DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed November 11, 2022 is pending.
Claims 1-44 are pending.
Interview Summary
In a telephonic interview with the attorney of record, James Remenick, on August 11, 2025, the Applicant requested clarification of the Species Election requirement that was mailed the same day. The Examiner explained that the Applicant was required to elect one species of immunogenic peptide comprising one specific SEQ ID NO as recited in claim 1 to be examined. The Examiner agreed that the Applicant could instead pick up to five SEQ ID NOs with similar structure to be examined. However, upon further consideration, the Examiner will search two species. See details below.
Election/Restriction
Applicant’s election with traverse to claims 1-7, 9-13, 22-27, 29-33, and 42-44 (drawn to immunogenic peptides; immunogenic compositions; and contiguous peptides sequences); and to SEQ ID NOs: 3 and 4 (encompass peptides containing sequences of peptidoglycan (PGN) and Lipoteichoic acid (LTA) of a gram positive Mycobacteria (with or without T cells epitope)); water; and saponin, in the reply filed August 12, 2025, is acknowledged.
The traversal is on the grounds that as recited under M.P.E.P. 803, restriction is appropriate only when the groups can be shown to be distinct and there would place a "serious burden" placed on the Examiner to examine more than one group at a time. Applicant asserts that no such serious burden is believed to be present, and requests that restriction and species requirement be withdrawn.
The Applicant argues that a search of the elected group of claims will likely result in a search of the unelected groups of claims and also species. For example, claim 1 recites that the sequences along the peptide are contiguous, which is limited to the Group II claims. Thus, it is respectfully noted that any search of peptides encompassed within the claims of Group I (claims 1-7, 9-13, 22-27, 29-33, and 42-44) will encompass the same documents as would a search of the Group II claims (claims 8 and 28), because all are recited to be contiguous. Further, the documents identified in a search of elected claims are believed to also disclose antibodies to the peptide and hybridomas in accordance with the claims of Groups II and IV and their respective species. Thus, the search of each Group and species would result in the same documents.
The Applicant ultimately argues that as the search of the elected claims and species is likely to result in a search of unelected claims and species, no serious searching burden is believed to be present. The Applicant has requested that the Restriction and Species Requirement mailed on August 11, 2025 be withdrawn.
This is not been found persuasive because all of the inventions and species listed in the Office Action mailed August 11, 2025 are independent or distinct for the reasons given the Office Action and there would be a serious search and/or examination burden if restriction were not required.
Applicant is reminded that where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
As such, the restriction and species election requirement mailed August 11, 2025 is proper and is therefore made FINAL.
Additionally, the Examiner acknowledges that in the telephonic interview with the Attorney of record, James Remenick, on August 11, 2025, detailed above, the Examiner agreed to the Applicant electing up to five SEQ ID NOs with similar structure to be examined. However, upon review of the instant disclosure and search, the Examiner realized that SEQ ID NOs: 22-24 comprise additional elements that require further search of the prior art and an additional examination burden. Thus, given that SEQ ID NOs: 22-24 are distinct from SEQ ID NOs: 3 and 4, SEQ ID NOs: 22-24 have been withdrawn from consideration. Only an immunogenic peptide comprising SEQ ID NOs: 3, 4, or a combination thereof is being examined. Once an immunogenic peptide comprising SEQ ID NO: 3, 4, or a combination thereof is found allowable, the Applicant will be entitled to the additional SEQ ID NOs recited in claim 1.
Claims 2, 8, 14-41, and 44 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions. Applicant timely traversed the restriction (election) requirement in the reply filed on August 12, 2025.
Claims 1, 3-7, 9-13, 42, and 43 are currently under consideration as they read on the elected invention and the species of SEQ ID NOs: 3 and 4.
Priority
Applicant’s claimed benefit of prior-filed U.S. provisional Applications: 63/333,780 filed April 22, 2022; and 63/278,759 filed November 12, 2021 is acknowledged. Claims 1-7, 9-13, 22-27, 29-33, and 42-44 are being examined with an effective filing date of November 12, 2021.
Claim Interpretation
The instant claims are drawn to a genus of immunogenic peptides comprising a contiguous sequence of either of the elected SEQ ID NOs: 3 or 4, or a combination thereof. See the annotated structures of SEQ ID NOs: 3 and 4 below.
SEQ ID NO: 3 comprises two of the peptidoglycan (PGN) epitope “AEKA” separated by a tetraglycine (“GGGG”) and an N-terminal tetanus universal T cell epitope (SEQ ID NO: 7) (e.g. see instant specification page 28, Table 1).
SEQ ID NO: 4 also comprises two of the peptidoglycan (PGN) epitope “AEKA” separated by a pentaglycine (“GGGGG”) linker and a C-terminal tetanus universal T cell epitope (SEQ ID NO: 7) (e.g. see instant specification page 28, Table 1).
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Annotated Snapshot of instant Table 1 on page 28 of the Specification
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 6, and 42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites the limitation "the sequence of a T-cell stimulating epitope" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 5 is dependent on claim 1 which is drawn to an immunogenic peptide comprising of one or more amino acid sequences that do not include the sequence of a T-cell stimulating epitope. Thus, for those sequences lacking the sequence of a T-cell stimulating epitope it is unclear to what the limitation in claim 5 is referring to. Amending the claim to recite “a sequence of a T-cell stimulating epitope” would obviate this part of the rejection.
Claim 6 recites the limitation "the sequence of a composite epitope" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 6 is dependent on claim 1 which is drawn to an immunogenic peptide comprising of one or more amino acid sequences that do not include the sequence of a composite epitope. Thus, for those sequences lacking the sequence of a composite epitope it is unclear to what the limitation in claim 6 is referring to. Amending the claim to recite “a sequence of a composite epitope” would obviate this part of the rejection.
Claim 42 recites the limitation “comprising an epitope of a bacterium and an epitope of a virus which includes one or more of the sequences selected from the group of sequences consisting of SEQ ID NOs: [3 and 4]” in lines 1-3. As the claim is currently written, it is unclear to the examiner if the contiguous peptide sequence, the epitope of a bacterium, or the epitope of a virus “includes one or more of the sequences selected from the group of sequences consisting of SEQ ID NOs: [3 and 4].” Furthermore, the elected species of SEQ ID NOs: 3 and 4 do not comprise an epitope of a virus and thus there is no antecedent basis for the limitation of “an epitope of a virus” in lines 1 and 2 of claim 42. Moreover, not all of the amino acid sequences of SEQ ID NOs: 1-41 comprise an epitope of a virus. Therefore, amending the claims to only include those sequences and combinations thereof that include an epitope of a bacterium and an epitope of a virus would obviate this part of the rejection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-7, 9-11, 13, 42, and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Malonis et al. 2020 (Chem. Rev., 120, 3210−3229) in view of Fischetti 2016 (Curr. Top. Microbiol. Immunol.; 409, 1-12), Gaikwad et al. 2019 (Clin. Exp. Vaccine Res.; 8(1): 27-34), and Pessi et al. 1990 (EP0378881A1).
Malonis et al. teach that the vast majority of vaccines against infectious diseases, the largest class of vaccines, consists of inactivated or live attenuated pathogens (e.g. see page 3211, left column, third paragraph). In general, inactive or attenuated pathogens can stimulate a robust immune response because they contain both B- and T-cell epitopes presented in a conformation that is relevant to the pathogen. Subunit vaccines that consist primarily of peptides or proteins, in contrast, can face limitations with respect to immunogenicity and thus may require multiple immunizations to achieve similar levels of immune response. Nonetheless, a variety of approaches to enhance subunit vaccine responses, including presentation of epitopes in multimeric format (e.g., virus-like particles, VLPs, or nanoparticles) or use of immunostimulatory adjuvants, have been utilized (e.g. see page 3211, left column, third paragraph).
The elicitation of epitope-specific antibodies is a primary mechanism of protection for many vaccines (e.g. see page 3211, paragraph spanning the left and right columns). For infectious diseases, often the targeted epitope is a site of susceptibility for “neutralization” by antibodies. For the most part, protective antibodies target epitopes that lie on the surface of the pathogen (e.g., the viral glycoprotein or bacterial capsid) (e.g. see page 3211, paragraph spanning the left and right columns).
Generally, the elicitation of protective antibodies requires affinity maturation from the germline, a process that is stimulated by cross-linking B-cell receptors (BCRs) on a specific B-cell (Figure1B) (e.g. see page 3211, right column, second paragraph). Consequently, monomeric peptides are often poorly immunogenic relative to those corresponding sequences on viral, bacterial, or parasitic external proteins because, when presented in those contexts, multiple copies of the epitope on the pathogen surface permit efficient cross-linking of BCRs (e.g. see page 3211, right column, second paragraph). To this end, one strategy to improve immunogenicity toward a desired epitope is to link the epitope to a VLP or nanoparticle to allow ordered, multivalent epitope presentation that can more efficiently cross-link BCRs (e.g. see page 3211, right column, second paragraph).
Stimulation of epitope-specific T-cells is another mechanism by which vaccines can induce protective immunity (e.g. see page 3212, left column, third paragraph). In the context of infectious diseases, recruitment of T-cells can result in the rapid destruction and clearing of the pathogen itself or of infected host cells, thereby stemming the spread of the infection (e.g. see page 3212, left column, third paragraph).
In typical peptide vaccination protocols, the epitope of interest is conjugated to a carrier protein or presented in a multimeric format (VLP or nanoparticle) (e.g. see page 3213, paragraph spanning left and right columns). Such strategies can boost immune responses by increasing the half-life of the epitope by decreasing renal clearance and susceptibility to proteolytic degradation. Linkage to carrier proteins is typically achieved by chemical conjugation. The carriers are generally known to have immunogenic properties, and thus the simple covalent linking of epitopes to immunogenic species can often be sufficient to enhance the immune response. Related to this, the immunogenicity of peptide or protein sequences can be augmented through linkage to short sequences that are known to stimulate an immune response. An example of this is PADRE, a universal helper T-cell epitope that can be fused to peptide or protein sequences to stimulate antibody responses (e.g. see page 3213, paragraph spanning left and right columns).
Furthermore, most vaccines are injected with an adjuvant to stimulate an immune response (e.g. see page 3214, left column, second paragraph). Given the route of administration of most vaccines is injection, it is understood by those of ordinary skill in the art that the formulation that is being injected would be in the form of an aqueous liquid so as to solubilize the vaccine and permit efficient administration of the vaccine. Therefore, Malonis et al.’s vaccines would necessarily be comprised in an immunogenic composition that includes water in order to allow for injection.
The reference teachings differ from the instant invention by not teaching the specific immunogenic peptides comprised of a contiguous sequence of any one of the sequences of the elected SEQ ID NOs: 3, 4, or a combination thereof.
Fischetti teaches that the high internal pressure of bacterial cells (roughly 10–15 atmospheres
for gram positives) is controlled by the highly cross-linked cell wall PGN (e.g. see page 3, paragraph under “mechanism of action”). Any disruption in the wall’s integrity will result in the extrusion of the cytoplasmic membrane and ultimate hypotonic lysis (e.g. see page 3, paragraph under “mechanism of action”). Thus, the cell-surface PGN is essential to a bacterium’s survival. Furthermore, Fischetti teaches that the cell wall peptidoglycan of Staphylococcus aureus (S. aureus), a pathogen responsible for severe secondary infections in immunocompromised individuals, as well as disease in otherwise healthy individuals and is the most common cause of human bacterial infections worldwide (e.g. see page 2, first paragraph under “Introduction”), comprises a stem peptide which links the large glycan strands of PGN (e.g. see page 4, Figure 1). As seen in Figure 1 (copied below), the stem peptide has the amino acid sequence of L-Ala (L-alanine), D-iso-Glu (D-iso-glutamic acid), L-Lys (L-lysine), D-Ala (D-alanine), or “AEKA.” The PGN can be further stabilized by cross-linking adjacent stem peptides via a pentaglycine (in the case of S. aureus) (e.g. see page 4, Figure 1). The integrity of the cell-surface PGN, which is facilitated by this stem peptide, is essential for pathogen survival. Therefore, Fischetti teaches AEKA-GGGGG-AEKA-GGGGG-AEKA (see Figure 1 copy below).
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Figure 1 from Fischetti 2016 (Curr. Top. Microbiol. Immunol.; 409, 1-12)
While Fischetti teaches linking the PGN stem epitope “AEKA” with pentaglycine, it is also known in the art that epitopes in a multimeric vaccine can be linked by tetraglycine linkers. For example, Gaikwad et al. teach the design of a recombinant epitope-repeat protein (rERP) gene encoding eight repeats of an epitope separated by tetra-glycine linkers (e.g. see page 28, left column, third paragraph and Figure 1A, copied below, where the tetra-glycine linkers are shown in red). Graphic visualization of tertiary structure of top predicted models for rERP protein suggests that epitope reactive antibodies would be freely accessible to epitopes separated by tetra-glycine linkers in tertiary dimensional space (e.g. see page 30, paragraph spanning left and right columns and Figure 1B, copied below). Gaikwad et al. explicitly state that the tetra-glycine linker was used as linker in between epitopes as it provides flexibility due to lack of β-carbon and is preferred linker in multi-epitope proteins (e.g. see paragraph spanning pages 32 and 33).
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Figure 1 from Gaikwad et al. 2019 (Clin. Exp. Vaccine Res.; 8(1): 27-34)
Pessi et al. teach the design of synthetic peptides for their use as universal carriers in the preparation of immunogenic conjugates. Pessi et al. also teach the use of said conjugates in the development of synthetic vaccines that are able to induce protective immunity against different pathogenic agents which are not genetically restricted or only slightly so (e.g. see [0001]). Genetic restriction refers to those peptide fragments that are restricted in their interaction with the T lymphocyte receptor (TCR) by the proteins with which they are associated (i.e. MHC) (e.g. see [0021]). Thus, Pessi et al.’s invention relates to the identification, within a natural antigen, those T cell epitopes with absent or minimum genetic restriction which are suitable for the development of synthetic acellular vaccines with wide effectiveness, i.e. able to induce protective immunization against the pathogenic agent of interest in individuals with different MHC gene sets (or without being presented to the TCR by an MHC) (e.g. see [0022]).
This has been very often overcome by using, as the source of T cell epitopes, a macromolecule, also known as a carrier, to which a natural or synthetic peptide or polysaccharide hapten, derived from a pathogenic agent of interest, is covalently bound (e.g. see [0023]). Examples of carriers suitable for this purpose are the tetanus toxoid (TT), the diphtheria toxoid (CRM), serum albumin and lamprey hemocyanin (KLH) in that they provide the resultant conjugate with minimum genetic restriction (e.g. see [0023]). Conjugates comprising said carriers, known also as universal carriers, are able to function as T cell clone activators in individuals having very different gene sets (e.g. see [0023]). Even though this approach to the problem has proved effective, the use of macromolecular-hapten carrier conjugates in a process of immunization against a pathogenic agent still has numerous drawbacks due to the difficulty of standardizing their various preparation stages, the possible alteration of the antigenic properties of the hapten as a result of the conjugation reaction, and finally the phenomenon known as "epitope suppression induced by the carrier" which causes suppression of anti-hapten antibody production in an individual already immunized with only the carrier (e.g. see [0024]).
Thus, Pessi et al. aimed to localize, within the tetanus toxin, T cell epitopes able to be recognized by numerous human T cell clones within the context of a wide range of alleles of the human major histocompatibility complex (MHC) (e.g. see [0029]). Pessi et al. teach that these T cell epitopes are used as universal carriers in the preparation of immunogenic conjugates (e.g. see [0031]). These immunoconjugates comprise the T cell epitopes that are covalently bound to a natural or synthetic peptide or polysaccharide hapten derived from a pathogenic agent of interest (e.g. see [0032]). Pessi et al. explicitly state that the “particularly preferred” universal carriers are the synthetic peptides corresponding to the regions 830-843 (TT=2) and 830-844 of the TT, and the analogs of the TT=2 peptide (e.g. see [0088]).
It is noted that TT=2 has the same amino acid sequence as the instant tetanus universal T cell epitope (SEQ ID NO: 7) which is incorporated into elected SEQ ID NOs: 3 and 4 as an immunogenic carrier protein.
Pessi et al. demonstrate that isolated mononucleated cells of peripheral blood (PBMC) proliferate responsively both to the TT=2 peptide, and the entire molecule of the Tetanus Toxoid presented by autologous APC cells, thus evidencing their specificity towards TT (e.g. see [0148]). Pessi et al.’s results show that TT=2 is universally recognized after immunization with TT and that it is capable of becoming associated to different MHCII-class molecules (e.g. see [0149]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Malonis et al. to incorporate the teachings of Fischetti, Gaikwad et al., and Pessi et al. to include the specific immunogenic peptides comprising a contiguous sequence of either of the elected species of SEQ ID NOs: 3, 4, or a combination thereof as a subunit vaccine.
Subunit vaccines consist primarily of peptides or proteins. Subunit vaccines face limitations with respect to immunogenicity, which are generally overcome by inactive or attenuated pathogens given that these platforms contain both B- and T-cell epitopes presented in a conformation that is relevant to the pathogen (Malonis et al.). A variety of approaches to enhance subunit vaccine responses, including presentation of epitopes in multimeric format or use of immunostimulatory adjuvants, have been utilized (Malonis et al.). The elicitation of epitope-specific antibodies is a primary mechanism of protection for many vaccines and, generally, requires affinity maturation from the germline, a process that is stimulated by cross-linking of BCRs (Malonis et al.). To this end, monomeric peptides are often poorly immunogenic relative to those corresponding sequences on viral, bacterial, or parasitic external proteins because, when presented in those contexts, multiple copies of the epitope on the pathogen surface permit efficient cross-linking of BCRs and thus stimulate antibody affinity maturation (Malonis et al.). Furthermore, stimulation of epitope-specific T-cells is another mechanism by which vaccines can induce protective immunity
In typical subunit-based vaccination protocols, an epitope of interest is conjugated to a carrier protein or presented in a multimeric format (Malonis et al.). The carriers are generally known to have immunogenic properties, and thus the simple covalent linking of epitopes of interest to an immunogenic carrier protein can often be sufficient to enhance the immune response toward the selected epitopes (Malonis et al.). Moreover, the immunogenicity of peptide or protein sequences can be augmented through its linkage to short sequences, such as universal helper T-cell epitopes, that are known to stimulate an immune response (Malonis et al.).
Thus, Malonis et al. teach a general platform for designing subunit or peptide vaccines which are comprised of an epitope(s) of interest, such as a conserved cell-surface peptide and/or a peptide that is essential to pathogenicity or pathogen survival, where the epitope(s) is presented in an immunogenically-favored multimeric and/or immunogenic carrier-conjugated format.
For infectious diseases, often the epitope of interest is a site of susceptibility for “neutralization” by antibodies and for the most part, protective antibodies target epitopes that lie on the surface of a pathogen (Malonis et al.).
Thus, the epitope of interest may include the stem peptide found in the cell wall peptidoglycan on the surface of S.aureus. This stem peptide has the amino acid sequence of Ala-Glu-Lys-Ala and is a conserved tetrapeptide that links the large glycan strands of PGN (Fischetti). It is noted that this tetrapeptide is identical to instant SEQ ID NO: 5 and is incorporated into instant SEQ ID NOs: 3 and 4. The PGN can be further stabilized by cross-linking adjacent stem peptides via a pentaglycine (Fischetti). The integrity of the cell-surface PGN, which is facilitated by this stem peptide, is essential for pathogen survival (Fischetti).
Nonetheless, as is stated above, monomeric peptides are often poorly immunogenic and it is preferred that epitopes be presented in multimeric formats in order to permit efficient cross-linking of BCRs and in turn stimulate antibody affinity maturation (Malonis et al.). Thus, the design of multiepitope proteins, wherein the epitopes are separated by linkers, is desirable in order to elicit an efficient immune response (Gaikwad et al.). Such inter-epitope linkers include tetra-glycine linkers because they provide flexibility due to lack of β-carbon and are the preferred linkers in multi-epitope proteins (Gaikwad et al.), or pentaglycine linkers with are the naturally occurring linkers that bridge the stem peptide (“AEKA”) in PGN (Fischetti).
To further enhance the immunogenicity of such multi-epitope proteins that comprise tetra- or penta-glycine linkers, the multi-epitope proteins may be conjugated to a carrier, such as short sequences that are known to stimulate an immune response, including universal T-cell epitopes.
The universal T-cell epitope-based carriers include the “particularly preferred universal carrier” synthetic peptide corresponding to regions 830-843 of tetanus toxin (TT=2) (Pessi et al.).
Thus, given the general platform for subunit or peptide vaccine design presented by Malonis et al., the enhanced immunogenicity of multimeric and immunogenic carrier protein-conjugated subunit vaccines, the surface-exposed and conserved nature of the “AEKA” stem peptide in the structurally integral PGN of S. aureus, the preference for tetra-glycine linkers in multi-epitope proteins given their flexibility or the naturally occurring penta-glycine linkers in the PGN of S. aureus, and the high immunogenicity of the TT=2-based carrier peptides; it would have been obvious to a skilled artisan, with the aim of engineering a robustly immunogenic peptide vaccine against S. aureus and/or M. tuberculosis, to have experimented with designing a multimeric vaccine that is comprised of two of Fischetti’s PGN “AEKA” epitopes separated by a penta- (found in nature, see Fischetti) or Gaikwad et al.’s tetra-glycine linker and further conjugated to Pessi et al.’s immunogenic TT=2 carrier peptide with a reasonable expectation of success. Regarding the different lengths of the glycine linkers in SEQ ID NOs: 3 and 4, tetra-glycine linkers have exceptional flexibility and have been successfully applied in multi-epitope proteins (Gaikwad et al.) and a pentaglycine linker connects the stem peptides of PGN in S. aureus. Thus, it would have been obvious to a skilled artisan to try incorporating either a tetra- or pentaglycine linker to separate the “AEKA” epitopes in a subunit vaccine with a reasonable expectation of success. Furthermore, regarding the positioning of Pessi et al.’s TT=2 carrier protein on the N- or C-terminus of the ”AEKA”-epitope based multimeric vaccine; it would have been obvious to a skilled artisan to try either configuration given that there are only two options.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Malonis et al. 2020 (Chem. Rev., 120, 3210−3229) in view of Fischetti 2016 (Curr. Top. Microbiol. Immunol.; 409, 1-12), Gaikwad et al. 2019 (Clin. Exp. Vaccine Res.; 8(1): 27-34), and Pessi et al. 1990 (EP0378881A1), as applied to claims 1, 9, and 10, and further in view of Wang et al. 2020 (J. Med. Chem.; 63(6), 3290-3297).
The combined teachings of Malonis et al. in view of Fischetti, Gaikwad et al., and Pessi et al., pertaining to claims 1, 9, and 10, and the rationale for combining them, is outlined in the 103 rejection above.
The combined reference teachings differ from the instant invention by not teaching that the adjuvant comprises saponin.
Wang et al. teach that vaccine adjuvants are the substances used with a vaccine to potentiate host’s immune responses to the specific antigen(s) introduced by the vaccine (e.g. see page 3290, left column, first paragraph). They can also tune the immune system to the desirable responses for certain pathogens. For example, QS-21, a saponin and a mixture of two isomers, is an FDA-approved adjuvant known for its capacity of potentiating a balanced Th1/Th2 response with antigen-specific cytotoxic T lymphocyte production, which is valuable for vaccines against intracellular pathogens and cancers. It has potential for a wide range of clinical applications and thus to be in high demand. However, the supplies of QS-21 are very limited. The natural products are isolated from the tree bark of Quillaja saponaria Molina (QS), an evergreen tree native to warm temperate central Chile. Overexploitation of the natural source has resulted in ecological and economic consequences even under the current demand. Moreover, the abundance of QS-21 in QS tree bark extracts is low and its isolation is laborious. QS-21 also has a chemical instability issue due to two hydrolytically unstable ester moieties that complicates its formulation; and its dose-limiting toxicity prevents it from reaching the full potency (e.g. see page 3290, left column, first paragraph).
In pursuit of practical alternatives to QS-21 to overcome its aforementioned drawbacks while inherit its favorable adjuvant activity profile, Wang et al. demonstrated that derivatization of Momordica saponin (MS) I and MS II could potentially be a viable way to achieve the goal (e.g. see page 3290, paragraph spanning left and right columns). These unnatural saponins showed significantly different immunostimulant activity profiles, suggesting that the structure of side chain, triterpenoid core, and oligosaccharide domain together orchestrate each saponin’s characteristic potentiation of immune responses (e.g. see page 3294, left column, first paragraph). Among the various adjuvant candidates, VSA-2 a derivative of MS II, constantly enhanced IgG2a production when it was immunized with either OVA or rHagB antigen. With antigen rHagB, it induced a significantly higher IgG2a response than the positive control GPI-0100, a well-studied semisynthetic saponin adjuvant derived from QS saponins known for its ability to induce a balanced Th1/Th2 immunity. These results confirm that Momordica saponins are a viable natural source for preparation of unnatural saponin adjuvants with different adjuvant activities through simple chemical derivatization and identify VSA-2 as another promising MS-based immunostimulant (in addition to the previously reported VSA-1) for further development owing to its distinctive ability in potentiating the IgG2a response.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Malonis et al. in view of Fischetti, Gaikwad et al., and Pessi et al., pertaining to claim 1, 9, and 10, and to incorporate the teachings of Wang et al. to include the adjuvant of the immunogenic composition comprises saponin.
Saponins have long been incorporated into vaccination platforms as adjuvants given their well-known immunogenicity (Wang et al.). In particular, among various saponin-based adjuvant candidates, VSA-2, a derivative of MS II, constantly enhanced IgG2a production when it was immunized with either OVA or rHagB antigen (Wang et al.). Thus, given the general applicability of saponin-based adjuvants and Wang et al.’s especially promising VSA-2; it would have been obvious to a skilled artisan with the intention of enhancing the immunogenicity of the immunogenic composition comprising the immunogenic peptide taught by Malonis et al. in view of Malonis et al. in view of Fischetti, Gaikwad et al., and Pessi et al. to include a saponin-based adjuvant with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-7, 9-11, 13, 42, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 12-28 of U.S. Application No. 18/380,479 (the ‘479 Application) in view of Malonis et al. 2020 (Chem. Rev., 120, 3210−3229), Fischetti 2016 (Curr. Top. Microbiol. Immunol.; 409, 1-12), Gaikwad et al. 2019 (Clin. Exp. Vaccine Res.; 8(1): 27-34), and Pessi et al. 1990 (EP0378881A1).
The instant claims are drawn to immunogenic peptides comprised of a contiguous sequence of either of the sequences of SEQ ID NOs: 3 or 4, or a combination thereof; immunogenic compositions; and contiguous peptide sequences.
The claims in the ‘479 Application are drawn to an immunogenic peptide comprising a contiguous peptide sequence of multiple viral, bacterial, and/or parasitic epitopes; immunogenic compositions; a method to treat or prevent an infection by a pathogen; and a method to treat an infection by a pathogen.
The claims in the ‘479 Application differ from the instant invention by not teaching the specific immunogenic peptides comprised of a contiguous sequence of either of the sequences of the elected SEQ ID NOs: 3 or 4, or a combination thereof.
The teachings of Malonis et al., Fischetti, Gaikwad et al., and Pessi et al. are outlined in the 103 rejections above.
It would be obvious to one of ordinary skill in the art to modify the of immunogenic peptides encompassed by the claims in the ‘479 Application to incorporate the teachings of Malonis et al., Fischetti, Gaikwad et al., and Pessi et al. to include the specific immunogenic peptides comprised of a contiguous sequence of either of the sequences of the elected SEQ ID NOs: 3 or 4, or a combination thereof for a subunit vaccine.
Subunit vaccines consist primarily of peptides or proteins. Subunit vaccines face limitations with respect to immunogenicity, which are generally overcome by inactive or attenuated pathogens given that these platforms contain both B- and T-cell epitopes presented in a conformation that is relevant to the pathogen (Malonis et al.). A variety of approaches to enhance subunit vaccine responses, including presentation of epitopes in multimeric format or use of immunostimulatory adjuvants, have been utilized (Malonis et al.). The elicitation of epitope-specific antibodies is a primary mechanism of protection for many vaccines and, generally, requires affinity maturation from the germline, a process that is stimulated by cross-linking of BCRs (Malonis et al.). To this end, monomeric peptides are often poorly immunogenic relative to those corresponding sequences on viral, bacterial, or parasitic external proteins because, when presented in those contexts, multiple copies of the epitope on the pathogen surface permit efficient cross-linking of BCRs and thus stimulate antibody affinity maturation (Malonis et al.). Furthermore, stimulation of epitope-specific T-cells is another mechanism by which vaccines can induce protective immunity
In typical subunit-based vaccination protocols, an epitope of interest is conjugated to a carrier protein or presented in a multimeric format (Malonis et al.). The carriers are generally known to have immunogenic properties, and thus the simple covalent linking of epitopes of interest to an immunogenic carrier protein can often be sufficient to enhance the immune response toward the selected epitopes (Malonis et al.). Moreover, the immunogenicity of peptide or protein sequences can be augmented through its linkage to short sequences, such as universal helper T-cell epitopes, that are known to stimulate an immune response (Malonis et al.).
Thus, Malonis et al. teach a general platform for designing subunit or peptide vaccines which are comprised of an epitope(s) of interest, such as a conserved cell-surface peptide and/or a peptide that is essential to pathogenicity or pathogen survival, where the epitope(s) is presented in an immunogenically-favored multimeric and/or immunogenic carrier-conjugated format.
For infectious diseases, often the epitope of interest is a site of susceptibility for “neutralization” by antibodies and for the most part, protective antibodies target epitopes that lie on the surface of a pathogen (Malonis et al.).
Thus, the epitope of interest may include the stem peptide found in the cell wall peptidoglycan on the surface of S.aureus. This stem peptide has the amino acid sequence of Ala-Glu-Lys-Ala and is a conserved tetrapeptide that links the large glycan strands of PGN (Fischetti). It is noted that this tetrapeptide is identical to instant SEQ ID NO: 5 and is incorporated into instant SEQ ID NOs: 3 and 4. The PGN can be further stabilized by cross-linking adjacent stem peptides via a pentaglycine (Fischetti). The integrity of the cell-surface PGN, which is facilitated by this stem peptide, is essential for pathogen survival (Fischetti).
Nonetheless, as is stated above, monomeric peptides are often poorly immunogenic and it is preferred that epitopes be presented in multimeric formats in order to permit efficient cross-linking of BCRs and in turn stimulate antibody affinity maturation (Malonis et al.). Thus, the design of multiepitope proteins, wherein the epitopes are separated by linkers, is desirable in order to elicit an efficient immune response (Gaikwad et al.). Such inter-epitope linkers include tetra-glycine linkers because they provide flexibility due to lack of β-carbon and are the preferred linkers in multi-epitope proteins (Gaikwad et al.), or pentaglycine linkers with are the naturally occurring linkers that bridge the stem peptide (“AEKA”) in PGN (Fischetti).
To further enhance the immunogenicity of such multi-epitope proteins that comprise tetra- or penta-glycine linkers, the multi-epitope proteins may be conjugated to a carrier, such as short sequences that are known to stimulate an immune response, including universal T-cell epitopes.
The universal T-cell epitope-based carriers include the “particularly preferred universal carrier” synthetic peptide corresponding to regions 830-843 of tetanus toxin (TT=2) (Pessi et al.).
Thus, given the general platform for subunit or peptide vaccine design presented by Malonis et al., the enhanced immunogenicity of multimeric and immunogenic carrier protein-conjugated subunit vaccines, the surface-exposed and conserved nature of the “AEKA” stem peptide in the structurally integral PGN of S. aureus, the preference for tetra-glycine linkers in multi-epitope proteins given their flexibility or the naturally occurring penta-glycine linkers in the PGN of S. aureus, and the high immunogenicity of the TT=2-based carrier peptides; it would be obvious to a skilled artisan, with the aim of engineering a robustly immunogenic peptide vaccine against S. aureus and/or M. tuberculosis, to have experimented with designing a multimeric vaccine that is comprised of two of Fischetti’s PGN “AEKA” epitopes separated by a penta- (found in nature, see Fischetti) or Gaikwad et al.’s tetra-glycine linker and further conjugated to Pessi et al.’s immunogenic TT=2 carrier peptide with a reasonable expectation of success. Regarding the different lengths of the glycine linkers in SEQ ID NOs: 3 and 4, tetra-glycine linkers have exceptional flexibility and have been successfully applied in multi-epitope proteins (Gaikwad et al.) and a pentaglycine linker connects the stem peptides of PGN in S. aureus. Thus, it would be obvious to a skilled artisan to try incorporating either a tetra- or pentaglycine linker to separate the “AEKA” epitopes in a subunit vaccine with a reasonable expectation of success. Furthermore, regarding the positioning of Pessi et al.’s TT=2 carrier protein on the N- or C-terminus of the ”AEKA”-epitope based multimeric vaccine; it would be obvious to a skilled artisan to try either configuration given that there are only two options.
Therefore, the claims in the `479 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-7, 9-11, 13, 42, and 43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims in the following co-pending Application (the ‘952 Application) in view of Malonis et al. 2020 (Chem. Rev., 120, 3210−3229), Fischetti 2016 (Curr. Top. Microbiol. Immunol.; 409, 1-12), Gaikwad et al. 2019 (Clin. Exp. Vaccine Res.; 8(1): 27-34), and Pessi et al. 1990 (EP0378881A1) for similar reasons to the NSDP rejection to the claims in the ‘479 Application above.
The instant claims are drawn to immunogenic peptides comprised of a contiguous sequence of either of the sequences of SEQ ID NOs: 3 or 4, or a combination thereof; immunogenic compositions; and contiguous peptide sequences.
Claims 1-26 of co-pending Application No. 18/388,952 are drawn to compositions comprising an immunogenic portion of a peptidoglycan and an immunogenic portion of a heat shock protein; a vaccine; and a method of treating or preventing an infection in a mammal.
Claims 1-7, 10-13, 16, 19, 20, and 22-24 of co-pending Application No. 19/182,300 are drawn to a composition for the prevention or treatment of a microbial infection comprised of an amount of contiguous peptide sequence of multiple viral, bacterial and/or parasitic epitopes.
Claims 1, 3-7, 9, 10, 13-23, and 28-32 of co-pending Application No. 18/366,915 are drawn to immunogenic compositions; and methods to treat or prevent a pathogenic infection.
Claims 1-25 of co-pending Application No. 18/162,032 are drawn to immunogenic compositions; a vaccine; and a method for treating or preventing an infection of a pathogen.
The claims in the co-pending Application differ from the instant invention by not teaching the specific immunogenic peptides comprised of a contiguous sequence of either of the sequences of the elected SEQ ID NOs: 3 or 4, or a combination thereof.
The teachings of Malonis et al., Fischetti, Gaikwad et al., and Pessi et al. are outlined in the 103 rejections above.
It would be obvious to one of ordinary skill in the art to modify the of immunogenic peptides encompassed by the claims in the co-pending Application to incorporate the teachings of Malonis et al., Fischetti, Gaikwad et al., and Pessi et al. to include the specific immunogenic peptides comprised of a contiguous sequence of either of the sequences of the elected SEQ ID NOs: 3 or 4, or a combination thereof for a subunit vaccine.
Subunit vaccines consist primarily of peptides or proteins. Subunit vaccines face limitations with respect to immunogenicity, which are generally overcome by inactive or attenuated pathogens given that these platforms contain both B- and T-cell epitopes presented in a conformation that is relevant to the pathogen (Malonis et al.). A variety of approaches to enhance subunit vaccine responses, including presentation of epitopes in multimeric format or use of immunostimulatory adjuvants, have been utilized (Malonis et al.). The elicitation of epitope-specific antibodies is a primary mechanism of protection for many vaccines and, generally, requires affinity maturation from the germline, a process that is stimulated by cross-linking of BCRs (Malonis et al.). To this end, monomeric peptides are often poorly immunogenic relative to those corresponding sequences on viral, bacterial, or parasitic external proteins because, when presented in those contexts, multiple copies of the epitope on the pathogen surface permit efficient cross-linking of BCRs and thus stimulate antibody affinity maturation (Malonis et al.). Furthermore, stimulation of epitope-specific T-cells is another mechanism by which vaccines can induce protective immunity
In typical subunit-based vaccination protocols, an epitope of interest is conjugated to a carrier protein or presented in a multimeric format (Malonis et al.). The carriers are generally known to have immunogenic properties, and thus the simple covalent linking of epitopes of interest to an immunogenic carrier protein can often be sufficient to enhance the immune response toward the selected epitopes (Malonis et al.). Moreover, the immunogenicity of peptide or protein sequences can be augmented through its linkage to short sequences, such as universal helper T-cell epitop