DETAILED ACTION
Applicant’s amendment and remarks filed July 28, 2026 are acknowledged and entered.
The elected species under examination 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 Claims 6, 18 and 32 are withdrawn from consideration being directed non-elected species. Any prior objection or rejection that is not repeated or addressed below is either moot or withdrawn in view of Applicant’s amendment.
Claims Summary
Claims 1-5, 7, 9-13, 34, 35 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 1), 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 encoded by the nucleic acid (claim 34). 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, 36-45
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 nucleic acid sequence comprises a nucleotide sequence having at least 85% sequence identity SEQ ID NO: 1, 2 or 4. 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 36 is directed to a vaccine comprising the recombinant virus comprising a pharmaceutically acceptable carrier, and further comprises an adjuvant (claim 37). The virus in the vaccine is deactivated (claim 38).
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 RABV. Claim 41 is directed to a method of providing immunity against a RABV in a subject. Claim 42 is directed to a method of preventing a disease or disorder associated with a RABV 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
Claim 28 is objected to because of the following informality:
Claim 28, line 2, recites, “the rabies virus”, which should be “a rabies virus”.
Claims 29-31, 33 and 36-45 are included in this objection because they depend from claim 28. 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.
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. 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 a G sequence or portion thereof positioned immediately 3’ to N. The nucleic acid that encodes the virus comprises, in the alternative:
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
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
Some embodiments do not represent a rabies virus having a complete rabies virus genome with the claimed modifications to the N and G genes. A virus that is encoded by SEQ ID NO: 1 represents a full rabies virus genome with modifications. A virus that is encoded by a nucleic acid comprising SEQ ID NO: 2 represents a virus having RABV N, or a portion thereof, and MOKV G DNA. A virus that is encoded by a nucleic acid comprising SEQ ID NO: 3 represents a virus having RABV N, or a portion thereof, and a chimeric MOKV/RABV glycoprotein DNA.
The vaccines of claims 36-38 are understood to protect against disease caused by any lyssavirus. The method of claim 40 vaccinates against rabies virus. The method of claim 41 provides immunity against rabies virus which is understood to be protective immunity. The method of claim 42 prevents any rabies virus disorder or disease. The virus that is administered to effect these outcomes is described above.
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.
Applicant’s amendment and remarks filed July 28, 2026 are acknowledged. Applicant notes that claims 40-42 have been amended to recite rabies virus.
In response, the amendment to claims 40-42 has no effect on claims 36-38 as it pertains to the rejection outlined above. The amendment is not effective to overcome the rejection of claims 40-42 in light of the rejection outlined above which addresses rabies virus. Vaccines for rabies virus, methods of vaccinating and protecting against rabies virus would be enabled if the virus administered is the construct set forth as LyssaVax (as in Figure 2A) including all of its genomic content, not just the N and G portions.
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 14-17, 19, 20, 26 and 27 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 and elected species are summarized above and correlated with the teachings of the prior art in bold font below.
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 14, 19 and 20). 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 15-17, 26 and 27). Therefore, the claims are anticipated by the prior art.
Applicant’s remarks filed July 28, 2026 are acknowledged. Applicant notes that claim 8 was amended to recite sequences that are free of the prior art. In response, claims 14-17, 19, 20, 26 and 27 do not recite any sequences. Therefore, the rejection is maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
Claims 1-5, 7, 9-13, 21-25, 34, 35 and 46-48 are allowable.
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.
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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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