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
This action is in response to the papers filed January 30, 2026.
Claim Amendments
Applicant’s amendment to the claims filed 01/30/2026 is acknowledged.
Claims 1-64, 66-68, 76-77 have been cancelled.
Claims 65 and 82 are amended.
Claims 87-89 are newly added.
Claims 65, 69-75, 78-89 are pending.
Claims 74 and 78 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 65, 69-73, 75, 79-89 are under examination.
Election/Restrictions
The following is a summary of the restriction/election requirements in the present application:
Applicant’s elected without traverse of the invention of Group 2, drawn to a method of treating a disorder, in the reply filed 05/19/2025.
Applicant further elected without traverse to prosecute the invention of the antigenic construct having the amino acid sequence of SEQ ID NO: 1. This construct comprises no signal peptide and the lumazine-synthase antigen clustering domain having the amino acid sequence of SEQ ID NO: 1759. (The elected construct also contains the rotavirus VP8* protein having the amino acid sequence of SEQ ID NO: 42, the P2 helper peptide having the amino acid sequence of SEQ ID NO: 1750, and no transmembrane domain. In addition, the elected SEQ ID NO: 1 is identical to SEQ ID NO: 96 in the application). See interview summary mailed 07/31/2025.
In view of the above restriction/election requirements, claims 74 and 78 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention.
Priority
The instant application 17/620,047 was filed on 12/16/2021. This application is a national stage of international application PCT/EP2020/067036 filed 06/18/2020, claiming priority based on European patent application PCTEP2019066107 filed 06/18/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawal of Prior Rejections/Objections
Rejections and/or objections not reiterated from the previous Office action mailed 07/31/2025 are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
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 69-70 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.
This rejection is repeated for the same reasons provided in the previous Office action.
Claims 69-70 recite that the rotavirus VP8* protein is mutated to delete at least one or all predicted glycosylation sites. The recitation is found to be indefinite. In this case, how the glycosylation sites are “predicted” is not defined by the claims, and the specification does not define or limit all the residues that may be a “predicted glycosylation site” for each of the claimed rotavirus VP8* proteins (i.e., SEQ ID NOs: 19-45). Therefore, the application does not inform the ordinary skilled artisan of all the possible “predicted glycosylation sites” claimed. One methodology, software program or researcher may “predict” glycosylation sites differently from another methodology, software program or researcher depending on the criteria employed. For example, applicant’s specification contemplates that the glycosylation sites may be predicted from any codon of the nucleic acid sequence encoding for asparagine (see, e.g., pg. 17, ll. 29-33). However, another methodology, software program or researcher may limit the prediction to those asparagine residues on the protein tertiary structure which are sterically permissible for glycosylation, or they may also include codons encoding for other amino acids, such as serine or threonine, in their criteria for predicting glycosylation sites. In addition, the term “predicted” suggests that the scope of the claims may change in the future as more discoveries in relation to the claimed rotavirus VP8* proteins. For example, one may predict, at an earlier time, that a particular codon encoding asparagine may be a glycosylation site, but then, at a later time, new experimental evidence and modelling reveals that glycosylation of said asparagine is very unlikely. Therefore, the “predicted glycosylation sites,” and consequently the claim scope, are subject to change from one moment in time to another. For these reasons, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Response to arguments:
Applicant’s remarks filed 01/30/2026 have been carefully considered, but are not found persuasive.
Applicant argues that "predicted glycosylation sites" are identified using established, sequence-based prediction approaches routinely employed in the art, including artificial neural network-based tools such as the NetNGlyc 1.0 Server. The specification further provides examples of VP8* variants in which predicted N-glycosylation sites have been identified and intentionally removed by amino acid substitution. Therefore, the specification does not leave the term "predicted glycosylation site" open-ended or subjective. Instead, it defines the term by reference to recognized computational prediction methods and anchors that definition with specific amino acid positions and substitutions that exemplify deletion of predicted glycosylation sites in VP8*. See pages 5-6 of applicant’s reply.
Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In this case, the claims do not define the prediction methodology used to determine the "predicted glycosylation sites." Although the specification contemplates using NetNGlyc 1.0 Server to define the "predicted glycosylation sites," such a feature is not claimed.
Amending claim 70 by deleting the word “predicted” would be remedial.
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.
Claims 65, 69-73, 75, 79-89 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/081110 A1 to Rauch et al.; in view of Bellido et al. (2009) “Brucella spp. lumazine synthase as a bovine rotavirus antigen delivery system” Vaccine, 27:136-145.
This rejection is newly applied.
Rauch discloses rotavirus vaccines comprising an mRNA encoding for rotavirus VP8* protein. See Abstract. In particular, the mRNA encodes for the VP8* protein according to SEQ ID NO: 559 (pg. 25, Table 1), which is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the present application. See alignment:
PNG
media_image1.png
441
874
media_image1.png
Greyscale
The mRNA comprises, from 5’ to 3’, a 5’ Cap structure, a 5’ UTR, at least one coding sequence encoding the rotavirus VP8* protein, a heterologous 3’ UTR, and a poly(A) sequence. The poly(A) sequence comprises 64 adenosine nucleotides. Pg. 59; pg. 70, ll. 5-14; pg. 75; pg. 77, ll. 27, to pg. 77, ll. 11.
The mRNA is further complexed with a cationic lipid (pg. 79-80) and formulated in a pharmaceutically acceptable carrier (pg. 78, ll. 31, to pg. 79, ll. 8). The mRNA is administered by injection. Pg. 89, ll. 4-9; pg. 105-106.
Rauch further teaches that the mRNA vaccine is administered to a subject for the treatment or prophylaxis of rotavirus infections. Abstract; pg. 78, ll. 27-29; pg. 102, ll. 33, to pg. 103, ll. 5. The subject is a mammal (pg. 89, ll. 13-16; pg. 91, ll. 19-20) or human (pg. 97, ll. 28-29), and vaccination is reported to stimulate a humoral immune response in the subject (Example 2, pg. 112-113; fig. 2, pg. 107, ll. 16-17).
Rauch does not disclose that the coding sequence additionally encodes a lumazine synthase antigen clustering domain, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Bellido teaches that lumazine synthase has been reported as a carrier for antigen delivery, possessing immunostimulatory properties, and eliciting an antigen-specific cellular response and a strong and long-lasting humoral response. Lumazine synthase has also been previously evaluated as a carrier for systemic immunization in studies fusing lumazine synthase to antigenic peptides, recognizing that insertion of peptides and protein domains is possible without disturbing its multimer conformation. Pg. 136, Introduction.
In Bellido’s study, a rotavirus VP8* protein was fused to lumazine synthase to enhance immunization against rotavirus infection in a suckling mouse model. The results demonstrated that the fusion protein is properly folded and stable and significantly enhanced antibody response and protection against rotavirus challenge relative to controls. Abstract; pg. 137, col. 1-2, joining paragraph; Table 3; Figures 1 and 7. Bellido concludes that the plasticity of the lumazine synthase scaffold for the production of polyvalent chimeras suggest that VP8* from different strains can be coupled to lumazine synthase in order to elicit wide-protecting neutralizing antibodies against different field strains of rotavirus. Pg. 144.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the mRNA vaccine of Rauch by fusing the rotavirus VP8* protein to a lumazine synthase, as taught by Bellido, with a reasonable expectation of success because the fusion enables polymeric display of VP8* (antigen clustering), significantly enhances antibody response, and induces a protective immune response at lower doses. Abstract; pg. 143-144, Discussion.
For these reasons, the method according to claim 65 would have been prima facie obvious over the prior art.
Regarding dependent claims 69-70, Rauch further discloses that the rotavirus VP8* protein is mutated to delete at least one or all predicted glycosylation sites. Pg. 16, ll. 9-14; pg. 37, ll. 21, to pg. 38, ll. 25.
Regarding dependent claim 71, SEQ ID NO: 559 (pg. 25, Table 1) is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the present application. See alignment.
Regarding dependent claims 72-73 and 75, the coding sequence additionally encodes a signal peptide (pg. 32, ll. 15-29), a linker (pg. 29), a helper peptide or P2 helper peptide (pg. 28, ll. 21, to pg. 29, ll. 6; pg. 30, ll. 1-2), and/or a transmembrane domain (pg. 45-46).
Regarding dependent claim 79, Rauch teaches or fairly suggest that the mRNA is stabilized by nucleotide or nucleobase modifications (pg. 70, ll. 24-29; pg. 71, ll. 5-17; pg. 72, ll. 16-18), which includes replacing the uracil nucleotides or uridines with pseudouridine-5'-triphosphate (pg. 72, ll. 4, 7-8) or 1-methyl-pseudouridine (pg. 73, ll. 14).
Regarding dependent claim 80, Rauch teaches that the 5’ Cap structure is a Cap1 structure. Pg. 75, ll. 26-31.
Regarding dependent claim 81, Rauch teaches that the poly(A) tail is added to the 3’-end of the mRNA. Pg. 10, ll. 14-19; pg. 70, ll. 5-14.
Regarding dependent claim 82, Rauch teaches or fairly suggests that the vaccine composition comprises two or more different RNA, each encoding a rotavirus protein from a different rotavirus serotype/genotype. Pg. 52, ll. 18, to pg. 53, ll. 2; pg. 55, ll. 11-30; pg. 96.
Regarding claim 83, Rauch teaches administration by intramuscular injection. Pg. 89, ll. 4-9; pg. 105-106.
Regarding dependent claims 84-86, Rauch teaches that the mRNA is complexed with cationic lipid to form one or more liposomes, lipoplexes, or lipid nanoparticles. Pg. 79-80. The lipid nanoparticles comprise the cationic lipid, a neutral lipid, cholesterol (steroid), and PEGylated lipid (polymer conjugate lipid). Pg. 79, ll. 28-35; pg. 111, ll. 18-21.
Regarding dependent claims 87-89, the composition comprises RNAs encoding Rotavirus VP8* protein from Rotavirus genotypes P[8], P[4] and P[6]. Pg. 15, ll. 23-28; pg. 55, ll. 26-30.
Response to arguments:
Applicant’s remarks filed 01/30/2026 have been carefully considered, but are not found persuasive.
Applicant argues that Bellido teaches a protein-based vaccine comprising a VP8-derived antigen fused to a lumazine synthase antigen clustering domain; whereas, the claimed invention is directed to mRNA-based vaccines comprising a VP8-derived antigen fused to a lumazine synthase antigen clustering domain. Based on these differences, applicant asserts there would have been no reasonable expectation of success, prior to the effective filing date of the instantly claimed invention, that the fusion polypeptide would properly translate, fold, assemble, and function intracellularly in a mammalian cell following RNA delivery, as in the case of the claimed mRNA vaccine. See pages 7-9 of applicant’s reply.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In this case, the primary reference, Rauch (WO 2017/081110 A1), demonstrates that VP8-derived antigen fusion polypeptides would be expected to properly translate, fold, assemble, and function intracellularly in a mammalian cell following RNA delivery. Further, as noted by applicant, Bellido demonstrated that the particular fusion polypeptide comprising a lumazine synthase antigen clustering domain, as instantly claimed, would be expected to properly fold and function for the purposes of “stimulating a humoral immune response in a mammalian subject” (preamble of claim 65). Applicant provides no specific argument or evidence supporting the assertion that the particular fusion with a lumazine synthase antigen clustering domain, as taught by Bellido, would have lacked an expectation of success when delivered by RNA, as claimed, when Rauch demonstrates that other VP8-derived antigen fusion polypeptides would have been successful when delivered by RNA. The standard for a reasonable expectation of success is not anticipation.
Applicant further asserts unexcepted or superior results in stimulating an immune response relative to other possible antigen designs. In particular, applicant points to Example 9 (Table 16 and Figure 16) to show that an RNA encoding a VP8*-derived fusion polypeptide comprising a lumazine synthase antigen clustering domain stimulated higher antibody titers compared to RNAs that did not include comprising a lumazine synthase antigen clustering domain. Figure 18A further shows that the RNA including a lumazine synthase antigen clustering domain stimulated the highest levels of neutralizing antibodies. The argument continues by discussing a “Figure 19B-C.” See pages 8-9 of applicant’s reply.
The argument is not persuasive for the following reasons because (1) there is no Figure 19 in the instant application and (2) enhanced stimulation of an immune response by inclusion of a lumazine synthase antigen clustering domain would have been an expected result prior to the effective filing date of the instantly claimed invention. For example, Bellido discloses that a VP8*-derived fusion polypeptide comprising a lumazine synthase antigen clustering domain stimulated higher antibody titers and neutralizing antibodies relative to constructs that did not include comprising a lumazine synthase antigen clustering domain. See, e.g., pg. 141, right column; Figure 7; and Table 2. Overall, Bellido concludes that the evidence demonstrates that the VP8*-derived fusion polypeptide comprising a lumazine synthase antigen clustering domain (BLS-VP8d chimeric protein) is properly folded and stable, providing a potent antigen delivery system that enhances the antibody response against rotavirus and elicits complete homotypic passive protection in a suckling mouse model (Abstract).
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 65, 69-73, 75, 79-89 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,413,346 B2, in view of WO 2017/081110 A1 to Rauch et al., and Bellido et al. (2009) “Brucella spp. lumazine synthase as a bovine rotavirus antigen delivery system” Vaccine, 27:136-145. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the reference claims.
This rejection is newly applied.
The reference claims recite, in claim 1, a method of stimulating an anti-rotavirus response in a patient comprising administering, by injection, an effective amount of an immune stimulating composition comprising a lipid nanoparticle (LNP) comprising an mRNA molecule comprising at least one region encoding a polypeptide comprising at least 100 amino acids of a VP8* cleavage product of a rotavirus VP4 protein, wherein the mRNA comprises a 5′ Cap and a poly(A) tail of 60 to about 250 adenosine at the 3′ end of the mRNA. Claim 12 recites that the mRNA molecule is at least partially complexed with a cationic or polycationic compound or polymeric carrier. Claim 13 further recites that the composition comprises a pharmaceutical carrier.
The reference claims do not recite that the VP8* protein has an amino acid sequence according to SEQ ID NO: 42, as instantly claimed.
WO 2017/081110 A1 is the PCT publication of the reference patent and was published prior to the effective filing date of the instantly claimed invention. The specification of WO 2017/081110 A1 discloses rotavirus vaccines comprising an mRNA encoding for rotavirus VP8* protein. See Abstract. In particular, the mRNA encodes for the VP8* protein according to SEQ ID NO: 559 (pg. 25, Table 1), which is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment, above.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the reference claims by using a VP8* protein having an amino acid sequence according to SEQ ID NO: 559, as disclosed in the specification published in WO 2017/081110 A1, with a reasonable expectation of success because said VP8* protein is disclosed as suitable for the methods of the reference claims and stimulates an anti-rotavirus immune response in a patient in need thereof.
The published specification (WO 2017/081110 A1) further teaches that the mRNA comprises, from 5’ to 3’, a 5’ Cap structure, a 5’ UTR, at least one coding sequence encoding the rotavirus VP8* protein, a heterologous 3’ UTR, and a poly(A) sequence. The poly(A) sequence is 64 adenosine nucleotides. Pg. 59; pg. 70, ll. 5-14; pg. 75; pg. 77, ll. 27, to pg. 77, ll. 11. The mRNA is further complexed with a cationic lipid (pg. 79-80) and formulated in a pharmaceutically acceptable carrier (pg. 78, ll. 31, to pg. 79, ll. 8). The mRNA vaccine is administered to a subject for the treatment or prophylaxis of rotavirus infections. Abstract; pg. 78, ll. 27-29; pg. 102, ll. 33, to pg. 103, ll. 5. The subject is a mammal (pg. 89, ll. 13-16; pg. 91, ll. 19-20) or human (pg. 97, ll. 28-29), and vaccination is reported to stimulate a humoral immune response in the subject (Example 2, pg. 112-113; fig. 2, pg. 107, ll. 16-17).
Neither the reference claims nor published specification fairly suggest that the coding sequence additionally encodes an antigen clustering domain from lumazine synthase, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Bellido teaches that lumazine synthase has been reported as a carrier for antigen delivery, possessing immunostimulatory properties, and eliciting an antigen-specific cellular response and a strong and long-lasting humoral response. Lumazine synthase has also been previously evaluated as a carrier for systemic immunization in studies fusing lumazine synthase to antigenic peptides, recognizes that insertion of peptides and protein domains is possible without disturbing its multimer conformation. Pg. 136, Introduction.
In Bellido’s study, a rotavirus VP8* protein was fused to lumazine synthase to enhance immunization against rotavirus infection in a suckling mouse model. The results demonstrated that the fusion protein is properly folded and stable and significantly enhanced antibody response and protection against rotavirus challenge relative to controls. Abstract; pg. 137, col. 1-2, joining paragraph; Table 3; Figures 1 and 7. Bellido concludes that the plasticity of the lumazine synthase scaffold for the production of polyvalent chimeras suggest that VP8* from different strains can be coupled to lumazine synthase in order to elicit wide-protecting neutralizing antibodies against different field strains of rotavirus. Pg. 144.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the mRNA vaccine of the reference claims by fusing the rotavirus VP8* protein to a lumazine synthase, as taught by Bellido, with a reasonable expectation of success because the fusion enables polymeric display of VP8* (antigen clustering), significantly enhances antibody response, and induces a protective immune response at lower doses. Abstract; pg. 143-144, Discussion.
For these reasons, the method according to claim 65 would have been prima facie obvious over the cited references.
Regarding claims 69-70, reference claim 6 recites the at least one region encoding at least one epitope is mutated to delete at least one predicted glycosylation site. The published specification discloses that the rotavirus VP8* protein is mutated to delete at least one or all predicted glycosylation sites. Pg. 16, ll. 9-14; pg. 37, ll. 21, to pg. 38, ll. 25.
Regarding claim 71, SEQ ID NO: 559 (pg. 25, Table 1) is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment.
Regarding claims 72-73 and 75, the reference claims further recite that the mRNA further comprises a sequence encoding a linker (claim 3), a helper peptide (claim 3) or P2 helper peptide (claim 17), a signal peptide (claim 5), a transmembrane domain (claim 7), and a peptide enabling virus-like particle (VLP) formation (claim 8). The published specification discloses that the coding sequence additionally encodes a signal peptide (pg. 32, ll. 15-29), a linker (pg. 29), a helper peptide or P2 helper peptide (pg. 28, ll. 21, to pg. 29, ll. 6; pg. 30, ll. 1-2), and/or a transmembrane domain (pg. 45-46).
Regarding claim 79, the reference claims recite that the mRNA comprises a nucleotide analogue (claim 18), wherein the nucleotide analogue is pseudouridine or 1-methyl-pseudouridine (claim 19). The published specification teaches or fairly suggests that the mRNA is stabilized by nucleotide or nucleobase modifications (pg. 70, ll. 24-29; pg. 71, ll. 5-17; pg. 72, ll. 16-18), which includes replacing the uracil nucleotides or uridines with pseudouridine-5'-triphosphate (pg. 72, ll. 4, 7-8) or 1-methyl-pseudouridine (pg. 73, ll. 14).
Regarding claim 80, reference claim 16 recites that the 5′ Cap structure is a Cap1. The published specification teaches that the 5’ Cap structure is a Cap1 structure. Pg. 75, ll. 26-31.
Regarding claim 81, reference claim 1 recites that the poly(A) tail is at the 3’ end of the mRNA. The published specification teaches that the poly(A) tail is added to the 3’-end of the mRNA. Pg. 10, ll. 14-19; pg. 70, ll. 5-14.
Regarding claim 82, the reference claims recite that the VP8* cleavage product is derived from the P[4], P[6], or P[8] serotype (claim 2); the mRNA molecule further comprises at least a second region encoding at least one epitope of a structural or non-structural protein of a different serotype of a rotavirus (claim 9); and the method induces a cross-reactive immune response to multiple serotypes of rotavirus (claim 15). The published specification teaches or fairly suggests that the vaccine composition comprises two or more different RNA, each encoding a rotavirus protein from a different rotavirus serotype. Pg. 52, ll. 18, to pg. 53, ll. 2; pg. 55, ll. 11-30; pg. 96.
Regarding claim 83, reference claim 1 recites that the composition is administered by intramuscular injection. The published specification teaches administration by intramuscular injection. Pg. 89, ll. 4-9; pg. 105-106.
Regarding claims 84-86, reference claims recite that the mRNA molecule is at least partially complexed with a cationic or polycationic compound or polymeric carrier (claim 12); a lipid nanoparticle (LNP) comprises the mRNA (claim 1); and the LNP comprises an ionizable amino lipid, phospholipid, cholesterol and a PEGylated lipid (claim 20). The published specification teaches that the mRNA is complexed with cationic lipid to form one or more liposomes, lipoplexes, or lipid nanoparticles. Pg. 79-80. The lipid nanoparticles comprise the cationic lipid, a neutral lipid, cholesterol (steroid), and PEGylated lipid (polymer conjugate lipid). Pg. 79, ll. 28-35; pg. 111, ll. 18-21.
Regarding claims 87-89, reference claim 2 recites the VP8* cleavage product is derived from the P[4], P[6], or P[8] serotype. The published specification discloses the composition comprises RNAs encoding Rotavirus VP8* protein from Rotavirus genotypes P[8], P[4] and P[6]. Pg. 15, ll. 23-28; pg. 55, ll. 26-30.
Claims 65, 69-73, 75, 79-89 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,786,590 B2, in view of WO 2017/081110 A1 to Rauch et al., and Bellido et al. (2009) “Brucella spp. lumazine synthase as a bovine rotavirus antigen delivery system” Vaccine, 27:136-145. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the reference claims.
This rejection is newly applied.
The reference claims recite, in claim 1, a pharmaceutical composition comprising a purified RNA molecule comprising a region encoding a polypeptide comprising at least 100 amino acids of a VP8* cleavage product of a rotavirus VP4 protein, said RNA comprising a 5′ Cap structure and a poly(A) region of 60 to 250 adenosine nucleotides, wherein said RNA is formulated with a lipid nanoparticle (LNP). Claim 6 recites that the RNA is a mRNA that comprises, from 5′ to 3′, a 5′ Cap structure, a 5′ untranslated region (UTR), the region encoding the polypeptide, a 3′ UTR; and the poly(A) region. Claim 16 recites instructions for administering said composition.
The reference claims do not recite that the VP8* protein has an amino acid sequence according to SEQ ID NO: 42, as instantly claimed.
WO 2017/081110 A1 is the PCT publication of the reference patent and was published prior to the effective filing date of the instantly claimed invention. The specification of WO 2017/081110 A1 discloses rotavirus vaccines comprising an mRNA encoding for rotavirus VP8* protein. See Abstract. In particular, the mRNA encodes for the VP8* protein according to SEQ ID NO: 559 (pg. 25, Table 1), which is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment, above.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the reference claims by using a VP8* protein having an amino acid sequence according to SEQ ID NO: 559, as disclosed in the specification published in WO 2017/081110 A1, with a reasonable expectation of success because said VP8* protein is disclosed as suitable for the methods of the reference claims and stimulates an anti-rotavirus immune response in a patient in need thereof.
The published specification (WO 2017/081110 A1) further teaches that the mRNA comprises, from 5’ to 3’, a 5’ Cap structure, a 5’ UTR, at least one coding sequence encoding the rotavirus VP8* protein, a heterologous 3’ UTR, and a poly(A) sequence. The poly(A) sequence has 64 adenosine nucleotides. Pg. 59; pg. 70, ll. 5-14; pg. 75; pg. 77, ll. 27, to pg. 77, ll. 11. The mRNA is further complexed with a cationic lipid (pg. 79-80) and formulated in a pharmaceutically acceptable carrier (pg. 78, ll. 31, to pg. 79, ll. 8).
The reference claims do not recite a method of stimulating a humoral immune response in a mammalian subject by administration of the composition.
However, the published specification discloses that the claimed pharmaceutical composition is administered to a subject for the treatment or prophylaxis of rotavirus infections. Abstract; pg. 78, ll. 27-29; pg. 102, ll. 33, to pg. 103, ll. 5. The subject is a mammal (pg. 89, ll. 13-16; pg. 91, ll. 19-20) or human (pg. 97, ll. 28-29), and vaccination is reported to stimulate a humoral immune response in the subject (Example 2, pg. 112-113; fig. 2, pg. 107, ll. 16-17). Administration is performed by injection. Pg. 89, ll. 4-9; pg. 105-106.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to administer the claimed pharmaceutical composition of the reference claims of the patent in a method of stimulating a humoral immune response in a mammalian subject, as described in the specification published in WO 2017/081110 A1, with a reasonable expectation of success because the pharmaceutical composition would immunize the subject against rotavirus infection, thereby providing a beneficial and therapeutic effect.
Neither the reference claims nor published specification fairly suggest that the coding sequence additionally encodes an antigen clustering domain from lumazine synthase, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Bellido teaches that lumazine synthase has been reported as a carrier for antigen delivery, possessing immunostimulatory properties, and eliciting an antigen-specific cellular response and a strong and long-lasting humoral response. Lumazine synthase has also been previously evaluated as a carrier for systemic immunization in studies fusing lumazine synthase to antigenic peptides, recognizes that insertion of peptides and protein domains is possible without disturbing its multimer conformation. Pg. 136, Introduction.
In Bellido’s study, a rotavirus VP8* protein was fused to lumazine synthase to enhance immunization against rotavirus infection in a suckling mouse model. The results demonstrated that the fusion protein is properly folded and stable and significantly enhanced antibody response and protection against rotavirus challenge relative to controls. Abstract; pg. 137, col. 1-2, joining paragraph; Table 3; Figures 1 and 7. Bellido concludes that the plasticity of the lumazine synthase scaffold for the production of polyvalent chimeras suggest that VP8* from different strains can be coupled to lumazine synthase in order to elicit wide-protecting neutralizing antibodies against different field strains of rotavirus. Pg. 144.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the mRNA vaccine of the reference claims by fusing the rotavirus VP8* protein to a lumazine synthase, as taught by Bellido, with a reasonable expectation of success because the fusion enables polymeric display of VP8* (antigen clustering), significantly enhances antibody response, and induces a protective immune response at lower doses. Abstract; pg. 143-144, Discussion.
For these reasons, the method according to claim 65 would have been prima facie obvious over the cited references.
Regarding claims 69-70, reference claim 5 recites the polypeptide comprises an amino acid substitution to remove at least one predicted glycosylation site. The published specification discloses that the rotavirus VP8* protein is mutated to delete at least one or all predicted glycosylation sites. Pg. 16, ll. 9-14; pg. 37, ll. 21, to pg. 38, ll. 25.
Regarding claim 71, SEQ ID NO: 559 (pg. 25, Table 1) is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment.
Regarding claims 72-73 and 75, the reference claims further recite that the mRNA further comprises a sequence encoding a helper peptide (claim 12), a signal peptide (claim 14), and a virus-like particle (VLP) forming peptide (claim 9). The published specification discloses that the coding sequence additionally encodes a signal peptide (pg. 32, ll. 15-29), a linker (pg. 29), a helper peptide or P2 helper peptide (pg. 28, ll. 21, to pg. 29, ll. 6; pg. 30, ll. 1-2), and/or a transmembrane domain (pg. 45-46).
Regarding claim 79, reference claim 15 recites that the RNA comprises 1-methyl-pseudouridine substitutions. The published specification teaches or fairly suggests that the mRNA is stabilized by nucleotide or nucleobase modifications (pg. 70, ll. 24-29; pg. 71, ll. 5-17; pg. 72, ll. 16-18), which includes replacing the uracil nucleotides or uridines with pseudouridine-5'-triphosphate (pg. 72, ll. 4, 7-8) or 1-methyl-pseudouridine (pg. 73, ll. 14).
Regarding claim 80, reference claim 2 recites that the 5′ Cap structure is a Cap1. The published specification teaches that the 5’ Cap structure is a Cap1 structure. Pg. 75, ll. 26-31.
Regarding claim 81, reference claim 3 recites that the poly(A) tail is at the 3’ terminus of the RNA. The published specification teaches that the poly(A) tail is added to the 3’-end of the mRNA. Pg. 10, ll. 14-19; pg. 70, ll. 5-14.
Regarding claim 82, the reference claims recite that the VP8* cleavage product is derived from the P[4], P[6], or P[8] serotype (claim 4), and the composition comprises at least a second RNA encoding a VP8* cleavage product of a rotavirus VP4 from a different rotavirus strain as the first RNA (claim 7). The published specification teaches or fairly suggests that the vaccine composition comprises two or more different RNA, each encoding a rotavirus protein from a different rotavirus serotype. Pg. 52, ll. 18, to pg. 53, ll. 2; pg. 55, ll. 11-30; pg. 96.
Regarding claim 83, the published specification teaches administration by intramuscular injection. Pg. 89, ll. 4-9; pg. 105-106.
Regarding claims 84-86, reference claims recite that the RNA is formulated with a lipid nanoparticle (claim 1), and the lipid nanoparticle (LNP) comprises an ionizable amino lipid, phospholipid, cholesterol and a PEGylated lipid (claim 8). The published specification teaches that the mRNA is complexed with cationic lipid to form one or more liposomes, lipoplexes, or lipid nanoparticles. Pg. 79-80. The lipid nanoparticles comprise the cationic lipid, a neutral lipid, cholesterol (steroid), and PEGylated lipid (polymer conjugate lipid). Pg. 79, ll. 28-35; pg. 111, ll. 18-21.
Regarding claims 87-89, reference claim 4 recites the VP8* cleavage product is derived from the P[4], P[6], or P[8] serotype. The published specification discloses the composition comprises RNAs encoding Rotavirus VP8* protein from Rotavirus genotypes P[8], P[4] and P[6]. Pg. 15, ll. 23-28; pg. 55, ll. 26-30.
Claims 65, 69-73, 75, 79-89 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,318,444 B2, in view of WO 2017/081110 A1 to Rauch et al., and Bellido et al. (2009) “Brucella spp. lumazine synthase as a bovine rotavirus antigen delivery system” Vaccine, 27:136-145. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the reference claims.
This rejection is newly applied.
The reference claims recite, in claim 1, an immune stimulating composition comprising purified RNA molecules encoding rotavirus VP4 antigens from at least two serotypes of rotavirus, wherein each purified RNA molecule encodes a polypeptide comprising at least 100 amino acids of a VP8* cleavage product of the rotavirus VP4 antigen, said purified RNA molecules comprising: a m7GpppN 5′ Cap, at least one heterologous untranslated region (UTR) and Poly-A sequence, wherein the purified RNA molecules are formulated in a pharmaceutically acceptable carrier comprising lipid nanoparticles (LNPs). Claim 11 recites the poly(A) sequence is 60 to 250 adenosine nucleotides in length. Claim 13 recites that the purified RNA molecules are mRNAs. Claim 14 recites that the at least one heterologous UTR comprises a heterologous 5′ UTR and a heterologous 3′ UTR.
The reference claims do not recite that the VP8* protein has an amino acid sequence according to SEQ ID NO: 42, as instantly claimed.
WO 2017/081110 A1 is the PCT publication of the reference patent and was published prior to the effective filing date of the instantly claimed invention. The specification of WO 2017/081110 A1 discloses rotavirus vaccines comprising an mRNA encoding for rotavirus VP8* protein. See Abstract. In particular, the mRNA encodes for the VP8* protein according to SEQ ID NO: 559 (pg. 25, Table 1), which is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment, above.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the reference claims by using a VP8* protein having an amino acid sequence according to SEQ ID NO: 559, as disclosed in the specification published in WO 2017/081110 A1, with a reasonable expectation of success because said VP8* protein is disclosed as suitable for the methods of the reference claims and stimulates an anti-rotavirus immune response in a patient in need thereof.
The published specification (WO 2017/081110 A1) further teaches that the mRNA comprises, from 5’ to 3’, a 5’ Cap structure, a 5’ UTR, at least one coding sequence encoding the rotavirus VP8* protein, a heterologous 3’ UTR, and a poly(A) sequence. The poly(A) sequence is 64 adenosine nucleotides. Pg. 59; pg. 70, ll. 5-14; pg. 75; pg. 77, ll. 27, to pg. 77, ll. 11. The mRNA is further complexed with a cationic lipid (pg. 79-80) and formulated in a pharmaceutically acceptable carrier (pg. 78, ll. 31, to pg. 79, ll. 8).
The reference claims do not recite a method of stimulating a humoral immune response in a mammalian subject by administration of the composition.
However, the published specification discloses that the claimed immune stimulating composition is administered to a subject for the treatment or prophylaxis of rotavirus infections. Abstract; pg. 78, ll. 27-29; pg. 102, ll. 33, to pg. 103, ll. 5. The subject is a mammal (pg. 89, ll. 13-16; pg. 91, ll. 19-20) or human (pg. 97, ll. 28-29), and vaccination is reported to stimulate a humoral immune response in the subject (Example 2, pg. 112-113; fig. 2, pg. 107, ll. 16-17). Administration is performed by injection. Pg. 89, ll. 4-9; pg. 105-106.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to administer the claimed immune stimulating composition of the reference claims of the patent in a method of stimulating a humoral immune response in a mammalian subject, as described in the specification published in WO 2017/081110 A1, with a reasonable expectation of success because the immune stimulating composition would immunize the subject against rotavirus infection, thereby providing a beneficial and therapeutic effect.
Neither the reference claims nor published specification fairly suggest that the coding sequence additionally encodes an antigen clustering domain from lumazine synthase, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Bellido teaches that lumazine synthase has been reported as a carrier for antigen delivery, possessing immunostimulatory properties, and eliciting an antigen-specific cellular response and a strong and long-lasting humoral response. Lumazine synthase has also been previously evaluated as a carrier for systemic immunization in studies fusing lumazine synthase to antigenic peptides, recognizes that insertion of peptides and protein domains is possible without disturbing its multimer conformation. Pg. 136, Introduction.
In Bellido’s study, a rotavirus VP8* protein was fused to lumazine synthase to enhance immunization against rotavirus infection in a suckling mouse model. The results demonstrated that the fusion protein is properly folded and stable and significantly enhanced antibody response and protection against rotavirus challenge relative to controls. Abstract; pg. 137, col. 1-2, joining paragraph; Table 3; Figures 1 and 7. Bellido concludes that the plasticity of the lumazine synthase scaffold for the production of polyvalent chimeras suggest that VP8* from different strains can be coupled to lumazine synthase in order to elicit wide-protecting neutralizing antibodies against different field strains of rotavirus. Pg. 144.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the mRNA vaccine of the reference claims by fusing the rotavirus VP8* protein to a lumazine synthase, as taught by Bellido, with a reasonable expectation of success because the fusion enables polymeric display of VP8* (antigen clustering), significantly enhances antibody response, and induces a protective immune response at lower doses. Abstract; pg. 143-144, Discussion.
For these reasons, the method according to claim 65 would have been prima facie obvious over the cited references.
Regarding claims 69-70, reference claim 6 recites that the rotavirus VP4 antigens are mutated to delete at least one predicted glycosylation site. The published specification discloses that the rotavirus VP8* protein is mutated to delete at least one or all predicted glycosylation sites. Pg. 16, ll. 9-14; pg. 37, ll. 21, to pg. 38, ll. 25.
Regarding claim 71, SEQ ID NO: 559 (pg. 25, Table 1) is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment.
Regarding claims 72-73 and 75, the reference claims further recite that the mRNA further comprises a sequence encoding a linker (claim 3), a helper peptide (claim 3), a signal peptide (claim 5), a transmembrane domain (claims 7, 20), and a virus-like particle (VLP) forming peptide (claims 8, 20). The published specification discloses that the coding sequence additionally encodes a signal peptide (pg. 32, ll. 15-29), a linker (pg. 29), a helper peptide or P2 helper peptide (pg. 28, ll. 21, to pg. 29, ll. 6; pg. 30, ll. 1-2), and/or a transmembrane domain (pg. 45-46).
Regarding claim 79, the reference claims recite that the purified mRNA molecules comprise a nucleotide analogue (claim 15), wherein the nucleotide analogue is pseudouridine or 1-methyl-pseudouridine (claim 16). The published specification teaches or fairly suggests that the mRNA is stabilized by nucleotide or nucleobase modifications (pg. 70, ll. 24-29; pg. 71, ll. 5-17; pg. 72, ll. 16-18), which includes replacing the uracil nucleotides or uridines with pseudouridine-5'-triphosphate (pg. 72, ll. 4, 7-8) or 1-methyl-pseudouridine (pg. 73, ll. 14).
Regarding claim 80, reference claim 1 recites that the 5′ Cap structure is a m7GpppN 5′ Cap. The published specification teaches that the 5’ Cap structure is a Cap1 structure. Pg. 75, ll. 26-31.
Regarding claim 81, the published specification teaches that the poly(A) tail is added to the 3’-end of the mRNA. Pg. 10, ll. 14-19; pg. 70, ll. 5-14.
Regarding claim 82, the reference claims recite that the composition comprises purified RNA molecules encoding rotavirus VP4 antigens from at least two serotypes of rotavirus (claim 1); the at least two serotypes of rotavirus are the P[4], P[6], or P[8] serotype (claim 2); he purified RNA molecules encode rotavirus VP4 antigens from at least three serotypes of rotavirus (claim 18); and the at least three serotypes of rotavirus are the P[4], P[6], and P[8] serotypes (claim 19). The published specification teaches or fairly suggests that the vaccine composition comprises two or more different RNA, each encoding a rotavirus protein from a different rotavirus serotype. Pg. 52, ll. 18, to pg. 53, ll. 2; pg. 55, ll. 11-30; pg. 96.
Regarding claim 83, the published specification teaches administration by intramuscular injection. Pg. 89, ll. 4-9; pg. 105-106.
Regarding claims 84-86, reference claims recite that the RNA is formulated with a lipid nanoparticle (claim 1), and the lipid nanoparticle (LNP) comprises an ionizable amino lipid, phospholipid, cholesterol and a PEGylated lipid (claim 17). The published specification teaches that the mRNA is complexed with cationic lipid to form one or more liposomes, lipoplexes, or lipid nanoparticles. Pg. 79-80. The lipid nanoparticles comprise the cationic lipid, a neutral lipid, cholesterol (steroid), and PEGylated lipid (polymer conjugate lipid). Pg. 79, ll. 28-35; pg. 111, ll. 18-21.
Regarding claims 87-89, reference claims 2 and 19 recite the VP8* cleavage product is derived from the P[4], P[6], or P[8] serotype. The published specification discloses the composition comprises RNAs encoding Rotavirus VP8* protein from Rotavirus genotypes P[8], P[4] and P[6]. Pg. 15, ll. 23-28; pg. 55, ll. 26-30.
Claims 65, 69-73, 75, 79-89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable the reference claims of U.S. Application No. 19/199,197 (reference to claim listing filed 09/22/2025), in view of WO 2017/081110 A1 to Rauch et al., and Bellido et al. (2009) “Brucella spp. lumazine synthase as a bovine rotavirus antigen delivery system” Vaccine, 27:136-145. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims would have been prima facie obvious over the reference claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
This rejection is newly applied.
The reference claims recite a method of stimulating an anti-rotavirus response in a mammalian patient comprising a step of administering to the mammalian patient a composition. The composition comprises RNA molecules formulated in a pharmaceutical carrier, said RNA molecules comprising at least one region encoding a rotavirus VP4 antigen comprising at least 100 amino acids of a VP8* cleavage product, wherein the RNA molecules comprise a 5' Cap and a poly(A) sequence of 60 to 250 consecutive adenosines, wherein the composition is administered by injection. See reference claims 79-80.
The mRNA sequence(s) comprise a 5’ Cap structure, a 5’ UTR, the coding region encoding the rotavirus protein, a 3’ UTR, and a poly(A) sequence (claims 79-80, 88-89); and the mRNA sequence(s) is complexed with a cationic or polycationic compound and/or a lipid nanoparticle (claims 94-95).
The reference claims do not recite that the VP8* protein has an amino acid sequence according to SEQ ID NO: 42, as instantly claimed.
WO 2017/081110 A1 is the PCT publication of the reference application and was published prior to the effective filing date of the instantly claimed invention. The specification of WO 2017/081110 A1 discloses rotavirus vaccines comprising an mRNA encoding for rotavirus VP8* protein. See Abstract. In particular, the mRNA encodes for the VP8* protein according to SEQ ID NO: 559 (pg. 25, Table 1), which is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment, above.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the reference claims by using a VP8* protein having an amino acid sequence according to SEQ ID NO: 559, as disclosed in the specification published in WO 2017/081110 A1, with a reasonable expectation of success because said VP8* protein is disclosed as suitable for the methods of the reference claims and stimulates an anti-rotavirus immune response in a patient in need thereof.
The published specification (WO 2017/081110 A1) further teaches that the mRNA comprises, from 5’ to 3’, a 5’ Cap structure, a 5’ UTR, at least one coding sequence encoding the rotavirus VP8* protein, a heterologous 3’ UTR, and a poly(A) sequence. The poly(A) sequence is 64 adenosine nucleotides. Pg. 59; pg. 70, ll. 5-14; pg. 75; pg. 77, ll. 27, to pg. 77, ll. 11. The mRNA is further complexed with a cationic lipid (pg. 79-80) and formulated in a pharmaceutically acceptable carrier (pg. 78, ll. 31, to pg. 79, ll. 8). The mRNA vaccine is administered to a subject for the treatment or prophylaxis of rotavirus infections. Abstract; pg. 78, ll. 27-29; pg. 102, ll. 33, to pg. 103, ll. 5. The subject is a mammal (pg. 89, ll. 13-16; pg. 91, ll. 19-20) or human (pg. 97, ll. 28-29), and vaccination is reported to stimulate a humoral immune response in the subject (Example 2, pg. 112-113; fig. 2, pg. 107, ll. 16-17). Administration is performed by injection. Pg. 89, ll. 4-9; pg. 105-106.
Neither the reference claims nor published specification fairly suggest that the coding sequence additionally encodes an antigen clustering domain from lumazine synthase, as instantly claimed.
Prior to the effective filing date of the instantly claimed invention, Bellido teaches that lumazine synthase has been reported as a carrier for antigen delivery, possessing immunostimulatory properties, and eliciting an antigen-specific cellular response and a strong and long-lasting humoral response. Lumazine synthase has also been previously evaluated as a carrier for systemic immunization in studies fusing lumazine synthase to antigenic peptides, recognizes that insertion of peptides and protein domains is possible without disturbing its multimer conformation. Pg. 136, Introduction.
In Bellido’s study, a rotavirus VP8* protein was fused to lumazine synthase to enhance immunization against rotavirus infection in a suckling mouse model. The results demonstrated that the fusion protein is properly folded and stable and significantly enhanced antibody response and protection against rotavirus challenge relative to controls. Abstract; pg. 137, col. 1-2, joining paragraph; Table 3; Figures 1 and 7. Bellido concludes that the plasticity of the lumazine synthase scaffold for the production of polyvalent chimeras suggest that VP8* from different strains can be coupled to lumazine synthase in order to elicit wide-protecting neutralizing antibodies against different field strains of rotavirus. Pg. 144.
Therefore, prior to the effective filing date of the instantly claimed invention, it would have been prima facie obvious to one of ordinary skill in the art to modify the mRNA vaccine of the reference claims by fusing the rotavirus VP8* protein to a lumazine synthase, as taught by Bellido, with a reasonable expectation of success because the fusion enables polymeric display of VP8* (antigen clustering), significantly enhances antibody response, and induces a protective immune response at lower doses. Abstract; pg. 143-144, Discussion.
For these reasons, the method of claim 65 would have been prima facie obvious over the cited references.
Regarding claims 69-70, the published specification discloses that the rotavirus VP8* protein is mutated to delete at least one or all predicted glycosylation sites. Pg. 16, ll. 9-14; pg. 37, ll. 21, to pg. 38, ll. 25.
Regarding claim 71, SEQ ID NO: 559 (WO 2017/081110 A1) is an amino acid sequence comprising the sequence according to SEQ ID NO: 42 of the instant application. See alignment.
Regarding claims 72-73 and 75, the reference claims further recite that the mRNA further comprises a sequence encoding a helper peptide (claims 82-83), a signal peptide (claim 84), a transmembrane domain (claim 85), and a peptide enabling virus-like particle (VLP) formation (claim 86). The published specification discloses that the coding sequence additionally encodes a signal peptide (pg. 32, ll. 15-29), a linker (pg. 29), a helper peptide or P2 helper peptide (pg. 28, ll. 21, to pg. 29, ll. 6; pg. 30, ll. 1-2), and/or a transmembrane domain (pg. 45-46).
Regarding claim 79, the reference claims recite the mRNA molecules comprise a nucleotide analogue (claim 90), including pseudouridine or 1-methyl-pseudouridine (claims 91-93). The published specification teaches or fairly suggests that the mRNA is stabilized by nucleotide or nucleobase modifications (pg. 70, ll. 24-29; pg. 71, ll. 5-17; pg. 72, ll. 16-18), which includes replacing the uracil nucleotides or uridines with pseudouridine-5'-triphosphate (pg. 72, ll. 4, 7-8) or 1-methyl-pseudouridine (pg. 73, ll. 14).
Regarding claim 80, the published specification teaches that the 5’ Cap structure is a Cap1 structure. Pg. 75, ll. 26-31.
Regarding claim 81, the published specification teaches that the poly(A) tail is added to the 3’-end of the mRNA. Pg. 10, ll. 14-19; pg. 70, ll. 5-14.
Regarding claim 82, the reference claims recite that the at least two serotypes of rotavirus are P[4], P[6], or P[8] serotype (claim 81). The published specification teaches or fairly suggests that the vaccine composition comprises two or more different RNA, each encoding a rotavirus protein from a different rotavirus serotype/genotype. Pg. 52, ll. 18, to pg. 53, ll. 2; pg. 55, ll. 11-30; pg. 96.
Regarding claim 83, reference claim 79 recites that the composition is administered by injection. The published specification teaches administration by intramuscular injection. Pg. 89, ll. 4-9; pg. 105-106.
Regarding claims 84-86, reference claims recite that the mRNA molecule is complexed with a cationic or polycationic compound or polymeric carrier or lipid nanoparticle (claims 94-95). The LNPs comprise an ionizable amino lipid, phospholipid, cholesterol, and a PEGylated lipid (claim 96). The published specification teaches that the mRNA is complexed with cationic lipid to form one or more liposomes, lipoplexes, or lipid nanoparticles. Pg. 79-80. The lipid nanoparticles comprise the cationic lipid, a neutral lipid, cholesterol (steroid), and PEGylated lipid (polymer conjugate lipid). Pg. 79, ll. 28-35; pg. 111, ll. 18-21.
Regarding claims 87-89, reference claim 81 recites the VP8* cleavage product is derived from the P[4], P[6], or P[8] serotype. The published specification discloses the composition comprises RNAs encoding Rotavirus VP8* protein from Rotavirus genotypes P[8], P[4] and P[6]. Pg. 15, ll. 23-28; pg. 55, ll. 26-30.
Response to arguments:
Applicant’s remarks filed 01/30/2026 have been carefully considered, but are not found persuasive.
Applicant argues that it is improper to use a different citation of the same application in an attempt to make an end-run around the established policy that the specification underlying the cited claims cannot be used as prior art in a double patenting rejection. See page 9 of applicant’s reply.
The argument is not persuasive because the NSDP rejections do not rely on the specification of the cited patent or copending application. Rather, the NSDP rejections cites and relies on the WO 2017/081110 A1 publication, which qualifies as prior art under 35 U.S.C. 102(a)(1). The Applicant cites no authority to support the assertion that WO 2017/081110 A1 cannot be used as prior art in a NSDP rejection.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES J GRABER whose telephone number is (571)270-3988. The examiner can normally be reached Monday-Thursday: 9:00 am - 4:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James D Schultz can be reached at (571)272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAMES JOSEPH GRABER/Examiner, Art Unit 1631