucleic acid molecule sequence as taught in Green because Green teaches that doing so would provide a highly efficient method to identify polypeptides and effectively screen a vast amount of sequences.
Regarding claim 83, Gan teaches hybridizing biotinylated reverse primers (immobilized oligonucleotides) linked to beads (solid surface) to nucleic acid templates that encode for proteins (library of nucleic acids encoding a plurality of polypeptides) to amplify the nucleic acid templates (nucleic acid molecules) (hybridizing an immobilized oligonucleotide to a nucleic acid molecule) (pg. 1108 column 1 1st full paragraph lines 1-21; pg. 1109 column 2 1st full paragraph lines 1-17; pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 1).
Regarding claim 84, Gan teaches that the proteins are directly linked on the ends of the nucleic acid templates linked to beads (processed nucleic acid) (pg. 1108 column 1 1st full paragraph lines 3-9).
Regarding claim 86, Gan teaches labeling and assaying the bead-DNA-protein complexes through flow cytometry comprises assaying and determining the relative binding activity (assay comprises a binding assay) (pg. 1110 column 2 1st full paragraph lines 1-18).
Regarding claim 88, Gan teaches screening the bead-DNA-protein complexes with flow cytometry in two rounds (second round of flow cytometry screening assay comprises performing an additional assay on the polypeptide) (pg. 1111 paragraph bridging column 1 & 2 lines 20-34).
Regarding claim 90, Gan teaches screening the bead-DNA-protein complexes with flow cytometry in two rounds (first and second round of flow cytometry screening assay (assay and additional assay) performed sequentially) (pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 5).
Regarding claim 92, Gan teaches screening the bead-DNA-protein complexes with flow cytometry in two rounds in which the second round comprised using a lower amount of input nucleic acid template, different gating, and selection of 13 specific samples for further sequencing (first and second round of flow cytometry screening assay (assay and additional assay) are performed under varying conditions) (pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 5).
Regarding claim 93, Gan teaches labeling and assaying the bead-DNA-protein complexes with a fluorescent labeled antibody through flow cytometry (performing the assay comprises fluorescent imaging) (pg. 1110 column 2 1st full paragraph lines 1-18; pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 4; Figure 5).
Regarding claim 95, Gan teaches labeling and assaying the bead-DNA-protein complexes with a fluorescent labeled antibody through flow cytometry (solid surface comprises a flow cell) (pg. 1110 column 2 1st full paragraph lines 1-18; pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 4; Figure 5).
Regarding claim 96, Gan teaches that around 0.5x106 nucleic acid molecules were used a the nucleic acid templates (library of nucleic acids) for the different mutants (library of nucleic acids comprises at least 1x105 nucleic acid variants) (pg. 1110-1111 paragraph bridging pg. 1110 & 1111 lines 10-27).
Regarding claim 97, Gan teaches the protein (polypeptide) comprises antibodies (plurality of polypeptides comprises a library of antibodies or binding fragments) (pg. 1109 paragraph bridging column 1 & 2 lines 1-4; pg. 1109 column 2 1st full paragraph lines 1-5; Figure 1).
Regarding claim 98, Green teaches the library of polypeptides comprises antigens (plurality of polypeptides comprises a library of antigens) (paragraph [0047] lines 1-4 & 19-21).
Regarding claim 99, Gan teaches a method for coupling protein to its coding DNA on magnetic microbeads comprising biotinylated reverse primers (immobilized oligonucleotides) linked to beads (solid surface) (providing a solid surface comprising a plurality of immobilized oligonucleotides) and nucleic acid templates that encode for proteins (library of nucleic acids encoding a plurality of polypeptides), amplifying the nucleic acid templates (library of nucleic acids encoding polypeptides) with the bead linked reverse primer (immobilized oligonucleotides) (generating a process nucleic acid molecule suing an immobilized oligonucleotide and a nucleic acid molecule wherein the process nucleic acid encodes a polypeptide and is immobilized on the solid surface), then expressing proteins in an emulsion creating a bead-DNA-protein complex (expressing the polypeptide from the processed nucleic acid molecule), labeling the bead-DNA-protein complexes with a fluorescent labeled antibody and then assaying through flow cytometry (performing an assay on the polypeptide to identify one or more properties of the polypeptide), followed by an additional round of screening comprising selection and sequencing of samples (performing an assay on the polypeptide and sequencing performed on the same bead system instrument) (abstract lines 1-16; pg. 1108 column 1 1st full paragraph lines 1-21; pg. 1108 column 2 1st full paragraph lines 1-14; pg. 1109 paragraph bridging column 1 & 2 lines 1-4; pg. 1109 column 2 1st full paragraph lines 1-17; pg. 1110 column 2 1st full paragraph lines 1-18; pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 1).
Gan does not teach that the process nucleic acid molecule is specifically sequence to identify a processed nucleic acid molecule sequence.
Green teaches a method for screening and identifying polypeptides that provide a biological response in a living cell comprising the use of an emulsion system comprising obtained a population of nucleic acid molecules comprising sequences that encode different polypeptides (nucleic acid molecules encoding a plurality of polypeptides), incubating the encoding nucleic acid molecules (processing nucleic acid molecule) under conditions that permit expression of polypeptides (expressing the polypeptide from processed nucleic acid molecule), and testing cells for biological response to polypeptides and isolating encoding nucleic acid molecules associated with polypeptides to analyze the biologically active polypeptide in which candidate polypeptides remain associated with their coding nucleic acid sequences (processed nucleic acid molecules) through beads and emulsion system so that active polypeptides can be identified by sequencing of the coding nucleic acid sequences (sequencing processed nucleic acid molecules to identify a processed nucleic acid molecule sequence and linking one or more properties of the polypeptide to the process nucleic acid molecule sequence) (paragraph [0008] lines 1-14; paragraph [0011] lines 1-18; paragraph [0111] lines 1-9). Green also teaches that this method provides the ability to effectively screen a vast diversity of sequences and a highly efficient method to identify polypeptides (paragraph [0008] lines 1-4; paragraph [0111] lines 21-27).
Gan and Green are considered to be analogous to the claimed invention because they are all in the same field of analysis and identification of polypeptides through nucleic acid libraries. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of coupling protein to its coding DNA on magnetic microbeads comprising labeling and assaying bead-DNA-protein complexes through flow cytometry, followed by an additional round of screening comprising selection and sequencing of samples in Gan to incorporate the specific sequencing of coding nucleic acid sequences (processed nucleic acid molecules) to identify polypeptides as taught in Green because Green teaches that doing so would provide a highly efficient method to identify polypeptides and effectively screen a vast amount of sequences.
Regarding claim 100, Gan teaches assaying the bead-DNA-protein complexes with an additional round of screening through flow cytometry comprising selection and sequencing of samples (performing an assay on the polypeptide and sequencing performed on the same bead system instrument) (pg. 1111 paragraph bridging column 1 & 2 lines 20-34; Figure 1).
Regarding claim 101, Green teaches sequencing was performed with Illumina MiSeq nest-generation sequencing instrument (sequencing is performed on an instrument configured to perform sequencing by synthesis) (paragraph [0375] lines 1-3).
Claim(s) 85 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan (Gan, Yamanaka, Kojima, & Nakano; Biotechnol. Prog., Vol. 24, pages 1107-1114, September 2008), as cited in the IDS dated 02/23/2023, and Green (United States Patent Application Publication US 2015/0018236 A1), as cited in the IDS dated 02/23/2023 as applied to claims 82-84, 86, 88, 90, 92, 93, & 95-101 above, and further in view of Khatwani (Khatwani et al.; Bioorganic & Medicinal Chemistry, Vol. 20, pages 4532-4539, May 2012).
The teachings of Gan and Green with respect to claims 82 & 84 are discussed above.
Regarding claim 85, Gan and Green does not teach covalently linking the polypeptide to the processed nucleic acid molecule.
Khatwani teaches a method of covalently linking protein (polypeptide) to oligodeoxynucleotides (nucleic acid molecules) through a click reaction (abstract lines 1-9; pg. 4534 column 2 1st full paragraph lines 1-10). Khatwani also teaches that this method is a simple and versatile method to covalently link proteins to nucleic acids compared to methods comprising copper (abstract lines 13-14).
Gan, Green, and Khatwani are considered to be analogous to the claimed invention because they are all in the same field of linking polypeptides to nucleic acids. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of linking proteins (polypeptides) on the ends of the nucleic acid templates linked to beads (processed nucleic acid) in Gan to incorporate the covalently linking the proteins to nucleic acids as taught in Khatwani because Khatwani teaches that doing so would provide a simple and versatile method to covalently link proteins to nucleic acids.
Claim(s) 87 & 91 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan (Gan, Yamanaka, Kojima, & Nakano; Biotechnol. Prog., Vol. 24, pages 1107-1114, September 2008), as cited in the IDS dated 02/23/2023, and Green (United States Patent Application Publication US 2015/0018236 A1), as cited in the IDS dated 02/23/2023 as applied to claims 82-84, 86, 88, 90, 92, 93, & 95-101 above, and further in view of Hulme (Hulme & Trevethick; British Journal of Pharmacology, Vol. 161, pages 1219-1237, February 2010), as cited on the IDS dated 02/23/2023.
The teachings of Gan and Green with respect to claim 82 are discussed above.
Regarding claim 87, Gan and Green does not teach that the binding assay comprises an equilibrium binding assay.
Hulme teaches equilibrium binding assays for analysis of ligand binding under equilibrium conditions comprising strategies and experimental designs to appropriately measure binding at equilibrium (abstract lines 1-12; pg. 1220 column 1 3rd full paragraph lines 1-13; pg. 1220 column 2 1st full paragraph lines 1-10). Hulme also teaches that equilibrium binding assays are a straightforward method to analyze data and extract quantitative estimates of rate constant, affinity constants, and cooperativities (pg. 1220 column 1 3rd full paragraph lines 1-13).
Gan, Green, and Hulme are considered to be analogous to the claimed invention because they are all in the same field of analyzing binding activity of polypeptides. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of labeling and assaying the bead-DNA-protein complexes through flow cytometry comprises assaying and determining the relative binding activity in Gan to incorporate the use of an equilibrium binding assay as taught in Hulme because Hulme teaches that doing so would provide a straightforward method to analyze quantitative estimates of rate constant, affinity constants, and cooperativities.
Regarding claim 91, Hulme teaches particular set of equilibrium binding assay conditions ma lead to an upper limit on apparent affinity measured and that performing these binding assays at different temperatures to further analyze binding (assay performed under varying conditions) (abstract lines 7-9; pg. 1235 column 1 3rd full paragraph lines 1-11).
Claim(s) 89 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan (Gan, Yamanaka, Kojima, & Nakano; Biotechnol. Prog., Vol. 24, pages 1107-1114, September 2008), as cited in the IDS dated 02/23/2023, and Green (United States Patent Application Publication US 2015/0018236 A1), as cited in the IDS dated 02/23/2023 as applied to claims 82-84, 86, 88, 90, 92, 93, & 95-101 above, and further in view of Elshal (Elshal & McCoy; Methods, Vol. 38, pages 317-323, November 2005).
The teachings of Gan and Green with respect to claims 82 & 88 are discussed above.
Regarding claim 89, Gan teaches assaying the bead-DNA-protein complexes with flow cytometry in two rounds (second round of flow cytometry screening assay comprises performing an additional assay on the polypeptide) (pg. 1111 paragraph bridging column 1 & 2 lines 20-34).
Gan and Green does not teach that the assay and the additional assay are performed simultaneously.
Elshal teaches a method of multiplex bead array assay for the detection of multiple target proteins in 96-well plate formats enabling simultaneous measurement and assaying of multiple target proteins comprising a cytometric (flow cytometry) array (assay and additional assay are performed simultaneously) (abstract lines 1-10; pg. 320 column 1 1st full paragraph lines 1-5; pg. 320 column 1 2nd full paragraph lines 1-8; pg. 320 column 1 3d full paragraph lines 1-3; pg. 323 column 1 1st full paragraph lines 1-5). Elshal also teaches that this multiplex bead array assay provides a high throughput analysis of numerous analytes comprising protein analytes (abstract lines 3-4 & 8-10).
Gan, Green, and Elshal are considered to be analogous to the claimed invention because they are all in the same field of assaying polypeptides through flow cytometry. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of assaying the bead-DNA-protein complexes with flow cytometry in two rounds (assay and additional assay) in Gan to incorporate the performing these rounds of assays simultaneously as taught in Elshal because Elshal teaches that doing so would provide a high throughput analysis of numerous analytes comprising protein analytes.
Conclusion
Claims 82-93 & 95-101 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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