DETAILED ACTION
Disposition of Claims
Claims 1-6, 13, 15-19, 32-38, and 47 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20250283882A1, Published 09/11/2025.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/04/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
The drawings are objected to because of the reference to color without a petition having been submitted and accepted to allow color drawings. See e.g. figure legends for Figs. 1-5 and 8. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The specification is objected to because of the following informalities: the use of hyperlinks or ]other browser-executable links is not permitted. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See ¶[0007] “www.cdc.gov/coronavirus/2019-ncov/variants/”; ¶[0181] “https://www.cdc.gov/coronavirus/2019-ncov/variants/”.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet preferably within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of implied phraseology (e.g. “The present disclosure relates…”).
Claim Objections
Claim 1 is objected to because of the following informalities: the definition of “SARS-CoV-2” has not been provided. For clarity, the first recitation of an abbreviation in the claim set should be preceded by its unabbreviated form (e.g. “…presence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in a sample…”). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 1, 6, 19, and 33 and dependent claims 2-5, 13, and 15-18 thereof 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.
The term “specific for” in claim 1 is a relative term which renders the claim indefinite. The term “specific for” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While the specification at ¶[0059] defines a “target-specific binding peptide”, this is not the same as the limitations or phrasing utilized in claim 1, part i). The claim does not specify the SARS-CoV-2 antigen or epitope bound by the nanobody in part i). In in part iii), this “specific binding” usage benefits from the definition at ¶[0059] as it is in relation to the “target-specific binding peptide”. However, in relation to the nanobody of part i) it is unclear if it only recognizes mature SARS-CoV-2 virions, fragments of SARS-CoV-2 proteins, or other aspects of the virus. The claim does not clarify the binding affinity or selectivity required for the binding to be “specific”, the permissible degree of cross-reactivity with other coronaviruses or viral antigens, or the assay conditions under which “specificity” is determined.
Furthermore, in part iii), the antecedent basis of “target-specific binding peptides” in line 13 should be clarified as in part iii), lines 12-13 refers to “one or more target-specific binding peptides”[emphasis added].
Claims 6, 19, and 33 are also rejected for similar reasoning for claiming a “nanobody” with “specific” binding.
For at least these reasons, claims 1, 6, 19, and 33 are rejected on the grounds of being indefinite. Claims 2-5, 13, and 15-18 are also rejected for depending upon claims 1, 6, 19, or 33, but not clarifying the metes and bounds of claims 1, 6, 19, or 33.
Claims 2 and 34 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.
Claims 2 and 34 recite that the DNA nanostructure is selected from the group consisting of: a single-stranded DNA molecule, a three-helix bundle, a four-helix bundle, a six-helix bundle, a triangular DNA origami structure, a tetrahedral wireframe cage, a block-like origami cuboid, reconfigurable tweezers, double crossover tiles, branched three-way junctions, and a three-legged stool. The metes and bounds of some of these limitations, namely “reconfigurable tweezers”, “three-legged stool”, and “block-like origami cuboid”, are unclear. The claims does not define what structural features are required for a DNA nanostructure to be “reconfigurable tweezers”, including what elements form the tweezer arms, what conformational change is required, what stimulus or condition causes reconfiguration, or what degree of movement or tunability is encompassed. The claim also does not define what structural features are required of a “three-legged stool”, including what DNA elements correspond to the “legs”, whether a central hub or seat-like region is required, and how the structure is distinguished from a branched three-way junction or other branched DNA scaffold. Similarly, it is not clear what structural features are required to be “block like origami cuboid”, including what degree of cuboid geometry is required, what makes the feature “block-like”, whether the particular dimensions, faces, layers, regions, or scaffold/staple arrangements are required, and how this structure is distinguishable from other 3-D DNA origami structures.
For at least these reasons, the metes and bounds of claims 2 and 34 are unclear.
Claim 6 is 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.
Claim 6 is drawn to wherein the capture molecule comprises a nanobody that specifically binds to the N-terminal domain of the SARS-CoV-2 spike protein. However, it is not clear if Applicant is claiming a specific functional region of SARS-CoV-2 (“NTD”) that comprises amino acid residues 14-306 of the S1 subunit of the Spike protein that facilitates viral entry, modulates immune evasion, and serves as a significant target for neutralizing antibodies, or if Applicant is claiming any arbitrary N-terminal region that includes amino acids not within the functional NTD. One suggestion is to specifically define the regions that are encompassed by the limitation so it is clear what amino acids of the S protein are, or are not, included in this claim.
For at least these reasons, the metes and bounds of claim 6 are unclear.
Claim 32 and dependent claims 33-38 thereof 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.
Claim 32 at lines 8-9 and 10 comprise the limitation of “V-AB complex”, and at line 11 recites “the C-AB complex”, making the antecedent basis of the limitation of “the C-AB complex” unclear. As claim 32 appears to be drawn to the reverse configuration of independent claim 1, it appears as though “V-AB complex” is likely meant to be “the C-AB complex” in order to differentiate from the nanobody-virus complex of claim 1 (“V-AB complex”) versus the apparent DNA-peptide hybrid-nanostructure-virus complex of claim 32 (“C-AB complex”). Regardless, the metes and bounds of what is being claimed in claim 32 is unclear.
For at least these reasons, claim 32 is rejected on the grounds of being indefinite. Claims 33-38 are also rejected for depending upon claim 32, but not clarifying the metes and bounds of claim 32.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a method of detecting the presence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in a sample from a subject, the method comprising:
i) contacting the sample to a capture molecule, the capture molecule comprising a nanobody specific for SARS-CoV-2, wherein the capture molecule is linked to a solid support;
ii) incubating the sample in the presence of the capture molecule under conditions for SARS-CoV-2 in the sample to bind to the capture molecule, thereby forming a “V-AB” complex;
iii) contacting the V-AB complex with a detection molecule under conditions to allow the detection molecule to bind the V-AB complex, the detection molecule comprising a DNA-peptide hybrid molecule, the DNA-peptide hybrid molecule comprising a DNA nanostructure chemically linked to one or more target-specific binding peptides, wherein the target-specific binding peptides specifically binds SARS-CoV-2;
iv) detecting the presence of SARS-CoV-2 in the sample based on the presence of the bound detection molecule.
Further limitations on the method of claim 1 are wherein the DNA nanostructure of the detection molecule comprises one of: a single-stranded DNA molecule, a three-helix bundle, a four-helix bundle, a six-helix bundle, a triangular DNA origami structure, a tetrahedral wireframe cage, a block-like origami cuboid, reconfigurable tweezers, double crossover tiles, branched three-way junctions, and a three-legged stool (claim 2); wherein the DNA nanostructure is linked to more than one target-specific binding peptide (claim 3); wherein the DNA nanostructure is linked to three target-specific binding peptides (claim 4); wherein one or more of the target-specific binding peptides comprises LCB1 (claim 5); wherein the capture molecule comprises a nanobody that specifically binds to the N-terminal domain of the SARS-CoV-2 spike protein (claim 6); wherein the DNA nanostructure comprises a single stranded DNA molecule (claim 13), wherein detection comprises a primer exchange reaction (PER)(claim 15), further comprising contacting the detection molecule with fluorescently labeled oligonucleotides that hybridize with the product of the PER (claim 16); wherein the target-specific binding peptide binds SARS-CoV-2 alpha, beta, gamma, and delta spike protein variants (claim 17); and wherein the method further comprises treating the subject based on the detection of SARS-CoV-2 in the sample (claim 18).
Claim 19 is drawn to a kit for detecting the presence of SARS-CoV-2 in a sample comprising:
i) a capture molecule linked to a solid support, wherein the capture molecule is a nanobody specific for SARS-CoV-2;
ii) a detection molecule comprising a DNA nanostructure linked to one or more target-specific binding peptides, wherein the one or more target-specific binding peptides bind SARS-CoV-2.
Claim 32 is drawn to a method of detecting the presence of SARS-CoV-2 in a sample from a subject, the method comprising:
i) contacting the sample to a capture molecule, the capture molecule comprising a DNA-peptide hybrid molecule, the DNA-peptide hybrid molecule comprising a DNA nanostructure chemically linked to one or more target-specific binding peptides, wherein the capture molecule is linked to a solid support;
ii) incubating the sample in the presence of the capture molecule under conditions for SARS-CoV-2 in the sample to bind to the capture molecule, thereby forming a “V-AB” complex;
iii) contacting the V-AB complex with a detection molecule under conditions to allow the detection molecule to bind the C-AB complex, the detection molecule comprising a SARS-CoV-2 specific binding molecule (SBM);
iv) detecting the presence of SARS-CoV-2 in the sample based on the presence of the bound detection molecule.
Further limitations on the method of claim 32 are wherein the detection molecule comprises a nanobody specific for SARS-CoV-2 (claim 33); wherein the DNA nanostructure is selected from the group consisting of: a single-stranded DNA molecule, a three-helix bundle, a four-helix bundle, a six-helix bundle, a triangular DNA origami structure, a tetrahedral wireframe cage, a block-like origami cuboid, reconfigurable tweezers, double crossover tiles, branched three-way junctions, and a three-legged stool (claim 34); wherein the DNA nanostructure is linked to more than one target-specific binding peptide (claim 35); wherein the DNA nanostructure is linked to three target-specific binding peptides (claim 36); wherein one or more of the target specific binding peptides are LCB1 (claim 37); wherein the capture molecule binds to the receptor binding domain of the SARS-CoV-2 spike protein (claim 38).
Claim 47 is drawn to a kit for detecting the presence of SARS-CoV-2 in a sample comprising:
i) a capture molecule comprising a DNA nanostructure linked to one or more target-specific binding peptides, wherein the one or more target-specific binding peptides bind SARS-CoV-2, wherein the capture molecule is linked to a solid support;
ii) a detection molecule comprising a SARS-CoV-2 specific antibody (SAB).
Claim Rejections - 35 USC § 112(a); First Paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 13, 15-19, 32-38, and 47 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
The written description requirement is separate and distinct from the enablement requirement. To satisfy the written description requirement, the specification must reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention as of the filing date. Possession may be shown by a description of the complete structure of the claimed invention, a representative number of species falling within the scope of a claimed genus, or relevant identifying characteristics sufficient to show that the inventor had possession of the claimed subject matter.
Claims 1 and 19 recite a method or kit for detecting SARS-CoV-2 using a capture molecule comprising “a nanobody specific for SARS-CoV-2” and a detection molecule comprising a DNA nanostructure linked to one or more target-specific binding peptides that bind SARS-CoV-2. Claims 32 and 47 recite the reverse orientation, in which the capture molecule comprises a DNA-peptide hybrid molecule, and the detection molecule comprises a SARS-CoV-2 specific binding molecule or SARS-CoV-2 specific antibody. The dependent claims further recite specific assay components, including DNA nanostructure formats, multivalent peptide display, LCB1, NTD binding, RBD binding, PER, variant binding, and treating a subject based on the detection of SARS-CoV-2.
The specification describes a DLISA concept using a nanobody coating on a plate as a capture domain and a mini-binder conjugated with DNA-fluorophore as an amplified signal probe (¶[0031][0183]). The specification states that the nanobody capture domain possesses high-affinity binding with the N-terminal domain of spike protein, whereas LCB1 targets the RBD domain of spike (¶[0183]). The specification further states that LCB1 can be conjugated with ssDNA or attached to a trivalent nanostructure, and that the construct is expected to enhance sensitivity and specificity in identifying SARS-CoV-2 variants of concern (¶[0183]). The specification also describes LCB1 as a peptide having the sequence DKEWILQKIYEIMRLLDELGHAEASMRVSDLIYEFMKKGDERLLEEAERLLEEVER (SEQ ID NO: 2)(¶[0008]). The specification states that target-specific binding peptides may be chemically linked to DNA nanostructures, that more than one target-specific binding peptide may be linked to a single DNA nanostructure, and that LCB1 is a target-specific binding peptide (¶[0008-0010]). The specification further states that capture molecules may be antibodies, Fabs, or nanobodies, and identifies exemplary nanobodies by reference to Schoof et al (¶[0060]).
However, the scope of claims 1-6, 13, 15-19, 32-38, and 47 is not limited to the embodiments described in the specification. The claims broadly encompass any nanobody specific for any SARS-CoV-2 variant used as the capture molecule, any SARS-CoV-2 specific binding molecule or SARS-CoV-2 specific antibody used as the detection molecule, and any target-specific binding peptide that binds to any aspect SARS-CoV-2 when chemically linked to the claimed DNA nanostructure. The claims also encompass multiple DNA scaffold formats, a variety of target antigens or epitopes on SARS-CoV-2, a variety of SARS-CoV-2 variants and mutants, and different assay orientations. The specification does not describe a sufficient number of species representative of that scope.
The claimed nanobodies and SARS-CoV-2 specific binding molecules are defined, at least in part, by the recited function of binding “SARS-CoV-2.” However, the specification does not describe a representative number of nanobodies falling within the claimed scope, as the specification does not provide the amino acid sequences, CDR sequences, epitope definitions, binding footprints, or structural features common to nanobodies that are “specific for SARS-CoV-2” and suitable for use as the claimed capture molecule, nor does the specification note which epitope(s) on SARS-CoV-2 are targeted by the binding molecules and if said binding molecules are cross-reactive for a variety of SARS-CoV-2 variants. The disclosure of a desired binding property, without a sufficient description of the antibodies or nanobodies encompassed by the claims, does not demonstrate possession of the full scope of the claimed genus.
The specification also does not describe a representative number of SARS-CoV-2 specific binding molecules or SARS-CoV-2 specific antibodies for the reverse assay orientation of claims 32-38 and 47. Claim 32 recites a detection molecule comprising a SARS-CoV-2 specific binding molecule, while claim 47 recites a detection molecule comprising a SARS-CoV-2 specific antibody. The specification describes the general idea of a SARS-CoV-2 sandwich assay, but does not identify structural features common to the broader class of SARS-CoV-2 specific binding molecules or antibodies that would allow one skilled in the art to recognize which additional molecules fall within the scope of the claims and function in the claimed detection format.
The specification describes LCB1 as an identified SARS-CoV-2 mini-binder and provides SEQ ID NO: 2 (¶[0158][0008]). However, claims 1, 19, 32, and 47 are not limited to LCB1, as the claims also encompass additional target-specific binding peptides that bind SARS-CoV-2. The specification fails to describe representative SARS-CoV-2 binding peptides across that broader genus, and also does not identify structural features common to SARS-CoV-2 binding peptides that would allow one skilled in the art to recognize additional members of the genus. Instead, one skilled in the art would be required to select additional binding peptides not described in the specification and determine whether those additional peptides bind SARS-CoV-2 and function in the claimed DNA-peptide hybrid assay.
Claims 2 and 34 further recite that the DNA nanostructure may be selected from several different DNA structures, including a single-stranded DNA molecule, helix bundles, DNA origami structures, a tetrahedral wireframe cage, a block-like origami cuboid, reconfigurable tweezers, double crossover tiles, branched three-way junctions, and a three-legged stool. The specification identifies several proposed or exemplary DNA structures in the figures and describes that proteins and peptides can be attached to certain helix ends or nick points (¶[0015][0161-0163]; Fig. 3). The specification also states that the inventors “will primarily focus on simpler DNA nanostructures” and “will test structures like four- and six-helix bundles,” three-way tile junctions, tetrahedral cages, and other wireframe assemblies (¶[0162]).
However, the claims are not limited to the DNA structures actually shown with SARS-CoV-2 binding peptides in a working diagnostic assay. The claims encompass materially different DNA-peptide hybrid constructs that differ in scaffold shape, rigidity, attachment position, peptide copy number, and display geometry. The specification does not describe representative examples showing possession of those different scaffold-peptide combinations in the claimed SARS-CoV-2 detection methods and kits. The presence of a list of possible DNA structures does not reasonably convey possession of the broader group of functional SARS-CoV-2 detection constructs recited in the claims.
The specification describes preliminary data in which LCB1 was conjugated to DNA handles and incorporated into three- and four-helix DNA bundles (Figs. 3, 5; ¶[0165]). The specification states that the monomeric LCB1-DNA conjugate bound equally well as the protein alone and that a trivalent DNA-peptide hybrid molecule bound RBD better than monomeric LCB1 (¶[0165]). However, the claims are not limited to three- and four-helix bundle LCB1 constructs, as the claims also encompass other DNA nanostructures and other SARS-CoV-2 binding peptides, including constructs having different attachment sites, different geometries, and different capture/detection roles in the assay. The specification does not describe representative examples across that broader scope or identify structural features sufficient to show possession of the broader group of constructs.
Claim 17 further recites that the target-specific binding peptide binds SARS-CoV-2 alpha, beta, gamma, and delta spike protein variants, and the specification identifies certain Alpha, Beta, Gamma, and Delta mutations and variants (¶[0005][0025][0075-0078]; Fig. 13). The specification also states that preliminary data show the mini-binder has high-affinity binding with spike protein and variants (¶[0181]). However, claim 17 is not limited to the disclosed mini-binder; instead, claim 17 broadly encompasses any target-specific binding peptide that binds all four recited variant spike proteins. The specification does not describe representative peptides across that scope, identify variant-specific binding data for the full claimed genus, or describe structural features that distinguish peptides that bind all four variants from peptides that do not.
Claim 18 further recites treating the subject based on the detection of SARS-CoV-2 in the sample. The specification defines “treating” generally as alleviating symptoms, eliminating causation of symptoms, preventing or slowing appearance of symptoms, or reversing progression or severity of a named disease or disorder (¶[0074]). However, the specification does not describe a treatment method for COVID-19 that is tied to the claimed detection result. The specification does not identify a therapeutic agent, dosage, timing, route of administration, subject population, disease stage, or treatment decision rule based on the claimed assay output. The disclosure of a diagnostic assay does not reasonably convey possession of the broader treatment method recited in claim 18.
Dependent claims 2-6, 13, 15-17, 33-38, and 47 do not cure the deficiencies discussed above because the claims continue to encompass unsupported portions of the broader genera incorporated from claims 1, 19, and 32. The additional limitations of particular DNA scaffold lists, LCB1, multivalent display, PER, NTD binding, RBD binding, or variant binding narrow certain aspects of the claims, but they do not provide adequate written-description support for the full scope of the SARS-CoV-2 specific nanobodies, SARS-CoV-2 specific binding molecules, SARS-CoV-2 specific antibodies, target-specific binding peptides, and functional DNA-peptide hybrid assay constructs encompassed by the claims.
Accordingly, the disclosure does not reasonably convey to one skilled in the art that the inventor had possession of the full scope of the subject matter recited in claims 1-6, 13, 15-19, 32-38, and 47 at the time the application was filed.
Claims 1-6, 13, 15-19, 32-38, and 47 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for a limited SARS-CoV-2 DLISA assay using specifically disclosed SARS-CoV-2 binding reagents, LCB1-based DNA-peptide hybrid detection molecules, and the particular assay conditions described in the specification, does not reasonably provide enablement for the broader claimed scope of any of the claimed capture molecules and any of the claimed detection molecules accurately and reliably detecting any SARS-CoV-2 in any sample. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). The factors to be considered include: (1) the breadth of the claims; (2) the nature of the invention; (3) the state of the prior art; (4) the level of one of ordinary skill; (5) the level of predictability in the art; (6) the amount of direction provided by the inventor; (7) the existence of working examples; and (8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. The factors are considered as a whole in determining whether any necessary experimentation would have been undue.
Nature of the invention and breadth of the claims
The claimed invention is directed to methods and kits for detecting SARS-CoV-2 using DNA-peptide hybrid molecules in a sandwich assay format. Independent claim 1 recites a method in which a capture molecule comprising a nanobody specific for SARS-CoV-2 is linked to a solid support, the SARS-CoV-2 virus is bound by the capture molecule, and the captured complex is contacted with a detection molecule comprising a DNA nanostructure chemically linked to one or more target-specific binding peptides that specifically bind SARS-CoV-2. Independent claim 19 recites a corresponding kit. Independent claim 32 recites the reverse orientation, in which the DNA-peptide hybrid molecule is the capture molecule, and the detection molecule comprises a binding molecule specific for SARS-CoV-2. Independent claim 47 recites a corresponding kit.
The specification describes a DLISA platform using SARS-CoV-2 binding reagents and DNA-based signal amplification. The specification describes target-specific binding peptides and states that “target-specific” molecules may have high affinity, including a Kd of less than 1 micromolar, preferably less than 5 nanomolar (¶[0059]). The specification also identifies LCB1 as a SARS-CoV-2 mini-binder and describes capture molecules, including nanobodies disclosed in Schoof et al (¶[0058-0060]). The specification further describes DNA-peptide hybrid molecules, primer exchange reaction amplification, and exemplary DNA nanostructure formats (¶[0039][0041][0046][0053-0055][0057-0059]).
However, claims 1-6, 13, 15-19, 32-38, and 47 are not limited to the disclosed embodiments. The claims encompass any nanobody “specific for SARS-CoV-2,” any SARS-CoV-2-specific binding molecule in the reverse assay orientation, and broad target-specific binding peptides chemically linked to DNA nanostructures. The claims also encompass multiple DNA scaffold formats, different valencies, different peptide spacings, different chemical attachment positions, different solid-support formats, and both capture/detection orientations. Claim 17 further extends the method to peptides that bind Alpha, Beta, Gamma, and Delta variants. These are not small changes at the edge of the disclosure as these variations materially affect binding, avidity, steric access, assay background, and signal amplification. As the independent claims are not specific to any aspect of what aspect of SARS-CoV-2 is detected by either capture or detection reagent, this also affects the ability of the claimed methods to accurately bind to any variant, isolate, or mutant of SARS-CoV-2, because it is unclear if the capture/detection reagent recognizes a conserved protein or epitope or if said reagent binds to a highly mutable protein, such as the spike (S) surface protein.
The claimed scope therefore extends beyond the embodiments described in the specification. The disclosure may teach that certain LCB1-based DNA constructs and certain nanobody/minibinder assay arrangements can be made and tested, but it does not teach how to make and use the full genus of SARS-CoV-2-specific nanobody capture molecules, SARS-CoV-2-specific detection molecules, and DNA-peptide hybrid constructs across the full range of DNA nanostructures and assay orientations recited in the claims.
State of the prior art and predictability of the art
At the time the application was filed, it was known that SARS-CoV-2-binding nanobodies could be identified by screening and improved by additional engineering. Schoof et al. (Schoof M, et. al. Science. 2020 Dec 18;370(6523):1473-1479. Epub 2020 Nov 5.) stated: “By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2.” Schoof further noted that “Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody” with improved neutralizing activity. This reference shows that useful SARS-CoV-2 nanobodies were not simply known as a predictable class by naming the virus. They were selected, characterized, and then further engineered for binding mode and functional effect.
The teachings of Schoof also shows why the claimed breadth is technically significant. The reference distinguished nanobodies by binding behavior, including nanobodies that bound Spike and the spike receptor binding domain (RBD) and nanobodies that bound Spike but not RBD. This matters in the instant application, because the instant claims are not limited to a particular antigen, epitope, nanobody sequence, nanobody class, or capture/detection orientation. A nanobody that binds one spike conformation, one domain, or one epitope is not reasonably predictive of all SARS-CoV-2-specific nanobodies functioning as solid-support capture reagents in the claimed DNA-peptide hybrid assay.
At the time the application was filed, it was also known that SARS-CoV-2 miniprotein binders, including LCB1-related binders, could be generated by computational design and selection. Cao et. al. (Cao L, et. al. Science. 2020 Oct 23;370(6515):426-431. Epub 2020 Sep 9.) stated that “Computer-generated scaffolds were either built around an ACE2 helix or docked against the RBD to identify new binding modes,” and that “sequences were designed to optimize target binding, folding, and stability.” Cao et al. further reported that “Ten designs bound the RBD, with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of Vero E6 cells.” Cao supports the existence of particular SARS-CoV-2 miniprotein binders, but does not support the proposition that any target-specific binding peptide, after chemical linkage to any DNA nanostructure in any spacing or orientation, would retain useful SARS-CoV-2 binding in a sandwich assay. Cao instead shows design, selection, and validation of specific binders. That state of the art does not make the much broader claimed DNA-peptide hybrid genus predictable.
Case et. al. (Case JB, et. al. Cell Host Microbe. 2021 Jul 14;29(7):1151-1161.e5. Epub 2021 Jun 24.) further illustrates that SARS-CoV-2 miniprotein performance was construct-specific and variant-dependent. Case stated: “Previously, we used a structural design approach to develop picomolar range miniproteins targeting the SARS-CoV-2 spike receptor-binding domain. Here, we investigated the capacity of modified versions of one lead miniprotein, LCB1.” Case further stated that LCB1v1.3 protected against “a historical strain (WA1/2020), an emerging B.1.1.7 strain, and a strain encoding key E484K and N501Y spike protein substitutions.” Case supports the use of modified LCB1 binders against certain SARS-CoV-2 strains, and it also shows that the art did not treat all SARS-CoV-2-binding peptides as interchangeable. The art has also shown that SARS-CoV-2 variants can escape binding from LCB1 and derivatives of LCB1 (Jin H, et. al. Viruses. 2023 Dec 25;16(1):36.) Case studied modified versions of a lead miniprotein and tested them against particular viral strains, but that evidence does not justify extrapolating from LCB1-type binders to the full scope of target-specific binding peptides recited in the claims, including the variant-binding scope of claim 17, especially in light of the breadth of SARS-CoV-2 variants claimed and the ability of said variants to escape binging to known miniproteins.
Primer exchange reaction technology was known before the filing date. Hollenstein et. al. (Hollenstein M. Chembiochem. 2018 Mar 2;19(5):422-424. Epub 2018 Jan 24.) notes: “The autonomous synthesis of single-stranded DNA molecules of arbitrary size and sequence composition can easily be achieved by primer exchange reaction (PER) cascades.” Hollenstein further stated that PER cascades may have “potential” for applications in DNA nanotechnology. Hollenstein shows that PER was available as a DNA synthesis or amplification tool, but it does not show that the full claimed combination of SARS-CoV-2 nanobody capture, DNA-peptide hybrid binding, solid-support assay geometry, and signal amplification would be predictable across all claimed scaffolds and binding reagents. The fact that one could synthesize DNA does not answer which DNA-peptide constructs would bind intact virus or spike antigen with acceptable sensitivity and specificity in the claimed assay.
DNA origami and DNA nanostructure methods were also known in the art at the time of filing. Dey et. al. (Dey S, et. al. DNA origami. Nat Rev Methods Primers 1, 13 (2021).) described DNA origami as an approach involving design, synthesis, functionalization, and characterization of DNA nanostructures. Dey also discussed challenges in the field, including size limits, stability issues, and scale of production. While Dey supports that a skilled artisan would have had tools for making DNA nanostructures, Dey does not establish that the full list of DNA nanostructures recited in the claims would function equivalently when chemically linked to SARS-CoV-2 binding peptides and used in a DLISA assay. DNA nanostructure geometry, rigidity, handle placement, local concentration, and steric presentation can change whether a displayed binding peptide actually reaches its target. The art was therefore not sufficiently predictable to support extrapolation from the disclosed LCB1-based embodiments to the full claimed scope.
Accordingly, the results obtained using the disclosed SARS-CoV-2 nanobody/minibinder assay embodiments would not have reasonably established that the broader claimed scope could be practiced without further experimentation.
Level of skill in the art
One skilled in the art would have been familiar with ELISA and sandwich immunoassays, nanobody screening, SARS-CoV-2 spike-binding assays, DNA conjugation chemistry, DNA nanostructure assembly, fluorescence detection, and primer exchange reaction amplification. One skilled in the art would also have been able to prepare candidate DNA-peptide conjugates and test binding using known assays such as ELISA, SPR, and fluorescence-based readouts. However, the existence of known methods for preparing and testing candidate embodiments does not establish that one skilled in the art would have known, without further undue experimentation, which additional nanobodies, binding peptides, DNA nanostructures, attachment positions, valencies, and assay orientations would satisfy the claimed limitations. The difficulty is not the absence of tools; the difficulty is that the claims require successful functional combinations, and the specification does not teach how to identify those combinations across the full scope claimed.
Working examples
The specification provides working or proposed examples directed to particular DNA-peptide hybrid constructs and SARS-CoV-2 assay formats. The specification describes use of LCB1 as a SARS-CoV-2 mini-binder, DNA-peptide hybrid molecules, and PER-based signal amplification (Examples 1-;3 ¶[0147-0211]). The specification also describes exemplary DNA nanostructures and assay figures directed to SARS-CoV-2 detection and signal amplification (¶[0044][0049][0068][0149-0154][0158]; Fig. 2; Example 2 at ¶[0180]).
The specification does not provide working examples directed to the full scope of SARS-CoV-2-specific nanobodies recited in claims 1 and 19. The specification also does not provide working examples for each claimed DNA nanostructure format used as a SARS-CoV-2 DNA-peptide hybrid capture or detection molecule. It does not show that each scaffold can be chemically linked to the claimed target-specific binding peptides in a manner that preserves binding, provides acceptable assay background, and permits detection of SARS-CoV-2 in the claimed sample. The specification does not test the range of possible SARS-CoV-2 antigens (e.g. whole virion, viral RNA, protein antigen, etc.) across the range of potential variants of concern. The specification does not test the breadth of possible samples, such as blood, plasma, saliva, sputum, urine, or the like to show that said detection method is predictable across the claimed breadth.
The specification also does not provide working examples across the full reverse-orientation scope of claims 32-38 and 47. In that orientation, the DNA-peptide hybrid molecule is immobilized as the capture molecule, and the SARS-CoV-2-specific binding molecule is used as the detection molecule. That arrangement is not merely the same experiment turned around. Immobilization can change access to the binding peptide, restrict scaffold movement, alter avidity, and increase nonspecific background. The disclosed examples therefore do not establish enablement across the full scope of claims 1-6, 13, 15-19, 32-38, and 47.
Guidance in the specification
The specification provides guidance regarding the general DLISA concept, target-specific binding peptides, LCB1, nanobody capture molecules, DNA-peptide hybrid molecules, and PER-based amplification. The specification also provides general guidance that DNA nanostructures can be used to present binding groups at selected spacing and valency (¶[0149-0150]).
However, the specification does not provide sufficient guidance regarding how to practice the full claimed scope. In particular, the specification does not explain how to select a SARS-CoV-2-specific nanobody that will function as a capture molecule with the full range of claimed DNA-peptide hybrid detection molecules. It does not explain how to select target-specific binding peptides other than the specifically disclosed LCB1-type examples that will retain SARS-CoV-2 binding after chemical linkage to different DNA nanostructures. It does not provide rules for choosing scaffold geometry, arm spacing, peptide copy number, linker chemistry, or attachment position across the claimed structures.
The specification also does not provide sufficient guidance for determining which embodiments will detect Alpha, Beta, Gamma, and Delta variants as recited in claim 17. Variant binding depends on the viral antigen, the epitope, the spike conformation, and the binding molecule used. As claim 17 is drawn to the spike protein, this protein is the most non-conserved and highly mutable protein in SARS-CoV-2, and it is unclear how the methods and reagents would detect the spike protein across a range of variants, strains, and mutants. A general statement that a binding peptide is target-specific does not teach how to practice the full variant-binding scope without making and testing additional embodiments.
Quantity of experimentation necessary
To practice the full scope of claims 1-6, 13, 15-19, 32-38, and 47, one skilled in the art would need to identify or generate additional SARS-CoV-2-specific nanobodies and binding peptides, determine their antigen and epitope compatibility, prepare DNA-peptide hybrid molecules using different DNA nanostructures, vary linker chemistry and attachment position, test whether binding is retained after conjugation, optimize surface immobilization, measure assay background, and confirm detection of SARS-CoV-2 variants across the claimed assay orientations. For claim 17, one skilled in the art would also need to confirm binding to the recited spike protein variants.
Such experimentation would not merely involve the routine application of known methods to embodiments reasonably expected to work. Instead, one skilled in the art would need to prepare and test additional embodiments to determine whether they satisfy the claimed functional requirements of specifically binding to any aspect of any SARS-CoV-2 and detecting any SARS-CoV-2 variant in the claimed assay. Although the individual methods used to prepare and test candidate embodiments may have been known in the art, the relevant inquiry is not whether one skilled in the art could perform the required assays; instead, the relevant inquiry is whether the specification provides sufficient guidance to identify and practice the embodiments falling within the full scope of the claims without undue experimentation. Here, one skilled in the art would need to prepare and test additional nanobodies, binding peptides, DNA nanostructures, conjugates, and assay formats to determine which embodiments satisfy the claimed binding and detection functions.
Amgen
The Supreme Court has explained that a specification need not describe with particularity how to make and use every embodiment within a claimed class. However, the disclosure must enable one skilled in the art to make and use the full scope of the claimed invention. A reasonable amount of experimentation may be permissible depending on the nature of the invention and the underlying art. Amgen Inc. v. Sanofi, 598 U.S. 594, 610-13 (2023).
In the instantly claimed invention, the specification describes particular SARS-CoV-2 DLISA embodiments involving disclosed SARS-CoV-2 binding reagents, LCB1-based DNA-peptide hybrid molecules, and PER-based detection. The claims, however, also encompass materially broader classes of SARS-CoV-2-specific nanobody capture molecules, SARS-CoV-2-specific detection molecules, target-specific binding peptides, DNA nanostructures, valency arrangements, and assay orientations. The specification does not identify a general quality or provide sufficient guidance that would allow one skilled in the art to practice that broader scope without undue experimentation.
Conclusion
For the reasons discussed above, the specification does not enable one skilled in the art to make and use the full scope of the invention recited in claims 1-6, 13, 15-19, 32-38, and 47 without undue experimentation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
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Claims 1-6, 13, 15-19, 32-38, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18/701,901 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a DNA-peptide hybrid molecule comprising a DNA nanostructure chemically linked to one or more target-specific binding peptides, wherein the one or more target-specific binding peptides are specific for SARS-CoV-2. Both claim wherein the DNA nanostructure is selected from the group consisting of: a three-helix bundle, a four-helix bundle, a six-helix bundle, a triangular DNA origami structure, a tetrahedral wireframe cage, a block-like origami cuboid, reconfigurable tweezers, double crossover tiles, branched three-way junctions, and a three-legged stool, namely a three-helix or four-helix bundle. Both claim the target-specific binding peptide is LCB1. Both claim binding to SARS-CoV-2 S protein alpha, beta, gamma, and delta variants. The main difference is that the instant claims use the DNA-peptide hybrid molecule in a specific method of detection of SARS-CoV-2. However, the use of the DNA-peptide hybrid molecule as a capture or detection reagent in a detection assay would be an obvious variation of the claimed subject matter. The additional recitation of a nanobody or SARS-CoV-2 specific binding molecule as the complementary assay reagent does not render the claims patentably distinct, because the instant claims use those binding molecules in a conventional sandwich ELISA to detect the same viral targets.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-6, 13, 15-19, 32-38, and 47 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7 and 9-10 of copending Application No. 18/701,898 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim DNA-peptide hybrid molecules comprising a DNA nanostructure chemically linked to one or more target-specific binding peptides, wherein one or more of the target-specific binding peptides is a nanobody. Both claim wherein the hybrid molecule comprises more than one target-specific binding peptide, wherein said target-specific binding peptides can bind to different regions of the same target molecule. Both claim the DNA nanostructure is selected from the group consisting of: a three-helix bundle, a four-helix bundle, a six-helix bundle, a triangular DNA origami structure, a tetrahedral wireframe cage, a block-like origami cuboid, reconfigurable tweezers, double crossover tiles, branched three-way junctions, and a three- legged stool. The main difference is that the instant claims use the DNA-peptide hybrid molecule in a specific method of detection, namely in a method to detect SARS-CoV-2. However, the instant claims do not recite a patentably distinct invention, in that simply because the DNA-peptide hybrid is used as a capture or detection reagent in a binding assay for the target. That use if an obvious variation of the broadly claimed DNA-peptide hybrid molecule and its target-binding function. The additional recitation of SARS-CoV-2, nanobody capture, SARS-CoV-2 specific detection antibody, solid support, and kit format does not render the claims patentably distinct, because these limitations place the same DNA-peptide hybrid molecule into a routine binding-assay format for detecting the target to which the peptide binds.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure and is listed below.
Zhou C, et. al. Anal Chim Acta. 2023 Sep 22;1275:341590. Epub 2023 Jul 10. Teaches nanostructure-based detection of SARS-CoV-2. Post-filing art relating to the instant claims.
Xu Y, Zheng R, Prasad A, Liu M, Wan Z, Zhou X, Porter RM, Sample M, Poppleton E, Procyk J, Liu H, Li Y, Wang S, Yan H, Sulc P, Stephanopoulos N. High-affinity binding to the SARS-CoV-2 spike trimer by a nanostructured, trivalent protein-DNA synthetic antibody. bioRxiv [Preprint]. 2023 Sep 19:2023.09.18.558353. Post-filing applicant-related art that details aspects of the instant claims.
Zheng R, Xu Y, Prasad A, Liu M, Wan Z, Jiang J, Zhou X, Porter RM, Sample M, Poppleton E, Procyk J, Liu H, Doherty A, Nyaupane P, Li Y, Wang S, Yan H, Sulc P, Stephanopoulos N. IgG-inspired, multivalent protein-DNA nanostructures for high-affinity, tunable, and reversible binding to biomolecular targets. bioRxiv [Preprint]. 2026 Mar 7:2023.09.18.558353. Post-filing applicant-related art that details aspects of the instant claims; Version 2 of the Xu et. al. 2023 reference supra.
Girt et. al. (Girt GC, et. al. R Soc Open Sci. 2021 Sep 30;8(9):211016.; hereafter “Girt”). Teaches nanobody-nanobody ELISA for detection of SARS-CoV-2. Not utilized as rejection would be redundant to those set forth supra and said art fails to teach the DNA-peptide component of the ELISA.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights