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
Disposition of Claims
Claims 1-4 and 6-21 are pending.
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not). In the present application, the claim set skips “claim 5”. Therefore, currently numbered claims 6-21 are being objected to. In the interest of compact prosecution, the claims will be examined according to how they are numbered, but the claim numbering, and pendency of dependent claims, must be updated to be considered a complete response to this Office action.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240408194A1, Published 12/12/2024.
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 10/18/2024 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 in the drawings and figure legends (See e.g. Figs. 2-6, 9. 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
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 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…”). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not). In the present application, the claim set skips “claim 5”. Therefore, currently numbered claims 6-21 are being objected to. In the interest of compact prosecution, the claims will be examined according to how they are numbered, but the claim numbering, and pendency of dependent claims, must be updated to be considered a complete response to this Office action.
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, 3, 11, and 13 and dependent claims 2, 4, 6-10, 12, and 14-21 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” in claim 1 is a relative term which renders the claim indefinite. The term “specific” 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. The term in relation to the “SARS-COV-2 specific binding peptide (SBP)” of claim 1 is unclear because the claim does not identify the SARS-CoV-2 molecular target to which the peptide binds or provide an objective standard for determining when binding is, or is not, “specific”. While the specification at ¶[0070] defines a “target-specific binding peptide”, this is not the exact same as the limitations or phrasing utilized in claim 1, and that paragraph only uses the SARS-CoV-2 surface glycoprotein target as the only embodiments when it comes to affinity and dissociation constant (Kd) values. It is therefore unclear whether the term encompasses any peptide that binds any SARS-CoV-2 associated molecule, requires binding to the spike (S) glycoprotein or a particular S domain, or requires preferential binding to SARS-CoV-2 relative to other coronaviruses.
Claims 3, 11, and 13 are also rejected for similar reasoning for claiming a peptide with “specific” binding.
For at least these reasons, claims 1, 3, 11, and 13 are rejected on the grounds of being indefinite. Claims 2, 4, 6-10, 12, and 14-21 are also rejected for depending upon claims 1, 3, 11, and 13, but not clarifying the metes and bounds of claims 1, 3, 11, and 13.
Claims 2 and 12 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 12 recite that the DNA nanocarrier is selected from the group consisting of: an icosahedron, 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 12 are unclear.
Claims 3, 4 and 13-14 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 4 and 14 recite an icosahedron comprising “12 four-helix bundles, or 12 three-helix bundles each linked to three SBPs.” It is unclear whether the limitation “each linked to three SBPs” modifies both the “12 four-helix bundles” and “12 three-helix bundles”, or modifies only the “12 three-helix bundles”. Under the latter interpretation, the claims do not require the “12 four-helix bundles” to be linked to any SBPs. Under the former interpretation, both helix bundles are linked to SBPs.
Claims 3 and 13 have similar issues, as it is unclear if the four-helix bundle is to be linked to SBPs or not.
As there are two separate and distinct reasonable interpretations of the claims, it is unclear as to the exact metes and bounds of the claims.
For at least these reasons, the metes and bounds of claims 3-4 and 13-14 are unclear.
Claims 6 and 16 and dependent claims 7 and 17 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 6 recites the limitation "spike proteins" in line 1. There is insufficient antecedent basis for this limitation in the claim, as claim 1 only recites one spike protein. Since only one spike protein is recited in claim 1, it is unclear how there are to be multiple different spike proteins.
Claim 16 is rejected for similar reasoning.
For at least these reasons, the metes and bounds of claims 6 and 16 are unclear. Claims 7 and 17 are rejected for depending upon claim 6 or 16, but not clarifying the metes and bounds of claim 6 or 16.
Claims 7 and 17 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 7 and 17 depend from claims requiring the DNA nanocarrier to be linked to two or more non-identical SARS-CoV-2 Spike (S) proteins, but recite that “the spike proteins comprise the spike protein from the SARS-COV-2 alpha, beta, gamma, or delta variants.” It is unclear which two or more non-identical S proteins are required by claims 7 and 17. The recited language may require S proteins from two or more of the listed variant strains, or it may require only one spike protein from a listed variant strain together with another unidentified spike protein. The scope of the claimed combination of the non-identical spike proteins is therefore unclear.
For at least these reasons, the metes and bounds of claims 7 and 17 are unclear.
Claim 21 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 21 recites that the administration of the composition “elicits an immune response to more than one variant strain of SARS-COV-2.” It is unclear what response is sufficient to satisfy this limitation. The specification discusses different immune-response measurements, including antibody production, neutralizing activity, cellular responses, and protection from infection, but claim 21 does not identify which type of response is required or provide an objective threshold for determining whether an immune response to a variant strain has been elicited. Accordingly, it is unclear whether any detectable immune response is sufficient or whether the claim requires a neutralizing, protective, or other clinically meaningful response to each of the more than one variant strain of SARS-CoV-2.
For at least these reasons, the metes and bounds of claim 21 are unclear.
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 composition for eliciting an immune response against SARS-COV-2 comprising: a DNA nanocarrier linked to (1) a SARS-COV-2 specific binding peptide (SBP), and (2) a SARS-CoV-2 spike protein or antigenic fragment thereof.
Further limitations on the composition of claim 1 are wherein the DNA nanocarrier is selected from the group consisting of: an icosahedron, 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 nanocarrier comprises at least one four-helix bundle or at least one three-helix bundle linked to three SARS-COV-2 specific binding peptides (SBP)(claim 3); wherein the composition comprises a DNA icosahedron comprising 12 four-helix bundles, or 12 three-helix bundles each linked to three SBPs (claim 4); wherein the SARS-COV-2 spike proteins are not identical (claim 6), wherein the spike proteins comprise the spike protein from the SARS-COV-2 alpha, beta, gamma, or delta variants (claim 7); further comprising an adjuvant (claim 8), wherein the adjuvant is selected from the group consisting of aluminum containing compounds, CpG nucleotides, monophosphoryl lipid A (MPL), oil in water emulsion of squalene, and extracts of Quillaja Saponaria (claim 9), and wherein the adjuvant comprises CpG nucleotides (claim 10).
Claim 11 is drawn to a method of eliciting an immune response against SARS-COV-2 spike protein, the method comprising administering a composition comprising a DNA nanocarrier linked to (1) a SARS-CoV-2 specific peptide, and (2) a SARS-COV-2 spike protein or antigenic fragment thereof.
Further limitations on the method of claim 11 are wherein the DNA nanocarrier is selected from the group consisting of: an icosahedron, 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 12); wherein the DNA nanocarrier comprises at least one four-helix bundle linked or at least one three-helix bundle to three SARS-COV-2 specific binding proteins (SBPs)(claim 13); wherein the composition comprises a DNA icosahedron comprising 12 four-helix bundles, or comprising 12 three-helix bundles each linked to three SBPs (claim 14); wherein the SARS-COV-2 spike protein is bound to one or more of the SBPs (claim 15); wherein the SARS-COV-2 spike proteins are not identical (claim 16), wherein the spike proteins comprise the spike protein from the SARS-COV-2 alpha, beta, gamma, or delta variants (claim 17); wherein the composition further comprises an adjuvant (claim 18), wherein the adjuvant is selected from the group consisting of aluminum containing compounds, CpG nucleotides, monophosphoryl lipid A (MPL), oil in water emulsion of squalene, and extracts of Quillaja Saponaria (claim 19), wherein the adjuvant is CpG nucleotides (claim 20); and wherein administration of the composition elicits an immune response to more than one variant strain of SARS-COV-2 (claim 21).
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 1-4 and 6-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for preparing an icosahedral DNA-origami nanocarrier displaying SARS-CoV-2 RBD through DNA-conjugated LCB1, does not reasonably provide enablement for the broader claimed scope encompassing other SARS-CoV-2 specific peptides, other spike proteins or antigenic fragments, materially different nanocarriers, and the use of those compositions to elicit the claimed immune responses. 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 a composition comprising a DNA nanocarrier linked to a SARS-CoV-2-specific binding peptide (SBP) and a SARS-CoV-2 spike (S) protein or antigenic fragment thereof, as well as methods of administering the composition to elicit an immune response against the S protein.
The specification describes LCB1, comprising SEQ ID NO:2, as an exemplary SARS-CoV-2 SBP. The specification states that a target-specific binding peptide may have a dissociation constant below 1 micromolar or, preferably, below 5 nanomolar, and identifies LCB1 as a nonlimiting SBP (¶[0060][[0070-0071]). The specification also describes an icosahedral DNA origami having three DNA-LCB1 conjugates at each vertex (¶[0167]). RBD is incubated with DNA-LCB at a 1:1 ratio, and the resulting DNA-LCB-RBD complexes are assembled onto the DNA origami through complimentary hybridization (¶[0167-0170]).
However, the claims are not limited to the disclosed embodiments of LCB1 (SEQ ID NO:2), an LCB1-like sequence, or even a peptide that binds RBD of S. The claims also encompass any peptide described as SARS-CoV-2 specific, without identifying the SARS-CoV-2 protein or molecular region to which it must bind. The specification uses the terms “protein”, “peptide”, and “polypeptide” interchangeably and defines them as polymers of any size, structure, or function (¶[0064]). The claims also encompass full-length spike proteins and any antigenic fragment thereof, where under broadest reasonable interpretation, an antigenic fragment is not limited by sequence, length, domain, conformation, epitope, or minimum immune activity. Dependent claims further encompass combinations of nonidentical spike proteins, while claim 21 requires any immune response to more than one variant strain. Claims 2 and 12 extend the scope further by listing an icosahedron, three-, four-, or six-helix bundles, triangular DNA origami structures, tetrahedral wireframe cages, block-like origami cuboids, reconfigurable tweezers, double crossover tiles, branched three-way junctions, and three-legged stools. These structures differ in shape, size, rigidity, valency, available attachment options/locations, and spatial arrangement of the displayed antigen.
The claimed scope therefore extends well beyond the embodiments described in the specification.
State of the prior art and predictability of the art. At the time the application was filed, it was known that DNA origami permitted controlled antigen placement, but the resulting immune response depended on how the antigen was arranged. Veneziano et. al. (Veneziano R, et. al. Nat Nanotechnol. 2020 Aug;15(8):716-723. Epub 2020 Jun 29.) tested the effects of antigen copy number, spacing, dimensionality, and scaffold rigidity using DNA-origami particles displaying the HIV antigen eOD-GT8. Veneziano reported that B-cell signaling was maximized using as few as five appropriately spaced antigens and that “scaffold rigidity is essential for robust B-cell triggering.” These results show that the ability to attach an antigen to a DNA structure did not make immunity activity across different structures and antigen arrangements predictable.
Cao et. al. (Cao L, et. al. Science. 2020 Oct 23;370(6515):426-431. Epub 2020 Sep 9.) used computational design followed by experimental testing to identify SARS-CoV-2 RBD-binding miniproteins. Cao reported that ten designs bound RBD, with affinities ranging from about 100 picomolar to 10 nanomolar, while the strongest species, including LCB1, resulted from further optimization and experimental selection. The need to prepare and test multiple designs, followed by additional optimization, indicates that the binding activity of an arbitrary peptide could not be predicted merely from the desired function of binding to SARS-CoV-2.
The activity of spike-directed antibodies also varied among SARS-CoV-2 variants. Planas et. al. (Planas D, et. al. Nature. 2021 Aug;596(7871):276-280. Epub 2021 Jul 8.) reported that the Delta variant was resistant to neutralization by certain anti-NTD and anti-RBD antibodies and that those antibodies showed impaired binding to the variant S protein. Neutralizing titers after two vaccine doses were three- to five-fold lower against Delta than against Alpha, showing that activity against one S sequence did not reliably establish comparable activity against another variant.
The art was not sufficiently predictable to support extrapolation from a composition of icosahedral DNA origami having three DNA-LCB1-RBD conjugates at each vertex to any composition comprising any DNA nanocarrier, any SARS-CoV-2 specific binding protein, and any S protein or fragment thereof, especially in methods to elicit any immune response against any SARS-COV-2 spike protein. Accordingly, the results obtained using the DNA-LCB1-RBD 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 DNA-origami assembly, peptide-DNA conjugation, recombinant protein production, chromatography, gel electrophoresis, electron microscopy, binding assays, animal immunization, ELISAs, and viral neutralization assays. 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 experimentation, which additional peptides could be conjugated to a DNA nanocarrier while retaining the required SARS-CoV-2 binding activity. Nor would the known methods identify what fragments, scaffold configurations, antigen densities, adjuvants, or combination of variant spike protein sequences would satisfy the claimed limitations of producing the desired immune response. The relevant variables would still need to be selected and tested.
Working examples. The specification provides one working example directed to the claimed vaccine compositions. The example concerns an approximately 42-nanometer icosahedral DNA origami displaying RBD through DNA-conjugated LCB1. The specification reports physical construction of the particle, approximately 71.6% protein coverage, macrophage uptake, and increased IL-6 and IL1B mRNA relative to RBD and PBS controls (¶[0166-0171]).
The specification does not provide working examples directed to immunization of any test animal or human subject with the constructed DNA-LCB1-RBD particles. It does not provide measured antigen-specific antibody titers, virus-neutralization results, protection against viral challenge (homologous or heterologous challenge), or heterosubtypic immunity. The specification states the vaccine composition “will be evaluated” in mouse and rabbit models to measure antibody responses, neutralization, protection, and heterosubtypic immunity (¶[0165]).
Additionally, the specification does not show DNA-LCB1-RBD particles wherein variants of RBD were utilized and successfully attached to the DNA-LCB1 structure. It does not show the use of any other DNA nanocarrier or any other SARS-CoV-2 SBP aside from LCB or P1. It does not report a working vaccine containing a non-RBD antigenic spike fragment, nor does it test any other adjuvant aside from CpG. Macrophage internalization and increased inflammatory marker mRNA does not establish that the composition elicits antibodies against the displayed antigen, much less neutralizing or protective antibodies. It is unclear whether or not such a composition could be administered more than once, as it is unclear if the DNA nanocarrier and/or SBP elicit an immune response against this structure in the host that precludes multiple administrations of the same compound in a vaccine setting.
Accordingly, the disclosed examples do not establish enablement across the full scope of the claims.
Guidance in the specification. The specification provides guidance regarding the generation of icosahedral DNA origami displaying SARS-CoV-2 S protein RBD fragment through DNA-conjugated LCB1 (¶[0166-0167]). The specification also provides optional affinity values for target-specific peptides and identifies LCB1 as an exemplary SBP (¶[0070-0071]).
However, the specification does not provide sufficient guidance regarding identifying other peptides falling within the claimed SARS-CoV-2-specific genus. It does not explain which SARS-CoV-2 targets must be bound, which peptides structures are suitable (e.g. short peptides, antibodies, antibody fragments, etc.), which attachment sites on the DNA nanostructure will preserve binding, or which linker and which scaffold arrangements will permit the peptide to capture and present the antigen in an immunogenically relevant conformation. In particular, the specification does not explain which fragments of the S protein will remain antigenic after capture by the SBP. It does not identify how much of the spike sequence may be removed, which conformations must be preserved, or which displayed epitopes will produce the claimed immune response.
The disclosure lists multiple DNA structures but does not provide vaccine-specific design instructions for adapting each structure to display the claimed peptide and spike antigen. It does not identify the appropriate antigen valency, spacing, orientation, or scaffold rigidity for those structure. This omission is material because the specification itself recognizes that spatial arrangement, copy number, stiffness, and scaffold size affect early B-cell activation and humoral immunity (¶[0166]).
For the non-identical S protein and multivariant embodiments, the specification does not identify which variant combinations should be selected or how each antigen should be distributed on the scaffold. It also does not provide data showing that antibodies elicited by a mixed-variant particle bind or neutralize more than one variant. The specification instead proposes creating combinatorial libraries containing random peptide or protein combinations and selecting the resulting structures based on their performance (¶[0161]). This proposed screening confirms that the disclosure does not itself identify which additional combinations will satisfy the claimed limitations.
Quantity of experimentation necessary. To practice the full scope of the claims, one skilled in the art would need to identify additional SARS-CoV-2 targets and obtain or design peptides that bind those targets. Each peptide would need to be produced, conjugated to a DNA nanoscaffold, and tested to determine whether DNA attachment preserves the required binding activity. The skilled artisan would have to select spike proteins and antigenic fragments thereof, determine whether the SBP capture those antigens, and establish whether the captured antigen retains the appropriate antigenic conformation. Different attachment sites, linker lengths/types/sequences, antigen-to-binder ratios, and scaffold positions would need to be evaluated. For each materially different DNA nanocarrier, the artisan would also need to design and assemble the structure, determine its stability under physiological conditions, and optimize antigen valency spacing, assembly, and adjuvant placement. A configuration that physically assembles would still need to be tested for uptake, antigen processing, B-cell activation, antibody production, neutralization, and protection. The limitations in dependent claims 6, 7, 16, 17, and 21 would require additional experimentation because the skilled artisan would need to select combinations of nonidentical spike proteins, determine whether each remains displayed, and test whether the resulting particle elicits responses against more than one variant. Binding of LCB1 to several RBD variants does not establish that a composition displaying those variants will elicit a useful immune response to each variant.
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 (e.g. peptides, DNA nanostructures, Spike proteins and fragments, and combinations thereof) to determine whether they satisfy the claimed binding and immune-response limitations.
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. 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, the specification provides one narrow construction example and leaves the broader claimed embodiments to iterative selection, optimization, and biological testing.
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 an icosahedral DNA origami particle displaying RBD through DNA-conjugated LCB1, but the claims also encompass structurally undefined SARS-CoV-2-specific peptides, broadly defined antigenic spike fragments, multiple distinct scaffold structure, nonidentical spike combinations, and methods requiring immune responses against one or more variants. 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 the claims without undue experimentation.
Claims 1-4 and 6-21 are rejected under 35 U.S.C. 112(a), or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
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 1-4 and 6-21 recite compositions or methods comprising a DNA nanocarrier linked to a SARS-CoV-2 specific binding peptide (SBP). Certain dependent claims refer to the binding material as an SBP or a SARS-CoV-2 SBP. The claimed binding peptides are defined, at least in part, by the function of being “specific for SARS-CoV-2”.
The specification describes LCB1, comprising the amino acid sequence of SEQ ID NO:2, and states that LCB1 may be chemically linked to a DNA nanostructure (¶[0060]). The specification also identifies LCB1 as an exemplary SARS-CoV-2 binding peptide and states that, in some embodiments, an SBP binds the SARS-CoV-2 surface glycoprotein with a dissociation constant of less than 1 micromolar or less than 5 nanomolar (¶[0070-0071]). The specification additionally identifies the RBD-binding peptide P1, comprising SEQ ID NO: 5, in connection with a peptide-DNA conjugate (¶[0011]). The exemplified vaccine construct uses LCB1 covalently attached to DNA and uses LCB1 to bind RBD on an icosahedral DNA-origami structure (¶[0166-0171]).
However, the scope of the claims is not limited to these embodiments described in the specification. The claims broadly encompass other peptides having unrelated amino acid sequences, different structures, and binding properties that may be characterized as specific for SARS-CoV-2. The claims also do not identify the SARS-CoV-2 molecule or molecular region to which the peptide must bind. Accordingly, the claims encompass peptides that bind different SARS-CoV-2 proteins or different regions of the spike protein, without requiring a particular epitope, sequence, binding mode, or affinity.
The specification does not describe a sufficient number of binding-peptide species representative of the claimed scope. The specification also does not describe structural features common to the claimed genus which would allow one skilled in the art to recognize which additional peptides are SARS-CoV-2-specific binding peptides that fall within the scope of the claimed invention. The specification at ¶[0070-0071] describes the desired binding function and provides optional affinity values, but does not identify an amino acid motif, scaffold, conserved residue, 3D-structure, or other structural feature shared by the broader genus. LCB1 and P1 do not establish a structural boundary for all peptides capable of binding to SARS-CoV-2.
Instead, one skilled in the art would be required to select additional peptide sequences not described in the specification and determine whether those additional embodiments satisfy the recited limitations of selectivity and affinity. The specification itself discusses creating combinatorial libraries containing different peptides or protein combinations and selecting resulting nanostructures based on their binding properties (¶[0161]). That contemplated selection process does not identify the structures of the additional claimed binders or demonstrate that the inventors possessed those binders at the time of filing.
The claimed binding peptides are defined, at least in part, by the recited function of specifically binding to SARS-CoV-2. However, the specification does not establish a correlation between the disclosed structural features and the recited function sufficient to identify the additional peptides falling within the scope of the claim. The specification describes only LCB1 and P1 and discusses performing a library screen in the future, but does not identify structural features common to the broader claimed genus which would allow one skilled in the art to recognize other members of the genus of peptides that can “specifically bind” to SARS-CoV-2. It is unclear what structural aspect of SARS-CoV-2 said peptide is meant to bind (e.g. what protein, epitope, nucleic acid, or other structural aspect relevant to the virus). The disclosure of the desired function, without a sufficient description of the claimed genus, does not demonstrate possession of the full scope of the claim.
The specification describes a specific aspect of the spike protein, namely the receptor binding domain (RBD), that is then bound to the SBP. The spike protein is given as SEQ ID NO: 1 (¶[0104]), and different variant mutations are described in accordance to that base sequence (¶[0104-0108]). It is not clear what portion of SEQ ID NO: 1 was used for the RBD in the experiments; in general, the RBD is recognized as being approximately amino acids 319 to 541. However, the claims are not limited to those constructs. The claims also encompass constructs that differ in sequence, as noted that the different spike protein variants have known mutations at certain amino acids. The claims also encompass full-length spike protein, full-length spike protein variants of SEQ ID NO:1, and fragments of the spike protein (e.g. S1 domain, S2 domain, NTD, etc.). The claims are not specific to any particular domain of the spike protein, epitope, structural feature, length, or sequence. The specification does not describe representative examples across that scope or identify structural features sufficient to show possession of the broader group of constructs.
The specification describes an icosahedral DNA origami (Ico) with a diameter of approximately 42 nm, extending three ssDNA overhangs at each vertex to assemble the RBD protein in situ (¶[0168]). However, the claims encompass the broader genus of DNA nanocarriers, and claims different structural DNA nanocarriers, such as an icosahedron, 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 specification does not describe representative compositions across the claimed scope or identify characteristics sufficient to show possession of the broader group of combinations. It is not clear that the broadly claimed SBP can bind to the DNA nanocarriers as claimed and also bind to the Spike protein as claimed while maintaining the proper immunogenic structure of all components. The disclosure of the singular specific composition of the icosahedral DNA origami does not reasonably convey possession of the substantially broader scope of DNA nanocarriers recited in the claims.
The specification describes future, prophetic treatment of the DNA-SBP-RBD in an in vivo mouse model (¶[0165]). However, the method claims broadly encompass eliciting any immune response against any SARS-COV-2 spike protein. The specification does not describe representative embodiments across that scope or otherwise demonstrate possession of the broader claimed method. It is unclear if the immune response is homotypic or heterotypic, as spike proteins are highly mutable, or if the immune response is limited to a specific type of response (e.g. T-cell or B-cell response). The disclosure of the DNA-SBP-RBD taken up by macrophages in vitro does not reasonably convey possession of methods using any of the claimed DNA nanocarriers attached to any SBP and any SARS-CoV-2 spike protein to elicit any type of anti-spike immune response in vivo.
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 the claims at the time the application was filed.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4, 8-15, and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Bathe et. al. (US20200237903A1, Pub. 07/30/2020; hereafter “Bathe”) in view of Smith et. al. (US20210145972A1, Pub. 05/20/2021; hereafter “Smith”) and Cao et. al. (Cao L, et. al. Science. 2020 Oct 23;370(6515):426-431. Epub 2020 Sep 9.; hereafter “Cao”.)
The Prior Art
Bathe teaches compositions containing a nucleic acid nanostructure having a desired geometric shape, such as a 4-helix bundle, 6-helix bundle, or icosahedron, and antigens bound to its surface (entire document; see abstract; ¶[0017][0128]; instant claims 2-3, 12-13). Bathe teaches the helical bundles may be shaped further into polyhedrons, such as icosahedrons (¶[0129]).
Bathe teaches cationic polymers and minor groove binders (as monomers, oligomers or polymers) may be used to coat the DNA nanoparticles for stabilization from endonuclease degradation (¶[0025]), and that proteins or guide RNAs can be used to attach secondary molecules to the DNA scaffold (¶[0050]). Bathe teaches that antigens may be bound to the DNA scaffold (¶[0076]) either covalently or non-covalently (¶[0083]), and may be bound directly or indirectly to the nanostructure (¶[0088]), and one or more copies may be presented on the scaffold in a specific orientation for eliciting an immune response (¶[0078]). Bathe teaches that purification tags, such as a protein, may be bound to the DNA scaffold to enable affinity binding to the nanostructure, and also include antigen-binding fragments of antibodies (¶[0141]). Bathe teaches the antigens may be viral surface proteins (¶[0091]) such as antigens from severe acute respiratory syndrome (SARS) coronavirus (CoV)(¶[0095]). Bathe teaches that the DNA scaffolds may be in pharmaceutical compositions which further comprise such agents as adjuvants (¶[0228]; instant claims 8, 18), such as synthetic oligodeoxynucleotides (ODN), such as CpG ODN (¶[0252]; instant claims 9-10, 19-20). Bathe teaches the pharmaceutical compositions can be used to induce an immune response, such as a prophylactic or therapeutic immune response that would induce production of neutralizing antibodies (¶[0269-0273]).
Smith teaches nanostructures comprising nucleic acid scaffolds and at least two peptide moieties, wherein the peptide moieties bind to a molecule expressed on the surface of a virus (entire document; see abstract.) Smith teaches the surface glycoproteins may be the class I fusion protein S2 of the SARS coronavirus (¶[0053][0100]; reference claim 7).
While Bathe teaches the DNA origami scaffolds, and teaches that antigens may be bound to said scaffolds via binding proteins, and that said antigens may be viral surface proteins from SARS CoV, Bathe fails to specifically teach that the binding proteins are specific to SARS-CoV-2 or that the SARS CoV surface protein is the spike protein, namely the receptor binding domain (RBD). Smith teaches DNA scaffolds wherein a peptide is bound to the surface of said scaffold, and targets a viral surface protein, such as a portion of the spike protein of SARS CoV. Smith also fails to specifically teach that the binding proteins are specific to SARS-CoV-2. However, known peptides that have specificity for spike protein of SARS-CoV-2 were known in the art at the time of filing, as taught by Cao.
Cao teaches the design of peptides to target the RBD of SARS-CoV-2 in order to prevent the binding of the virus to the ACE2 receptor on target cells (entire document; see abstract.) Cao teaches that ten specific peptides bound to the RBD with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of cells (abstract). LCB1 was identified as a minipeptide with high affinity for the RBD (Figs. 1-5).
It would have been obvious to a skilled artisan to modify the antigen-presenting DNA nanostructure of Bathe to include a scaffold-linked virus-binding peptide as taught by Smith. It would have been further obvious to select a binding peptide such as LCB1, as both Bathe and Smith taught that SARS coronavirus antigens could be used/targeted/bound to the surface of the DNA nanostructure. One of ordinary skill would have had a reasonable expectation of success because Smith teaches that scaffold-linked peptide moieties retain the ability to bind to viral surface proteins, while Cao demonstrates that LCB1 binds to SARS-CoV-2 RBD with high affinity. It would be further obvious to use such a structure to elicit immune responses against SARS-CoV-2 S protein, as the presentation of the S protein on the surface of the nanostructures would allow the bound RBD to maintain its native structure, as shown by the studies of Cao. Arriving at the limitations of instant claims 1, 11, and 15 would be obvious to a skilled artisan, given the combined teachings of Bathe, Smith, and Cao.
It would have been obvious to provide the twelve-vertex icosahedral DNA nanostructure of Bathe (¶[0046]) with a three peptide molecule at each vertex , based on the teaching of Smith that three scaffolded virus-binding peptides should be positioned to engage the three binding sites of a trimeric protein (¶[0034]). Bathe teaches one or more antigens of interest can be displayed in varying copy numbers with precise control over inter-antigen spacing, number, and spatial organization in 1, 2, and 3 dimensions (¶[0067]). The resulting structure would have twelve vertex modules and thirty-six binding peptides, thus rendering obvious the limitations of instant claims 4 and 14.
It would have been obvious to one of ordinary skill in the art to modify the DNA nanostructure compositions and immunization methods taught by Bathe in order to include a DNA-linked virus-binding peptide as taught by Smith and to use LCB1 as the binding peptide and SARS-CoV-2 RBD as the bound antigen as taught by Cao, thereby providing a DNA nanocarrier that captures and multivalently presents SARS-CoV-2 RBD for eliciting an immune response. One would have been motivated to do so, given the suggestion by Bathe that DNA nanostructures may be used to capture, orient, and display protein antigens in controlled numbers and spatial arrangements, together with the suggestion by Smith that virus-binding peptides attached to a nucleic acid scaffold may bind viral surface proteins through multivalent interactions. There would have been a reasonable expectation of success, given the knowledge that scaffold-linked peptide moieties retain their ability to bind a corresponding viral surface protein, as taught by Smith, and also given the knowledge that LCB1 binds the SARS-CoV-2 spike RBD with high affinity, as taught by Cao. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 6-7, 16-17, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Bathe, Smith, and Cao as applied to claims 1-4, 8-15, and 18-20 above, and further in view of Anosova et. al. (US20240269270A1, Priority 08/24/2020; hereafter “Anosova”.)
The Prior Art
The teachings of Bathe, Smith, and Cao have been set forth supra. While Bathe and Smith both teach that the DNA nanostructures would comprise SARS CoV surface antigens, such as spike protein fragments, and Cao teaches LCB1, which binds with high affinity to SARS-CoV-2 RBD, none of the references specifically teach wherein the DNA nanostructures comprise S protein antigens from different strains or variants of SARS-CoV-2. However, using such a platform to elicit an immune response against multiple antigenically distinct variants of SARS-CoV-2 would be obvious to a skilled artisan, given the teachings of Anosova.
Anosova teaches vaccine compositions for prophylactic treatment of SARS-COV-2 infections and COVID-19 and methods of making the vaccines, wherein the vaccines contain an oil-in-water emulsion comprising tocopherol and squalene (entire document; see abstract.) Anosova teaches that in the vaccine or immunogenic composition, said composition would comprise one, two, three, or more different recombinant SARS-COV-2 S proteins, wherein one or more of the S proteins is present as a trimer (¶[0012-0013]; instant claims 6, 16), and wherein said different S proteins are from Alpha, Beta, Delta, or Gamma variants (¶[0086][0338-0363]; instant claims 7, 17) and said compositions elicit neutralizing antibody responses against one or more variants of SARS-CoV-2 (¶[0338-0363]; instant claim 21.)
It would have been obvious to one of ordinary skill in the art to further modify the DNA nanostructure compositions and immunization methods resulting from the combination of Bathe, Smith, and Cao to include nonidentical SARS-CoV-2 S proteins, including a D614 spike protein and a B.1.351 Beta-variant spike protein, as taught by Anosova, thereby providing a multivalent composition capable of eliciting immune responses against more than one SARS-CoV-2 variant. One would have been motivated to do so, given the suggestion by Bathe that multiple structurally different antigens may be displayed on the same DNA nanostructure and the suggestion by Anosova that a bivalent composition containing D614 and B.1.351 spike proteins broadens neutralizing activity against antigenically different SARS-CoV-2 variants. There would have been a reasonable expectation of success, given the knowledge that DNA nanostructures may present multiple distinct protein antigens while controlling their copy number and spatial arrangement, as taught by Bathe, and also given the knowledge that administration of the D614 and B.1.351 spike protein combination elicited neutralizing responses against multiple SARS-CoV-2 variants, as taught by Anosova. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 6-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10-19, and 13-27 of copending Application No. 18/701,901 (reference application) in view of Smith, Bathe, Cao, and Anosova (supra). 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 binding to SARS-CoV-2 S protein alpha, beta, gamma, and delta variants. The main difference is that the instant claims do not identify LCB1 as the SBP in the DNA-peptide hybrid molecule, and that the instant claims note the DNA-peptide hybrid can have more than one different type of SARS-CoV-2 S protein antigen. Further, the reference claims note that the SBP can be a nanobody, and may comprise a cleavable linker. However, these differences are obvious, especially given the teachings of Smith, Bathe, Cao, and Anosova, detailed supra. To further detail those teachings, Smith details that the linkers which join the peptide moieties to the nucleic acid scaffolds can be cleavable (¶[0110]) and that the linkers may be coupled to the nucleic acid scaffold by copper-free Click chemistry (¶[0185]). Bathe teaches the peptide moieties may be nanobodies (¶[0218]).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-4 and 6-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-10, 12-18, and 20-21 of copending Application No. 18/701,898 (reference application) in view of Bathe, Smith, and Anosova (all supra). 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. 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 a SBP as one of the linkers in the DNA-peptide hybrid molecule, and that said DNA-peptide hybrid is used in specific methods of treatment, namely in a method to treat SARS-CoV-2 infections, and that the DNA-peptide hybrid can have more than one different type of SARS-CoV-2 S protein antigen. Further, the reference claims note that the SBP is a nanobody, and do not claim the presence of adjuvants in the composition. However, these differences are obvious, especially given the teachings of Smith, Bathe, and Anosova, detailed supra. To further detail those teachings, Smith details that the linkers which join the peptide moieties to the nucleic acid scaffolds can be cleavable (¶[0110]) and that the linkers may be coupled to the nucleic acid scaffold by copper-free Click chemistry (¶[0185]). Bathe teaches the peptide moieties may be nanobodies (¶[0218]). Therefore, the differences between the instant claims and the ‘898 claims are not patentably distinct, especially given the teachings of Smith, Bathe, and Anosova.
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.
Trafton, A. Engineers use “DNA origami” to identify vaccine design rules. MIT News. 06/29/2020. https://news.mit.edu/2020/dna-origami-vaccine-design-rules-0629. Teaches DNA origami to build 3D-virus like shapes to display antigens, such as viral antigens from SARS-CoV-2. Not utilized as rejection would be redundant to those set forth supra.
Smith DM, et. al. Adv Nanobiomed Res. 2021 Mar;1(3):2000049. Epub 2021 Jan 6. Teaches how DNA nanotechnology is applied to detect, prevent, and treat infectious diseases. It highlights that DNA nanostructures (DDNs) offer immense potential for precise diagnostics, targeted drug delivery, and viral neutralization. Not utilized as rejection would be redundant to those set forth supra.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
Prosecution Insights