DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 21, 2026 has been entered.
Claims Summary
Claim 1 is directed to a stabilized recombinant flavivirus E glycoprotein, comprising a flavivirus E backbone, specifically Dengue virus (claim 2, elected species) and amino acid substitutions 259W and 262R (elected species), wherein the numbering is based on SEQ ID NO: 6 (DENV2 E) or comprises SEQ ID NO: 6 having A259W and T262R (claim 7). The glycoprotein comprises SEQ ID NO: 26, representing DENV2 IntFc2 which has A259W and T262R (see paragraph [0109]) (claim 8). The E glycoprotein backbone comprises a soluble ectodomain of DI, DII and DIII, and/or wherein the E glycoprotein comprises at least one quaternary epitope (claim 5). Also claimed is a stabilized recombinant flavivirus E glycoprotein dimer comprises two flavivirus E glycoproteins (claim 205), wherein the melting point of the dimer is about 0.5°C to about 45°C higher than that of a wildtype flavivirus E glycoprotein of the corresponding backbone, and/or wherein the dimer has a dimer affinity of about 18 µM or lower as measured at 37°C (claim 206). Also claimed is a flavivirus particle or VLP comprising the glycoprotein (claim 208), a population of particles (claim 211), and a VLP that does not comprise pre-membrane (pr) (claim 213). Claim 212 is directed to a composition comprising the glycoprotein in a pharmaceutically acceptable carrier. Also claimed are methods of inducing an immune response (claim 214), inhibiting a flavivirus infection (claim 215), protecting a subject from the effects of a dengue virus infection (claim 217) by administering an effective amount of the glycoprotein to a subject. Claim 227 is directed to a method of producing a stabilized recombinant E glycoprotein by introducing substitutions 259W and 262R into a flavivirus E glycoprotein backbone, thereby stabilizing the glycoprotein into dimer conformation.
In another embodiment, the glycoprotein comprises SEQ ID NO: 147, representing soluble E of DENV1, and having A259W and S262R (claim 139). The glycoprotein comprises SEQ ID NO: 149, representing DENV1 IntFc2 which has A259W and S262R (claim 140).
In another embodiment, the glycoprotein comprises SEQ ID NO: 152, representing soluble E of DENV3, and having A257W and T260R (claim 147). The glycoprotein comprises SEQ ID NO: 154, representing DENV3 IntFc2 which has A257W and T260R (claim 148).
In another embodiment, the glycoprotein comprises SEQ ID NO: 169, representing soluble E of DENV4, and having A259W and S262R (claim 179). The glycoprotein comprises SEQ ID NO: 171, representing DENV4 IntFc2 which has A259W and S262R (claim 180).
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 217 remains 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 a method of inhibiting a dengue virus infection or inducing an immune response against a dengue viral infection, does not reasonably provide enablement for protecting a subject from the effects of a dengue virus infection. 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.
Claim 217 is directed to method of protecting a subject from the effects of a flavivirus infection by administering a stabilized recombinant flavivirus E glycoprotein, comprising a flavivirus E backbone, having amino acid substitutions 259W and 262R, wherein the numbering is based on SEQ ID NO: 6 (DENV2 E). The breadth of the claims encompasses prevention from the effects of any dengue virus infection, in any subject, including humans.
The nature of the invention is the induction of an immune response via immunization with a stabilized flavivirus E glycoprotein that will, upon subsequent challenge, protect against disease.
The specification’s guidance and working examples show that stabilized glycoproteins are produced consistent with the instant claims, however, it does not appear that any experiments were conducted in animal models to show vaccine efficacy (i.e., challenge experiments). Without in vivo evidence, immunogenicity alone is not a predictor of therapeutic efficacy nor protective efficacy. Basheer et al. (Front Immunol. 2023 Nov 17; 14:1273838, 19 pages) discloses that there remains a need in the art for vaccines against Dengue virus, noting that Dengvaxia (a live, attenuated, tetravalent vaccine) is useful for a limited population, i.e., children of a certain age range that have been exposed to Dengue before (see pages 2-3, bridging paragraph). Basheer’s construct is a tetravalent subunit composition against DENV, making use of epitopes from EDIII, prM and NS1 proteins (see abstract). While Basheer’s in silico methods show promising results, no in vivo experiments were performed to confirm efficacy. The Basheer reference is cited to show the state the art generally, and the state of the art with regard to subunit constructs for Dengue virus.
Silva and Fernandez-Sesma (Journal of General Virology, 2023, 104:001831, 12 pages, “Silva”) states that there is no specific treatment for dengue, rather one licensed vaccine (see abstract). They present a review of the challenges associated with dengue vaccine development concerning the various constructs, including subunits and VLPs (see Table 1 and page 8, V180 and DSV4 constructs). While these constructs are immunogenic and confer protection in mice against certain serotypes, the challenges remain for vaccine efficacy against all four serotypes, limited animal models and ADE (see pages 9-10, bridging paragraph).
In view of the breadth of the claims, the nature of the invention, the state of the art, the limited guidance and working examples, and the low level of predictability, it would require undue experimentation to practice the claimed methods for preventing disease symptoms of any dengue virus infection.
Applicant’s remarks filed January 21, 2026 are acknowledged. Applicant argues that inhibition of a flavivirus infection is expected to lead to protection against the effects of an infection since the subject will not develop illness. Applicant points to Silva’s abstract, noting that one in four infected individuals will become ill. Applicant reasons that since inhibiting an infection will protect against the effects of an infection (i.e., illness), the specification enables a protective immune response that prevents or reduces the incidence, severity, and/or duration of disease or manifestation of infection (see paragraph [0076] of the specification).
In response, the specification has not enabled one to even partially protect against dengue disease. Applicant’s logic (i.e., inhibition leads to protection) does not account for the art-recognized difficulties in the art pertaining to protection, as discussed in Basheer and Silva (above). Immunogenicity is expected to result in some degree of inhibition of an infection, however, that does not translate to protection in humans. Challenge experiments in an acceptable animal model of human disease speak to protection in humans. Therefore, the claims remain rejected for reasons of record.
Conclusion
No claim is allowed. Claims 1, 2, 5, 7, 8, 139, 140, 147, 148, 179, 180, 205, 206, 208, 211-215 and 227 are objected to for reciting non-elected species, but would otherwise be allowable if limited to the elected species.
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/STACY B CHEN/Primary Examiner, Art Unit 1672