DETAILED ACTION
Disposition of Claims
Claims 1-66 were pending. Claims 2-6, 8, 11-15, 17-41, 43-45, 47, 49-51, 53-54, 57-58, 61-62, and 66 have been cancelled. New claims 67-70 are acknowledged and entered. Claims 1, 7, 9-10, 16, 42, 46, 48, 52, 55-56, 59-60, 63-65, and 67-70 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 US20230165952A1, Published 06/01/2023. Amendments presented to the specification on 10/15/2025 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.
The Power of Attorney filed 09/17/2025 is acknowledged and entered.
Response to Arguments
Applicant's arguments filed 10/15/2025 regarding the previous Office action dated 07/15/2025 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 If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn.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arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Specification
(Objection withdrawn.) The objection to the abstract of the disclosure is withdrawn in light of the amendments to the abstract.
Nucleotide and/or Amino Acid Sequence Disclosures
(Objection withdrawn.) The objection to the disclosure regarding sequence disclosures is withdrawn in light of the amendments to the specification.
Claim Objections
(Objection withdrawn.) The objection to Claims 5-15 and 19-66 under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim is withdrawn in light of the amendments to the claims.
(New objection.) Claim 9 is objected to because of the following informalities: the definition of the abbreviation “RBD” is not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … receptor binding domain (RBD)...).
Appropriate correction is required.
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 Claim 4 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 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.
(New rejection – necessitated by amendment.) Claim 42 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 42 is drawn to the vaccine according to claim 1, wherein said targeting unit i) comprises antibody binding regions with specificity for surface molecules or receptors on antigen presenting cells (APCs),and/or ii) has affinity for a chemokine receptor selected from CCR1, CCR3 and CCR5, or iii) has affinity for MHC class II proteins. However, the use of “and/or” after item “i)” at line 5 in conjunction with the use of “or” after item “ii)” at line 6 makes it unclear what combinations of “i)”, “ii)”, and “iii” are (or are not) intended. The claim will be interpreted as having “and/or” at line 6 after item “ii)” for the purpose of examination, but the wording must be updated to clarify the metes and bounds of what is being claimed.
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 vaccine comprising an immunologically effective amount of:
(i) a polynucleotide comprising a nucleotide sequence encoding a targeting unit that interacts with surface molecules on antigen-presenting cells, a dimerization unit and an antigenic unit, wherein the antigenic unit comprises at least one betacoronavirus epitope; or
(ii) a polypeptide encoded by the polynucleotide as defined in (i), or
(iii) a dimeric protein consisting of two polypeptides encoded by the polynucleotide as defined in (i); and
a pharmaceutically acceptable carrier.
Further limitations on the vaccine according to claim 1 are wherein the at least one betacoronavirus epitope comprises or is a part of the spike protein (claim 7); wherein the at least one betacoronavirus epitope comprises or is the receptor binding domain (RBD) or a part of the RBD (claim 9), wherein the at least one betacoronavirus epitope comprises or consists of an amino acid sequence having at least 70% sequence identity to the amino acid sequence of SEQ ID NO: 231 or SEQ ID NO: 802, or SEQ ID NO: 803 or SEQ ID NO: 804 or SEQ ID NO: 805 (claim 10); wherein the at least one betacoronavirus epitope is a T cell epitope and the antigenic unit comprises multiple T cell epitopes which are separated by linkers (claim 16); wherein said targeting unit i) comprises antibody binding regions with specificity for surface molecules or receptors on antigen presenting cells (APCs), ii) has affinity for a chemokine receptor selected from CCR1, CCR3 and CCR5, and/or iii) has affinity for MHC class II proteins (claim 42); wherein the targeting unit is human MIP-1alpha (claim 46); wherein the dimerization unit comprises a hinge region, or wherein the dimerization unit comprises a hinge region, another domain that facilitates dimerization, and a dimerization unit linker, which connects the hinge region and the other domain that facilitates dimerization (claim 48); wherein the vaccine comprises the polynucleotide (claim 52); wherein said betacoronavirus is one selected from SARS-CoV, MERS-CoV, SARS-CoV- 2, HCoV-OC43 and HCoV-HKU1 (claim 55); a polynucleotide as defined in claim 1, or a vector comprising a polynucleotide as defined in claim 1 (claim 56); a polypeptide encoded by the polynucleotide as defined in claim 1 (claim 59); a dimeric protein consisting of two polypeptides as defined in claim 59 (claim 60); wherein the vaccine comprises the polynucleotide and wherein the polynucleotide comprises a nucleotide sequence encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 233 (amino acid sequence of signal peptide and mature peptide of hMIP1α (LD78b), human hinge region 1 from IgG3, human hinge region 4 from IgG3, glycine-serine linker, human CH3 domain of IgG3 and glycine-leucine linker; claim 67); wherein the vaccine comprises the polynucleotide and wherein the polynucleotide comprises a nucleotide sequence encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 295 (amino acid sequence of VB2129; claim 68); wherein the vaccine comprises the polynucleotide and wherein the polynucleotide comprises a nucleotide sequence encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 255 (amino acid sequence of VB2060; claim 69); and wherein the vaccine comprises the polynucleotide and wherein the polynucleotide comprises the nucleotide sequence of SEQ ID NO: 294 (nucleotide sequence encoding VB2129) or SEQ ID NO: 254 (nucleotide sequence encoding VB2060; claim 70).
Claim 63 is drawn to a method of preparing the vaccine according to claim 1, wherein the vaccine comprises the polypeptide or the dimeric protein and wherein said method comprises:
a) transfecting cells with the polynucleotide as defined in claim 1;
b) culturing the cells;
c) collecting and purifying the dimeric protein or the polypeptide expressed from the cells; and
d) mixing the dimeric protein or polypeptide obtained from step c) with the pharmaceutically acceptable carrier.
Claim 64 is drawn to a method for preparing the vaccine according to claim 1, wherein the vaccine comprises the polynucleotide and wherein the method comprises:
a) preparing the polynucleotide;
b) optionally cloning the polynucleotide into an expression vector; and
c) mixing the polynucleotide obtained from step a) or the vector obtained from step b) with the pharmaceutically acceptable carrier.
Claim 65 is drawn to a method for treating a subject having suffering from a betacoronavirus infection or being in need of prevention thereof, the method comprising administering to the subject the vaccine as defined in claim 1.
Claim Rejections - 35 USC § 102
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). Claim 1 remains rejected under 35 U.S.C. 102(a)(2) as being anticipated by Cheresh et. al. (WO2021216954A1, Priority 04/23/2020; hereafter “Cheresh”) as evidenced by Bogen et. al. (US20180030155A1, Pub. 02/01/2018; hereafter “Bogen”.) This rejection is withdrawn with respect to cancelled claims 2-4 and is extended to include claims 7, 9, 42, 48, 52, 55-56, and 59-60 in light of the amendments to the claims.
The Prior Art
Cheresh teaches methods of inhibiting viruses, such as severe acute respiratory syndrome coronavirus type 2 (SARS CoV-2) and other beta-coronaviruses, that depend on arginine-glycine-aspartic acid (RGD) and/or arginine-leucine-aspartic acid (RLD) integrin binding motifs on the virus structural proteins for entry into cells (entire document; see abstract.) Cheresh teaches methods of treating, reducing the severity of, or preventing RGD and/or RLD-dependent virus infections using integrin antagonists such as antibodies or fragments or derivatives thereof, peptides, or peptidomimetics targeted to alpha V integrins that recognize RGD binding motifs, integrin αMβ2 that recognizes RLD binding motifs, or integrin αvβ3 that recognizes both RGD and RLD binding motifs, along with compositions useful for carrying out these methods (entire document; see abstract.) Cheresh teaches that the spike (S) protein of SARS CoV-2 comprises a RGD motif within the receptor binding domain (RBD) that mediates viral attachment to the receptor ACE2 (Fig. 5, ¶[0027]). Cheresh teaches bispecific antibodies, bispecific binding moieties, and fragments thereof, such as the binding moieties found in vaccibodies (¶[0049-0072]), that can target one or more integrins on a cell surface along with comprising a component that would bind to another entity on the integrin-comprising cell, such as ACE2 (¶[0062]). Therefore, the second entity may be SARS CoV-2 spike (S) protein antigen, especially one comprising the RGD or RBD of the spike protein, as said protein binds to ACE2 as taught by Cheresh (¶[0003]; instant claims 7, 9, 55). Cheresh teaches these binding moieties may be within pharmaceutical compositions which include pharmaceutically-acceptable carriers (¶[0085-0086]). As evidenced by Bogen, a vaccibody is a recombinant molecule comprised by at least one targeting unit and at least one antigenic unit connected through a dimerization motif (entire document; see abstract; Fig. 1 of Bogen; instant claim 48). Therefore, with the teachings of Cheresh, the RBD of SARS CoV-2 would be the antigenic unit that binds to ACE2, and the targeting unit would be the antibody which binds to integrin per the claimed construct of vaccibodies, as evidenced by Bogen, thus teaching the limitations of instant claims 1 and 59-60.
As alpha-v integrins, like αvβ3, αvβ5, and αvβ8, are present on antigen presenting cells (APCs), and Cheresh teaches these integrins may be targeted with antibody binding regions specific to these integrins (¶[0028]; reference claims 26-29), Cheresh teaches the limitations of instant claim 42. Cheresh teaches polynucleotides which encode the protein integrin antagonist (¶[0019]; instant claims 52, 56).
For at least these reasons, Cheresh, as evidenced by Bogen, teaches the limitations of instant claims 1, 7, 9, 42, 48, 52, 55-56, and 59-60.
Response to Arguments
Applicant's arguments filed 10/15/2025 have been fully considered but they are not entirely persuasive. The rejection of claims 2-4 is withdrawn due to the cancellation of said claims.
Applicant argues that Cheresh as evidenced by Bogen fails to teach the vaccine composition of instant claim 1 as presently amended, as Cheresh details aspects that only could be included, but did not detail the same specific construct as outlined in instant claim 1. The Office disagrees. A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination.” Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962)). See MPEP §2131. As Cheresh teaches the “vaccibodies” that structurally comprise the main elements of the instant claim in that a vaccibody is a recombinant molecule comprised by at least one targeting unit and at least one antigenic unit connected through a dimerization motif, and since Cheresh teaches SARS CoV-2 S protein binds to integrins, the antigenic unit may be derived from the spike (S) protein of a SARS CoV-2 virus (a betacoronavirus) to act as a peptidomimetic, and Cheresh teaches that said composition may be within a pharmaceutically acceptable carrier, it remains that one of skill in the art would be able to “at once envisage” the claimed arrangement as provided for in the instant claims given the guidance from Cheresh.
Further, MPEP § 2111.02 (II) recites, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the pre-amble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limita-tions, then the preamble is not considered a limitation and is of no significance to claim construction.” Presently, the recitation of “vaccine” in instant claim 1 is interpreted as intended use and therefore, will not be read as a limitation into the claimed invention.
Even in arguendo if “vaccine” was to hold patentable weight in regards to claim 1, the recitation that the composition is a “vaccine” is not a positive limitation but only requires the ability to so perform. It does not constitute a limitation in any patentable sense. In re Hutchison, 69 USPQ 138 (CCPA 1946); In re Swinehart, 169 USPQ 226 (CCPA 1971); and In re Schreiber, 44 USPQ2d 1429 (Fed. Cir. 1997). A patent applicant is free to recite features of an apparatus either structurally or functionally. See In re Swinehart, 439 F.2d 210, 212, 169 USPQ 226, 228 (CCPA 1971) (“ [T]here is nothing intrinsically wrong with [defining something by what it does rather than what it is] in drafting patent claims.”). Yet, choosing to define an element functionally, i.e., by what it does, carries with it a risk. As our predecessor court stated in In re Swinehart, 439 F.2d at 213, 169 USPQ at 228:
where the Patent Office has reason to believe that a functional limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on
Therefore, the feature of the composition being a “vaccine” would be an inherent characteristic of the composition of Cheresh since the composition of Cheresh meets all the structural limitations of the claimed “vaccine” composition.
Applicant further argues that Cheresh fails to teach the limitations of instant claim 1 in that it fails to comprise “a targeting unit that interacts with surface molecules on antigen-presenting cells” and that through this interaction the protein delivers the antigenic protein to said APC. The Office disagrees. Cheresh teaches the targeting unit (antibody) in the protein that binds to integrins, which are a class of proteins found on the surface of APCs (e.g. LFA-1 on the surface of T cells, VLA-4 important for helper T cell differentiation, Beta-2 integrins such as CD11c, CD11b, and CD103 on dendritic cells (DCs)(see e.g. Schittenhelm L, et. al. Rheumatology (Oxford). 2021 Mar 2;60(3):1533-1542.)) If the distinction is in the specific APC targeted, or specific molecule on the surface of said APC that is targeted, or how said protein acts after binding to said APC, it should be clearly claimed as such, as it is improper to import limitations from the specifications into the claims. As presently claimed, Cheresh teaches every structural element of instant claim 1, in that it teaches the vaccibody which comprises a peptidomimetic that could bind to RGD and/or RLD-dependent binding motifs, such as full-length or a fragment thereof of a SARS Cov-2 S protein, and an antibody which targets and “interacts” with at least one protein present on an APC, and said protein is within a pharmaceutically acceptable carrier. Therefore, this argument is not persuasive.
Applicant argues that the integrin antagonists disclosed by Cheresh are not vaccines and their mode of action is fundamentally different from vaccines. Again, the argument regarding the intended use of the composition is not relevant for the reasons set forth supra. Cheresh discloses, as noted by Applicant, specific embodiments where the protein construct does not interact with lymphocytes. However, as this is one embodiment, alternate embodiments are also encompassed by Cheresh.
At ¶[0062]:
“In some embodiments, the antibody or a fragment or derivative thereof may be a bispecific antibody or a fragment or derivative thereof. The bispecific antibody or a fragment or derivative thereof may bind a second antigen present on a cell comprising an integrin…”
At ¶[0065]:
“In some embodiments, the second domain (the Fc domain) specifically binds a protein on the surface of a myeloid-derived cell to mediate antibody-dependent cytotoxicity of cells expressing the target antigen.” (NB: dendritic cells (DCs), macrophages, and monocytes are all APCs descending from myeloid cells.)
Therefore, Cheresh discloses alternate embodiments where the binding does occur at these APCs. Again, it is suggested that to distinguish the structural differences between Cheresh and the instant claims that specific limitations not provided for in Cheresh, such as targeting to specific cell types using specific receptors, be drafted into the claims.
Finally Applicant notes that Cheresh is “factually incorrect” when describing vaccibodies, in that Applicant claims that vaccibodies are not “antibody fragments”. As noted further in that same paragraph in Cheresh (¶[0072]), it is clearly defined that “In some embodiments, the term “antibody fragment” as used herein may also include any protein construct that is capable of binding a target antigen.” A skilled artisan, reading the entire passage, would reasonably assert what Cheresh is describing with the use of vaccibodies in that the art has adequately described what vaccibodies are, how they can be constructed, what types of binding domains they include, and what types of antigens they may carry. Taking the combined teachings of Cheresh, one of skill in the art would still reasonably interpret that under the large breadth of the instant claims, Cheresh teaches the structural limitations of the composition of instant claim 1. Therefore, this argument is not persuasive.
For at least these reasons, Applicant’s arguments are not persuasive, and the rejection has been maintained.
Claim Rejections - 35 USC § 103
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.) Claim 16 remains rejected under 35 U.S.C. 103 as being unpatentable over Cheresh as evidenced by Bogen as applied to claim 1 above, and further in view of Bogen (supra) and Malone et. al. (Malone B, et. al. bioRxiv 2020.04.21.052084; Now published in Scientific Reports.; hereafter “Malone”). This rejection is withdrawn with respect to cancelled claims 2-4 and 17-18 and is extended to include claims 7, 9, 42, 48, 52, 55-56, and 59-60 (included in the 35 USC 102 rejection supra) and instant claims 46 and 63-65 in light of the amendments to the claims.
The Prior Art
The teachings of Cheresh have been set forth supra. While Cheresh teaches the generation of vaccibodies that would bind to integrin and have a molecule that would bind to ACE2 as well, such as the S protein from SARS CoV-2, Cheresh fails to specifically identify that the S protein would comprise a T-cell epitope. However, engineering a vaccibody to comprise an antigen that would elicit a T-cell immune response would be an obvious modification of the system of Cheresh, given the teachings of Bogen. Further, the attempt to utilize a universal T cell epitope that would provide cross-reactive immune responses across variants of concern (VOCs), other SARS CoV-2 strains, and other betacoronavirus species and strains would be an obvious modification to make, given the teachings of the art at the time of filing, as evidenced by Malone.
Bogen teaches recombinant antibody-based molecules that trigger both T-cell and B-cell immune responses, wherein the recombinant molecules comprise at least one targeting unit and at least one antigenic unit connected through a dimerization motif (entire document; see abstract.) Bogen teaches that these “vaccibodies” can be engineered to trigger both a T cell and B cell response (entire document; see abstract; ¶[0002]), and that in their design the antigenic unit in the vaccibody can be a viral surface protein antigen found in the viral envelope (reference claims 1, 24-26, 38, 60-62; Example 16 at ¶[0114]). Bogen teaches wherein the antigenic unit would ideally comprise the complete protein in its native conformation (¶[0007][0009]), which would inherently, under broadest reasonable interpretation, include multiple epitopes linked together by native, non-immunogenic amino acids (which can be reasonably interpreted as “linkers”), and would induce both humoral and cellular T cell responses (¶[0009]; instant claim 16). Bogen teaches the targeting unit can target surface molecules on antigen presenting cells (APC) such as HLA, CD14, CD40, toll-like receptors (TLRs), or chemokine receptors (reference claims 51-53; ¶[0082]) or MHC class II proteins (¶[0013-0018][0040]; instant claim 42). Bogen teaches the targeting unit may be MIP-1α (¶[0061]; reference claims 11-12, 46-47), and teaches the divalent molecule would comprise a flexible hinge region (¶[0009-0010]; instant claim 48). Bogen teaches the vaccibody may be encoded by a nucleotide, such as DNA or RNA, and can be introduced into a cell via vectors, such as viral vectors (¶[0010][0045-0046]; instant claims 52, 56, 59). Bogen teaches that Vaccibodies are produced and secreted as functional dimerized molecules (¶[0083]; instant claim 60). Bogen teaches methods of making the vaccibodies, including transfecting cells with nucleic acids encoding said vaccibodies, culturing the cells, and collecting the supernatant from said cells (¶[0015-0016][0031][0036][0043]). Said supernatant could be purified for the secreted vaccibody in sterile PBS for use in immunogenic compositions (¶[0063]; instant claim 63). Bogen teaches pharmaceutical compositions which comprise vaccibody RNA, DNA, or proteins (¶[0010][0045]; instant claims 64-65).
Malone teaches that software can predict universal T cell epitopes for SARS CoV-2 vaccines (entire document; see abstract), not only for the highly mutable S protein, but more conserved coronavirus proteins as well, which would help in development of efficacious and universal T cell vaccines (p. 13, ¶3). Malone teaches the identification of HLA-specific alleles in the SARS CoV-2 genome (abstract), and notes that much of the research was focused on the spike (S) protein, which is the most “antibody exposed” structural protein on SARS CoV-2 (p. 3, ¶1). Malone teaches the most effective vaccine against SARS CoV-2 will raise both CD4 and CD8 T cell responses against the virus (pp. 4-5, ¶ bridging pages), with the S protein providing many dominant CD8 T cell responses (p. 5, ¶2; instant claims 7, 55). Malone teaches peptide epitopes from the spike (S) glycoprotein, the nucleoprotein (NP), and the membrane (M) protein (Table 1), wherein RLNEVAKNL is part of the S1 subunit close to the furin cleavage site, FIAGLIAIV is found at amino acids 1203–1211, and KLPDDFTGCV is a peptide within the S1 subunit, namely in the receptor binding domain (RBD; aa 424-433), which is crucial for viral binding to host cell receptors (Table 1; instant claim 9).
Given the teachings of Cheresh, one of skill in the art would be apprised as to the development of vaccibodies for the treatment of SARS CoV-2. Given the guidance from Bogen and Malone, one would be motivated to identify specific T cell epitopes from SARS CoV-2 proteins that could be utilized towards universal or cross-reactive antiviral treatments. Given the teachings of Bogen, one would be apprised as to how to generate vaccibodies and that both the protein and nucleic acid encoding said vaccibody protein could be used in methods of generating an immune response. Given the combined teachings of Cheresh, Bogen, and Malone, arriving at the limitations of instant claims 16 and 63-65 would be obvious to a skilled artisan. Further, as Bogen teaches one of the targeting units may be MIP-1α and teaches the use of murine MIP-1α in mice, it would be obvious to use the species-specific form of MIP-1α for human subjects, especially given the teachings of Cheresh (which teach the use of mammalian, specifically human, subjects ¶[0123]), thus rendering obvious the use of human MIP-1α as required by instant claim 46.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Cheresh in order to include universal T cell epitopes, thereby generating a therapeutic that could potentially have cross-protection against multiple SARS CoV-2 strains or other coronaviruses. One would have been motivated to do so, given the suggestion by Malone that universal epitopes could be determined using modeling software, and then could be tested empirically. There would have been a reasonable expectation of success, given the knowledge that T cell epitopes were meant to be included as a part of vaccibodies, as taught by Bogen, and also given the knowledge that Bogen teaches the use of viral surface protein antigens in vaccibody constructs. 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.
Response to Arguments
Applicant's arguments filed 10/15/2025 have been fully considered but they are not entirely persuasive. The rejection of claims 2-4 and 17-18 is withdrawn due to the cancellation of said claims.
Applicant argues that one of ordinary skill would not have been motivated to combine the cited references. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicant argues that Cheresh is silent with respect to disclosing any vaccine that can attract immune cells and facilitate an amplifying effect of an immune response against a viral antigen. However, said functional features are not present in the claims as written, only that the vaccine composition must comprise certain structural features, which Cheresh discloses (as detailed and argued supra). Applicant is reminded that arguments must be commensurate in scope with the claimed invention, and in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “any vaccine that can attract immune cells and facilitate an amplifying effect of an immune response against a viral antigen”) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Cheresh recites the use of vaccibodies in vaccine compositions for treatment of SARS CoV-2, Bogen provides a more detailed disclosure regarding vaccibodies and the use of CD4 and CD8 T cell antigens from pathogens, and Malone provides motivation for discovering CD4 and CD8 T cell epitopes in the proteins from the pathogen SARS CoV-2. Furthermore, even in arguendo, there must be a structural difference that accounts for the function claimed. As Cheresh provides the structural limitations as presented in claim 1, it can be argued that it should also be able to perform these functional limitations claimed by the instant claims. If there is a specific distinction in the invention that allows for this specific function to be performed by the claimed invention, then said specific structural limitations (e.g. specific targeting units, specific betacoronavirus epitopes, etc.) should be drafted within the instant claims. Therefore, this line of argument is unpersuasive.
In response to applicant's argument that Cheresh and Bogen are nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Applicant appears to further argue that the disclosures of Cheresh and Bogen are unrelated, and therefore there would be no motivation to combine these references. Cheresh specifically cites the use of vaccibodies as the structural basis for their combined integrin/ACE2-binding protein. As SARS CoV-2 S binds to ACE2, and integrins are present on APCs, it is unclear how the teachings of Cheresh fail to anticipate the instantly claimed structure. Further, one of skill in the art would be able to take the teachings of Cheresh and reasonably find further information regarding vaccibody structures and sequences, and would be led to the analogous art of Bogen, which is one of the first descriptive patents detailing vaccibodies. Therefore, Cheresh and Bogen are analogous art, and regardless as to intended use of the product, are reasonably pertinent to the particular problem with which the inventor was concerned, which is a vaccine that would treat SARS CoV-2 infections. Therefore, this line of argument is not persuasive.
In response to applicant's argument that Cheresh alone, or Cheresh, Bogen, and Malone fail to teach or suggest all the limitations of the pending claims (item B of “Remarks”), a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. For the reasons detailed supra, Cheresh still anticipates the structural limitations of the nucleic acid/protein of claim 1. Applicant continues the argument that the structure of Cheresh would fail to perform the function of “a vaccine comprising an antigenic unit that, when delivered to an antigen-presenting cell, ensures a rapid, strong immune response raised through B cells and/or T cells to the antigen comprised in the antigenic unit” is again arguing features which are not claimed, and it is unclear how the structure of Cheresh, which teaches every structural element required by instant claim 1, would be unable to perform the intended use. Again, it is highly suggested that claim 1 be amended to recite the specific antigens and specific targeting moieties that would distinguish the protein and nucleic acids encoding said protein of claim 1 structurally from that of Cheresh.
Applicant argues surprising and/or unexpected results in item (C) of their “Remarks”. Respectfully, an argument of unexpected or surprising results must be commensurate in scope for the invention as claimed, and the large breadth of instant claim 1 and the invention it encompasses, including both nucleic acid and protein vaccines, and the structure of said proteins encoded by the nucleic acid or the structure of the proteins within the vaccines, is quite large. The breadth of possible targeting units that could “interact with surface molecules on antigen-presenting cells”, the breadth of “antigen-presenting cells”, the breadth of “dimerization unit”, the breadth of “antigenic unit” being that of any antigen of any betacoronavirus is extraordinarily large. The limited examples provided for in the specification which provided said “unexpected” or “surprising” result is not commensurate in scope with the large breadth of each of these possible limitations, and the criticality of parameters to provide such unexpected results is unclear. It is not clear if a specific type of APC must be targeted, or a specific target on APCs be present on the protein, or if said APC surface molecule must be targeted using a specific mechanism (e.g. use of a protein which mimics its natural receptor binding partner, or use of an antibody which recognizes said receptor). Furthermore, it is unclear which betacoronavirus is being claimed, and which antigen/epitope from said betacoronavirus is critical for the “surprising” results. While unexpected results are not expected to be shown over the entire range as claimed, the unexpected results must at least be shown for a single member of a claimed subgenus, or a narrow portion of a claimed range to allow a skilled artisan to ascertain a trend in the exemplified data that would allow him to reasonably extend the probative value thereof. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (MPEP §2145). Therefore, as the breadth of the claims is not commensurate in scope with the limited examples provided for in the specification, such an argument is not persuasive.
For at least these reasons, the rejection has been maintained.
(New rejection – necessitated by amendment.) Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Cheresh, Bogen, and Malone as applied to claims 1, 7, 9, 16, 42, 46, 48, 52, 55-56, 59-60, 63-65 above, and further in view of Granum et. al. (US20190022202A1, Pub. 01/24/2019; hereafter “Granum”.)
The Prior Art
The teachings of Cheresh, Bogen, and Malone have been set forth supra. While Cheresh and Bogen teach about vaccibodies, and Bogen describes the vaccibodies in detail, neither together or alone provide sequences for the vaccibodies as instantly claimed. Malone fails to cure this deficiency. However, sequences for vaccibody frameworks were known in the art, as evidenced by the teachings of Granum.
Granum teaches vaccibodies, namely vaccine compositions which comprise a polynucleotide comprising a nucleotide sequence encoding a targeting unit, a dimerization unit, a first linker and an antigenic unit, wherein said antigenic unit comprises n−1 antigenic subunits, each subunit comprising at least a part of an epitope sequence, or the vaccine comprises a polypeptide encoded by the polynucleotide or a dimeric protein consisting of two polypeptides encoded by the polynucleotide (entire document; see abstract.) Granum teaches SEQ ID NO: 3, which is 100% identical to instant SEQ ID NO: 233 (see ABSS sequence search in file wrapper regarding 16/068,449).
Given the teachings of Cheresh, Bogen, and Granum, one would be apprised as to the usefulness of vaccibodies in the targeted delivery of antigens to APCs. Given the teachings of Cheresh and Malone, one of skill in the art would be apprised to the usefulness of using the vaccibody platform for delivery of SARS CoV-2 antigens. Given the teachings of Granum, one would be apprised as to at least one framework for vaccibodies for which antigens could be inserted. Therefore, arriving at the limitations of instant claim 67 would be obvious for a skilled artisan, given the combined teachings of Cheresh, Bogen, Malone, and Granum.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Cheresh in order to utilize known frameworks for the vaccibodies, thereby generating a therapeutic that could potentially have cross-protection against multiple SARS CoV-2 strains or other coronaviruses. One would have been motivated to do so, given the suggestion by Malone that universal epitopes could be determined using modeling software, and then could be tested empirically. There would have been a reasonable expectation of success, given the knowledge that T cell epitopes were meant to be included as a part of vaccibodies, as taught by Bogen and Granum, and also given the knowledge that Bogen teaches the use of viral surface protein antigens in vaccibody constructs. There would be further reasonable expectation of success, given that known sequences for vaccibody constructs were available in the art, given the teachings of Granum. 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.
(New rejection – necessitated by amendment.) Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Cheresh, Bogen, and Malone as applied to claims 1, 7, 9, 16, 42, 46, 48, 52, 55-56, 59-60, 63-65 above, and further in view of Zion et. al. (US20210346490A1, Priority 04/10/2020; hereafter “Zion”.)
The Prior Art
The teachings of Cheresh, Bogen, and Malone have been set forth supra. While Cheresh and Bogen teach about vaccibodies, and Cheresh and Malone describe SARS CoV-2 antigens, neither together or alone provide specific longer sequences for SARS CoV-2 S protein as instantly claimed. However, sequences for SARS CoV-2 immunogenic S proteins were known in the art, as evidenced by the teachings of Zion.
Zion teaches fusion proteins comprising SARS CoV-2 S proteins, namely those portions which comprise the highly antigenic receptor binding domain (RBD) of said protein (entire document; see abstract.) Zion teaches the S protein linked to a fragment of an antibody (Fc fragment; entire document; see abstract.) Zion teaches SEQ ID NO: 2, which is 100% identical to instant SEQ ID NO: 231 (see ABSS sequence search in file wrapper regarding 17/226,690; ¶[0009]). Zion teaches the proteins may be used in pharmaceutical compositions to treat disease caused by SARS CoV-2 (entire document; see abstract; reference claim 19.) Zion teaches that conjugation of the antigen to the Fc domain increases the plasma half-life due to its interaction with the neonatal Fc-receptor (FcRn) in addition to slower renal clearance of the Fc fusion protein due to the large molecule size, resulting in in vivo recycling of the molecule achieving prolonged activity of the linked peptide and improved solubility and stability of the Fc fusion protein molecule (¶[0007]).
Given the teachings of Cheresh, Bogen, and Granum, one would be apprised as to the usefulness of vaccibodies in the targeted delivery of antigens to APCs. Given the teachings of Cheresh and Malone, one of skill in the art would be apprised to the usefulness of using the vaccibody platform for delivery of SARS CoV-2 antigens. Given the teachings of Zion, one would be apprised as to highly antigenic S protein sequences which could be used in such a platform. Therefore, arriving at the limitations of instant claim 10 would be obvious for a skilled artisan, given the combined teachings of Cheresh, Bogen, Malone, and Zion.
It would have been obvious to one of ordinary skill in the art to modify the methods and compositions taught by Cheresh in order to utilize known SARS CoV-2 S protein antigens for the vaccibodies, thereby generating a therapeutic that could treat SARS CoV-2 infections therapeutically or prophylactically. One would have been motivated to do so, given the suggestion by Malone that SARS CoV-2 epitopes could be determined using modeling software, and then could be tested empirically. There would have been a reasonable expectation of success, given the knowledge that T cell epitopes were meant to be included as a part of vaccibodies, as taught by Bogen and Granum, and also given the knowledge that Bogen teaches the use of viral surface protein antigens in vaccibody constructs. There would be further reasonable expectation of success, given that known sequences for SARS CoV-2 highly immunogenic RBDs were available in the art, given the teachings of Zion, and given that Zion provided motivation to fusing the RBD to antibody regions to increase stability, targeting, and half-life of the antigen. 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.
(New rejection – necessitated by amendment.) Claims 1, 7, 9-10, 16, 42, 46, 48, 52, 55-56, 59-60, 63-65, 67, and 69 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19, 21, 26, 38, 40, 42, 44, 46, 48, 50, 54, 57, and 63 of copending Application No. 18/560,279 in view of Bogen and Zion (supra). Both are drawn to vectors comprising nucleic acids encoding a targeting unit that targets antigen-presenting cells, a multimerization unit, such as a dimerization unit, and an antigenic unit comprising one or more antigens or parts thereof. Both claim the antigens may be from pathogens. Both claim the targeting unit comprises a moiety that interacts with surface molecules on the antigen-presenting cells, such as TLRs. Both claim the multimerization unit comprises a hinge region, a linker, and can promote dimerization of the resulting molecule. Both claim the vector may be within a pharmaceutically acceptable composition. Both claim the composition may be used to treat infectious disease. Both claim the vector may be introduced into a host cell for expression of the peptide.
While the instant and reference claims are both drawn to nucleic acids which may encode the vaccibody, the ‘279 claims provide that the nucleic acid is a vector that also encodes a further “immunostimulatory compound” as a separate molecule. However, such a difference would be obvious given the teaching of Bogen, which teach that the vaccibody may be delivered via a vector, specifically a viral vector, and under broadest reasonable interpretation, the viral proteins encoded by said viral vector can reasonably be interpreted as “immunostimulatory molecules”(¶[0046] of Bogen). Additionally, the ‘279 claims are drawn generically to any pathogen and using said vector to treat infection; the inclusion of SARS CoV-2 antigens in such a construct would be an obvious modification to the system, given the combined teachings of Bogen and Zion (detailed supra). Therefore, the differences between the instant claims and the ‘279 claims would be obvious modifications to employ for a skilled artisan given the teachings of the prior art, and the claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection.
Allowable Subject Matter
(New objection – necessitated by amendment.) Claims 68 and 70 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: SEQ ID NOs: 254, 294, and 295 appear to be novel and nonobvious sequences. It should be noted that SEQ ID NO: 255 is also disclosed in applicant-related later filed application, 18/560,279, and while parts of this sequence appear to be claimed in the copending reference application (see NSDP rejection supra), the sequence which is 100% identical to instant SEQ ID NO: 255 itself is not presently claimed in the ‘279 application.
Conclusion
No claims are allowed. Claims 68 and 70 are objected to.
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.
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