Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of species in the reply filed on 04/16/2026 is acknowledged.
Applicant elected the following:
Examiner Note: In the election, the applicant wrote “The promoters” rather than “The protomers”(see below). However, these elections are being interpreted as “The protomers” as stated in the claims.
Claim 5: The promoters further comprise amino acid substitutions to add arginine residues to a GP1/GP2 cleavage site at positions 256-259.
Claim 9: The promoters of the trimer comprise or consist of the amino acid sequence set forth as residues 59-419 of SEQ ID NO: 2.
Claim 13: The promoters of the trimer fused to the trimerization domain comprise or consist of the amino acid sequence set forth as residues 59-448 of SEQ ID NO: 2.
Claim 19: Directly fused to the transmembrane domain.
Claim 24: The combination of the self-assembling protein nanoparticle is encapsulin and the LASV GPC ectodomain trimer is linked to the subunits of the self-assembling protein nanoparticles using a spytag/spycatcher system.
Claims 1-2, 4-6, 9, 11-13, 15-19, 21-24, and 26-37 are under consideration.
Priority
It is acknowledged that this application is a 371 of PCT/US2022/027136, filed 04/29/2022 which as provisional application 63/329,886, filed on 04/12/2022 and a provisional 63/181,519, filed 04/29/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/26/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 9, 13, 24 are objected to because of the following informalities:
Claim 1: Change “positioning to positions” for improved clarity. Change “protein sequence set forth as” to “amino acid sequence set forth as”.
Claim 9: Remove the colon after wherein so that it reads, “The LASV GPC ectodomain trimer of claim 1, wherein the protomers…”.
Claim 13: Remove the colon after wherein so that it reads, “The LASV GPC ectodomain trimer of claim 11, wherein the protomers…”.
Claim 24: Remove the colon after wherein, for example, “of claim 22, wherein the self…”. Also, remove the semicolon after encapsuling, for example, “nanoparticle is encapsuling and…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 37 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for generating neutralizing antiserum in guinea pigs (see FIG. 8), does not reasonably provide enablement for inhibiting LASV infection in the subject (examples of subjects in the specification include guinea pigs and humans). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
See claim 37 as submitted 04/16/2026.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Here, instant claim 37 is broadly drawn to a method, wherein the immune response inhibits LASV infection in the subject. It is noted that the term “inhibits” was interpreted in an absolute sense to mean to always keep something from happening or arising.
The level of skill in the art is high and would include, e.g., Ph.D. level scientists. Warner et al. (2024)(See PTO-892 Notice of References Cited) teaches the “high burden of disease in Africa underscores the need for development of preventative and therapeutic measures against LASV. There are currently no FDA-approved therapeutics or drugs for the treatment of LF, though the off-label use of ribavirin and convalescent immune plasma have been used for treating LF patients for many years”(p. 2, Introduction). Warner also teaches “[s]everal different vaccine platforms have been developed and tested against LASV in animal models, ranging from small animal models to non-human primates [NHPs] (Table 1). These vaccines have included live and replication-deficient recombinant viral vectors expressing LASV glycoprotein, nucleic acids, nanoparticle or virus-like particle vaccines, and reassortant viruses. Phase I clinical trials for DNA-, measles virus-, or vesicular stomatitis virus-based vaccines have been completed or are ongoing, and a phase II trial of one vesicular stomatitis virus-based candidate is ongoing (NCT03805984, NCT04055454, NCT04794218, NCT05868733, PACTR202108781239363)(p. 2 and Table 1). Warner further teaches “[o]ne of the major considerations for vaccine development against LASV is the induction of an appropriate immune response that will be protective. During natural infection, LASV can effectively antagonize both the innate and adaptive immune response, leading to faulty clearance of infection and progression of disease…Determining immune correlates of protection for LF has been an area of debate, with most studies suggesting that T cell responses and cell-mediated immunity are critical, while there is some evidence that non-neutralizing antibodies can play a protective role…It is difficult to assess the role of cell-mediated immunity in protection against LF in guinea pigs, the most used small animal model of infection, therefore much of the evidence comes from smaller NHP studies or retrospective human data. This is an area of research interest that will have important implications in the design, development, and testing of vaccine candidates for LASV and will be an important component of reports of vaccine efficacy”(pp. 2-3). And finally, Warner teaches [a]nother important consideration is the significant genetic diversity of LASV throughout West Africa. There are at least seven distinct lineages, or clades, of LASV that have been identified. Clades I, II, and III are found in Nigeria, where genetic epidemiology suggests the virus originated…Clade IV is found in Sierra Leone, Guinea, and Liberia, while clades V through VII have been more recently described and have emerged in Mali, Côte d’Ivoire, Nigeria, Benin and Togo...Many of the mutations that have accumulated in LASV linages over time are seen in the surface glycoprotein (GPC), possibly as means of immune escape in the rodent reservoir. However, these changes also result in potential divergence in antigenicity of the GPC between LASV clades which may have important implications for broad protection of vaccines across West Africa (p. 3).
The specification only exemplifies and reduces to practice the generation of neutralizing immune serum in guinea pigs using a modified LASV GPC with the wild type LASV GPC Josiah serving as the reference strain. It doesn’t effectively demonstrate in the specification or in the experimental data provided inhibiting LASV infection in the subject.
In view of the foregoing, and in light of the difficulty suggested by Warner et al to generate an effective composition and method, including the significant genetic diversity of LASV throughout West Africa, a vast quantity of experimentation, including extensive animal and clinical trials, would be required to use the invention based on the content of the disclosure.
Taken together, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4-6, 9, 11-13, 15-19, 21-24, 26-37 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.
See claims 1-2, 4-6, 9, 11-13, 15-19, 21-24, 26-37 as submitted 04/16/2026.
Claim 1: Claim recites “comprise cysteine substitutions at GPC positions 207 and 326 that form a non-natural interprotomer disulfide bond”. As written, it is unclear if the non-natural disulfide bond is between the cysteines at 207 and 326 (and if so, they must be on different protomers to satisfy “an interprotomer” versus an “intra-protomer" bond) or with other cysteine residues on one of the other two protomers. For compact prosecution purposes, the disulfide bond is being interpreted as being between the cysteines at 207 and 326 but with each located on different protomers.
Claims 1, 4, 5, 6, 9, 11, 13, 15, 16, 17, 19, 26, 27 recite “protomers” such as “substitutions in protomers of the trimer”(such as recited in claim 1) or “the protomers comprise”(as recited in claim 4), or “the protomers of the trimer comprise”(as recited in claim 6), etc. However, it is unclear if each of the protomers comprise the limitation written or do the protomers, in aggregate, comprise the limitation written. It appears the trimer includes protomers but it is unclear if each protomer comprise some of these substitutions or if the trimer as a whole does.
Claims 2, 4, 5, 6, 9, 11-13, 15-19, 21-24, 26-37: All of these claims refer back to “The LASV GPC ectodomain” in claim 1 and as written, there is insufficient antecedent basis. Note: there are two LASV GPC sequences noted in claim 1 – first, the recombinant Lassa virus (LASV) Glycoprotein Complex (GPC) and 2 – the LASV GPC reference sequence as set forth in SEQ ID NO: 1. To overcome this rejection, use “recombinant LASV GPC ectodomain trimer” in subsequent claims.
Claim 2: Claim 2 recites the limitation “the cysteine substitutions are R207GC…”. However, in reality, this is not only a cysteine substitution but a Glycine and Cysteine substitution. Additionally, claim 1 recites “wherein the amino acid substitutions comprise cysteine substitutions at GPC positions 207 and 326”. There is insufficient antecedent basis for this limitation – a Glycine and Cysteine substitution - in the claim.
Claims 2, 4, 5, and 6 all detail different amino acid positions but do not include a reference sequence, e.g., “according to a reference LASV GPC amino acid sequence set forth as SEQ ID NO: 1”. It is unclear if it is indeed SEQ ID NO: 1 or something else. For compact prosecution purposes, the claim is being interpreted as positions in SEQ ID NO: 1.
Claims 9, 13, and 16: Claims 9, 13, and 16 are dependent on claim 1 (wherein the amino acid substitutions comprise cysteine substitutions at GPC positions 207 and 326). However, claims 9, 13 and 16 all include sequences which include a R207GC substitution (p. 8 of the specification). Accordingly, there is insufficient antecedent basis for this limitation – a Glycine and Cysteine substitution - in the claim.
Claim 21: It is unclear what exactly is conjugated to a heterologous carrier.
Claim 29: It is unclear if the nucleic acid encodes all three protomers or only one protomer as suggested by “a protomer”.
Claim 33: It is unclear what “or a vector comprising the nucleic acid molecule” refers to. For compact prosecution, it is interpreted as “or a vector comprising the nucleic acid molecule of claim 29”. To overcome the rejection, amend to read “or a vector comprising the nucleic acid molecule of claim 29”.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Hastie et al. (Hastie 2017)(Structural basis for antibody-mediated neutralization of Lassa virus; as cited in the IDS submitted 10/26/2023)) & Hastie et al. (Hastie 2019)(Convergent Structures Illuminate Features for Germline Antibody Binding and Pan-Lassa Virus Neutralization)(See PTO-892 Notice of References Cited) teaches genetically modified the LASV glycoprotein ectodomain by (i) making the point mutations R207C and G360C to covalently link GP1 and GP2 together (p.3)(instant claim 1). Hastie 2019 teaches GPCysR4 fused to a C-terminal, exogeneous trimerization domain (GPCysR4-TD) (p. 1011)(instant claim 11). Hastie 2019 further teaches soluble GPC monomers and trimers (p. 1011)(instant claim 18). Regarding L326 (but no substitution), Hastie 2017 teaches L326 in Figure 4. (p. 4). Hastie 2019 also teaches L326 (but no substitution) in Figure 1 – “The CDRs from each Fab (colored as in A) bind in the same location between two GPC monomers and recognize residues 62–63 of GP1 and residues 356–362 and 387–408 of GP2 in site A and residues 266–275 and 324–326 of GP2 in site B” (p. 1006).
Jasny et al. (Jasny)(2020)(WO2020002525A1)(as cited in the IDS submitted 10/26/2023) teaches amino acid substitutions allowing a covalent link of GP1 and GP2, preferably by introduction of two additional cysteine residues, preferably at position 207 or 206 (reference claim 5)(instant claim 1). Jasny teaches replacing the native GP1-GP2 cleavage site (S1 P) with a furin cleavage site, e.g. RRLL to RRRR to facilitate efficient processing of the mRNA encoded antigenic protein in target cells, preferably by amino acid substitutions L258R, L259R or L257R, L258R (reference claim 5)(instant claim 5 and 6).
Guirakhoo et al. (Guirakhoo)(WO2019018501-A1)(See PTO-892 Notice of References Cited) teaches Lassa virus Josiah glycoprotein (GP) mutant SEQ ID 10 with a R207C mutation (p. 3)(instant claim 1); nanoparticle formulations (p. 30)(instant claim 22) ; vector comprising a nucleic acid molecule encoding a LASV GPC ectodomain trimer (reference claim 1)(instant claim 31), pharmaceutical compositions and pharmaceutically acceptable carriers (reference claim 16)(instant claim 35), methods of administering to a subject and effective amount of a Lassa virus glycoprotein based composition(reference claim 26)(instant claim 36).
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Cornelius whose telephone number is (571) 272-0860. The examiner can normally be reached M-F, 0930-1700.
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/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672
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