Granted Patent
B2
US 12,491,241 · App. 18/526,015 · Granted Dec 9, 2025
Coronavirus vaccine formulations
Inventors:
Gale Smith (Germantown, MD); Michael J. Massare (Mt. Airy, MD); Jing-Hui Tian (Germantown, MD)
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Abstract
Disclosed herein are coronavirus Spike (S) proteins and nanoparticles comprising the same, which are suitable for use in vaccines. The nanoparticles present antigens from pathogens surrounded to and associated with a detergent core resulting in enhanced stability and good immunogenicity. Dosages, formulations, and methods for preparing the vaccines and nanoparticles are also disclosed.
Claims (18)
1 . A method of manufacturing a nanoparticle comprising a coronavirus (CoV) S glycoprotein and a non-ionic detergent core, comprising:
(i) binding a protein extract comprising a first detergent and a CoV S glycoprotein to a protein purification column, wherein the CoV S glycoprotein comprises two modifications compared to a wild type CoV S glycoprotein wherein
(a) the first modification is an inactivated furin cleavage site consisting of mutation of amino acids 669-672 to QQAQ (SEQ ID NO: 7); and
(b) the second modification is mutation of amino acids 973 and 974 to proline;
(ii) performing a detergent exchange by substantially replacing the first detergent with a second detergent; and
(iii) eluting the bound CoV S glycoprotein from the column in the presence of the second detergent to provide the nanoparticle, the non-ionic detergent core of the nanoparticle comprising the second detergent;
wherein the CoV S glycoprotein is numbered according to the polypeptide of SEQ ID NO: 2; and
wherein the second detergent is selected from the group consisting of PS20, PS40, PS60, PS65, and PS80.
2 . The method of claim 1 , wherein the CoV S glycoprotein has at least 95% identity to the CoV S glycoprotein of SEQ ID NO: 2.
3 . The method of claim 1 , wherein the first detergent is NP-9.
4 . The method of claim 1 , wherein the second detergent is PS80.
5 . The method of claim 1 , comprising suspending the CoV S glycoprotein in a pharmaceutically acceptable buffer.
6 . The method of claim 5 , wherein the pharmaceutically acceptable buffer comprises sodium chloride.
7 . The method of claim 5 , wherein the pharmaceutically acceptable buffer comprises sodium phosphate.
8 . The method of claim 1 , wherein the nanoparticle comprises CoV S glycoprotein trimers.
9 . The method of claim 1 , wherein the protein purification column is an affinity chromatography column.
10 . The method of claim 1 , wherein the protein purification column is a lentil lectin column.
11 . The method of claim 1 , comprising eluting the CoV S glycoprotein with methyl alpha-D-mannopyranoside (MMP).
Assignments (2)
SECURITY INTEREST
Recorded Feb 25, 2026
From: NOVAVAX, INC.
To: MIDCAP FINANCIAL TRUST
Reel/Frame 074976/0089 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 19, 2024
From: SMITH, GALE; MASSARE, MICHAEL J.; TIAN, JING-HUI
To: NOVAVAX, INC.
Reel/Frame 066181/0333 →
Continuity (10)
Continuation
16997001
· Aug 19, 2020
Provisional Application
63054182
· Jul 20, 2020
Provisional Application
63051706
· Jul 14, 2020
Provisional Application
63048945
· Jul 7, 2020
Provisional Application
62983180
· Feb 28, 2020
Provisional Application
62976858
· Feb 14, 2020
Provisional Application
62966271
· Jan 27, 2020
References Cited (219)
US 4900549A
· De Vries et al.
· 1990
[cited by applicant]
US 4911928A
· Wallach
· 1990
[cited by applicant]
US 5057540A
· Kensil et al.
· 1991
[cited by applicant]
US 5620690A
· Kersten et al.
· 1997
[cited by applicant]
US 5629021A
· Wright
· 1997
[cited by applicant]
US 6231859B1
· Kensil
· 2001
[cited by applicant]
US 6352697B1
· Cox et al.
· 2002
[cited by applicant]
US 6387373B1
· Wright et al.
· 2002
[cited by applicant]
US 6428807B1
· MacFarlan et al.
· 2002
[cited by applicant]
US 6524584B2
· Kensil
· 2003
[cited by applicant]
US 6558670B1
· Friede et al.
· 2003
[cited by applicant]
US 6846489B1
· Garcon et al.
· 2005
[cited by applicant]
US 7776343B1
· Cox et al.
· 2010
[cited by applicant]
US 8173141B2
· Cox et al.
· 2012
[cited by applicant]
US 8541003B2
· Anderson et al.
· 2013
[cited by applicant]
US 8821881B2
· Morein et al.
· 2014
[cited by applicant]
US 20060121065A1
· Morein et al.
· 2006
[cited by applicant]
US 20120107353A1
· Morein et al.
· 2012
[cited by applicant]
US 20140335049A1
· Morein et al.
· 2014
[cited by applicant]
US 20160184427A1
· Morein et al.
· 2016
[cited by applicant]
US 20180369368A1
· Morein et al.
· 2018
[cited by applicant]
US 20200215189A1
· Morein et al.
· 2020
[cited by applicant]
US 20200345840A1
· Morein et al.
· 2020
[cited by applicant]
US 20220332765A1
· Smith et al.
· 2022
[cited by applicant]
US 20230070886A1
· Smith et al.
· 2023
[cited by applicant]
AU 2003245220B2
· 2009
[cited by applicant]
CA 2491457C
· 2012
[cited by applicant]
CN 1472332A
· 2004
[cited by applicant]
EP 0109942A2
· 1984
[cited by applicant]
EP 0242380B1
· 1991
[cited by applicant]
EP 0180564B1
· 1991
[cited by applicant]
EP 0436620B1
· 1994
[cited by applicant]
EP 0362279B1
· 1995
[cited by applicant]
EP 0889736B1
· 2003
[cited by applicant]
EP 1539231B1
· 2009
[cited by applicant]
JP 2018532703A
· 2018
[cited by applicant]
RU 2403063C1
· 2010
[cited by applicant]
RU 2639559C2
· 2017
[cited by applicant]
WO WO8809336A1
· 1988
[cited by applicant]
WO WO9003184A1
· 1990
[cited by applicant]
WO WO9611711A1
· 1996
[cited by applicant]
WO WO9730728A1
· 1997
[cited by applicant]
WO WO9836772A1
· 1998
[cited by applicant]
WO WO2004004762A1
· 2004
[cited by applicant]
WO WO2004085633A1
· 2004
[cited by applicant]
WO WO2005002620A1
· 2005
[cited by applicant]
WO WO2009081285A2
· 2009
[cited by applicant]
WO WO2013049342A1
· 2013
[cited by applicant]
WO WO2014153087A1
· 2014
[cited by applicant]
WO WO2015042373A1
· 2015
[cited by applicant]
WO WO2015080973A1
· 2015
[cited by applicant]
WO WO2017041100A2
· 2017
[cited by applicant]
WO WO2017161151A1
· 2017
[cited by applicant]
WO WO2018081318A1
· 2018
[cited by applicant]
WO WO2018170347A1
· 2018
[cited by applicant]
WO WO2021147025A1
· 2021
[cited by applicant]
WO WO2021154763A1
· 2021
[cited by applicant]
WO WO2021155323A1
· 2021
[cited by applicant]
WO WO2022046634A1
· 2022
[cited by applicant]
Frauenfeld et al., “A novel lipoprotein nanoparticle system for membrane proteins,” Nat Methods 13(4): 345-351 (Year: 2016).
[cited by examiner]
Dorr et al., “Detergent-free isolation, characterization, and functional reconstitution of a tetrameric K+ channel: The power or native nanodiscs,” PNAS, vol. 111, No. 52: 18607-18612 (Year: 2014).
[cited by examiner]
Thermoscientific, “Tech Tip #19: Remove detergent from protein samples,” TR00192 (Year: 2010).
[cited by examiner]
United Arab Emirates Ministry of Economy, “Office Action Summary”, App. No. P6001416/2022, Dec. 16, 2024, 7 pgs.
[cited by applicant]
United Arab Emirates Ministry of Economy, “Search Report”, App. No. P6001416/2022, Dec. 16, 2024, 4 pgs.
[cited by applicant]
Federal Institute for Intellectual Property Rights (Rospatent), Office Action and Information Search Report, App. No. 2022122879, Jun. 6, 2024, 11 pgs. (w/English Translation).
[cited by applicant]
“Safety Evaluation of Certain Food Additives and Contaminants Quillaia Extracts,” WHO Food Additives Series:48, 14 pages (1996).
[cited by applicant]
Ahlberg et al., Global transcriptional response to ISCOM-Matrix adjuvant at the site of administration and in the draining lymph node early after intramuscular injection in pigs, Developmental and Comparative Immunology…
[cited by applicant]
Anonymous, “Novavax to Present at the 2013 Stifel Nicolaus Healthcare Conference,” Reuters, 1 page http://in.reuters.com/article/2013/09/05/idUSnGNX7PTmrq+1d8+GNW20130905 (2013).
[cited by applicant]
Anonymous, “Stifel 2013 Healthcare Conference,” pp. 1-35, http://www.novavax.com/download/file/2013_09_12%20Novavax_Stifel_presentation.pdf (2013).
[cited by applicant]
Barr et al., “ISCOMs and other saponin based adjuvants,” Advanced Drug Delivery Reviews, (1998), 32: 247-271.
[cited by applicant]
Behboudi et al., “Quillaja Saponin Formulations that Stimulate Proinflammatory Cytokines Elicit a Potent Acquired Cell-Mediated Immunity,” Scand. J. Immunol. 50:371-377 (1999).
[cited by applicant]
Bengtsson et al., “ISCOM technology-based Matrix™ adjuvant: success in future vaccines relies on formulation,” Expert. Rev. Vaccines 10(4):401-403 (2011).
[cited by applicant]
Bengtsson et al., Matrix-M adjuvant increases immunogenicity of seasonal influenza vaccine for the elderly, manuscript in preparation, pp. 1-27 (2014).
[cited by applicant]
Boulter, et al., Evaluation of recombinant sporozoite antigen SPAG-1 as a vaccine candidate against Theileria annulata by the use of different delivery systems, Tropical Medicine and International Health, vol. 4, pages …
[cited by applicant]
Chan et al., “Functional Characterization of Heptad Repeat 1 and 2 Mutants of theSpike Protein of Severe Acute Respiratory Syndrome Coronavirus,” Journal of Virology 3225-3237 (2006).
[cited by applicant]
Chatterjee et al., “The 2019 novel coronavirus disease (COVID-19) pandemic: A review of the current evidence,” Indian J Med Res 151(2-3):147-159 (Year: 2020).
[cited by applicant]
Chen et al., “RNA based mNGS approach identifies a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan outbreak,” Emerging Microbes & Infections 9(1):313-319 (2019).
[cited by applicant]
Chen, Y. et al., “Emerging coronaviruses: Genome structure, replication, and pathogenesis”; Journal of Medical Virology; (Jan. 22, 2020); vol. 92; issue 4, pp. 418-423.
[cited by applicant]
Cheng et al., “Use of convalescent plasma therapy in SARS patients in Hong Kong,” Eur. J. Clin. Microbiol. Infect. Dis. 24(1):44-46 (2005).
[cited by applicant]
Coleman et al., “Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice,” Vaccine 32(26):3169-3174 (2014).
[cited by applicant]
“Committee for Veterinary Medicinal Products, Quillaia Saponins, Summary Report”, The European Agency for the rgJ Evaluation of Medicinal Products, EMEA/MRL/055/95-FINAL, Feb. 1996, pp. 1-2.
[cited by applicant]
Copland et al., “Hydration of lipid films with an aqueous solution of Quil A: a simple method for the preparation of immune-stimulating complexes,” International Journal of Pharmaceutics 196:135-139 (2000).
[cited by applicant]
Coulter, et al., Studies on experimental adjuvanted influenza vaccines: comparison of immune stimulating complexes(Iscoms) and oil-in-water vaccines; Vaccine, vol. 16, No. 11/12, pp. 1243-1253 (1998), Elsevier Science L…
[cited by applicant]
Cox, et al., Development of an Influenza-ISCOM Vaccine, in Vaccine Design (eds. G. Gregoriadis et al.), Springer Science+Business Media, New York (1997), pp. 33-49.
[cited by applicant]
Cox, et al., Evaluation of a virosomal H5N1 vaccine formulated with Maxtrix M adjuvant in phase I clinical trial, Elsevier Ltd, Vaccine, 29, pp. 8049-8059, Aug. 22, 2011.
[cited by applicant]
Cox, et al., Prospects for the Development of New Vaccine Adjuvants, BioDrugs, vol. 12(6), pp. 439-453 (1999), Ad is International Limited.
[cited by applicant]
Danaei et al., “Impact of particle Size and Polydispersity Index on the Clinical Applications of Lipidic nanocarrier Systems”, Pharmaceutics, 2018, pp. 1-17, vol. 10.
[cited by applicant]
Database UniProt [Online], “SubName: Full=S Protein {ECO:0000313|EMBL:AGN70973.1},” EBI accesion No. UNIPROT:R9UQ53, Database accession No. R9UQ53 (2013), 2 pages.
[cited by applicant]
Delmas and Laude, “Assembly of Coronavirus Spike Protein into Trimers and its Role in Epitope Expression,” Journal of Virology 64(11):5367-5375 (1990).
[cited by applicant]
Demana et al., “A comparison of pseudo-ternary diagrams of aqueous mixtures of Quil A, cholesterol and phospholipid prepared by lipid-film hydration and dialysis,” Journal of Pharmacy and Pharmacology 56:573-580 (2004).
[cited by applicant]
Demana et al., “Pseudo-ternary phase diagrams of aqueous mixtures of Quil A, cholesterol and phospholipid prepared by the lipid-film hydration method,” International Journal of Pharmaceutics 270:229-239 (2004).
[cited by applicant]
Drane et al., “ISCOMATRIX adjuvant for prophylactic and therapeutic vaccines”, Expert Review Vaccines, 2007, vol. 6, No. 6, pp. 761-772.
[cited by applicant]
Du et al., “The spike protein of SRS-CpV—a target for vaccine and therapeutic development,” Nat. Rev. Microbiol. 7(3):226-236 (2009).
[cited by applicant]
Du, L., et al., “Identification of a Receptor-Binding Domain in the S Protein of the Novel Human Coronavirus Middle East Respiratory Syndrome Coronavirus as an Essential Target for Vaccine Development,” J. Virol. 87(17)…
[cited by applicant]
Duan, et al., An overview of the novel coronavirus MERS-CoV, Chin J Viral Dis, 3(4):245-249 (2013).
[cited by applicant]
Eckert et al., “Mechanisms of Viral Membrane Fusion and Its Inhibition,” Annual Review of Biochemistry 70:770-810 (2001).
[cited by applicant]
Ekstrom et al., “Iscom and iscom-matrix enhance by intranasal route the IgA responses to OVA and rCTB in local and remote mucosal secretions,” Vaccine 17:2690-2701 (1999).
[cited by applicant]
Ennis et al., “Augmentation of Human Influenza A Virus-Specific Cytotoxic T Lymphocyte Memory by Influenza Vaccine and Adjuvanted Carriers (ISCOMS),” Virology 25:256-261 (1999).
[cited by applicant]
Extended European Search Report for European Application No. EP21747453.5 dated Jan. 12, 2024, 18 pages.
[cited by applicant]
Eyles et al., “Immunodominant Francisella tularensis antigens identified using proteome microarray,” Proteomics 7:2172-2183 (2007).
[cited by applicant]
Follis et al., “Furin cleavage of the SARS coronavirus spike glycoprotein enhances cell-cell fusion but does not affect virion entry,” Virology 350(2):358-369 (2006).
[cited by applicant]
Fossum et al., Early inflammatory response to the saponin adjuvant Matrix-M in the pig, Veterinary Immunology and Immunopathology, http://dx.doi.org/10.1016/j.vetimm.2013.07.007 (2013), pp. 1-9, Elsevier B.V.
[cited by applicant]
Genocea Biosciences, Genocea Reports Positive Initial Phase 1/2A Results for GEN-003, it's Pioneering Therapeutic Vaccine Candidate for the Treatment of Herpes Simplex Virus-2 (HSV-2), at ICAAC 2013, press release, Camb…
[cited by applicant]
Gillim-Ross et al., “Emerging Respiratory Viruses: Challenges and Vaccine Strategies,” Clin. Microbiol. Rev. 19(4):614-636 (2006).
[cited by applicant]
Gonzalez-Reyes et al., “Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion,” Proc. Natl. Acad. Sci. USA 98(17):9859-9864 (2001).
[cited by applicant]
Gretebeck et al., “Animal models for SARS and MERS coronaviruses,” Virology, 13:123-129 (Year: 2015).
[cited by applicant]
Gruenke et al., “New Insights into the Spring-Loaded Conformational Change of Influenza Virus Hemagglutinin,” Journal of Virology, May 2002, 76:(9) 4456-4466 (2002).
[cited by applicant]
Hilgenfeld et al., “From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses,” Antiviral Res. 100(1):286-295 (2013).
[cited by applicant]
Hoffman, M. et al., “Priming Time: How Cellular Proteases Arm Coronavirus Spike Proteins”; Coronavirus Spike Protein: Springer International Publishing AG; (2018); pp. 71-98; DOI: 10.1007/978-3-319-75474-1_4.
[cited by applicant]
International Search Report and Written Opinion issued by the International Searching Authority for Application No. PCT/US21/15220, dated Jun. 30, 2021, 14 pages.
[cited by applicant]
Jackson et al., “An mRNA Vaccine against SARS-CoV-2 Preliminary Report,” The New England Journal of Medicine, pp. 1-12 (2020).
[cited by applicant]
Jiang et al., “A predicted receptor-binding and critical neutralizing domain in S protein of the novel human coronavirus HCoV-EMC”, Journal of Infection (66):464-466 (2013).
[cited by applicant]
Johansson et al., “Iscoms with different quillaja saponin components differ in their immunomodulating activities,” Vaccine 17:2894-2900 (1999).
[cited by applicant]
Kam et al., “Antibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate FcgammaRII-dependent entry into B cells in vitro,” Vaccine 25(4):729-740 (2007).
[cited by applicant]
Kensil, “Saponins as Vaccine Adjuvants,” Critical Reviews in Therapeutic Drug Carrier Systems, vol. 13(1&2), pp. 1-55 (1996), Begell House, Inc.
[cited by applicant]
Kersten et al., On the structure of immune-stimulating saponin-lipid complexes (iscoms) Biochimica et Biophysica Acta, 1062:165-171 (1991).
[cited by applicant]
Kirchdoerfer et al., “Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis.,” Scientific Reports, (2018); 8(1):15701.
[cited by applicant]
Kleine-Weber et al., Functional analysis of potential cleavage sites in the MERS coronavirus spike protein, Scientific Reports vol. 8, No. 1, article 16597, pp. 1-11 (2018).
[cited by applicant]
Korber et al., “Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus,” Cell 182:1-16 (2020).
[cited by applicant]
Kuroiwa, Y., et al., “Antigen-specific human polyclonal antibodies from hyperimmunized cattle,” Nat. Biotechnol. 27(2):173-181 (2009).
[cited by applicant]
Lavelle et al., “Cholera Toxin Promotes the Induction of Regulatory T Cells Specific for Bystander Antigens by Modulating Dendritic Cell Activation,” Journal of Immunology 171:2384-2392 (2003).
[cited by applicant]
Li et al., “Immunogenicity and Protection Efficacy of Monomeric and Trimeric Recombinant SARS Coronavirus Spike Protein Subunit Vaccine Candidates,” Viral Immunology 26(2):126-132 (2013).
[cited by applicant]
Liu et al., “Chimeric severe acute respiratory syndrome coronavirus (SARS-CoV) S glycoprotein and influenza matrix 1 efficiently form virus-like particles (VLPs) that protect mice against challenge with SARS-CoV,” Vacci…
[cited by applicant]
Lovgren et al., The Requirement of Lipids for the Formation of Immunostimulating Complexes (Iscoms), Biotechnol. Appl. Biochem. 10:161-172 (1988).
[cited by applicant]
Lovgren-Bengtsson, 6 Preparation and Use of Adjuvants; Methods in Microbiology, vol. 25, pp. 471-502 (1998), Academic Press Ltd.
[cited by applicant]
Lovgren-Bengtsson et al., “4.5 Preparation and Use of Adjuvants,” Methods in Microbiology 32:551-588 (2002).
[cited by applicant]
Lu et al., “Immune responses against severe acute respiratory syndrome coronavirus induced by virus-like particles in mice,” Immunol. 122:496-502 (2007).
[cited by applicant]
Lucy et al., “Structure and Assembly of Macromolecular Lipid Complexes Composed of Globular Micelles,” Journal of Molecular Biology, (1964), 8: 727-748.
[cited by applicant]
Magnusson et al., Immune enhancing properties of the novel Matrix-M adjuvant leads to potentiated immune responses to an influenza vaccine in mice, Vaccine, http://dx.doi.org/10.1 016/j.vaccine.2013.01.039 (2013), pp. 1…
[cited by applicant]
Magnusson et al., Matrix-M adjuvanted envelope protein vaccine protects against lethal lineage 1 and 2 West Nile virus infection in mice, Vaccine vol. 32, pp. 800-808 (2014), Elsevier Ltd.
[cited by applicant]
Matsushita et al., “Triple immunoglobulin gene knockout transchromosomic cattle: bovine lambda cluster deletion and its effect on fully human polyclonal antibody production,” PLOS One 9(3):1-14 (2014).
[cited by applicant]
McKenzie et al., ISCOMATRIX vaccines: Safety in human clinical studies, Human Vaccines, vol. 6, No. 3, pp. 237-246 (2010), Landes BioScience.
[cited by applicant]
Morein et al., “Current status and potential application of ISCOMs in veterinary medicine,” Advanced Drug Delivery Reviews 56:1367-1382 (2004).
[cited by applicant]
NCT01669512, Adjuvanting Viral Vectored Malaria Vaccines with Matrix M, dated Mar. 9, 2014, pp. 1-4.
[cited by applicant]
NCT04368988, Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS Nanoparticle Vaccine With/Without Matrix-M Adjuvant, dated Apr. 30, 2020, 21 pages.
[cited by applicant]
NCT04533399, A Study Looking at the Effectiveness and Safety of a COVID-19 Vaccine in South African Adults, dated Aug. 31, 2020, 18 pages.
[cited by applicant]
NCT04583995, A Study Looking at the Effectiveness, Immune Response, and Safety of a COVID-19 Vaccine in Adults in the United Kingdom, dated Oct. 12, 2020, 11 pages.
[cited by applicant]
NCT04611802, A Study to Evaluate the Efficacy, Immune Response, and Safety of a COVID-19 Vaccine in Adults â%
[cited by applicant]
NCT04834869, COVID-19 Vaccines Safety Tracking (CoVaST), dated Apr. 8, 2021, 11 pages.
[cited by applicant]
NCT04889209, Delayed Heterologous SARS-CoV-2 Vaccine Dosing (Boost) After Receipt of EUA Vaccines, dated May 17, 2021, 16 pages.
[cited by applicant]
NCT04961541, Evaluation of the Safety and Immunogenicity of Influenza and COVID-19 Combination Vaccine, dated Jul. 14, 2021, 14 pages.
[cited by applicant]
NCT05029856, Evaluation of the Safety and Immunogenicity of SII Vaccine Constructs Based on the SARS-CoV-2 (COVID-19) Variant in Adults, dated Sep. 1, 2021, 13 pages.
[cited by applicant]
NCT05112848, a study to evaluate safety and immunogenicity of a covid-19 vaccine in people living with HIV at Risk for SARS-CoV-2 (COVID-19), dated Nov. 9, 2021, 16 pages.
[cited by applicant]
NCT05236491, Covid-19 Vaccine Booster in Immunocompromised Rheumatic Diseases, Dated Feb. 11, 2022, 9 pages.
[cited by applicant]
NCT05249816, Phase 3 Study to Evaluate a Single Booster of the NVX-CoV2373 COVID19 Vaccine in Adults, dated Feb. 22, 2022, 11 pages.
[cited by applicant]
NCT05372588, Phase 3 Booster Study for the SARS-CoV-2 rS Vaccines, dated May 12, 2022, 12 pages.
[cited by applicant]
Nord, “Novel acetylated triterpenoid saponins in a chromatographic fraction from Quilaja saponinaria Molina,” Carb. Res. 329:817-829 (2000).
[cited by applicant]
Ozel et al., “Quaternary Structure of the Immunostimulating Complex (Iscom), ”Journal of Ultrastructure and Molecular Structure Research 102:240-248 (1989).
[cited by applicant]
Pallesen et al., Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci US A. Aug. 29, 2017;114(35):E7348-E7357. doi: 10.1073/pnas.1707304114. Epub Aug. 14, 2017.
[cited by applicant]
Parrish, “Novavax creates MERS-COV vaccine candidate,” http://vaccinenewsdaily.com/vaccine_development/325407-novavax-creates-mers- cov-vaccine-candidate/ (2013), 2 pages.
[cited by applicant]
Pedersen et al., Matrix-M adjuvanted virosomal H5N1 vaccine confers protection against lethal viral challenge in a murine model, Influenza and Other Respiratory Viruses. DOI: 1 0.1111/j.1750-2659.2011.00256.x (2011 ), p…
[cited by applicant]
Pedersen, et al.; T-Helper 1 Cells Elicited by H5N1 Vaccination Predict Seroprotection, Journal of Infectious Disease, 206, pp. 158-166, Jul. 15, 2016.
[cited by applicant]
Poulsen et al., “Limits for Antibody Affinity Maturation and Repetoire Diversification in Hyper vaccinated Humans,” J. Immunol. 187(8):4429-4235 (2011).
[cited by applicant]
Ranade et al., “Rapid, high throughput protein estimation method for saponin and alhydrogel adjuvanted R21 VLP Malaria vaccine based on intrinsic fluorescence,” Vaccine 40:600-601 (2022).
[cited by applicant]
Rey, F. A. et al., “Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines”; Cell; (Mar. 8, 2018); vol. 172; issue 6, pp. 1319-1334.
[cited by applicant]
Rimmelzwaan. et al., A randomized, double blind study in young healthy adults comparing cell mediated and 1 humoral immune responses induced by influenza ISCOM vaccines and conventional vaccines; Vaccine, 2001, vol. 19,…
[cited by applicant]
Ronnberg et al., “Adjuvant activity of non-toxic Quillaja saponaria Molina components for use in ISCOM matrix,” Vaccine, vol. 13, No. 14, pp. 1375-1382 (1995).
[cited by applicant]
Safety and Immunogenicity Study of Therapeutic HSV-2 Vaccine, Identifier NCT01667341, ClinicalTrials.gov, U.S. National Institutes of Health; available at http://clinicaltrials.gov/ct2/show/NCT01667341 ?term=matrix+m&ra…
[cited by applicant]
Sekimukai et al., “Gold nanoparticle-adjuvanted S protein induces a strong antigen-specific IgG response against severe acute respiratory syndrome-related coronavirus infection, but fails to induce protective antibodies…
[cited by applicant]
Shen, X. et al., “Neutralization of SARS-CoV-2 Variants B.1.429 and B.1.351,” N Engl J Med. (Apr. 7, 2021), pp. 1-3.
[cited by applicant]
Shimizu, “Chapter 32. Routes of Administration,” in The Laboratory Mouse, Hans Hedrich and Gillian Bullock, Eds., Elsevier Academic Press, 15 pages (2004).
[cited by applicant]
Sjolander et al., “ISCOMs: an adjuvant with multiple functions”, J Leukoc Biol. Dec. 1998; 64(6): 713-23.
[cited by applicant]
Sjolander, et al., Uptake and adjuvant activity of orally delivered saponin and ISCOM vaccines, Advanced Drug Delivery Reviews, vol. 34, pp. 321-338 (1998), Elsevier Science B.V.
[cited by applicant]
Skoberne et al., An adjuvanted herpes simplex virus 2 subunit vaccine elicits a T cell response in mice and is an effective therapeutic vaccine in Guinea pigs, J. Virol. 87:3930-3942 (2013).
[cited by applicant]
Song, F., et al., “Middle East Respiratory Syndrome Coronavirus Spike Protein Delivered by Modified Vaccinia Virus Ankara Efficiently Induces Virus-Neutralizing Antibodies,” J. Virol. 87(21):11950-11954 (2013).
[cited by applicant]
Sun et al., “Advances in saponin-based adjuvants”, Vaccine. Mar. 13, 2009; 27(12):1787-96. Epub Feb. 7, 2009.
[cited by applicant]
Sun et al., “ISCOMs and ISOMATRIX,” Vaccine 27:4388-4401 (2009).
[cited by applicant]
Third Party Observation: Additional Comments in Respect of WO2021154812, Document #11 issued for International Application No. PCT/US2021/015220 on May 27, 2022, 2 pages.
[cited by applicant]
Third Party Observation issued for International Application No. PCT/US2021/015220 on May 27, 2022, 11 pages.
[cited by applicant]
Tian et al., “SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 elicits immunogenicity in baboons and protection in mice,” Jun. 30, 2020, 50 pages.
[cited by applicant]
Tian et al., “SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice”, Nature Communications, Jan. 2021, vol. 12, No. 1, article 372, pp. 1-14.
[cited by applicant]
Van Boheemen et al., “Genomic Characterization of a Newly Discovered Coronavirus Associated with Acute Respiratory Distress Syndrome in Humans,” mBio 3(6):e00473-12, 9 pages (2012).
[cited by applicant]
Van Doremalen N. et al. ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. bioRxiv, 23 pages (2020).
[cited by applicant]
Wald, “A Novel Therapeutic Vaccine (GEN003) for Genital Herpes Reduces HSV-2 Shedding: Initial Results of Clinical Trial GEN003-001,” Presented at Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC …
[cited by applicant]
Wald et al., Novel Therapeutic Vaccine for Genital Herpes Reduces Genital HSV-2 Shedding, in ICAAC 2013, Denver, CO, Sep. 2013, cover page and p. 279, Abstract 183(G).
[cited by applicant]
Walls et al., “Functional Characterization of Heptad Repeat 1 and 2 Mutants of the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus,” Nature 531, 17 pages (2016).
[cited by applicant]
Wang et al., “Subunit Vaccines Against Emerging Pathogenic Human Coronaviruses,” Frontiers in Microbiology, 11:298, 19 pages (Year: 2020).
[cited by applicant]
Wrapp et al., “Cryo EM Structure of the 2019 nCoV spike in the Prefusion Conformation,” bioRxiv, posted Feb. 15, 2020 online at https://doi.org/10.1101/2020.02.11.944462, 30 pages.
[cited by applicant]
Wrapp et al., Cryo EM Structure of the 2019 nCoV spike in the Prefusion Conformation Science 10.1126/science.abb2507 (2020), 9 pages.
[cited by applicant]
Yeh, “Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital,” J. Antimicrob. Chemother. 56(5):919-922 (2005).
[cited by applicant]
Canadian Intellectual Property Office, “First Office Action”, App. No. 3,165,371, Apr. 4, 2024, 6 pgs.
[cited by applicant]
Karin Lovgren Bengtsson, Bror Morein & Albert DME Osterhaus, (2011), “ISCOM technology-based Matrix M adjuvant: success in future vaccines relies on formulation,” Expert Review of Vaccines, 10:4, 401-403, DOI: 10.1586/e…
[cited by applicant]
Federal Institute for Intellectual Property Rights (ROSPATENT), Office Action, App. No. 2022122879, Jan. 16, 2025, 6 pgs. (with English translation).
[cited by applicant]
GenBank: “Wuhan seafood market pneumonia virus isolate Wuhan-Hu-1, Complete Genome,” Accession No. MN908947.1; GenBank, Jan. 12, 2020, 11 pages.
[cited by applicant]
Japanese Patent Office, “Office Action,” App. No. 2022-545141, Dec. 6, 2024, 8 pgs. (w/English translation).
[cited by applicant]
Taiwan Intellectual Property Office, “First Office Action”, App. No. TW 110103013, Jan. 3, 2025, 11 pgs. (w/English Translation).
[cited by applicant]
United States Patent and Trademark Office, “Final Office Action”, U.S. Appl. No. 18/061,831, Jan. 28, 2025, 8 pgs.
[cited by applicant]
Liener, “The Lectins: Properties, Functions, and Applications in Biology and Medicine,” Elsevier, 2012.
[cited by applicant]
Sharon, N. and Lis, H. (1990), Legume lectins—a large family of homologous proteins. The FASEB Journal, 4: 3198-3208.
[cited by applicant]
Van Doremalen N. et al. A single dose of ChAdOx1 MERS provides protective immunity in rhesus macaques. Science Advances, 2020.
[cited by applicant]
Taiwan Intellectual Property Office, “Final Office Action”, App. No. TW 110103013, Jun. 25, 2025, 7 pgs. (w/English Translation).
[cited by applicant]