DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/16/2025 has been entered.
Status of Claims
3. Claims 1-2, 5, 7-10, 15, 17-18, 22-23, 25, 27, 32, 36-37, and 39-47 as amended and as filed on 12/16/2025 are pending and under examination in this office action.
Priority
4. Acknowledgment is made of applicant’s claim for priority based on US provisional application 63/222672 filed on 16 July 2021. The certified copy of foreign priority application PCT/US2022/073717 with an international filing date 14 July 2022 is received on 27 December 2023. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 12/27/2023, 12/09/2024, and 12/16/2025 are acknowledged. The submission is in-compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Claim Rejections
6. Withdrawn rejection of claims 1, 8-10, 15, 17, 18 and 32 under 35 U.S.C. § 102(a)(1) in response to applicant’s amendment to claim 1 that affected dependent claims as filed on 12/16/2025.
7. Withdrawn rejection of claims 2, 5, 7, 22, 23, 25, 27, 30, 33, 35, 36 and 37 under 35 U.S.C.§ 103 in response to applicant’s amendment to claim 1 that affected dependent claims as filed on 12/16/2025.
Claim Interpretation
8. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
The claim 1 is interpreted to be directed to an immunogenic composition comprising a nanoparticle (nanodisc) comprising a full-length M2 protein of an influenza A virus, amphipathic phospholipids that form the nanodisc and the full-length M2 protein is spontaneously incorporated in the nanodisc. The immunogenic composition also comprises whole inactivated influenza A virus. Thus, the composition comprises: “full-length M2 protein + nanodisc + whole inactivated influenza A virus”.
The methods claim 32 is directed to elicit an immune response against an influenza A virus by administering to a subject (human or porcine subject) by i/n and i/m route the immunogenic composition comprising “full-length M2 protein + nanodisc + whole inactivated influenza A virus”.
The claim 40 is interpreted to be directed to an immunogenic composition comprising a nanoparticle (nanodisc) comprising a full-length M2 protein of an influenza A virus, amphipathic phospholipids that form the nanodisc and the full-length M2 protein is spontaneously incorporated in the nanodisc. The immunogenic composition also comprises CpG oligonucleotide incorporated in the full-length M2 protein nanodisc. Thus the compositions comprises: “full-length M2 protein + nanodisc + CpG oligonucleotide”.
The method claims 45-47 is directed to elicit an immune response against an influenza A virus by administering to a subject (human or porcine subject) via i/n and i/m routes the immunogenic composition: “full-length M2 protein + nanodisc + CpG oligonucleotide”.
Claim Rejections - 35 USC § 103 (Amended)
9. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
10. Claims 1-2, 8-10, 15, 17-18, 22 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Junfeng et al (CN111450243A, published 28 July 2020), and further in view of Zepeda and Garcia (WO2012061239A3, published on 10 May 2012), Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6), Kitikoon et al 2009 (Vaccine. 2009 Dec 11;28(2):523-31), and Thueng-in et al 2010 (Vaccine. 2010 Sep 24;28(41):6765-77), and Elaish et al 2017 (PLoS One. 2017. Feb 2;12(2): e0171174).
Claims 1-2: Junfeng et al 2020 (CN111450243A) discloses an immunogenic composition of instant claim 1 by disclosing an influenza virus nano-vaccine comprising a full-length M2 matrix protein influenza A virus, and a membrane-like mimetic system nanodisc, wherein a transmembrane region of the matrix protein M2 is embedded in the nanodisc, and an extracellular region of the matrix protein M2 is on one side of the nanodisc and an intracellular region of M2 is on the other side of the nanodisc; wherein the extracellular region of matrix protein M2 forms a four-sided structure on the nanodisc; the nanodisc is formed by two membrane scaffold protein (MSP protein also known as amphipathic molecules) molecules wrapped around a phospholipid circle and has a diameter of 3-17 nm (See, claims 1-4 of Junfeng et al 2020, CN111450243A).
Junfeng et al 2020 (CN111450243A) has claimed two different length versions of M2 matrix protein:
“a matrix protein M2 of influenza A virus” based nanodisc (See, claims 1-4) and it is interpreted as a “full-length M2 of influenza A virus”.
“a short peptide AM2 truncated in an intracellular region” based nanodisc (See, claims 5-6, 9, Specification example 2-3) and it is interpreted as a “short-length M2 protein of influenza A virus”.
See, Phillips v. AWH Corp., 415 F. 3d 1303, 1315 (Fed. Cir. 2005) (“[T]he presence of a dependent claim that adds a particular limitation gives rise to a presumption that the limitation in question is not present in the independent claim.”). See also SRI Int’l v. Matsushita Elect. Corp. of America, 775 F.2d 1107, 1122 (Fed. Cir. 1985) (“It is settled law that when a patent claim does not contain a certain limitation and another claim does, that limitation cannot be read into the former claim … .”).
Junfeng et al 2020 does not teach the limitations on amino acid sequence of the full-length M2 protein and whole inactivated influenza virus.
Zepeda and Garcia 2012 (WO2012061239A2) disclose an influenza virus M2 full-length amino acid sequence and an inactivated whole virus. An influenza A virus immunogenic composition comprising, inter alia, a full-length M2 protein (SEQ ID NO: 44, database sequence = Db, as shown below) from A/California/07/2009 H1N1 pandemic influenza virus strain that has 100% identical amino acid sequence identity to the instant claimed SEQ ID NO: 3 (Query sequence = Qy, as shown below) (See, WO2012061239A3, page number 43 for SEQ ID NO:44; page 63, claim 13; para [0022]). The influenza virus antigen used in the immunogenic composition is in the form of a formalin or β-propiolactone inactivated whole virus (See, claim 20, para [0068]).
An immunogenic composition comprising inactivated whole influenza virus, a pharmaceutically acceptable carrier, and optionally an adjuvant is also disclosed (See, claim 22, para [0028]).
Query Match 100.0%; Score 512; Length 97;
Best Local Similarity 100.0%;
Matches 97; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSLLTEVETPTRSEWECRCSDSSDPLVIAANIIGILHLILWITDRLFFKCIYRRFKYGLK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSLLTEVETPTRSEWECRCSDSSDPLVIAANIIGILHLILWITDRLFFKCIYRRFKYGLK 60
Qy 61 RGPSTEGVPESMREEYQQEQQSAVDVDDGHFVNIELE 97
|||||||||||||||||||||||||||||||||||||
Db 61 RGPSTEGVPESMREEYQQEQQSAVDVDDGHFVNIELE 97
Fiers et al 2004 is in the art and provides a review on “A universal" human influenza A vaccine” directed to M2-protein vaccine or immunogenic compositions. Fiers et al 2004 teaches M2-protein is scarcely present on the virus but is abundantly expressed on virus-infected cells (See, abstract). Fiers et al 2004 reviewed and teaches M2e influenza vaccination approach but the shortcoming is that only a fraction of infected people develops anti-M2e antibodies, and there is no evidence that these low titer antibodies play a role in protection against a new infection by a heterologous strain. It is shown that M2e when presented in a large number of copies, 240 to be precise, on the surface of the HBc capsid, becomes highly immunogenic, especially in the presence of appropriate adjuvants. The resulting antibodies fully protect against a potentially lethal infection. Presumably, it operates at the level of the virus-infected cells, as these express the M2-protein fairly abundantly on their surface (See, page 176 col 1).
Kitikoon et al 2009 is in the art and teaches that Swine influenza full-length M2 (rM2) protein contributes to protection against infection with different H1 swine influenza virus (SIV) isolates. The rM2 in combination with the inactivated H1N1-vaccine (rM2+Vac) reduced the H1N1 virus (homologous vaccine virus) challenge induced fever but not virus shedding and reduced respiratory signs and pneumonic lesions to mild level (See, Fig 1, left panel, Table 2) . The rM2 vaccine alone also reduced respiratory signs and pneumonic lesions as compared to the unvaccinated negative control pigs following H1N1 challenge infection (See, Fig 1, left panel, Table 2) . This study found that the rM2 protein has potential as a vaccine for SIV-associated disease prevention. The recombinant M2 (rM2) protein for the used immunogenic composition was produced using a baculovirus expression system (See, abstract, methods, Figs 1-6, entire article).
Thueng-in et al 2010 teaches that M2 matrix protein liposome adjuvanted vaccine (L-M2) confers heterosubtypic immunity in mouse model to the challenge with mouse adapted pathogenic H5N1 influenza virus. As shown in table 1 the M2 protein used for the vaccine composition is full-length M2 (Table 1 shows M2 gene 291 bp amplicon size that corresponds to 97 amino acids) and Fig 1 shows M2 western blot (See, abstract, methods, results Tables 1-3, Fig 1-8).
Elaish et al 2017 is in the art and teaches supplementation of inactivated influenza virus vaccine with norovirus P particle- influenza A virus M2e chimeric vaccine enhances protection against homologous and heterologous virus challenge in chickens (See, abstract, results, figures, entire article).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify or substitute for an influenza virus full-length M2 protein nanodisc (nano-vaccine) composition of Junfeng et al comprising, inter alia, a full-length matrix protein M2 as claimed in claim 3 of Junfeng et al with the fell-length matrix protein M2 recited in SEQ ID NO: 44 and inactivated whole influenza virus and an adjuvant and/or pharmaceutically acceptable carrier of Zepeda and Garcia in order to arrive at the inventions of instant claims 1-2 and 22. One of the ordinary skills would have been motivated to do so given the motivational suggestions and teachings of Fiers et al 2004, Kitikoon et al 2009, Thueng-in et al 2010 and Elaish et al 2017 on significance of full-length M2 protein and or full-length M2 protein combined with inactivated influenza virus vaccine for a broader and heterosubtypic protective immune response against influenza virus subtype as recited supra to develop an immunogenic composition of instant claims 1-2 and 22 that could induce broadly reactive immune response and confer broader protection against homologous and heterologous influenza A virus subtypes or divergent influenza A virus strains in subjects (e.g. human, swine). There would have been a reasonable expectation of success to incorporate full-length M2 protein of Zepeda and Garcia to the nanodisc of Junfeng et al given the teachings of Junfeng et al on an influenza nanodisc composition comprising the full-length M2 protein. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1-2 and 22. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claims 8-10, 15, 17-18, and 32 (deriving dependency from claim 1 or interdependent claims): Junfeng et al 2020 (CN111450243A) teaches added limitations of the claims 8-10, 15, 17-18, and 32 as follow:
Claim 8: Junfeng et al 2020 teaches the added limitation of claim 8, wherein the amphipathic molecule comprises a protein or polypeptide by disclosing MSP protein molecules and MSP protein molecules by reciting the amino acid sequences (polypeptides) (See, Junfeng et al, claims 3-4).
Claims 9: Junfeng et al 2020 teaches the added limitation of claim 9 by disclosing a membrane scaffold protein (MSP) (See, claim 3, and page 5-6 para [0033].
Claim 10: Junfeng et al 2020 teaches the added limitation of claim 10 by disclosing the MSP proteins engineered from apolipoprotein Apo-AI (See, para [0038]- [0039]; the amino acid sequence of the MSP is at least 95% identical to instant SEQ ID NO:40 or MSP comprises or consists of SEQ ID NO:40 (See, for MSP amino acid sequence SEQ ID NO:5, para [0159]-[0199].
Instant SEQ ID NO:40 (Qy) shows 100% identity with Prior Art Junfeng et al 2020 CN111450243A, SEQ ID NO:5 (Db) and thus teaches the MSP claimed in instant claim 10.
Query Match 100.0%; Score 1444; DB 1; Length 278;
Best Local Similarity 100.0%;
Matches 278; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MGHHHHHHHDYDIPTTENLYFQGSTFSKLREQLGPVTQEFWDNLEKETEGLRQEMSKDLE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MGHHHHHHHDYDIPTTENLYFQGSTFSKLREQLGPVTQEFWDNLEKETEGLRQEMSKDLE 60
Qy 61 EVKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EVKAKVQPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDR 120
Qy 121 ARAHVDALRTHLAPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 ARAHVDALRTHLAPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLG 180
Qy 181 EEMRDRARAHVDALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSE 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 EEMRDRARAHVDALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSE 240
Qy 241 KAKPALEDLRQGLLPVLESFKVSFLSALEEYTKKLNTQ 278
||||||||||||||||||||||||||||||||||||||
Db 241 KAKPALEDLRQGLLPVLESFKVSFLSALEEYTKKLNTQ 278
Claim 15: Junfeng et al 2020 teaches the added limitation of claim 15, wherein the amphipathic molecule comprises an organic polymer by disclosing a few organic polymers including PG ((1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate- (1' -rac-glycerol)) and PEG-oleic acid (See, para [0046]- [0049]).
Claims 17-18: Junfeng et al 2020 teaches the added limitations of claims 17 and 18, by disclosing a few phospholipids, inter alia, including POP (1-glycero-5- (9-octadecanoyl) -sn-glycero-3-glycero-3-phosphoethanolamine), PP-5- (3-glycero-5-phosphoethanolamine), POPE (1-hexadecanoyl-2- (9Z-octadecenoyl) -sn-glycero-3-phosphoethanolamine), POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-glycero-phosphoethanolamine), the phospholipids ….. selected from PG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate- (1' -rac-glycerol)), POPE (1-hexadecanoyl-2- (9Z-octadecenoyl) -sn-glycero-3-phosphoethanolamine), POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-glycero-phosphoethanolamine), POPS (1-palmitoyl-sn-glycero-3-phosphoethanolamine), POP (1-glycero-5- (9-octadecanoyl) -sn-glycero-3-glycero-3-phosphoethanolamine), or PP-5- (3-glycero-5-phosphoethanolamine) (See, para [0046]- [0049]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to render obvious the claim 1 as recited supra with additional teachings of Junfeng et al on the added limitations as recited supra to arrive at the inventions of claims 8-10, 15, 17-18, and 32. One of the ordinary skills would have been motivated to do so to produce or develop an influenza virus derived full M2 protein nanodisc by incorporating optimal composition of amphipathic lipids/lipids to produce and develop a stable nanodisc incorporating an influenza virus derived full M2 protein for stability and to further combine with whole inactivated influenza virus to develop an immunogenic composition for commercial success that could induce broadly reactive immune response and confer broader protection against homologous and heterologous influenza A virus subtypes or divergent influenza A virus strains in subjects (e.g. human, swine). There would have been a reasonable expectation of success to incorporate full M2 protein of Zepeda and Garcia to the nanodisc of Junfeng et al given the teachings of Junfeng et al on an influenza nanodisc vaccine comprising a full-length M2 protein. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 8-10, 15, 17-18, and 32. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
11. Claims 5, 7 are rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Junfeng et al (CN111450243A, published 28 July 2020), Zepeda and Garcia (WO2012061239A3, published on 10 May 2012), Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6), Kitikoon et al 2009 (Vaccine. 2009 Dec 11;28(2):523-31), and Thueng-in et al 2010 (Vaccine. 2010 Sep 24;28(41):6765-77), and Elaish et al 2017 (PLoS One. 2017. Feb 2;12(2):e0171174) as applied to claims 1 above, and further in view of Silgar et al 2006 (US7083958B2, patent granted 01 August 2006).
Claims 5 and 7: The combined prior art teachings of Junfeng et al 2020, Zepeda and Garcia 2012, Fiers et al 2004, Kitikoon et al 2009, Thueng-in et al 2010, and Elaish et al 2017 teaches claim 1 as recited supra, however, does not teach added limitations of instant claim 5 and 7.
Silgar et al 2006 teaches a protein tag (instant claim 5 limitation) HisTEV tag, TEV is the tobacco viral protease, X is the factor ten protease site (See, US7083958B2, column 5, lines 55-67; column 77, SEQ ID NO: 48; table 19 SEQ ID NO: 48 for amino acid sequence of the protein tag); and (instant claim 7 limitation) the protein tag that comprise HisTEV tag with the amino acid sequence MGHHHHHHHDYDIPTTENLYFQG (that shows 100% identity with SEQ ID NO: 48 of Silgar et al (US7083958B2).
Qy = SEQ ID NO: 58 of instant application; Db = SEQ ID NO: 48 of Silgar et al (US7083958B2).
Query Match 100.0%; Score 146; Length 23;
Best Local Similarity 100.0%;
Matches 23; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MGHHHHHHHDYDIPTTENLYFQG 23
|||||||||||||||||||||||
Db 1 MGHHHHHHHDYDIPTTENLYFQG 23
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings that taught an immunogenic composition of claim 1 comprising full-length M2 protein of influenza A virus and fuse the protein tag of Silgar et al having an amino acid sequence GHHHHHHHDYDIPTTENLYFQG to arrive at the inventions of instant claim 5 and 7. One of the ordinary skills in the art would have been motivated to do so given the suggestion and teaching of Silgar et al that the affinity purification protein tag with the recited amino acid sequence are useful for metal affinity purification of expressed proteins and TEV sequence based proteolytic cleavage of the purified amphipathic protein from the tag (for example instant claim 5 and 7 influenza virus full-length M2 protein fused to the protein tag of SEQ ID NO: 58), used to form Nanodisc (col 12, lines 56-58; col 14 line 32-45;col 31 table 19; col 30 lines 66-67). There would have been a reasonable expectation of success given the teachings of Silgar et al on successful affinity purification of membrane scaffold protein (MSP) proteins development of Nanodisc for use in structural, biochemical and pharmaceutical techniques (See, col 5, lines 55-67, col 6 lines 1-3). Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. It is similar to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions in claims 5 and 7. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
12. Claims 23, 25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Junfeng et al (CN111450243A, published 28 July 2020), Zepeda and Garcia (WO2012061239A3, published on 10 May 2012), Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6), Kitikoon et al 2009 (Vaccine. 2009 Dec 11;28(2):523-31), and Thueng-in et al 2010 (Vaccine. 2010 Sep 24;28(41):6765-77), and Elaish et al 2017 (PLoS One. 2017. Feb 2;12(2):e0171174) as applied to claim 22 above and further in view of Kuai et al 2017 (published in Nature Materials (16), 489-496) and Kuai et al 2018 (Journal of Controlled Release 282 (2018) 131–139).
Claims 23, 25, and 27: The combined prior art teachings of Junfeng et al 2020, Zepeda and Garcia 2012, Fiers et al 2004, Kitikoon et al 2009, Thueng-in et al 2010, and Elaish et al 2017 teaches claim 22 as recited supra, however, does not teach added limitations of instant claim 23, 25 and 27.
Kuai et al 2017 discloses a designer vaccine Nanodiscs and thus Kuai et al is in the field of vaccine Nanodiscs for immunotherapy. Kuai et al discloses a synthetic high-density lipoprotein-mimicking nanodiscs (sHDL Nanodiscs) coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Kuai et al teaches successful incorporation of 98% of the cholesterol modified TLR-9 agonist CpG oligonucleotides/adjuvant molecules into the sHDL Nanodiscs (See, page 489 -abstract, introduction, col 2 for Engineering nanodiscs for antigen and adjuvant delivery, page 490 figure 1 and legends, col 1, page 491 figure 2 a, b, c and legends).
Kuai et al 2018 teaches dual TLR agonist nanodiscs as a strong adjuvant system for vaccines. Kuai et al 2018 teaches that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides to induce enhanced cellular and humoral immune response to protein antigen (See, abstract, methods, results, Figs 1-5, entire article).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings on immunogenic composition of claim 22 to incorporate cholesterol modified CpG adjuvant as taught by Kuai et 2017 and Kuai et al 2018 to arrive at the invention the immunogenic composition of instant claims 23 and 25 and 27. There would have been a reasonable expectation of success given the teachings of Kuai et al 2017 that successfully modified sHDL Nanodisc structure to incorporate 98% of the cholesterol modified CpG molecules. The motivation would have been to improve immunogen and CpG oligonucleotides /adjuvant co-delivery to lymphoid organs and sustain antigen/immunogen presentation on dendritic cells to elicit sustained enhanced immune response with higher magnitude as disclosed by Kuai et al 2017 and 2018. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. It is similar to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions in claims 23, 25 and 27. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
13. Claims 32, 36-37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Junfeng et al (CN111450243A, published 28 July 2020), Zepeda and Garcia (WO2012061239A3, published on 10 May 2012), Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6), Kitikoon et al 2009 (Vaccine. 2009 Dec 11;28(2):523-31), and Thueng-in et al 2010 (Vaccine. 2010 Sep 24;28(41):6765-77), and Elaish et al 2017 (PLoS One. 2017. Feb 2;12(2):e0171174) as applied to claims 1 above, and further in view of Dhakal et al 2018 (Front Immunol. 2018 May 2; 9:934), Greenbaum et al 2001 (J Med Virol. 2001 Sep;65(1):178-84), and Greenbaum et al 2002 (Vaccine 20 (2002) 1232–1239), Amorij et al 2017 (EP3111953A1, 01/04/2017) as evidenced by Avanthay et al 2024 (bioRxiv preprint doi: https://doi.org/10.1101/2024.03.27.586965; this version posted March 29, 2024).
Claims 32, 36-37 and 39: The combined prior art teachings of Junfeng et al 2020, Zepeda and Garcia 2012, Fiers et al 2004, Kitikoon et al 2009, Thueng-in et al 2010, and Elaish et al 2017 teaches the immunogenic composition claim 1 as recited supra.
The combined teachings that taught claim 1 do not teach added limitation of instant claim 37, wherein the subject is human; instant claim 39 limitation, wherein the immunogenic composition is administered to the subject intramuscularly and intranasally (the administration is interpreted as separate intramuscular and separate intranasally or both routes intramuscularly and intranasally).
Kitikoon et al 2009 teaches a method of eliciting an immune response against influenza A virus in a subject, comprising administering to the subject an effective amount of the immunogenic composition, and this method taught by Kitikoon et al 2009 is applicable to administer the immunogenic composition of instant claim 1 to a subject (e.g. human, mice or porcine). The immunogenic composition used for administration is taught by the combined prior art teachings as applied to claim 1 as recited supra. Kitikoon et al 2009 teaches administration of (i) a recombinantly expressed full-length matrix 2 (rM2) protein of swine influenza virus to porcine (pig) , and (ii) a recombinantly expressed full-length matrix 2 (rM2) protein + inactivated whole influenza A H1N1 virus of swine origin (rM2+ inactivated whole influenza A H1N1 virus , an immunogenic composition as a vaccine) to porcine or pigs that induces cellular and humoral immune responses and protection response in porcine against infection with homologous H1N1 vaccine virus and different heterologous H1N2 challenge swine influenza virus (SIV) isolates (See, abstract, entire article, Table 1). Pigs in the appropriate groups received an inactivated SIV vaccine described earlier and/or a recombinant M2 (rM2) protein vaccine at a different site at 3 and 5 weeks of age. The IA30 vaccine and/or rM2 vaccine were administered intramuscularly (IM) to pigs in groups 2–4 and 6–8 at a dose of 2 ml per pigs. Groups assigned to receive both the inactivated SIV vaccine and rM2 vaccine were injected IM at different sites. A concentration of 50 µg/ml of rM2 protein was combined with the same adjuvant used with the IA30 inactivated vaccine. Pigs were challenged by inoculated intratracheally with either the homologous virus A/Sw/IA/15/1930 H1N1 (IA30) (vaccine strain) or a heterologous virus A/Sw/MN/00194/2003 H1N2 (MN03) at 7 weeks of age (from trial day 0). The vaccine composition induced both humoral immune response (antibody) and cellular immune response (T cell) and protected immunized porcine (pigs) from serious disease and mortality after challenge with the viruses. Challenge virus replication/shedding was significantly reduced in vaccinated pigs (See, page 527 Fig 2). HI antibody titers to the vaccine antigen (IA30) were observed only in vaccinated pigs (groups 2, 3, 6 and 7) prior to SIV challenge (See, page 527, Fig 3). Cellular immune response (PBMC T cells) mean numbers of CD4 +, CD8+ and CD4/8+ T cells was induced following vaccination (See, page 529, Fig 6). Respiratory distress associated with SIV challenge was not observed in group of pigs that received inactivated vaccine +rM2 protein combined vaccination (H1N1 virus challenge) whereas only rM2 protein vaccine showed respiratory distress (See, page 526 Fig 1, left panel). Clinical evaluation (Fig 1) and necropsy evaluation (Table 2) of pigs showed that Inactivated IA30+rM2 combined immunogenic composition administered to group of pigs showed significantly lower pathology of lungs (See page 528 Table 2) with homologous vaccine virus H1N1 challenge as compared to unvaccinated pigs.
Dhakal et al 2018 teaches instant claim 39 added limitation, wherein the immunogenic composition is administered to the subject intranasally by disclosing in porcine (pigs) mucosal immunity, humoral and cellular immune response and protective efficacy of intranasal inactivated influenza vaccine is improved by chitosan nanoparticle delivery of killed SwIAV H1N2 (KAg) when encapsulated in chitosan polymer-based nanoparticles (CNPs-KAg) as compared to KAg without chitosan nanoparticle (See, abstract, Fig 1-2 and Fig 3-10, entire article).
Greenbaum et al 2001 teaches induction of serum and mucosal immunologic responses in children (human) following the administration of a new inactivated intra-nasal anti-influenza vaccine (See, abstract, entire article).
Greenbaum et al 2002 teaches induction of mucosal antibody (IgA) and serum antibody (IgG) immunologic responses in the humans aged 12–60 years after a single intra-nasal immunization with a new inactivated trivalent influenza vaccine (See, abstract, entire article).
Amorij et al 2017 teaches whole inactivated influenza virus (WIV) for use as adjuvant when raising an immune response to an antigen. The WIV is preferably used as adjuvant for raising a cellular immune response such as a CTL response against the antigen, preferably using a peptide comprising an epitope of the antigen as immunogen. The antigen can be an antigen of an infectious agent, e.g. a virus such as influenza virus. The WIV is particularly suitable for raising a cellular immune response against conserved, preferably non-surface exposed, epitopes of viruses such as influenza (See, abstract, claims 1-15). In the context of the invention, a "patient" or "subject" may be an animal (including humans). Preferably, a patient or subject is a human being (See, para [0034]).
Avanthay et al 2024 provide evidence that intramuscular prime/intranasal boost vaccination induce sterilizing immunity (highly protective immune responses) by mounting mucosal and humoral and cellular immune responses against influenza A virus infection (See, abstract, entire article).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to the immunogenic composition of claim 1 as recited supra and incorporate additional teachings on the methods of administration of a immunogenic composition as recited in Kitikoon et al 2009, Dhakal et al 2018, Greenbaum et al 2001, Greenbaum et al 2002, Amorij et al 2017 and as evidenced by Avanthay et al 2024 to arrive at the claimed methods in instant claims 32, 36-37 and 39. There would have been a reasonable expectation of success given the prior art teachings as applied to the claims 32, 36-37 and 39. The motivation would have been to optimize the methods for administration of the immunogenic composition(s) in different methods, optimize doses, administration routes i/m, i/n, or both i/m and i/n (for induction of both mucosal and humoral and cellular immune responses) and evaluate cellular, mucosal and humoral immune responses and efficacy of protection against the challenge with a virulent homosubtypic or heterosubtypic influenza A virus to evaluate the performance and efficacy of the vaccine composition(s) for commercial success. The motivations for protective effects and effect of administration of route of immunogenic composition/vaccine are also inferred from the prior art teachings as recited supra. Thus, the invention of claims 32, 36-37 and 39 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. It is similar to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions in claims 32, 36-37 and 39. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
14. Claims 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Junfeng et al 2020 (CN111450243A, published 28 July 2020), and further in view of Zepeda and Garcia 2012 (WO2012061239A3, published on 10 May 2012), Tao et al 2014 (Nanomedicine (Lond) 2014 February; 9(2): 237–251) and Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6).
Claims 40-41: Junfeng et al 2020 (CN111450243A, 07/28/2020) discloses an immunogenic composition comprising a full-length matrix protein M2 of influenza A virus, and a membrane-like mimetic system nanodisc, wherein a transmembrane region of the matrix protein M2 is embedded in the nanodisc, and an extracellular region of the matrix protein M2 is on one side of the nanodisc and an intracellular region of M2 is on the other side of the nanodisc; wherein the extracellular region of matrix protein M2 forms a four-sided structure on the nanodisc; the nanodisc is formed by two membrane scaffold protein (MSP protein also known as amphipathic molecules) molecules wrapped around a phospholipid circle and has a diameter of 3-17 nm (See, claims 1-3 of Junfeng et al 2020, CN111450243A).
Junfeng et al 2020 (CN111450243A) has claimed two different length versions of M2 matrix protein:
(i) “a matrix protein M2 of influenza A virus” based nanodisc (See, claims 1-4) and it is interpreted as a “full-length M2 of influenza A virus”.
(ii) “a short peptide AM2 truncated in an intracellular region” based nanodisc (See, claims 5-6, 9, Specification example 2-3) and it is interpreted as a “short-length M2 protein of influenza A virus”.
See, Phillips v. AWH Corp., 415 F. 3d 1303, 1315 (Fed. Cir. 2005) (“[T]he presence of a dependent claim that adds a particular limitation gives rise to a presumption that the limitation in question is not present in the independent claim.”). See also SRI Int’l v. Matsushita Elect. Corp. of America, 775 F.2d 1107, 1122 (Fed. Cir. 1985) (“It is settled law that when a patent claim does not contain a certain limitation and another claim does, that limitation cannot be read into the former claim … .”).
Junfeng et al 2020 (CN111450243A) does not teach the added limitation of instant claim 40 wherein: the amino acid sequence of the full-length M2 protein is at least 95% identical to any one of SEQ ID NOs: 1-8; and a CpG oligonucleotide; claim 41 added limitation, wherein the amino acid sequence of the full-length M2 protein comprises or consists of any one of SEQ ID NOs: 1-8.
Zepeda and Garcia 2012 (WO2012061239A2, 05/10/2012) teach an influenza A virus vaccine comprising, inter alia, a full length M2 protein amino acid sequence with a SEQ ID NO: 44 that is 100% identical to SEQ ID NO: 3 claimed in instant claim 40 (See, WO2012061239A3, page number 43 for SEQ ID NO:44; page 63, claim 13; para [0022]).
Query Match 100.0%; Score 512; Length 97;
Best Local Similarity 100.0%;
Matches 97; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSLLTEVETPTRSEWECRCSDSSDPLVIAANIIGILHLILWITDRLFFKCIYRRFKYGLK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSLLTEVETPTRSEWECRCSDSSDPLVIAANIIGILHLILWITDRLFFKCIYRRFKYGLK 60
Qy 61 RGPSTEGVPESMREEYQQEQQSAVDVDDGHFVNIELE 97
|||||||||||||||||||||||||||||||||||||
Db 61 RGPSTEGVPESMREEYQQEQQSAVDVDDGHFVNIELE 97
Zepeda and Garcia 2012 (WO2012061239A2, 05/10/2012) do not teach a CpG oligonucleotide.
Tao et al 2014 is directed to gold nanoparticle-M2e conjugate coformulated with CpG induces protective immunity against influenza A virus in a mouse influenza challenge model. Intranasal vaccination of mice with M2e-AuNP conjugates (M2e-AuNP vaccine without CpG) induced M2e-specific IgG serum antibodies, which significantly increased upon addition of CpG as adjuvant (M2e-AuNP + CpG vaccine). Upon challenge with lethal PR8, mice vaccinated with M2e-AuNP conjugates (M2e-AuNP vaccine without CpG) were only partially protected, while mice that received soluble CpG as adjuvant in addition to M2e-AuNP (M2e-AuNP + CpG vaccine) were fully protected (See, abstract, entire article).
Fiers et al 2004 is in the art and provides a review on “A "universal" human influenza A vaccine” directed to M2-protein vaccine or immunogenic compositions. Fiers et al 2004 teaches M2-protein is scarcely present on the virus but is abundantly expressed on virus-infected cells (See, abstract). Fiers et al 2004 teaches M2e influenza vaccination approach also but the shortcoming is that only a fraction of infected people develops anti-M2e antibodies, and there is no evidence that these low titer antibodies play a role in protection against a new infection by a heterologous strain. It is shown that M2e when presented in a large number of copies, 240 to be precise, on the surface of the HBc capsid, becomes highly immunogenic, especially in the presence of appropriate adjuvants. The resulting antibodies fully protect against a potentially lethal infection. Presumably, it operates at the level of the virus-infected cells, as these express the M2-protein fairly abundantly on their surface (See, page 176 col 1).
It would have been obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior teachings of Junfeng et al 2020 on influenza A virus full-length matrix protein nanodisc (nanoparticle) immunogenic composition to incorporate additional teachings of Zepeda and Garcia 2012 on influenza A virus full M2 protein sequence to develop the nanodisc, and Tao et al 2013 teachings on a method of administration of M2e+CpG oligonucleotide adjuvant enhanced immune-protective effects and motivation from Fiers et al 2004 to arrive at the inventions of claims 40-41. The motivation would be to develop an efficacious influenza A virus full M2 protein-based nanoparticle (nanodisc) immunogenic composition or vaccine comprising CpG oligonucleotide adjuvant to induce enhanced immune response for better protection of subjects and for commercial success. One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claims 40-41 given the disclosures of the combined prior art teachings as applied to the instant claims 40-41 as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 40-41. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
15. Claims 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Junfeng et al 2020 (CN111450243A, published 28 July 2020), Zepeda and Garcia 2012 (WO2012061239A3, published on 10 May 2012), Tao et al 2014 (Nanomedicine (Lond) 2014 February; 9(2): 237–251) and Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6) as applied to claim 40-41 above, and further in view of Kuai et al 2017 (Nature Materials (16), 489-496), and Kuai et al 2018 (Journal of Controlled Release 282 (2018) 131–139).
Claims 42-43: The combined teachings of Junfeng et al 2020, Zepeda and Garcia 2012, Tao et al 2014 and Fiers et al 2004 teaches claim 40 as recited above, however, does not teach the added limitations of claims 42-43.
Kuai et al 2017 discloses a designer vaccine Nanodiscs for personalized cancer immunotherapy and thus Kuai et al is in the field of vaccine Nanodiscs for immunotherapy. Kuai et al discloses a synthetic high-density lipoprotein-mimicking nanodiscs (sHDL Nanodiscs) coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Kuai et al teaches successful incorporation of 98% of the cholesterol modified TLR-9 agonist CpG oligonucleotides/adjuvant molecules into the sHDL Nanodiscs (See, page 489 -abstract, introduction, col 2 for Engineering nanodiscs for antigen and adjuvant delivery, page 490 figure 1 and legends, col 1, page 491 figure 2 a, b, c and legends, entire article).
Kuai et al 2018 teaches dual TLR agonist nanodiscs as a strong adjuvant system for vaccines. Kuai et al 2018 teaches that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides to induce enhanced cellular and humoral immune response to protein antigen (See, abstract, methods, results, Figs 1-5, entire article).
It would have been obvious to an artisan of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior teachings of Junfeng et al 2020, Zepeda and Garcia 2012, Tao et al 2013 and Fiers et al 2004 as applied to claims 41-42 above and incorporate teachings of Kuai et al 2017 and Kuai et al 2018 on incorporation or loading of CpG in the full-length M2 protein nanodisc to arrive at the inventions of claims 42-43. to incorporate cholesterol modified CpG adjuvant as taught and recited, supra, by Kuai et al and to arrive at the invention the immunogenic composition of instant claims 22-23 and 25 and 27. There would have been a reasonable expectation of success given the teachings of Kuai et al that successfully modified sHDL Nanodisc structure to incorporate 98% of the cholesterol modified CpG molecules. The motivation would have been to improve immunogen and CpG oligonucleotides /adjuvant co-delivery to lymphoid organs and sustain antigen/immunogen presentation on dendritic cells to elicit sustained enhanced immune response with higher magnitude as disclosed by Kuai et al (See, page 489, abstract). The motivation would be to develop an efficacious influenza A virus full M2 protein-based nanoparticle (nanodisc) composition comprising CpG oligonucleotide adjuvant for co-delivery of the M2 protein and CpG to the cells to induce enhanced immune response for better protection of subjects and for commercial success. One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claims 42-43 given the disclosures of the combined prior art teachings as applied to the instant claims 42-43 as recited supra. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 42-43. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
16. Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Junfeng et al 2020 (CN111450243A, published 28 July 2020), Zepeda and Garcia 2012 (WO2012061239A3, published on 10 May 2012), Tao et al 2014 (Nanomedicine (Lond) 2014 February; 9(2): 237–251) and Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6) as applied to claim 40-41 above, and further in view of additional teachings of Junfeng et al 2020 (CN111450243A).
Claim 44: The combined teachings of Junfeng et al 2020, Zepeda and Garcia 2012, Tao et al 2014 and Fiers et al 2004 teaches claim 40 as recited above.
Junfeng et al 2020 additionally teaches the added limitations of claim 44, wherein the amphipathic molecule comprises a protein or polypeptide by disclosing membrane scaffold protein (MSP) (See, Junfeng et al, claims 3-4 and page 5-6 para [0033]). Junfeng et al 2020 further teaches limitation the at least one phospholipid comprises a glycerophospholipid, an ether glycerophospholipid, or a sphingophospholipid by disclosing a few phospholipids, inter alia, including POP (1-glycero-5- (9-octadecanoyl) -sn-glycero-3-glycero-3-phosphoethanolamine), PP-5- (3-glycero-5-phosphoethanolamine), POPE (1-hexadecanoyl-2- (9Z-octadecenoyl) -sn-glycero-3-phosphoethanolamine), POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-glycero-phosphoethanolamine), the phospholipids ….. selected from PG (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate- (1' -rac-glycerol)), POPE (1-hexadecanoyl-2- (9Z-octadecenoyl) -sn-glycero-3-phosphoethanolamine), POPS (1-palmitoyl-2-oleoyl-sn-glycero-3-glycero-phosphoethanolamine), POPS (1-palmitoyl-sn-glycero-3-phosphoethanolamine), POP (1-glycero-5- (9-octadecanoyl) -sn-glycero-3-glycero-3-phosphoethanolamine), or PP-5- (3-glycero-5-phosphoethanolamine) (See, para [0046]- [0049]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to render obvious the claim 40 as recited supra with additional teachings of Junfeng et al on the added limitations on the amphipathic molecule MSP and a phospholipid as recited supra to arrive at the inventions of claim 44. One of the ordinary skills would have been motivated to do so to produce or develop an influenza virus derived full M2 protein nanodisc by incorporating optimal composition of amphipathic lipids/lipids to produce and develop a stable nanodisc incorporating an influenza virus derived full M2 protein for stability and to further combine with whole inactivated influenza virus to develop an immunogenic composition for commercial success that could induce broadly reactive immune response and confer broader protection against homologous and heterologous influenza A virus subtypes or divergent influenza A virus strains in subjects (e.g. human, swine). There would have been a reasonable expectation of success to incorporate full M2 protein of Zepeda and Garcia to the nanodisc of Junfeng et al given the teachings of Junfeng et al on an influenza nanodisc vaccine comprising a full-length M2 protein. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 44. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
17. Claim 44-47 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Junfeng et al 2020 (CN111450243A, published 28 July 2020), Zepeda and Garcia 2012 (WO2012061239A3, published on 10 May 2012), Tao et al 2014 (Nanomedicine (Lond) 2014 February; 9(2): 237–251) and Fiers et al 2004 (Virus Res. 2004 Jul;103(1-2):173-6) as applied to claim 40-41 above, and further in view of additional teachings of Kitikoon et al 2009 (Vaccine. 2009 Dec 11;28(2):523-31), Dhakal et al 2018 (Front Immunol. 2018 May 2; 9:934), Greenbaum et al 2001 (J Med Virol. 2001 Sep;65(1):178-84), and Greenbaum et al 2002 (Vaccine 20 (2002) 1232–1239), as evidenced by Avanthay et al 2024 (bioRxiv preprint doi: https://doi.org/10.1101/2024.03.27.586965; this version posted March 29, 2024).
Claims 45-47: The combined teachings of Junfeng et al 2020, Zepeda and Garcia 2012, Tao et al 2014 and Fiers et al 2004 teaches the immunogenic composition of claim 40 as recited above.
Claim 45: Tao et al 2014 is in the art and is directed to gold nanoparticle–M2e conjugate coformulated with CpG induces protective immunity against influenza A virus and thus teaches a method of eliciting an immune response against influenza A virus in a subject (See, Tao et al 2014: abstract, methods on page 5 including a section on immunization of mice, results and discussion pages 6-10, Figs 4-7), and Tao et al 2014 teachings on the method is equally applicable for administering to the subject an effective amount of the immunogenic composition of claim 40.
Claim 46: Tao et al 2014 teaches the added limitation of instant claim 46, wherein the immunogenic composition is administered to the subject intranasally (See, page 5, section on immunization of mice).
Tao et al 2014 does not teach claim 46 limitation administration of the immunogenic composition to the subject intramuscularly.
Claim 47: Tao et al 2014 does not teach claim 47 added limitation, wherein the subject is porcine or human.
The limitation of instant claim 46, wherein the immunogenic composition is administered to the subject intramuscularly and intranasally (the administration is interpreted as separate intramuscular and separate intranasally or both routes intramuscularly and intranasally).
Kitikoon et al 2009 teaches a method of eliciting an immune response against influenza A virus in a subject (a porcine or pig subject), and the method is applicable to administering to the subject an effective amount of the immunogenic composition of claim 40 by intramuscularly (IM) route to porcine. The teachings of Kitikoon et al 2009 as recited supra are incorporated here by reference as applicable to the instant claims 45-47 in context to the claim 40.
Dhakal et al 2018 teaches the immunogenic composition administration to the porcine or pig subject intranasally by disclosing mucosal immunity humoral and cellular immune response and protective efficacy of intranasal influenza vaccine as recited supra for are incorporated here by reference as applicable to the instant claims 45-47 in context to the claim 40.
Greenbaum et al 2001 teaches induction of serum and mucosal immunologic responses in children (human) following the administration of a intra-nasal influenza vaccine as recited supra for are incorporated here by reference as applicable to the instant claims 45-47 in context to the claim 40.
Greenbaum et al 2002 teaches induction of mucosal antibody (IgA) and serum antibody (IgG) immunologic responses in the humans aged 12–60 years after a single intra-nasal immunization with influenza vaccine as recited supra for are incorporated here by reference as applicable to the instant claims 45-47 in context to the claim 40.
Avanthay et al 2024 provide evidence that intramuscular prime/intranasal boost vaccination induce sterilizing immunity by mounting mucosal and humoral and cellular immune responses against influenza A virus infection (See, abstract, entire article).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teachings as applied to the immunogenic composition of claim 40 by incorporating the additional teachings on the methods of administration and inducting immune responses and protective response as recited in Kitikoon et al 2009, Dhakal et al 2018, Greenbaum et al 2001, Greenbaum et al 2002, and as evidenced by Avanthay et al 2024 to arrive at the claimed methods in instant claims 45-47. There would have been a reasonable expectation of success given the prior art teachings as applied to the claims 45-47. The motivation would have been to optimize the methods for administration of the immunogenic composition(s) in different methods, optimize doses, administration routes i/m, i/n, or both i/m and i/n (for induction of both mucosal and humoral and cellular immune responses) and evaluate cellular, mucosal and humoral immune responses and efficacy of protection against the challenge with a virulent homosubtypic or heterosubtypic influenza A virus to evaluate the performance and efficacy of the vaccine composition(s) for commercial success. The motivations for protective effects and effect of administration of route of immunogenic composition/vaccine are also inferred from the prior art teachings as recited supra. Thus, the invention of claims 45-47 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. It is similar to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed inventions in claims 45-47. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
Response to Arguments
18. Applicant’s arguments with respect to claims 1-2,5,7-10,15,17-18,22-23,25,27,30,32,36-37 and 39-47 amended and filed on 12/16/2025 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
The amended claims 1-2, 5, 7-10, 15, 17-18, 22-23, 25, 27, 30, 32, 36-37 and 39-47 as filed on 12/16/2025 are rejected under 35 USC 103 as recited in the office action supra.
(i) Applicant’s argument 1: REJECTION UNDER 35 U.S.C. § 102: Claims 1, 8-10, 15, 17, 18 and 32 were rejected under 35 U.S.C. § 102(a)(1) for allegedly being anticipated by Junfeng et al. (CN 111450243).
In Response 1: Withdrawn rejection of claims 1, 8-10, 15, 17, 18 and 32 under 35 U.S.C. § 102(a)(1) in response to applicant’s amendment to claim 1 as filed on 12/16/2025.
The claims amended (12/16/2025) claims 1, 8-10, 15, 17, 18 and 32 are now rejected under 35 U.S.C. § 103 as recited supra in the office action.
(ii) Applicant’s argument 2: REJECTIONS UNDER 35 U.S.C. § 103: Claim 2 was rejected under 35 U.S.C. § 103(a) for allegedly being obvious over the combination of Junfeng et al., Zepeda and Garcia (WO 2012/061239), Deng et al. 2015 (Vaccines, Vol. 3:105-136, 2015), Deng et al. 2018 (Nat Commun, Vol. 9:359, 1-12, 2018) and Lee et al. (J Clin Invest., Vol. 118:3478-3490, 2008). Claims 5 and 7 were rejected under 35 U.S.C. § 103(a) for allegedly being obvious over the combination of Junfeng et al. and Sligar et al. (U.S. Patent No. 7,083,958). Claims 22, 23, 25 and 27 were rejected under 35 U.S.C. § 103(a) for allegedly being obvious over the combination of Junfeng et al. and Kuai et al. (Nat Mater., Vol. 16:489-496, 2017). Claim 30 was rejected under 35 U.S.C. § 103(a) for allegedly being obvious over the combination of Junfeng et al., Deng et al. 2018, Elaish et al. (PLoS ONE 12(2):e0171174, 2017), and Zepeda and Garcia. Claims 33, 35 and 36 were rejected under 35 U.S.C. § 103(a) for allegedly being obvious over the combination of Junfeng et al., Elaish et al., Deng et al. 2018, Zepeda and Garcia, and Jean-Pierre Amorij et al. (EP31 l 1953). Claim 37 was rejected under 35 U.S.C. § 103(a) for allegedly being obvious over the combination of Junfeng et al., Elaish et al., Deng et al. 2018, Zepeda and Garcia, Jean-Pierre Amorij et al., and Zeng et al. (Vaccine, Vol. 33:3526-3532, 2015). Applicant traverses each of these rejections as they may apply to the amended claims submitted herewith.
In Response 2: The claims 2, 5, 7, 22-25, 27, 30, 33, and 35-37 are now rejected as recited supra in the office action under 35 U.S.C. § 103 in response to applicant’s amendment to claim 1 that affected dependent claims as filed on 12/16/2025.
(iii) Applicant’s argument 3: Scope of claim 40 and dependents New independent claim 40 and claims dependent thereon.
In Response 3: The claims 40-47 are now rejected as recited supra in the office action under 35 U.S.C. § 103 in response to applicant’s amendment to claims as filed on 12/16/2025.
19. “Affidavit-traversing rejections or objections rule 132” for “Evidence of Unexpectedly Superior Results” is considered but is not persuasive.
(i) The prior art of record as applied to the amended and new claims expressly suggests and demonstrate and have already achieved the results similar or equivalent to that of the applicant’s claimed evidence as “unexpected results”, and thus rendered obvious the claimed inventions and filed evidence of “unexpected results”.
(ii) The applied prior arts for 35 USC 103 rejections in this office action as recited supra teaches that immunogenicity of the full-length M2 protein because of “higher content of full-length M2 protein” in the composition compared to the “whole inactivated influenza A virus” alone has enhanced cellular, humoral and mucosal immune responses in different species e.g. mice, porcine, and chicken, and thus indicate that the prior arts has already achieved, demonstrated the results similar or equivalent to that of the applicant’s claimed evidence as “unexpected results”, and thus rendered obvious the claimed inventions and filed evidence of “unexpected results”.
(iii) The “Evidence of Unexpectedly Superior Results” filed on 12/16/2025 in affidavit by the applicant is not commensurate with the scope.
20. Relevant Prior Arts:
Deng L, Cho KJ, Fiers W, Saelens X. M2e-Based Universal Influenza A Vaccines. Vaccines (Basel). 2015 Feb 13;3(1):105-36.
Deng L et al. Double-layered protein nanoparticles induce broad protection against divergent influenza A viruses. Nat Commun. 2018 Jan 24;9(1):359.
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Conclusion
21. No claim is allowed.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600