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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12 January 2024 was filed before the mailing of an Office action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 12 and 15 are objected to because of the following informalities: claim 12, the acronym DOTAP should state N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP); claim 15, the acronyms GLA and MPL should contain their compound names glucopyranosyl lipid A (GLA) and monophosphoryl lipid A (MPL). Appropriate correction is required.
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 6 and 11-15 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 6 recites the limitation "said amount of RNA" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. It is unclear whether Applicant intended for claim 6 to depend from claim 5 which states “the amount of said RNA is effective…”
Claim 11 recites the limitation "said liquid lipid" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 12 recites the limitation "said cationic lipid" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 13 recites the limitation "said hydrophobic surfactant" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 14 recites the limitation "said hydrophilic surfactant" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 recites the limitation "said immunostimulatory adjuvant" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
It appears that claims 11-15 should depend from claim 9.
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 1-2, 4-10, 12, 14 and 16-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brito et al. (Molecular Therapy, 2014).
Regarding instant claim 1, Brito et al. disclose a cationic nanoemulsion (CNE) prepared by mixing an aqueous phase containing buffer and Tween 80 with an oil phase containing Span 85, DOTAP, and squalene, 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. disclose 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).
Regarding instant claim 2, Brito et al. disclose 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. disclose 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. disclose the immunogenicity of the SAM RNA (pg. 2119-2122; pg. 2124-2126).
Regarding instant claim 6, Brito et al. disclose 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. disclose 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. disclose 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. disclose 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. disclose CNE in complex with SAM comprising a cationic lipid, a hydrophobic surfactant, a hydrophilic surfactant, squalene and mRNA (Figure 1).
Regarding instant claim 10, Brito et al. disclose combining squalene, DOTAP, and sorbitan trioleate and heating to 37 °C to form an oil phase, and the resulting oil phase is then combined with an aqueous phase consisting of polysorbate 80 in 10 mmol/l citrate buffer at pH 6.5. The mixture is then homogenized to produce a primary emulsion (pg. 2126, Preparation of CNE).
Regarding instant claims 12 and 14, Brito et al. disclose 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. disclose 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. disclose 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).
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.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Brito et al. (Molecular Therapy, 2014).
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.
Claim 3 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).
Regarding instant claim 3, 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.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Brito et al. (Molecular Therapy, 2014) in view of Gerhardt et al. (bioRxiv, 2 February 2021).
Regarding instant claim 13, Brito et al. 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.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Brito et al. (Molecular Therapy, 2014) 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 (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.
Conclusion
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue Liu can be reached at (571) 272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/N.W.S/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616