DETAILED ACTION
Disposition of Claims
Claims 1, 10, 16, 18, 22, 26, 28-29, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 were pending. Amendments to claims 1, 10, 22, 26, 33, 35, 49-50, and 53-56 are acknowledged and entered. Claims 2-9, 11-21, 23-25, 27, 29-31, 34, 36-41, 43, 46, 48, 51-52, and 57-59 are cancelled. New claim 60 is acknowledged and entered. Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, 53-56, and 60 will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240277831A1, Published 08/22/2024. Amendments to the specification presented on 11/04/2025 are acknowledged and entered.
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.
Response to Arguments
Applicant's arguments filed 11/04/2025 regarding the previous Office action dated 08/04/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/04/2025 and 11/25/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
(Objection withdrawn.) The objection to the abstract of the disclosure is withdrawn in light of the amendments to the abstract.
(New objection.) This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below.
The specification is objected to because Table 3 comprises sequence that does not identify said sequence with a corresponding SEQ ID NO:. See detailed explanation below.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See Table 3 as noted supra.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
(Objection withdrawn.) The objection to the drawings is withdrawn in light of the amendments to the specification.
(Objection withdrawn.) The objection to the disclosure is withdrawn in light of the amendments to the specification.
Claim Objections
(Objection withdrawn.) The objection to Claim 10 is withdrawn in light of the amendments to the claim.
Claim Rejections - 35 USC § 112 –
Judicially Approved Rejection for Improper Markush Grouping
(New rejection – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, 53-56, and 60 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The polypeptides and nanoparticles claimed have distinct amino acid sequences, distinct assembly patterns, and distinct epitopes for the reasons outlined infra.
The claims recite discrete severe acute respiratory syndrome coronavirus type 2 (SARS CoV-2) antigenic proteins, such as portions of spike (S) protein (receptor binding domain (RBD)), full-length “no repacked” (no Rpk) S protein wild-type sequences, or wild-type versions or full-length S prefusion stabilized S proteins/S protein ectodomains in a trimeric arrangement (S-2P Trimer)(¶[0121]). The claims also recite fusion to distinct assembly proteins, such as I53-50A (trimeric nanoparticles; NB: the use of “I53-50A” and “I53-50A*” is noted throughout and it is unclear if these are the same or variants). As noted by the specification (¶[0121]), I53-50B pentameric subunits and I53-50A subunits are combined to form the final nanoparticle, wherein 12 pentamers of I53-50B and 20 trimers of I53-50A formulate the final nanoparticle. Additionally, the resulting fusion proteins have further distinct sequences added, such as His Tags, serine/glycine linkers of various lengths (¶[0121]), and foldon domains (See Tables 1-3; NB: the use of “he” is noted in the fusion proteins but it is unclear as to what this refers.) Finally, claims 1 and 10 provide for there to be “at least 95% amino acid sequence identity” to the claimed proteins, which accounts for variants of any portion of the entire fusion proteins claimed, including the SARS CoV-2 S protein-derived regions, the I53-50A protein-derived regions, and additional tags/regions thereof, and includes, but is not limited to, mutations that are insertions, deletions, and/or substitutions.
As noted by Rutten et. al. (Rutten L, et. al. Sci Rep. 2024 Mar 8;14(1):5735.), changes to the SARS CoV-2 S protein can greatly affect the function and immunogenicity of this protein, as Rutten notes the differences especially between prefusion and postfusion forms of the S protein (entire document; see abstract.) As noted by Sung et. al. (Sung HD, et. al. Int J Mol Sci. 2021 Dec 14;22(24):13445.), these I53-50-dervied nanoparticles distinct genera of nanoparticle platforms that elicit distinct immune responses, depending on the . Sung teaches that the multivalent display of the S protein of I53-50 nanoparticles enhances cognate B cell activation in vitro compared with a trimeric form of the S protein (SARS-CoV-2 S-I53.50A.1NT1), while the S protein-displaying I53-50 nanoparticles successfully induced neutralizing antibody responses in mice and rabbit models and S protein-specific B and T cell responses in cynomolgus macaques (p. 4, ¶1). Sung teaches that there were distinct differences in the responsiveness of the use of RBD and prefusion-stabilized S protein (S2Pro) (platforms described by instant disclosure in Examples), and that the RBD-presenting nanoparticles mixed with I53-50A and I53-50B multimers elicited potent neutralizing activity against pseudo and live SARS-CoV-2, whereas the monomeric form of RBD and S2Pro showed little to no neutralizing effect. In particular, although linker length and antigenic valency do not substantially affect the overall immunogenicity, RBD I53-50 nanoparticles with 12 and 16 glycine and serine linkers induced 10-fold higher neutralizing antibody titers and neutralizing activity compared with S2Pro. Furthermore, RBD-specific germinal center B cells, which are essential for forming a durable B cell memory, were significantly increased with RBD I53-50 nanoparticle treatment compared with those with treatment with the monomeric forms of RBD and prefusion-stabilized S protein (S2Pro) (Sect. 3; p. 5).
As taught by Dowling et. al. (Dowling QM, et. al. bioRxiv [Preprint]. 2023 Jun 17:2023.06.16.545393. Update in: Nature. 2025 Feb;638(8050):553-561.), the I53-50 nanoparticle components can tolerate certain mutations (pp. 2-3, ¶ bridging pages through to p. 4, Fig. 1.) Variants of I53-50A, such as I53-50A.1NT1, I53-50A.1PT1, I53-50A.1NT2, have different stabilities and form different structures depending on the sequence of the I53-50B partner Bale JB, et. al. Science. 2016 Jul 22;353(6297):389-94.) Additionally, there is a noted modification of the N-terminal Helix of I53-50A, wherein the first two amino acids (MK) of the native I53-50A sequence are frequently replaced with a GGSGGSGGSGGSEKAAKAEEAARK linker, which aids in projecting the antigen further from the nanoparticle surface while adding flexibility (US20200392187A1).
As the nanoparticles-generating fusion proteins encompassed by the instant claims do not comprise a singular structural similarity nor a common use, the Markush grouping is improper.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection withdrawn.) The rejection of Claims 1, 10, and 56 and dependent claims 16, 18, 22, 26, 28-29, 32-33, 35, 42, 44-45, 47, 49-50, and 53-55 thereof under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claims.
(Rejection withdrawn.) The rejection of Claims 16 and 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the cancellation of said claims.
(Rejection withdrawn.) The rejection of Claim 18 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the cancellation of said claim.
(Rejection withdrawn.) The rejection of Claim 50 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claim.
(Rejection withdrawn.) The rejection of Claims 53-54 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claims.
(Rejection withdrawn.) The rejection of Claim 55 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claim.
(Rejection withdrawn.) The rejection of Claim 56 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to said claim.
Claim Rejections - 35 USC § 112(d); Fourth Paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
(New rejection – necessitated by amendment). Claim 35 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 35 depends upon claim 10, wherein claim 10 notes that the second protein may be selected from the group consisting of SEQ ID NOs: 1, 2, 5, 6, 8-10, 13-16, 21-24, 142-151, 168, and 170, or a sequence 95% identical thereto. Claim 35 broadens this Markush group by claiming the inclusion of SEQ ID NOs: 3-4 and 7. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim 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 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170.
Claim 10 is drawn to a nanoparticle, comprising:
(a) a plurality of first assemblies, each first assembly comprising a plurality of identical first proteins; and,
(b) a plurality of second assemblies, each second assembly comprising a plurality of second proteins;
wherein the amino acid sequence of the first protein differs from the sequence of the second protein;
wherein the plurality of first assemblies non-covalently interact with the plurality of second assemblies to form the nanoparticle;
wherein the nanoparticle displays on its surface an immunogenic portion of a severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) antigen or a variant or homolog thereof, present in the at least one second protein, and
wherein the second proteins comprise an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170.
Further limitations on the nanoparticle of claim 10 are wherein:
(a) the plurality of second assemblies in total comprise 2, 3, 4, 5, 6, 7, 8, or more different SARS-CoV-2 antigens;
(b) the plurality of second assemblies in total comprise 2, 3, 4, 5, 6, 7, 8, or more polypeptides comprising the amino acid sequence of a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170;
(c) all second assemblies comprise at least one second protein comprising the amino acid sequence of a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170; and/or
(d) all second proteins comprise the amino acid sequence of a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170 (claim 22); wherein the first protein comprises an amino acid sequence that is at least 95% identical to the amino acid sequence selected the group consisting of SEQ ID NOS:152-159 (NB: I53-50B sequences; claim 26); wherein the first protein comprises the amino acid sequence of SEQ ID NO:155 (claim 28), wherein each first assembly is pentameric and each second assembly is trimeric (claim 32); wherein: (a) the first protein comprises the amino acid sequence of SEQ ID NO:155;
(b) at least 20% of the second proteins comprise an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:1 (claim 33); wherein:
(a) the first protein comprises the amino acid sequence of SEQ ID NO:155;
(b) all second proteins comprise an amino acid sequence selected from the group consisting of SEQ ID NO:1-8 (claim 35); a pharmaceutical composition comprising the nanoparticle of claim 10; and (b) a pharmaceutically acceptable carrier (claim 42), further comprising an adjuvant (claim 44); and a vaccine comprising the nanoparticle of claim 10 (claim 45).
Claim 47 is drawn to a method to treat or limit development of a SARS-CoV-2 infection, comprising administering to a subject in need thereof an amount effective to treat or limit development of the infection the pharmaceutical composition of claim 42.
Further limitations on the method of claim 47 are wherein the subject is not infected with SARS-CoV-2 and the administering elicits an immune response against SARS-CoV-2 in the subject that limits development of a SARS-CoV-2 infection in the subject (claim 49), wherein the administering comprises administering a first dose and a second dose, wherein the second dose is administered about 2 weeks to about 12 weeks after the first dose is administered, or about 4 weeks to about 12 weeks after the first dose is administered (claim 50); wherein the immune response comprises generation of neutralizing antibodies against SARS-CoV-2 (claim 53); wherein the immune response comprises generation of SARS-CoV-2 spike protein antibody-specific responses with a mean geometric titer of at least 1 x 10^5 (claim 54); and wherein the subject is infected with SARS-CoV-2, and the administering elicits an immune response against SARS CoV-2 in the subject that treats a SARS CoV-2 infection in the subject (claim 55).
Claim 56 is drawn to a kit, comprising:
(a) a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170; and
(b) a first protein comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected the group consisting of SEQ ID NOS:152-159.
Further limitations on the kit of claim 56 is wherein the first protein comprises the amino acid sequence of SEQ ID NO: 155 (claim 60).
Claim Rejections - 35 USC § 112(a); First Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain 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. Note the rejection of claims 16, 18, and 29 is withdrawn in light of the cancellation of said claims and is extended to include new claim 60.
The claims 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, 53-56, and 60 are rejected as lacking adequate descriptive support for generating any nanoparticle comprising any of the plurality of assemblies which displays any immunogenic portion of any SARS CoV-2 antigen, especially any nanoparticle that would be useful in generation of pharmaceutical compositions, such as vaccines, for the therapeutic or prophylactic treatment of any SARS CoV-2 infection in any host. Additionally, the claims are rejected as lacking adequate descriptive support for any polypeptide comprising any amino acid sequence at the percent identity claimed with the claimed optional sequences.
In support of the claimed genera (any polypeptide with the percent identity claimed with optional residues claimed), the application discloses fusion proteins that may be generated with the “base” nanoparticle-forming I53-50 or I3-01 sequences (e.g. Table 2 provides the sequences for the I53-50A and 2-I3-01 base proteins, I53-based “degreased” nanoparticle protein sequences, different serine/glycine (ser/gly) linkers of various lengths, and His and/or foldon tags) and provides for different SARS CoV-2 spike (S) glycoprotein sequences which may be fused to this “base” nanoparticle sequence. As presently claimed with the percent identity variation, this equates to a large amount of possible mutations (including, but not limited to, substitutions, insertions, and/or deletions) of the claimed fusion proteins. The mutations may occur anywhere within the fusion proteins, which have been narrowed to only include the I53-50A proteins which are fused to the S protein variants. Therefore, the S protein may be mutated, the I53-50A protein may be mutated, and/or any of the additional claimed regions (e.g. some of the proteins have ser/gly linkers, His tags, and other elements) may be mutated. While the claims have been narrowed to only those with 95% or greater identity to those sequences claimed, this still equates to a very large amount of possible proteins, and it brings into question whether or not Applicant or the art was in possession of the breadth of claimed fusion proteins. While certain derivatives, variants, and/or mutants thereof are disclosed for the SARS CoV-2 S protein portion of the fusion protein, it is unclear if any I53-50A fusion protein variants have been provided for and/or tested, especially for those I53-50A variants which would still possess the function of being able to form nanoparticles. Thus, the Application fails to provide a sufficient number of examples of species within the claimed genus.
In support of the claimed genera (any polypeptide with the percent identity claimed, and any nanoparticle comprising any SARS CoV-2 antigen), the application discloses examples in which specific SARS CoV-2 S protein receptor binding domain (RBD) constructs are bound to specific I53-50A protein sequences with ser/gly linkers of different lengths and also exhibit the ability to form nanoparticles, specifically immunogenic nanoparticles (See the example starting at ¶[0238]). The RBD was tested in either monomeric form (RBD), or as a pre-fusion stabilized trimeric ectodomain (S-2p)(¶[0127]). Table 3 provides for protein sequences which were formed and utilized to generate the nanoparticles (¶[0122]).
As the art noted the limited immunogenicity of this small, monomeric antigen, said RBD residues (328-531) were multivalently displayed on the exterior surface of the two-component protein nanoparticle I53-50. The I53-50 nanoparticle is a computationally designed, 28 nm, 120-subunit complex with icosahedral symmetry constructed from trimeric (I53-50A) and pentameric (I53-50B) components (all amino acid sequences provided in Table 3), and the nanoparticle can be assembled in vitro by simply mixing independently expressed and purified I53-50A and I53-50B. The specific sequence of SARS CoV-2 S RBD (residues 328-531) was genetically fused to I53-50A using linkers comprising 8, 12, or 16 glycine and serine residues (referred to as RBD-8GS-, RBD-12GS-, or RBD-16GS-I53-50A) to enable flexible presentation of the antigen on the nanoparticle surface (¶[0121]). Not all constructs bound to the known receptor (ACE2) or neutralizing antibodies with the same valency, and it was noted that the longer linkers between the “base” I53-50A peptide and RBD antigen allowed for better interaction (¶[0126][0132]).
No other variants, fragments, or derivatives of SARS CoV-2 S protein RBD were tested. No other SARS CoV-2 proteins from any other region on the S protein, including the full-length S protein, nor were any other non-S protein antigens tested on the nanoparticle platform. No other I53-50A sequences, variants, or mutants were tested. Current SARS CoV-2 drugs and vaccines used to treat or prevent COVID-19 are predominantly targeted to the S protein, but the rapid mutation in this region can easily lead to drug resistance. SARS CoV-2 encodes 16 nonstructural proteins (Nsp1-Nsp16) that form the replication and transcription complex (RTC). SARS CoV-2 also encodes the structural proteins spike (S) glycoprotein, nucleocapsid (N) protein, envelope (E) protein, and membrane (or Matrix) (M) glycoprotein (notably, the M protein is difficult to be expressed and purified.) No other fusion proteins aside from the I53-50A proteins fused to the RBD with a variable length flexible ser/gly linker were tested.
In other words, no derivatives, variants, or mutants thereof are disclosed that can achieve the ability to form stable SARS CoV-2 antigen-expressing nanoparticles aside from those three RBD-I53-50A nanoparticles (e.g. RBD-8GS-, RBD-12GS-, and RBD-16GS-I53-50A nanoparticles) of the instant specification which were specifically analyzed for immunogenicity and stability. As noted supra, the amount of possible SARS CoV-2 S protein mutants claimed, along with the possible flexible linkers claimed, along with the nanoparticle “base” protein mutants claimed, is extraordinarily large, and it brings into question whether or not Applicant or the art was in possession of the breadth of the polypeptides claimed, especially those polypeptides which could assemble into the nanoparticles claimed. Thus, the application fails to provide examples of a sufficient number of species within the claimed genera.
Further, while some of the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, there is no evidence that any SARS CoV-2 antigen of any size or any origin can be fused to any “base” nanoparticle protein sequence with or without any linker sequence and retain the ability to 1) formulate nanoparticles and 2) have said nanoparticles be sufficiently immunogenic to be useful therapeutically. Moreover, no correlation has been made as to which SARS CoV-2 antigens aside from RBD of S protein are required to bind to which “base” nanoparticle-forming sequence in order to achieve the claimed functions of forming nanoparticles and having said nanoparticles present the antigen in a way that is recognized by the host immune system.
The teachings of the art also fail to indicate that those in the art would have expected the full scope of all of the claimed fusion proteins and percent variants thereof to confer the claimed ability to formulate nanoparticles, and to formulate nanoparticles which also presented the antigen in a format sufficient for generation of a therapeutic immune response in any host. While the teachings of the art provide for how to make mutations to proteins, the sheer breadth of proteins claimed makes it difficult for a skilled artisan to know for certain that applicant was in possession of the breadth of not only the possible fusion proteins claimed, but those fusion proteins which could assemble into nanoparticles which would also be useful for immunogenic compositions.
As argued in the previous Office action, a search of the art indicates that modifications to biological molecules such as proteins are unpredictable, and require experimentation regarding the relationships between alterations in sequence bases/side chains and the function and structure of the protein in order to determine the actual effects of the modifications as discussed by Bowie et al. (Bowie JU, et. al. Science. 1990 Mar16;247(4948):1306-10; CITED ART OF RECORD; See page 1306). The art also shows that single amino acid mutations in the antibodies can greatly affect the ability of said antibody to bind to its target antigen (Winkler K, et. al. J Immunol. 2000 Oct 15;165(8):4505-14.; See also Kussie PH, et. al. J Immunol. 1994 Jan 1;152(1):146-52.; BOTH CITED ART OF RECORD) When single amino acid mutations are generated, or when the combination or order of CDRs within an antibody is altered, it affects the neutralizing capability of the resulting antibody or fragment thereof (Chen Z, et. al. Nat Commun. 2015 Mar 30;6:6714.; CITED ART OF RECORD.) The art has further highlighted the importance of the order of CDRs, the interaction of non-CDR domains with respect to antigen/epitope binding, and that antigen-antibody algorithms or epitope prediction software/rational antibody design is highly inaccurate (Sela-Culang I, et. al. Front Immunol. 2013 Oct 8;4:302.; CITED ART OF RECORD.) Computational in silico methods have traditionally struggled to predict the effect of mutations in antibody–antigen complexes on binding affinity, and generation of actual mutants in vitro of antibodies is the preferred and reliable method to determine the effect of mutations on antigen-antibody binding (Sirin S, et. al. Protein Sci. 2016 Feb;25(2):393-409. Epub 2015 Nov 6.; CITED ART OF RECORD.) The CDR positions are also vital, as it is shown the length and sequence of the CDR in the H3 position can affect the overall binding capability of the antibody (Tsuchiya Y, et. al. Protein Sci. 2016 Apr;25(4):815-25. Epub 2016 Jan 20.; CITED ART OF RECORD.) The antigen itself can determine what lengths of CDRs are tolerated (Collis AV, et. al. J Mol Biol. 2003 Jan 10;325(2):337-54.; CITED ART OF RECORD.). Further, CDRs may vary depending on the numbering system utilized. The Chothia, Kabat, Martin, IMGT, Honneger, and Gelfand numbering schemes all differ, and depending on the numbering system utilized, one may end up with wildly different antibodies with functional differences distinct from the original antibody (See e.g. Dondelinger M, et. al. Front Immunol. 2018 Oct 16;9:2278.; CITED ART OF RECORD.) While the majority of these examples focus on mutations to antibodies and how they affect the structure of said proteins, ability to bind to their original targets, and overall immune response, these results highlight the pitfalls in attempting to describe a protein functionally and/or with a percent identity to known sequence.
Even further, when generating nanoparticles (NPs) for vaccine development, several key physicochemical and biological factors must be examined to ensure they can effectively deliver antigens, stimulate a robust immune response, and remain safe for human use. The most critical considerations include particle size, surface charge (zeta potential), loading efficiency, stability, and safety profile (Pati R, et. al. Front Immunol. 2018 Oct 4;9:2224.) Extensive testing of the I53-50 platform and variants thereof show that significant assembly issues arise with different I53-50A and I53-50B sequence variants (see Examples starting at ¶[0103] of US20160122392A1.) As noted in the previous Office action and repeated in the 35 USC 112a scope of enablement rejection infra, the teachings of Bale show that mutations to the I53-50A sequences affected the ability of these peptides to form multimers and associate with cargo. Therefore, it is unclear from the art that the claimed fusion proteins would be able to confer the claimed function of formulating nanoparticles, especially when the additional binding partner for I53-50A is unclear.
Thus, in view of the above, there would have been significant uncertainty as to which fusion proteins Applicant was in possession of, and significant uncertainty as to which fusion proteins could be generated and be able to confer the claimed functions of formulating nanoparticles and having said nanoparticles be sufficiently functional to present antigens in a therapeutic setting. In view of this uncertainty and the lack of sufficient examples of the broadly claimed genera, the claims are rejected for lack of adequate written description support.
Response to Arguments
Applicant's arguments filed 11/04/2025 have been fully considered but they are not entirely persuasive.
Applicant argues that with the claims being amended to only be drawn to SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170 that since the specification describes these sequences and relates specifically to these fusion proteins of both SARS CoV-2 RBD and I53-50A joined with a ser/gly linker that they have demonstrated possession of the genera. The Office disagrees for the reasons elaborated upon supra. With such a large variable % identity claimed, and from the guidance and teachings of the art, it is not clear that Applicant demonstrated possession of the fusion proteins as claimed that would encompass those sequences with 95% identity to SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170. It is unclear that Applicant was in possession of the mutants and variants of these sequences of said fusion proteins, especially those that would formulate nanoparticles and/or be therapeutically relevant in the methods as claimed.
For at least these reasons, Applicant’s arguments are not persuasive, and the rejection has been maintained.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain 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 fusion proteins of SARS CoV-2 RBD peptides bound to I53-50A peptides through flexible ser/gly linkers, does not reasonably provide enablement for any SARS CoV-2 protein, variant, or homolog thereof bound to any peptide capable of being a “base” for nanoparticles with or without linkers and for the ability of said peptide to form nanoparticles, especially nanoparticles useful in therapeutic methods. Note the rejection of claims 16, 18, and 29 is withdrawn in light of the cancellation of said claims and is extended to include new claim 60. 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/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to polypeptides comprising an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170. The claims are also drawn to nanoparticles comprising:
(a) a plurality of first assemblies, each first assembly comprising a plurality of identical first proteins; and,
(b) a plurality of second assemblies, each second assembly comprising a plurality of second proteins;
wherein the amino acid sequence of the first protein differs from the sequence of the second protein;
wherein the plurality of first assemblies non-covalently interact with the plurality of second assemblies to form the nanoparticle;
wherein the nanoparticle displays on its surface an immunogenic portion of a severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) antigen or a variant or homolog thereof, present in the at least one second protein, and
wherein the second proteins comprise an amino acid sequence that is at least 95% identical to the amino acid sequence selected from the group consisting of SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170.
The claims are also drawn to kits which comprise said fusion polypeptides of claim 1 (I53-50A fusion peptides) and I53-50B peptides (SEQ ID NOs: 152-159); compositions which comprise said nanoparticles, and methods of using said compositions comprising said nanoparticles to treat or limit development of any SARS CoV-2 infection.
The breadth of an “immunogenic portion of a SARS-CoV-2 antigen or a variant or homolog thereof” includes not only all proteins encoded by SARS CoV-2, including all structural (e.g. E, S, M, N proteins) and non-structural (Nsp1-16) proteins, but immunogenic fragments of any of these proteins, wherein said fragment may comprise a linear and/or conformational epitope. The breadth also includes any homologous proteins to these SARS CoV-2 proteins, which includes proteins and fragments thereof from any other member of the family Coronaviridae, which includes, but is not limited to, such viruses as SARS CoV-1, MERS CoV, and human coronaviruses (HuCoV) -229E, -OC43, -NL63, and -HKU1. The breadth also includes any variants or mutants thereof of said SARS CoV-2 or homologs.
The breadth of the proteins encompassed by 95% amino acid sequence identity to any one of SEQ ID NOS: 1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170 is broad as per the rejections set forth supra, but at least includes any deletion, substitution, or insertion mutant which would be at least 95% identical to these sequences. Said sequences are fusion proteins which minimally comprise a SARS CoV-2 S protein RBD sequence fused to a I53-50A multimeric assembly sequence, wherein the fusion protein comprises a flexible serine/glycine linker of various lengths. Some sequences include additional sequence, such as a His tag. Said sequences being drawn to 95% identity may comprise any type of mutation(s), including deletions, insertions, and substitutions.
The breadth of “nanoparticle” is reasonably any microscopic particle comprising said proteins with at least one dimension measuring between 1 and 100 nm.
The breadth of “immunogenic portion” of the claimed SARS CoV-2 proteins, variants, mutants, and homologs thereof is any portion of these proteins that may trigger any type of immune response in any host, leading to the production of any innate or adaptive immune response in the host, wherein the adaptive immune response includes any humoral (antibody) or cellular (T-cell) immune response. It is important to note that many of the proteins expressed by SARS CoV-2 are glycosylated, and for proper folding and glycosylation patterns of said proteins, the expression system for said antigens is essential to ensure proper antigenicity in the host.
State of the prior art/Predictability of the art. With respect to the nanoparticle production comprising first and second assemblies, the prior art detailed the production of pairwise combinations of dimeric, trimeric, or pentameric building blocks to design two-component, 120-subunit protein complexes with three distinct icosahedral architectures, where the capsid-like nanostructures are large enough to hold nucleic acids or other proteins, and because they have two components, the assembly of cargoes such as drugs and vaccines can be done in a controlled way (Bale JB, et. al. Science. 2016 Jul 22;353(6297):389-94.; CITED ART OF RECORD). Bale tested a large variety of structures which fit this “first and second assemblies” architecture (p. 391, left col.), with only a subset of said assemblies showing the ability to form nanoparticles. The I53-50 nanoparticle architecture (formed from a combination of 12 pentameric building blocks and 20 trimeric building blocks aligned along the fivefold and threefold icosahedral symmetry axes, respectively) was one particular nanoparticle interface which displayed the ability to form assemblies that were stable. However, Bale showed that mutations to these I53-50 nanoparticle building blocks affected their ability to assemble and associate cargo, and also that the reagents in which the proteins were assembled (e.g. buffers and additional salt components) also affected their ability to associate correctly (See e.g. Fig. 2 of Bale).
With respect to SARS CoV-2, a coronavirus (CoV) highly related to SARS-CoV, this virus emerged in late 2019 and gave rise to a global pandemic. As noted supra, SARS CoV-2 is an enveloped virus that encodes structural (e.g. E, S, M, N proteins) and non-structural (Nsp1-16) proteins. Similar to other coronaviruses, SARS-CoV-2 entry into host cells is mediated by the transmembrane spike (S) glycoprotein, which forms prominent homotrimers protruding from the viral surface. Cryo-electron microscopy structures of SARS-CoV-2 S revealed its shared architecture with SARS-CoV S and provided a blueprint for the design of vaccines and antivirals. Both SARS-CoV-2 S and SARS-CoV S bind to angiotensin-converting enzyme 2 (ACE2), which serves as entry receptor. Structures of the SARS-CoV-2 S receptor-binding domain (RBD) in complex with ACE2 defined key residues involved in recognition and guide surveillance studies aiming to detect the emergence of mutants with altered binding affinity for ACE2 or distinct antigenicity. As the coronavirus S glycoprotein is surface-exposed and initiates infection, it is the main target of neutralizing antibodies (Abs) upon infection and the focus of vaccine design. S trimers are extensively decorated with N-linked glycans that are important for proper folding and for modulating accessibility to host proteases and neutralizing Abs (See e.g. Walls AC, et. al. bioRxiv [Preprint]. 2020 Aug 12:2020.08.11.247395. Update in: Cell. 2020 Nov 25;183(5):1367-1382.e17; CITED ART OF RECORD.)
With respect to generation of synthetic nanoparticles which display SARS CoV-2 antigens, the pre- and post-filing art shows that with the emergence of this novel, pandemic-causing virus, many known vaccine platforms were quickly adapted to express antigens of SARS CoV-2, namely the S protein. The I53-50 nanoparticle was one platform, wherein I53-50 is a computationally designed, 28 nm, 120-subunit complex with icosahedral symmetry constructed from trimeric (I53–50A) and pentameric (I53–50B) components. Said nanoparticle could be assembled in vitro by simply mixing independently expressed and purified I53–50A and I53–50B, a feature that has facilitated its use as a platform for multivalent antigen presentation. While these I53-50-based platforms with longer ser/gly flexible linkers showed the best immune response when displaying the RBD on the surface of the synthetic nanoparticle, post-filing art noted that these RBD nanoparticle vaccines were not expected to provide protection against distantly related coronaviruses (e.g., MERS-CoV) due to substantial sequence variation among the RBDs of coronavirus S glycoproteins. It was noted that optimizing the expression, stability, and multivalent display of prefusion S ectodomain trimers may lead to elicitation of even broader Ab responses based on the greater sequence and structural conservation of the S2 subunit (i.e., the fusion machinery) among coronaviruses and the fact that it contains conserved epitopes that are targeted by neutralizing Abs such as the fusion peptide. Although a single approach was suggested as possibly being enough for generating protective responses against multiple closely related coronaviruses (e.g., sarbecoviruses), the genetic diversity across lineages and genera will likely necessitate a combination of several vaccine design approaches (Walls, “Discussion”.)
Working examples. The working example disclosed in the specification utilized only the I53-50 nanoparticle platform, and no variants thereof, wherein said nanoparticle is a 28 nm, 120-subunit complex with icosahedral symmetry constructed from trimeric (I53–50A) and pentameric (I53–50B) components. SEQ ID NOs: 152-159 appear to be I53-50B variants (¶[0067]: I53-50B, I53-50B.1, I53-50B.1NegT2, I53-50B.4PosT1, I53-50B.4PosT1, I53-50-v4 pentameric component, I53-5-v1 pentameric component B, I53-50-v2 pentameric component B, i53-50-v3 pentameric component B). The SARS CoV-2 RBD was fused to the I53-50A subunit via flexible ser/gly linkers of various lengths and expressed in mammalian cells to ensure correct glycosylation of the RBD antigen. This single RBD antigen expressed on the I53-50 nanoparticle platform was tested in mouse models and non-human primates to determine the immune response elicited by said nanoparticles. Said compositions were used in combination with the ADDAVAX™ adjuvant, and mice were challenged with SARS CoV-2-mouse adapted virus. No other SARS CoV-2 antigens, including other RBD sequences, other full-length S protein sequences, any other structural or non-structural SARS CoV-2 proteins or fragments thereof, or other CoV proteins or fragments thereof were tested in this platform. No other non-I53-50 synthetic nanoparticle platforms were tested. All tests were performed with flexible ser/gly linkers joining the RBD to the I53-50A subunit of various lengths, namely 8, 12, and 16 amino acids. The RBD was not bound to the I53-50B subunit or any other synthetic nanoparticle subunit and tested. All challenge studies were performed with SARS CoV-2; no other non- SARS CoV-2 viruses were used for viral challenge to determine the level of cross-protection afforded by the I53-50A-linker-RBD nanoparticle compositions.
Guidance in the specification. The specification provides guidance towards generation of SARS CoV-2 spike protein RBD domains fused via a flexible ser/gly linker of 8 12, or 16 amino acids to I53-50A, and then to combine said RBD-linker-I53-50A with I53-50B to generate nanoparticles, wherein said nanoparticles elicit a therapeutic immune response specific to SARS CoV-2. It is not clear if the RBD nanoparticles provided cross-reactive protection against other SARS CoV-2 variants, and testing for cross-reactive protection against other SARS CoV or other CoV was not determined. No other SARS CoV-2 sequences for S protein (e.g. ectodomain, prefusion S protein, postfusion S protein, etc.) aside from the listed RBD (residues 328-531) of a singular SARS CoV-2 S protein were tested. No other SARS CoV-2 proteins were fused to the I53-50A sequence. No other I53-50A sequences (e.g. variants, mutants, etc.) were fused to any other SARS CoV-2 protein and tested for their ability to formulate nanoparticles.
Amount of experimentation necessary. Additional research is required in order to determine how to 1) make the breadth of proteins encompassed by the instant claims, 2) how to make the breadth of nanoparticles encompassed by the instant claims, and 3) how to use the breadth of nanoparticles encompassed by the instant claims in methods of therapeutic inoculation against infection from SARS CoV-2 and other SARS CoV.
Furthermore, in light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the large number of possible proteins which can be generated that fall under the breadth of the claimed invention is large as the fusion proteins and nanoparticles comprising said proteins is at 95% identity, and would require undue experimentation to synthesize and test a representative number of species that would be encompassed by this percent identity. It would require further undue experimentation to screen those proteins to determine which would formulate nanoparticles, and even further undue experimentation to determine which resulting nanoparticles could be utilized in immunogenic compositions for methods of inhibiting SARS CoV-2 infections, and whether or not said nanoparticles would aid in inhibiting infection from variants of SARS CoV-2.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed proteins, nanoparticles, and methods.
Response to Arguments
Applicant's arguments filed 11/04/2025 have been fully considered but they are not entirely persuasive.
Applicant argues that with the claims being amended to only be drawn to SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170 that since these sequences relates to a fusion protein of a SARS CoV-2 RBD bound to an I53-50A protein, that said sequences fall under the scope of those enabled proteins identified by the Office. The Office disagrees for the reasons elaborated upon supra. With such a large variable % identity claimed, and from the guidance and teachings of the art, it is not clear that the art or the specification is enabled for the breadth of potential variants or mutants of the fusion proteins as claimed that would encompass those sequences with 95% identity to SEQ ID NOS:1, 2, 5-6, 8-10, 13-16, 21-24, 142-151, 168, and 170. It would require extremely undue experimentation to generate these fusion proteins and test for their stability, and it would require a large and undue amount of further experimentation to determine which fusion proteins could then formulate nanoparticles with the other multimeric proteins as claimed, and which ones would be therapeutically relevant to use in the compositions, kits, and methods as claimed.
For at least these reasons, Applicant’s arguments are not persuasive, and the rejection has been maintained.
Double Patenting
The text regarding nonstatutory double patenting was presented in a previous Office action.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain 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. Note the rejection of claims 16, 18, and 29 is withdrawn in light of the cancellation of said claims and is extended to include new claim 60.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 10, 13-14, 17, 20-26, 34, 55, 88, and 97-98 of copending Application No. 19/118,077 (reference application). Note the rejection of claims 16, 18, and 29 is withdrawn in light of the cancellation of said claims and is extended to include new claim 60. The rationale behind this rejection was presented in a previous Office action and will not be repeated herein.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 49 and 74-98 of copending Application No. 18/884,675 (reference application) in view of Bale (supra) and Baker et. al. (US20150356240A1, Pub. 12/10/2015; hereafter “Baker”.) Note the rejection of claims 16, 18, and 29 is withdrawn in light of the cancellation of said claims and is extended to include new claim 60. The rationale behind this rejection was presented in a previous Office action and will not be repeated herein.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6, 12-16, 18, 27-32, and 36 of copending Application No. 18/853,519 (reference application). Note the rejection of claims 16, 18, and 29 is withdrawn in light of the cancellation of said claims and is extended to include new claim 60. The rationale behind this rejection was presented in a previous Office action and will not be repeated herein.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-10, 20, 27, 35-36, and 45-47 of copending Application No. 18/359,154 (reference application). Note the rejection of instant claims 16, 18, and 29 and reference claims 41-44 is withdrawn in light of the cancellation of said claims and is extended to include new instant claim 60. The rationale behind this rejection was presented in a previous Office action and will not be repeated herein.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(Rejection maintained in part and extended – necessitated by amendment.) Claims 1, 10, 22, 26, 28, 32-33, 35, 42, 44-45, 47, 49-50, and 53-56 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Pat. No. 12,129,465 in view of Bale (supra) and Baker et. al. (US20150356240A1, Pub. 12/10/2015; hereafter “Baker”.) Note the rejection of claims 16, 18, and 29 is withdrawn in light of the cancellation of said claims and is extended to include new claim 60. The rationale behind this rejection was presented in a previous Office action and will not be repeated herein.
Response to Arguments
Applicant's arguments filed 11/04/2025 have been fully considered but they are not entirely persuasive.
Applicant has requested that the non-statutory obviousness-type double patenting rejection be held in abeyance until allowable subject matter is indicated in the present application. However, said rejections must be maintained as a matter of record until the appropriate terminal disclaimers have been filed, or until the claims have been amended in such a way as to not claim patently identical subject matter.
For at least these reasons, Applicant’s arguments are not persuasive, and the rejections have been maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671