DETAILED ACTION
Election/Restrictions
Applicant’s election of species filed March 3, 2026 is acknowledged and entered. The elected species are a chimeric MOKV/RABV glycoprotein and a RABV clip/flap and MOKV core. Claims 6, 18 and 32 are withdrawn from consideration being directed non-elected species.
Specification
The disclosure is objected to because there is a reference to Figures 17C, D, G and H in paragraph [0228] of the published application US 2023/0398201 A1, however, the drawings filed May 1, 2023 do not have Figure 17. Appropriate correction is required.
Drawings
The drawings are objected to because Figure 1 present blurry text that cannot be read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claims Summary
Claims 1-5, 7-13, 34-38 and 46-48
Claim 1 is directed to an isolated nucleic acid encoding a recombinant lyssavirus comprising a nucleotide sequence encoding at least a portion of the genome of a rabies virus (RABV), specifically the SADB-19 RABV strain (claim 3). The nucleic acid encodes a recombinant RABV (claim 13). The portion of the genome of the RABV comprises a nucleotide sequence encoding a RABV nucleoprotein (N) or a portion thereof. The lyssavirus further comprises a nucleotide sequence encoding a glycoprotein (G) or a portion thereof positioned immediately 3’ (downstream) to the nucleotide sequence encoding the N (claim 1) and immediately 5’ (upstream) to a nucleotide sequence encoding a RABV phosphoprotein (P) (claim 7). The G is a chimeric MOKV/RABV glycoprotein (claim 2; elected species) comprising a R333E mutation (claim 4). (MOKV is Mokola virus.) The chimeric G comprises a nucleotide sequence encoding a RABV clip domain, a nucleotide sequence encoding a RABV flap domain, and a nucleotide sequence encoding a MOKV core domain (claim 5; elected species).
The nucleic acid sequence comprises a nucleotide sequence having at least 85% sequence identity (claim 8), at least 90% sequence identity (claim 9), at least 95% sequence identity (claim 10), at least 99% sequence identity (claim 11), or comprises SEQ ID NO: 1, 2 or 4 (claim 12).
SEQ ID NO: 1, which is 11354-nt, represents the construct BNSP333-CoG333-AG, a gene shuffled attenuated rabies vaccine expressing rabies virus glycoprotein optimized for codon use in mammalian animals (see paragraph [0052] of the published application US 2023/0398201 A1)
SEQ ID NO: 2, which is 1569-nt, represents a MOKV glycoprotein DNA
SEQ ID NO: 4, which is 1575-nt, represents a chimeric MOKV/RABV glycoprotein DNA
Also claimed is a vector comprising the nucleic acid (claim 35). Also claimed is a recombinant virus and vaccine encoded by the nucleic acid (claims 34 and 36, respectively), wherein the vaccine comprising a pharmaceutically acceptable carrier, and further comprises an adjuvant (claim 37). The virus in the vaccine is deactivated (claim 38). Claim 46 is directed to a method of increasing expression of a recombinant lyssavirus in a host cell by expressing in the host cell a nucleic acid sequence of claim 1, wherein the virus is RABV (claim 48), or wherein the host cell is a mammalian cell (claim 47).
Claims 14-17 and 19-27
Claim 14 is directed to an isolated nucleic acid comprising a nucleotide sequence encoding a RABV N or a portion thereof, and a nucleotide sequence encoding a G or a portion thereof positioned immediately 3’ to the nucleotide sequence encoding the N (claim 14) and immediately 5’ to a nucleotide sequence encoding a RABV phosphoprotein (P) (claim 19), and the P is positioned immediately 5’ to M, which is 5’ to L (claim 20). The portion of the genome of the RABV comprises a nucleotide sequence encoding a RABV nucleoprotein (N) or a portion thereof. The G is a chimeric MOKV/RABV glycoprotein (claim 15; elected species) comprising a R333E mutation (claim 16). The chimeric G comprises a nucleotide sequence encoding a RABV clip domain, a nucleotide sequence encoding a RABV flap domain, and a nucleotide sequence encoding a MOKV core domain (claim 17; elected species). The nucleic acid comprises a nucleotide sequence having at least 85% sequence identity (claim 21), at least 90% sequence identity (claim 22), at least 95% sequence identity (claim 23), at least 99% sequence identity (claim 24), or comprises SEQ ID NO: 1, 2 or 4 (claim 25). The nucleic acid is codon optimized for expression in a host cell (claim 26), a mammalian cell (claim 27).
Claims 28-31, 33 and 39-45
Claim 28 is directed to a recombinant virus encoded by a nucleic acid sequence comprising at least a portion of the genome of a rabies virus (RABV). The virus is a RABV (claim 33). The portion of the genome of the RABV comprises a nucleotide sequence encoding a RABV nucleoprotein (N) or a portion thereof. The nucleic acid sequence further comprises a nucleotide sequence encoding a glycoprotein (G) or a portion thereof positioned immediately 3’ to the nucleotide sequence encoding the N. The G is a chimeric MOKV/RABV glycoprotein (claim 29; elected species) comprising a R333E mutation (claim 30). The chimeric G comprises a nucleotide sequence encoding a RABV clip domain, a nucleotide sequence encoding a RABV flap domain, and a nucleotide sequence encoding a MOKV core domain (claim 31; elected species).
Claim 39 is directed to a method of generating an immune response against a lyssavirus in a subject in need thereof, specifically a mammal (claim 44), specifically RABV (claim 45). Claim 40 is directed to a method of vaccinating a subject against a lyssavirus. Claim 41 is directed to a method of providing immunity against a lyssavirus in a subject. Claim 42 is directed to a method of treating and/or preventing a disease or disorder associated with a lyssavirus in a subject in need thereof. Claim 43 is directed to a method of increasing immunogenicity against a lyssavirus in a subject in need thereof. The methods of claims 39-43 comprise administering to the subject an effective amount of the recombinant virus of claim 28.
Claim Objections
Claims 35 and 43 are objected to because of the following informalities:
Claim 35 recites “A vector comprising the nucleic acid of any one of claim 1” [emphasis added], which has a residual phrase from a prior version of the claim.
Claim 43 recites, “administering to the subject an effective amount of claim 28”. It is understood that the recombinant virus of claim 28 is administered.
Appropriate correction is required.
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 36-38 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 36 recites the limitation "the recombinant virus of claim 1”. Claim 1 is directed to an isolated nucleic acid. There is insufficient antecedent basis for this limitation in the claim. Claims 37 and 38 are included in this rejection because they depend from claim 36.
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.
Claims 36-38 and 40-42 are 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 an immunogenic composition or pharmaceutical composition and methods of generating an immune response wherein the recombinant virus has an attenuating mutation R333E in RABV G, does not reasonably provide enablement for a lyssavirus vaccine nor methods of vaccinating against a lyssavirus, providing immunity against a lyssavirus, treating a lyssavirus disease or disorder, or preventing a lyssavirus disease or disorder; either with or without the R333E mutation in RABV G. (Claim 36 is being treated as if dependent on claim 28; see indefiniteness rejection above.) Also enabled is a vaccine directed to RABV, and methods of vaccinating and protecting against RABV, provided that the virus is the construct set forth as LyssaVax (described below). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims encompasses a vaccine, which is understood to induce protective immunity against any virus. The vaccine comprises a virus that has a portion of a RABV genome that comprises RABV N or a portion thereof, and a nucleotide sequence encoding any G sequence or portion thereof positioned immediately 3’ to N. Note that the source of the G sequence is not identified (in contrast with claim 29, for example), and thus could be from any lyssavirus or non-lyssavirus. Thus, the vaccine broadly encompasses a vaccine against any virus as long as it has a RABV N or portion thereof, and a sequence of any G or portion thereof positioned immediately 3’ to N. The vaccine protects against disease caused by any lyssavirus (claim 40), provides immunity against any lyssavirus (claim 41) which is understood to be protective immunity, treats any existing lyssavirus disorders or diseases, and prevents any lyssavirus disorders or diseases.
The nature of the invention is a recombinant lyssavirus that will induce a level of immunity in a recipient such that upon future infection with a lyssavirus the recipient will be protected from diseases or disorders associated with infection. The nature of the invention also encompasses the treatment of existing diseases and disorders associated with lyssavirus infection.
The specification is directed to RABV having shuffled G sequences comprised of portions from both RABV G and MOKV G, which, when inactivated, induce protective immunity in mice against challenge with RABV and recombinant MOKV (see paragraph [0198] of the published application US 2023/0398201 A1). Applicant constructed LyssaVax, which is represented in Figure 2A:
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LyssaVax comprises a chimeric G protein having RABV clip, RABV flap, and MOKV core, represented in Figure 11E (elected species); Figure 11D is a reference to identify the clip, core and flap regions:
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Concerning attenuation, the specification teaches that moving the G sequence from the fourth position to the second position in the RABV genome contributes to attenuation, however, there is no indication in the examples that that alone is sufficient to confer attenuation that will render a live vaccine safe, since the types of viruses tested in vivo were either inactivated or carried the R333E mutation (LyssaVax) (see paragraphs [0203], [0205] and [0206]). Challenge experiments in mice show that LyssaVax is protective against RABV and recombinant MOKV (see paragraph [0212]). Protection against other lyssaviruses remains to be determined (see paragraphs [0226] and [0230]). There is no guidance in the specification with regard to treatment protocols, nor are there examples demonstrating treatment of existing diseases or disorders associated with RABV or any other lyssavirus. Additionally, there is no guidance on portions of a RABV genome, portions of RABV N, or portions of RABV/MOKV G, other than those described in the examples, which are directed to a complete RABV genome (including a complete RABV N) whose portions of G are those from RABV/MOKV as outlined above. No other portions of a RABV genome, portions of N or portions of any non-RABV or non-MOKV G are provided.
Applicant’s own work (Fisher et al., Cell Reports, 32, 107920, July 21, 2020, cited in the IDS filed 10/27/2025) confirms that one construct has been identified, i.e., inactivated LyssaVax, which is protective against recombinant RABV and recombinant MOKV, and that further work is needed to determine whether other lyssaviruses can be protected against (see abstract and page 9). As for treatment of an existing disorder or disease associated with lyssavirus, such as RABV, the World Health Organization (Rabies Fact Sheet, 2024, available from www.who.int/news-room/fact-sheets/detail/rabies) discloses that once clinical symptoms appear, there is no treatment and the outcome is fatal (see first page).
In view of the breadth of the claims, the nature of the invention, the teachings and working examples in the specification, the state of the art, and the low level of predictability with regard to protection and treatment against lyssaviruses and associated diseases/disorders, it would require undue experimentation to practice the claimed invention.
Amendment of the claims to recite an immunogenic composition or pharmaceutical composition wherein the virus has the R333E attenuating mutation in RABV G, and cancelation of claims 40-42 would overcome this rejection. Claims that recite a vaccine directed to RABV, and methods of vaccinating and protecting against RABV would be enabled provided that the virus is the exact construct set forth as LyssaVax.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5, 7, 13-17, 19, 20, 26-31, 33-36 and 38-48 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schell et al. (WO 2018/231974 A1, “Schnell”, cited in the IDS filed 9/19/2023). The claims are summarized above and correlated with the teachings of the prior art in bold font below. Claims 36, 38 and 40-42 are rejected on the basis of their enabled embodiments. See the scope of enablement rejection above.
Schnell discloses compositions comprising a nucleic acid encoding a recombinant RABV comprising chimeric G positioned immediately 3’ to RABV N, and immediately 5’ to RABV P, M and L, respectively, as well as vaccines comprising vectors and inactivated viruses with excipients for administration (pharmaceutically acceptable carrier) (see abstract, paragraphs [0037], [0021], [00107], [00114], and claim 10) (claims 1, 7, 13, 14, 19, 20, 28, 33-36 and 38). The chimeric G comprises RABV clip, RABV flap and MOKV core, is codon optimized (“co”), expressed in a mammal (host cells), and comprises the R333E mutation (see paragraphs [00100]), [00115] and Figures 3 and 4) (claims 2, 4, 5, 15-17, 26, 27, 29-31 and 46-48). The RABV is the SADB-19 strain (see paragraph [0085]) (claim 3). Methods of inducing an immune response are disclosed, including prophylactic administration for rabies (see paragraphs [0021], [00115], and claim 10) (claims 39-45). Therefore, the claims are anticipated by the prior art.
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.
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.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Schell et al. (WO 2018/231974 A1, “Schnell”, cited in the IDS filed 9/19/2023) as applied to claim 36 above, and further in view of DiStefano et al. (Vaccine, 2013, 31:4888-4893. Claim 37 is directed to an embodiment wherein the vaccine further comprises an adjuvant. Claim 37 is rejected on the basis of its enablement embodiment; see scope of enablement rejection above.
The teachings of Schell are outlined above. Schnell does not teach or suggest the use of an adjuvant with the inactivated RABV composition. However it would have been obvious to have used an adjuvant in combination with Schnell’s composition in order to improve its immunogenicity and efficacy in vivo, as is demonstrated by DiStefano (see abstract). One would have had a reasonable expectation of success given that Schnell’s viruses and DiStefano’s viruses are similar constructs of killed RABV. Therefore, the claimed embodiment would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claim is allowed.
Claims 8-12 and 21-25 are objected to for being dependent on a rejected claim but would otherwise be allowable if rewritten in independent form. Claims 8-12 and 21-25 require the presence of SEQ ID NO: 1, 2 and 4. SEQ ID NO: 1, 2 and 4 are free of the prior art of record, as are sequences that are at least 85%, at least 90%, at least 95%, and at least 99% identical to SEQ ID NO: 1, 2 and 4.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to Stacy B. Chen whose telephone number is 571-272-0896. The examiner can normally be reached on M-F (7:00-4:30). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone, can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/STACY B CHEN/Primary Examiner, Art Unit 1672
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