DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-2, 4-9, 11-20 and 24-25 are pending.
Withdrawn Rejections
Rejections and/or objections not reiterated from the previous Office Action are hereby withdrawn.
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 15 and 25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the limitation "said immunostimulatory adjuvant" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 15 depends from claim 12, which depends from claim 1. Instant claims 1 and 12 do not recite an immunostimulatory adjuvant. Claim 9 recites that the formulation as claimed in claim 1 further comprises an immunostimulatory adjuvant. The examiner recommends amending claim 15 to depend from claim 9.
The term “extended” in claim 25 is a relative term which renders the claim indefinite. The term “extended” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the period of time for storage required in the instant claim is unclear.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 5-6, 9, 11-14, 16-18, 20 and 24-25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Erasmus et al. (Science Translational Medicine, 2020).
Erasmus et al. disclose a vaccine platform termed “LION” (lipid inorganic nanoparticle). Erasmus et al. disclose repRNA-CoV2S, a stable and highly immunogenic formulation comprised of an RNA replicon formulated with a novel lipid inorganic nanoparticle (LION) (Abstract). Erasmus et al. disclose that the RNA is complexed with the pre-formed LION particles. This is achieved through electrostatic interaction between the negatively charged RNA and the positively charged DOTAP on the surface of the emulsion, effectively absorbing the RNA onto the carrier, ensuring stability and protection (Results, Fig. 1A). Erasmus et al. disclose the use of an alphavirus-derived replicon RNA (repRNA-CoV2S) which encodes the SARS-CoV-2 spike (S) protein (Abstract; Introduction; Results). Erasmus et al. show high titers of anti-Spike IgG and neutralization activity (effective immune response) (Fig. 2) and it further demonstrates protection in non-human primates (pigtail macaques) against SARS-CoV-2 challenge thus reducing the risk of infection (Fig. 4).
Regarding claim 1, Erasmus et al. disclose a liquid formulation comprising an Alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein (Abstract; pg. 2, Results); and lipid nanoemulsion particles named LION comprising squalene (liquid lipid), DOTAP (cationic lipid), Span 60 (sorbitan monostearate; hydrophobic surfactant), and Tween 80 (polysorbate 80; hydrophilic surfactant) (pg. 2, Results); wherein the RNA forms a stable complex with the particles carrier via electrostatic association of the DOTAP with RNA molecules (pg. 2-3, Results). When mixed, electrostatic association between anionic repRNA and cationic DOTAP molecules on the surface of LION promotes immediate complex formation, as confirmed by an increase in particle size to an intensity-weighted average diameter of 90 nm (pg. 3, col. 1). Erasmus et al. further disclose that LION and repRNA-CoV2S were complexed at a nitrogen-to-phosphate molar ratio of 15 in 10 mM sodium citrate and 20% sucrose buffer (pg. 7, col. 2).
Regarding claims 5-6, Erasmus et al. disclose that the LION/repRNA-CoV2S vaccine induced robust neutralization of SARS-CoV-2 in vaccinated mice and pigtail macaques, with a mean PRNT80 titer in all five macaques of 1:197. The data suggests that a 250 µg prime-only dose or a 50 µg prime/boost immunization with the LION/repRNA-CoV2S vaccine induced concentrations of neutralization antibodies that would be sufficient to protect nonhuman primates from infection and disease (pg. 6, col. 1).
Regarding claim 9, Erasmus et al. disclose that introduction of repRNA into cells initiates ongoing biosynthesis of antigen-encoding RNA that results in markedly increased expression and duration that enhances humoral and cellular immune responses. In addition, repRNA vaccines mimic an Alphavirus infection in which viral-sensing stress factors are triggered, and innate pathways are activated through Toll-like receptors and retinoic acid inducible gene I to produce interferons (IFNs), proinflammatory factors, and chemotaxis of antigen-presenting cells, as well as promoting antigen cross-priming. As a result, repRNA acts as its own adjuvant (pg. 2, col. 1).
Regarding claims 11-14, Erasmus et al. disclose LION consisting of 37.5 mg/ml squalene, 30 mg/ml DOTAP, and 37 mg/ml each of Span 60 and Tween 80 in the final formulation (pg. 7, col. 1, LION formulation of the repRNA vaccine).
Regarding claims 16 and 18, Erasmus et al. disclose that LION has an intensity-weighted average diameter of 52 nm (polydispersity index = 0.2) measured by dynamic light scattering (pg. 3, col. 1).
Regarding claim 17, Erasmus et al. disclose carrier particles that are within the scope of the instant claims. The Office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same functional characteristics of the claimed product. The zeta potential is descriptive and thus would be an inherent property of the claimed composition. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed products are functionally different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 U.S.P.Q.2d 1302, 1303 (PTO Bd. Pat. App. & Int. 1993), Ex parte Gray, 10 USPQ2d 1922, 1923 (PTO Bd. Pat. App. & Int.) and In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
Regarding claim 20, Erasmus et al. disclose that when mixed, electrostatic association between anionic repRNA and cationic DOTAP molecules on the surface of LION promotes immediate complex formation, as confirmed by an increase in particle size to an intensity-weighted average diameter of 90 nm (pg. 3, col. 1).
Regarding claim 24, Erasmus et al. disclose the aqueous phase, containing Tween 80 (polysorbate 80) and sodium citrate dihydrate solution in water (pg. 7, col. 1).
Regarding claim 25, Erasmus et al. disclose that the LION were designed to enhance vaccine stability, delivery, and immunogenicity. Erasmus et al. disclose that to evaluate short-term stability of the vaccine, they evaluated repRNA integrity and complex stability on 1, 4, and 7 days after mixing. LION maintained full integrity of the repRNA molecules (Fig. 1H) and complex size (Fig. 1I) at all time points (pg. 3, col. 1).
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.
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.
Claims 1-2, 4-9, 11-12, 14, 16-20 and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Brito et al. (Molecular Therapy, 2014) in view of Anderson et al. (The New England Journal of Medicine, 2020) and Polack et al. (The New England Journal of Medicine, 2020).
Regarding instant claim 1, Brito et al. teach a cationic nanoemulsion (CNE) prepared by mixing an aqueous phase containing buffer and Tween 80 (polysorbate 80; hydrophilic surfactant) with an oil phase containing Span 85 (sorbitan trioleate; hydrophobic surfactant), DOTAP, and squalene (liquid lipid), and the addition of self-amplifying mRNA to the CNE (pg. 2119, col. 1, Characterization of CNE delivery system before and after the addition of RNA). Brito et al. teach that CNE was prepared by combining squalene, DOTAP, and sorbitan trioleate and heated to 37 °C. The resulting oil phase was then combined with an aqueous phase consisting of polysorbate 80 in 10 mmol/l citrate buffer at pH 6.5. The mixture was homogenized to produce a primary emulsion. Nucleic acids (self-amplifying mRNA, mRNA, and pDNA) were complexed to CAN at a 7:1 nitrogen/phosphate (N/P) ratio (pg. 2126, Preparation of CNE, and Nucleic acid complexation). Brito et al. teach that no changes were observed regarding the stability (particle size and in vivo immunogenicity) of the CNE/RNA complex when stored on ice for 24 hours (pg. 2119, col. 2).
Brito et al. do not explicitly disclose RNA capable of expressing a variant of SARS-CoV-2 virus spike protein.
Anderson et al. teach an mRNA vaccine which encodes the stabilized perfusion SARS-CoV-2 spike protein (S-2P) in healthy adults, wherein the mRNA is encapsulated in lipid nanoparticles at a concentration of 0.5 mg per millimeter and diluted with normal saline to achieve the final target vaccine concentrations (Abstract; pg. 2428, MRNA A-1273 Vaccine).
Polack et al. teach a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a perfusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein, wherein the vaccine is effective for preventing Covid-19 (Abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to prepare the cationic nanoemulsion of Brito et al. for adsorbing the RNA according to Anderson et al. and Polack et al. that encode stabilized perfusion SARS-CoV-2 spike protein. A person of ordinary skill in the art would have been motivated to adsorb the RNA of Anderson et al. or Polack et al. on the CNE of Brito et al. in order to produce an effective mRNA vaccine for preventing infection with SARS-CoV-2.
Regarding instant claim 2, Brito et al. teach that nucleic acid (self-amplifying mRNA, mRNA, and pDNA) was prepared at 300 µg/ml and was added to an equal volume of CNE (pg. 2126, Nucleic acid complexation).
Regarding instant claim 4, Brito et al. teach that linearized DNA templates were transcribed into RNA using the MEGAscript T7 kit and purified by LiCl precipitation. RNA was then capped using the Vaccinia Capping System and purified by LiCl precipitation before formulation (pg. 2126, RNA synthesis).
Regarding the claimed purity, the Office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same characteristics of the claimed product. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed products are different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 U.S.P.Q.2d 1302, 1303 (PTO Bd. Pat. App. & Int. 1993), Ex parte Gray, 10 USPQ2d 1922, 1923 (PTO Bd. Pat. App. & Int.) and In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
Regarding instant claim 5, Brito et al. teach the immunogenicity of the SAM RNA (pg. 2119-2122; pg. 2124-2126).
Regarding instant claim 6, Brito et al. teach that CNE SAM vaccines were potent for both antibody and T-cell responses in macaques at doses less than 100 µg. Both the humoral and cellular responses elicited by CNE SAM vaccine were comparable to other experimental CMV vaccines including a pDNA primer/modified vaccinia virus boost in non-human primates, a VRP in phase 1 clinical trials, and an MF59 adjuvanted subunit vaccine in phase 2 trials (pg. 2124). Brito et al. teach that induction of immune responses was shown in multiple animal species, including rhesus macaques, at comparable level to responses elicited by an adjuvanted subunit vaccine or VRP delivery of the same RNA, and at doses much lower than those required for pDNA vaccines. The prospects for this novel nucleic acid vaccine technology are encouraging and could enable a new generation of potent, versatile, and easily produced SAM vaccines to address health challenges of the 21st century (pg. 2125-2126).
Regarding instant claim 7, Brito et al. teach SAM RNA constructed using Escherichia coli (pg. 2126, RNA synthesis). The instant specification teaches that in a preferred embodiment, for the synthesis of said RNA, a DNA template is prepared from a plasmid cultured in an E. coli cell line (pg. 6, ln. 15-19).
Regarding instant claim 8, Brito et al. teach that the self-amplifying mRNA, i.e., RNAs that encode not only an antigen of interest but also a viral RNA-dependent RNA polymerase to amplify the RNA in the cytoplasm of transfected cells, lead to significantly greater immune responses than conventional RNAs (pg. 2118, col. 2).
Regarding instant claim 9, Brito et al. teach CNE in complex with SAM comprising a cationic lipid, a hydrophobic surfactant, a hydrophilic surfactant, squalene and mRNA (Figure 1).
Regarding instant claim 11, Brito et al. teach preparation of CNE wherein the final weight by; weight percentages of squalene, DOTAP, sorbitan trioleate, and polysorbate 80 were 4.3, 0.4, 0.5, and 0.5% respectively (pg. 2126, Preparation of CNE).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to prepare compositions according to Brito et al. wherein the concentration of squalene can be modified slightly to less than 4.0 wt.% with the reasonable expectation that the resulting CNE would still be effective for adsorbing mRNA.
Regarding instant claims 12 and 14, Brito et al. teach preparation of CNE wherein the final weight by; weight percentages of squalene, DOTAP, sorbitan trioleate, and polysorbate 80 were 4.3, 0.4, 0.5, and 0.5% respectively (pg. 2126, Preparation of CNE).
Regarding instant claims 16-18 and 20, Brito et al. teach that before addition of RNA, the CNE had a number-weighted mean diameter was 69 nm and Z-average diameter was 101 nm, with a polydispersity index of 0.098. After the addition of RNA to CNE, the number-weighted mean diameter increased to 86 nm and Z-average diameter to 129 nm with a poly-dispersity index of 0.117 (pg. 2119, Characterization of CNE delivery system before and after the addition of RNA). The zeta potential for mRNA complexed to CNE is 26.5 mV (Supplementary Table S1).
Regarding instant claim 19, Brito et al. teach mRNA complexed to CNE. The CNE comprises the same components as instantly claimed. Therefore, the CNE would inherently be capable of adsorbing the same amount of mRNA as instantly claimed.
Regarding the claimed amount of mRNA that the carrier is capable of adsorbing, the Office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same characteristics of the claimed product. In the absence of evidence to the contrary, the burden is upon the applicant to prove that the claimed products are different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 U.S.P.Q.2d 1302, 1303 (PTO Bd. Pat. App. & Int. 1993), Ex parte Gray, 10 USPQ2d 1922, 1923 (PTO Bd. Pat. App. & Int.) and In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
Regarding claim 24, Brito et al. teach an aqueous phase consisting of polysorbate 80 in 10 mmol/l citrate buffer at pH 6.5 (pg. 2126, Preparation of CNE).
Regarding claim 25, Brito et al. teach that the CNE stabilized the mRNA from RNase (pg. 2119, col. 1-2).
Response to Arguments
Applicant's arguments filed 28 April 2026 have been fully considered but they are not persuasive. Applicant argues that Brito does not disclose, inter alia, Applicant's N:P ratio between 5 and 15. None of Anderson, Polack, Gerhardt or Coler cure this deficiency of Brito.
The examiner respectfully argues that Brito et al. teach that nucleic acids (self-amplifying mRNA, mRNA, and pDNA) were complexed to CAN at a 7:1 nitrogen/phosphate (N/P) ratio (pg. 2126, Nucleic acid complexation). Therefore, Brito et al. teach an nitrogen to phosphate ratio that is within the instantly claimed range of 5 to 15.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Brito et al. (Molecular Therapy, 2014) in view of Anderson et al. (The New England Journal of Medicine, 2020) and Polack et al. (The New England Journal of Medicine, 2020) as applied to claims 1-2, 4-9, 11-12, 14, 16-20 and 24-25 above, further in view of Gerhardt et al. (bioRxiv, 2 February 2021).
Regarding instant claim 13, Brito et al. teach sorbitan trioleate, but do not explicitly disclose a hydrophobic surfactant comprising sorbitan monostearate.
Gerhardt et al. teach a nanostructured lipid carrier (NLC) RNA vaccine delivery system, wherein the NLC delivery system consists of an oil core comprised of solid (trimyristin) and liquid (squalene) lipids surrounded by surfactants (sorbitan monostearate and polysorbate 80) and a cationic lipid (DOTAP). RNA complexes electrostatically to the outside of an NLC particle 15 (Abstract; pg. 3, ln. 12-15; Figure 1A). The liquid NLC alone maintains stability for at least 1 year of storage at refrigerated temperatures while lyophilized NLC/RNA complexes are shown to retain biophysical properties and ability to induce protein expression in vivo after at least 8 months of room temperature storage and at least 21 months at refrigerated temperatures (pg. 3, ln. 7-11).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to substitute the sorbitan trioleate of Brito et al. with the sorbitan monostearate of Gerhardt et al. as functionally equivalent hydrophobic surfactants for the preparation of RNA vaccines. A person of ordinary skill in the art would have a reasonable expectation of success because Brito et la. and Gerhardt et al. teach emulsions comprising squalene, DOTAP, sorbitan trioleate or sorbitan monostearate, polysorbate 80, and the RNA.
Response to Arguments
Applicant's arguments are the same as above. Therefore, the examiner’s response above is repeated herein.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Brito et al. (Molecular Therapy, 2014) in view of Anderson et al. (The New England Journal of Medicine, 2020) and Polack et al. (The New England Journal of Medicine, 2020) as applied to claims 1-2, 4-9, 11-12, 14, 16-20 and 24-25 above, further in view of Coler et al. (PLoS ONE, 2011).
Regarding instant claim 15, Brito et al. do not explicitly disclose an immunostimulatory adjuvant comprising GLA or MPL.
Coler et al. teach that many subunit vaccine antigens require adjuvants to enhance the strength and duration of the immune response to these antigens which may be weakly immunogenic on their own (pg. 1). Coler et al. teach that both (GLA) and monophosphoryl lipid A (MPL) are adjuvants that enhances immune responses to co-administered antigens (pg. 2, col. 1; pg. 8-11). GLA and MPL were prepared as an aqueous or oil-in-water stable emulsion formulations (pg. 4-5). GLA was prepared as a squalene-based oil-in-water emulsion (pg. 6, col. 2). When administered to mice in a stable oil-in-water emulsion (SE), GLA-SE induced strong systemic innate responses and priming of antigen-specific TH1 cells (pg. 10, col. 1).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date of the instant claims to include GLA or MPL as adjuvants to the formulations of Brito et al. in order to enhance the strength and duration of the immune response, as reasonably suggested by Coler et al.
Response to Arguments
Applicant's arguments are the same as above. Therefore, the examiner’s response above is repeated herein.
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.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nathan W Schlientz whose telephone number is (571)272-9924. The examiner can normally be reached 10:00 AM to 6:00 PM, Monday through Friday.
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/N.W.S/Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616
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