DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/18/2025 has been entered.
Priority
The disclosures of the prior-filed applications 16/925438 and 63/003254 fail to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Specifically, the prior applications do not disclose RNA or mRNA antigens. Thus, claims reciting RNA or mRNA antigens will only be given a priority date of application 17/204511 (filed March 17, 2021).
Claim Objections
Claims 12 and 22 are objected to because of the following informalities: Claim 12 should recite “wherein [[a]] the delivery system comprises a first compartment” and “comprises the lyophilized vaccine particles”. Claim 22 should recite “vaccine particles have a diameter”. Appropriate correction is required.
Withdrawn Rejections
The rejection of claims 12-22 and 24-31 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, has been withdrawn in view of applicant’s amendments to claim 12.
The rejection of claim 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, has been withdrawn in view of applicant’s amendments to claim 15.
The rejection of claims 15-20 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, has been withdrawn in view of applicant’s amendments to claim 15.
The rejection of claims 12-14 and 24-30 under 35 U.S.C. 103 as being unpatentable over Sorraya et al. (U.S. Patent No. 9603799), Maisano et al. (U.S. Patent Application No. 2019/0048062; published February 14, 2019), Smith et al. (U.S. Patent No. 10953089; filed August 19, 2020), He et al. (Journal of Virology, 2006, 80(12):5757-5767) and He et al. (Journal of Immunology, 2004, 173:4050-4057) has been withdrawn in view of applicant’s amendments to the claims to recite a delivery system with two compartments.
The rejection of claims 12, 14 and 19-22 on the ground of nonstatutory double patenting as being unpatentable over claims1, 2, 4-6 and 16 of U.S. Patent No. 11278617 has been withdrawn in view of applicant’s amendments to claim 12.
The rejection of claims 12, 14 and 19-22 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-6 and 16 of U.S. Patent Application No. 18/611277 has been withdrawn in view of applicant’s amendments to claim 12.
Claim Rejections - 35 USC § 103
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 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.
Claims 12-14, 19-22, 27-30 and 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Sorraya et al. (U.S. Patent No. 9603799), and further in view of VIPS Technical Note; published November 6, 2019), He et al. (Journal of Virology, 2006, 80(12):5757-5767) and He et al. (Journal of Immunology, 2004, 173:4050-4057).
The claims are directed to a method of manufacturing an immunogenic composition forming a vaccine, the method comprising:
providing an antigen comprising a spike protein;
providing a dry lipid blend;
forming vaccine particles, wherein forming vaccine particles further comprises;
hydrating the dry lipid blend with a buffer containing the antigen to form vaccine particles;
extruding the vaccine particles; and
lyophilizing the vaccine particles;
providing a delivery system, wherein the delivery system comprises a first compartment of compositions and a second compartment of compositions, wherein the first compartment of compositions comprises the lyophilized vaccine particle and the second compartment of compositions comprises a diluent; and
combining the second compartment of compositions and the first compartment of compositions to form a vaccine.
Sorraya et al. teaches liposomal vaccine compositions comprising a nanoparticle and an antigen entrapped within (see, the abstract and col. 4, lines 54-58). The liposomes are made as follows: DPPC, DOPC, cholesterol and DPPG were dissolved in a co-solvent containing chloroform, methanol, and water. The lipid blend was dried in a 45°C water bath under nitrogen gas, and then the residual solvent was removed under vacuum overnight, to ensure complete desiccation (see col. 22, lines 50-67) [claim 12 part (b)]. The dried lipid blend is then hydrated with TLC antigen stock buffer solution and then extruded ten times through two 800 nm polycarbonate filter in a 10 ml extruder using nitrogen gas (see col. 23, lines 13-33) [claim 12 parts (a), (c)(i) and (c)(ii)]. The compositions were then freeze-dried (see col. 23, lines 62-67) [claim 12 part (c)(iii)] and reconstituted with diluent (see col 24, lines 19-23) [claim 12 part (f)].
Sorraya et al. does not teach a delivery system comprising two compartments where the first compartment comprises the lyophilized vaccine particle and the second compartment comprises a diluent and combining the two compartments to form a vaccine. However, the VIPS Technical Note teaches a dual-chamber vial where one chamber contains the lyophilized vaccine and the other chamber contains the diluent (See figure in section 1.1). VIPS teaches that:
The reconstitution of vaccines for immunization represents a public health challenge due to the potential for error during the transfer of diluent to the vial containing lyophilized (freeze-dried) vaccine using a reconstitution syringe. Errors in using traditional reconstitution systems include: use of the incorrect volume of diluent; reuse of reconstitution syringes, causing contamination; use of improperly stored diluent that can render a vaccine ineffective; use of an incorrect diluent; or worse, using a potentially deadly liquid drug as a diluent by mistake. Adverse events as a result of reconstitution errors can include local abscesses, toxic shock syndrome, or even death.
Immunization programs may benefit from reconstitution technologies that eliminate or reduce the risk of error and are more convenient and safe when compared to the traditional, reconstitution method of diluent transfer using a needle and syringe.
Dual-chamber vials can be used for any vaccine that requires mixing of multiple components. This TN focuses on dual-chamber vials for vaccines for parenteral delivery that require mixing of a liquid (diluent) and dry (vaccine) component. Generally speaking, these devices are intended to emulate standard vials and a standard AD N&S can be used to withdraw the vaccine for injection.
(emphasis added) (see section 1.2)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use delivery systems such as the dual-chamber delivery system during the reconstitution stage of the method of Sorraya et al. One would have been motivated to do so to avoid the problems described by VIPS [Errors in using traditional reconstitution systems include: use of the incorrect volume of diluent; reuse of reconstitution syringes, causing contamination; use of improperly stored diluent that can render a vaccine ineffective; use of an incorrect diluent; or worse, using a potentially deadly liquid drug as a diluent by mistake]. There would have been a reasonable expectation of success given the teachings and findings outlined in VIPS.
Spike Protein
Sorraya et al. teaches that the antigen can be from a coronavirus (see col. 6, line 20). However, Sorraya et al. does not teach that the coronavirus antigen is the spike protein of coronavirus.
Regarding the coronavirus antigen, the spike protein, which comprises S1 and S2, is known as a vaccine candidate and has immunodominant epitopes. See He et al. 2006 and He et al. 2004, which teach that the coronavirus spike protein is responsible for receptor binding and virus fusion, is highly immunogenic during infection and immunizations, is a major antigen among the SARS-CoV proteins that induces protective antibody responses, and is considered a major target for vaccine design [claims 19-20].
Accordingly, it would be obvious for one of ordinary skill in the art to use the full spike protein of the coronavirus disclosed by Sorayya et al. as the antigen to combine with the liposome nanoparticles taught by Sorayya et al. There is motivation to do so and there would be a reasonable expectation of success in using the spike protein of coronavirus given the teachings of Sorayya et al. (the antigen can be from coronavirus) and the teachings of He et al. 2004 and He et al. 2006 (the spike protein of coronavirus (e.g., (SARS-CoV) is considered a major target for vaccine design).
Regarding claim 13, Sorraya et al. teaches that the lipids are completely desiccated (see col. 22, lines 64-67).
Regarding claim 14, Sorraya et al. teaches that the liposomes can contain positively charged lipids selected from stearylamine (SA), dioleoyl trimethylammoniumpropane (DOTAP), dimethyldioctadecylammonium (DDAB), ethylphosphocholine (Ethyl PC), dipalmitoyl trimethylammoniumpropane (DPTAP) and dipalmitoyl trimethylammonium (DPTMA) or can contain negatively charged lipids selected from dipalmitoyl phosphate (DPPA), dipalmitoyl phosphatidylglycerol (DPPG), dihexadecanoyl phosphoserine (DPPS), and ditetradecyl phosphoglycerol (Diether PG) (see col. 4, lines 46-53 and col. 5, lines 8-19). It would be obvious and well within the purview of one of ordinary skill in the art to determine the charge of the liposome depending on antigen to adhere to the liposome.
For claim 21, Sorraya et al. teaches that the composition comprising the liposomes maintains immunogenicity after lyophilization at a freezing temperature range between about −30° C to about −50° C in the presence of a lyoprotectant (e.g. sucrose or trehalose) (see col. 5, lines 58-67). Sorraya et al. does not teach at which step the lyoprotectant is added. However, it would be obvious and well within the purview of one of ordinary skill in the art to add the lyoprotectant in the hydrating step, which uses a buffer.
Regarding claim 22, Sorraya et al. teaches that the mean hydrodynamic particle diameter of the liposomes of the present invention is in the size range of 300-1000 nm (see col. 5, lines 58-67).
Regarding claim 27, in Example I, Sorraya et al. teaches that the production of nanoparticles from dried lipid blend and lysozyme as the antigen. After the dried lipid blend is created, a solution of sterile filtered lysozyme in PBS buffer is added to the dried lipid blend to hydrate the dried lipids. Thus, one of ordinary skill in the art would recognize that the antigen of choice, including the antigen from a coronavirus, can also be sterile filtered in the PBS buffer before combining with the dried lipid blend.
Regarding claim 28, Sorraya et al. teaches that the liposomes are extruded through 800 nm pore Nucleopore membranes or a 800 nm polycarbonate filter using nitrogen gas (see col. 21, lines 8-17 and col. 23, lines 29-33).
Regarding claim 29, Sorraya et al. teaches that all formulations were prepared in a laminar flow hood using depyrogenated vials and utensils (see col. 13, lines 29-32) and the extrusions are performed using nitrogen gas (see claim 28 above).
Regarding claim 30, Sorraya et al. teaches that all formulations were prepared in a laminar flow hood using depyrogenated vials and utensils (see col. 13, lines 29-32). This would include any dispensing steps into the vials.
Regarding claim 32, the dual-chambered delivery system taught by VIPS (Pfizer Injectable Act-O-Vial System) is a single unit comprising the two chambers (compartments).
Regarding claim 33, the dual-chambered delivery system taught by VIPS (Pfizer Injectable Act-O-Vial System) comprises a rubber plug that separates the diluent and dry lyophilized compartments. By depressing the plastic cap, the plug is dislodged and forced into the lower compartment. Diluent from the upper compartment flows into the lower compartment for mixing (see page 2, bottom figure).
Regarding claim 34, VIPS teaches that the dual-chamber vials typically require two components, the vials and a delivery syringe (see Table 5 on page 7).
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.
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Sorraya et al. (U.S. Patent No. 9603799), VIPS Technical Note; published November 6, 2019), He et al. (Journal of Virology, 2006, 80(12):5757-5767) and He et al. (Journal of Immunology, 2004, 173:4050-4057), as applied to claims 12-14, 19-22, 27-30 and 32-34 above, and further in view of Elia et al. (ACS Nano, January 22, 2021, 15(6): 9627–9637; originally posted October 15, 2020 at https://www.biorxiv.org/content/10.1101/2020.10.15.341537v1.full).
The instant claims are directed to the method of claim 12 where the vaccine particles further comprise a nucleic acid (claim 15), which can be mRNA (claim 16), where the nucleic acid encodes part of the spike antigen (claim 17).
The teachings of Sorraya et al., VIPS, He et al. (2004) and He et al. (2006) are outline above and incorporated herein. Sorraya et al., VIPS, He et al. (2004) and He et al. (2006) do not teach the limitations of claim 15-17. However, Elia et al. teaches the use of mRNA vaccines to immunize against SARS-CoV-2. The mRNA encodes the receptor binding domain (RBD) and is encapsulated in lipid nanoparticles (LNPs). Elia et al. found that LNP RBD mRNA developed substantial anti-spike IgG titers, a robust cellular response, and high levels of neutralizing antibodies after boost administration in both intramuscular and intradermal groups.
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 method of Sorraya et al. and include nucleic acids, such as mRNA, that encode the spike protein or the RBD in the nanoparticle composition. One would have been motivated to do so given the teachings of Elia et al. that mRNA vaccines developed substantial anti-spike IgG titers, a robust cellular response, and high levels of neutralizing antibodies. There would have been a reasonable expectation of success given the teachings and findings of Elia et al.
Further, the courts have said: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose . . . . [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.) See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious). (See MPEP §2144.06(I) – Combining Equivalents Known For The Same Purpose). In this case, applicants are combining two vaccines (protein subunit and mRNA) each separately taught in the art as being effective against coronavirus to create a third composition for the same purpose (vaccine against coronavirus).
Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
In the reply dated 9/18/2025, applicant argues that the cited references do not teach the limitation “providing a delivery system, wherein the delivery system comprises a first compartment of compositions and a second compartment of compositions, wherein the first compartment of compositions comprises the lyophilized vaccine particle and the second compartment of compositions comprises a diluent”. Applicant’s arguments have been fully considered and not found persuasive.
As outlined in the rejection above, the cited reference VIPS Technical Note teaches a delivery system comprising dual chambers (compartments).
Conclusion
No claim is allowed.
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/NICOLE KINSEY WHITE/Primary Examiner, Art Unit 1672