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 .
Priority
Applicant’s claim to priority from Foreign Applications Nos. PCT/EP2021/059460 filed 04/12/2021, PCT/EP2020/082602 filed 11/18/2020 and PCT/EP21/81675 filed 11/15/2021, and from Provisional Applications No. 63/135,723 filed 01/10/2021, 63/115,128 filed 11/18/2020, 63/115,588 filed 11/18/2020, and 63/114,478 filed 11/16/2020, is hereby acknowledged.
Election/Restrictions
Applicant’s election without traverse of Invention Group I (claims 1-2, 13, 16-17, 22, 29 and 32-33, drawn to a composition comprising lipid nanoparticles (LNPs) dispersed in an aqueous phase, wherein the LNPs comprise a cationically ionizable lipid and RNA) in the reply filed on 04/13/2026 is acknowledged.
Applicant’s election without traverse of Species A (claims 13 and 56) the
cationically ionizable lipid that (4) has the structure of I-3; Species B (claim 17), the composition comprises an additional lipid that is (1) a polymer conjugated lipid comprises a pegylated lipid; Species Group C (claims 22 and 64), the composition comprises an RNA wherein (2) the RNA is encapsulated within or associated with the LNPs; in the reply filed on 04/13/2026 is acknowledged.
Claims 90 and 94-95 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/13/2026.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Application Status
This Application is a National stage entry under 35 U.S.C. 371 of International Application No. PCT/EP21/81675 filed 11/15/2021.
Amendments to claims filed 04/13/2026 are hereby acknowledged. Claims 3-12, 14-15, 18-21, 23-28, 30-31, 34-89, and 91-93 are cancelled.
Therefore, claims 1-2, 13, 16-17, 22, 29, 32-33, 90 and 94-95 are pending. Claims 90 and 94-95 are withdrawn. Claims 1-2, 13, 16-17, 22, 29 and 32-33 are under consideration in this Office Action.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 12/20/2023, 01/29/2024, 03/08/2024, 12/12/2024, 09/03/2025, 10/31/2025, 01/16/2026, 04/13/2026 and 05/22/2026 are hereby acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
However, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for Figure 5 that appear on several sheets are followed by "Cont." instead of a capital letter such as FIG. 5A, FIG. 5B, etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see page 123, line 28). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms “ULTRAuFoil”, “Quantifoil” (page 189, line 29), “Gatan” (page 189, line 32), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 13, 16-17, 22, 29 and 32 are rejected under 35 U.S.C. §102(a)(2) as being anticipated by Sullivan ( Sullivan, S.M. et al. US Patent No. 11,744,887 B2, dated September 5, 2023, benefitting from priority from Provisional Applications Nos. 63/073,900 and 62/987,191 filed Sep.2,2020 and Mar.9,2020), as evidenced by PubChem pdf (Tris(hydroxymethyl)aminomethane-CID6503; created 03/26/2005) and Bhagavan (Bhagavan, N.V. “Water, Acids, Bases, and Buffers”. Medical Biochemistry (Fourth edition) Chapter 1, (2002), pp: 1-16).
Regarding claims 1 and 2, Sullivan teaches compositions comprising nucleic acid molecules encoding viral replication proteins and antigenic coronavirus proteins or fragments thereof (see title and abstract). Sullivan teaches compositions comprising TRIS buffer at a pH of about 7.0 to about 8.5 (see column 41, lines 3-7).
Sullivan teaches ionizable cationic lipid in the formulations (see column 6, lines 1-8; column 137, line 24). Sullivan teaches that when a liposome is used to carry a nucleic acid such as RNA, the nucleic acid will be contained within the liposomal compartment in an aqueous phase (see column 139, lines 1-4). Therefore, Examiner interprets that the lipids were dispersed into an aqueous phase before forming liposomes and entrapping some of the aqueous phase.
Sullivan teaches that the composition comprises RNAs (see column 1, lines 54-59; column 4, lines 3, 10-11, 24-25; column 5, lines 54-67).
Sullivan teaches that in some embodiments the TRIS buffer is at a concentration of about 7 mg/mL to about 15 mg/mL and also comprising NaCl at about 2.0 mg/mL to about 4.0 mg/mL. Therefore, Sullivan teaches composition comprising a TRIS buffer that also comprises a monovalent anion in the composition at lower concentration compared to the buffer substance in the composition (see column 41, lines 8-11).
Regarding claim 2(ix), Sullivan also teaches compositions comprising a cryoprotectant that can be sucrose, glycerol or a combination of both (see column 41, lines 12-16). Sullivan teaches that a lyophilized composition can comprise 85 to 95% w/v of a sugar, that can be sucrose (see column 41, lines 44-46).
Sullivan is silent on inorganic phosphate anions, citrate anions or anions of EDTA.
Regarding the claims reciting Tris “and its protonated form”, Bhagavan teaches that the Henderson-Hasselbalch equation can be used to calculate the protonated forms of physiological fluids and buffers (see page 5, right column). Applying the Henderson-Hasselbalch equation:
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or, for clarity:
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As evidenced by PubChem pdf, at a pH range of 7 to 9, the pKa of TRIS is 8.3 at 20 ºC and 7.82 at 37 ºC.
Therefore, Examiner interprets that the mean temperature of 28 ºC is closed to ambient temperature, and the mean pKa is 8.06.
At pH 8.0, 8.0 = 8.06 + log ([unprotonated]/[protonated]) gives :
0.06 = log ([unprotonated]/[protonated]).
According to Bhagavan, Table 1-3 (see page 6), when the Log([unprotonated]/[protonated]) which is equivalent to (pH-pKa), is 0.00, the solution is a buffer that is neutral with 50/50 (a ratio of 1:1) of both forms.
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This means that at pH 8.0, the ratio of unprotonated TRIS to protonated TRIS is about 0.06, higher then 0.00, but lower than 0.18. Therefore, the ratio is between 60/40 and 50/50; roughly the level of unprotonated TRIS in solution is about 54% and protonated TRIS is about 46%. Both molecules types coexist in a solution of TRIS at pH 8.0 at room temperature.
Regarding claim 13 (i), Sullivan teaches ionizable cationic lipid that are “protonatable” with a pKa in a range of about 4 to about 11, or of about 5 to about 7, or about 6 to about 7.
Examiner interprets that at physiological pH ranges of pH 7 to 9, the ionizable cationic lipid is protonated (see column 145, lines 41-49). Sullivan teaches that the ionizable cationic lipid comprises at least one Nitrogen atom (see Formula I, column 145, lines 50-63) as shown in general formula below:
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Regarding claims 16 and 17,Sullivan teaches that the composition can comprise additional lipids, named “helper lipids”. Sullivan teaches that the helper lipid can be DOPE, DMPC, DPPC, DSPC, among others (see column 39, lines 60-67; column 40, lines 33-61). Sullivan also teaches that other lipids can be conjugated/modified with polyethylene glycol, such as PEG-DMG (see column 40, lines 41-61).
Sullivan also teaches neutral lipids, such as phospholipids , e.g., sphingomyelin, phosphatidylethanolamine (see column 144, lines 17-41).
Sullivan also teaches sterols such as cholesterol and derivatives (see column 144, lines 45-58).
Regarding claim 22, Sullivan teaches that the RNA is encapsulated within the lipid formulation (column 140, lines 32-41).
Sullivan teaches that the RNA can comprise chemically-modified nucleotides, including pseudouridines, such as N1- methylpseudouridine (see column 55, lines 45-67; column 56, lines 1-3).
Sullivan teaches that the RN can comprise a 5’ cap1 or 5’ cap2 (see column 4, lines 12-16, 26-27).
Sullivan teaches that the RNA can have an 3’UTR and a polyA sequence (see Figure 14; column 3, lines 10-33).
Sullivan also teaches that the RNA encode one or more polypeptide comprising an epitope for inducing an immune response against an antigen in a subject (see title and abstract; column 1, lines 20-26; column 66, lines 60-67).
Regarding claim 29, Sullivan teaches composition wherein the RNA comprises an open reading frame (ORF) encoding a SARS-CoV-2 S (Spike) protein (see column 3, line 38-44; columns 43, lines 24-32; column 57, lines 38-44).
Regarding claim 32, Sullivan teaches that the composition can be frozen at a temperature below – 70 ºC (column 45, line 41-44, 54-59; column 164, lines 9-10; column 316, lines 49-54; column 318, lines 38-47).
Sullivan as evidenced by Pub Med and Bhagavan, discloses each and every limitation of claims 1-2, 13, 16-17, 22, 29 and 32, and therefore Sullivan as evidenced by Pub Med and Bhagavan anticipate the claimed invention.
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 (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.
Claim 33 is rejected under 35 U.S.C. §103 as being unpatentable over Sullivan (Sullivan, S.M. et al. US Patent No. 11,744,887 B2, dated September 5, 2023, benefitting from priority from Provisional Applications Nos. 63/073,900 and 62/987,191 filed Sep.2,2020 and Mar.9,2020), in view of PubChem pdf (Tris(hydroxymethyl)aminomethane-CID6503; created 03/26/2005) and Bhagavan (Bhagavan, N.V. “Water, Acids, Bases, and Buffers”. Medical Biochemistry (Fourth edition) Chapter 1, (2002), pp: 1-16), as applied to claims 1 and 32 above, and in further view of Smith (Smith, M. et al. WO 2017/218704 A1, published December 21, 2017; previously cited; also on IDS filed 12/20/2023).
It is noted that Sullivan anticipates claims 1 and 32. Therefore, the elements of these claims are rendered obvious by Sullivan.
Regarding claims 1, 32 and 33, Sullivan teaches compositions comprising nucleic acid molecules encoding viral replication proteins and antigenic coronavirus proteins or fragments thereof (see title and abstract). Sullivan teaches compositions comprising TRIS buffer at a pH of about 7.0 to about 8.5 (see column 41, lines 3-7).
Sullivan teaches ionizable cationic lipid in the formulations (see column 6, lines 1-8; column 137, line 24). Sullivan teaches that when a liposome is used to carry a nucleic acid such as RNA, the nucleic acid will be contained within the liposomal compartment in an aqueous phase (see column 139, lines 1-4). Therefore, Examiner interprets that the lipids were dispersed into an aqueous phase before forming liposomes and entrapping some of the aqueous phase.
Sullivan teaches that the composition comprises RNAs (see column 1, lines 54-59; column 4, lines 3, 10-11, 24-25; column 5, lines 54-67).
Sullivan teaches that in some embodiments the TRIS buffer is at a concentration of about 7 mg/mL to about 15 mg/mL and also comprising NaCl at about 2.0 mg/mL to about 4.0 mg/mL. Therefore, Sullivan teaches composition comprising a TRIS buffer that also comprises a monovalent anion in the composition at lower concentration compared to the buffer substance in the composition (see column 41, lines 8-11).
Sullivan is silent on inorganic phosphate anions, citrate anions or anions of EDTA.
Regarding the claim reciting “(Tris) and its protonated form”, Bhagavan teaches that the Henderson-Hasselbalch equation can be used to calculate the protonated forms of physiological fluids and buffers (see page 5, right column). Applying the Henderson-Hasselbalch equation:
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or, for clarity:
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As evidenced by PubChem pdf, at a pH range of 7 to 9, the pKa of TRIS is 8.3 at 20 ºC and 7.82 at 37 ºC.
Therefore, Examiner interprets that the mean temperature of 28 ºC is closed to ambient temperature, and the mean pKa is 8.06.
At pH 8.0, 8.0 = 8.06 + log ([unprotonated]/[protonated]) gives :
0.06 = log ([unprotonated]/[protonated]).
According to Bhagavan, Table 1-3 (see page 6), when the Log([unprotonated]/[protonated]) which is equivalent to (pH-pKa), is 0.00, the solution is a buffer that is neutral with 50/50 (a ratio of 1:1) of both forms.
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This means that at pH 8.0, the ratio of unprotonated TRIS to protonated TRIS is about 0.06, higher then 0.00, but lower than 0.18. Therefore, the ratio is between 60/40 and 50/50; roughly the level of unprotonated TRIS in solution is about 54% and protonated TRIS is about 46%. Both molecules types coexist in a solution of TRIS at pH 8.0 at room temperature.
Regarding claim 32, Sullivan teaches that the composition can be frozen at a temperature below – 70 ºC (column 45, line 41-44, 54-59; column 164, lines 9-10; column 316, lines 49-54; column 318, lines 38-47).
It would have been obvious to one with ordinary skills in the art to have combined obtained a composition with TRIS buffer at 7 mg/mL to about 15 mg/mL and also comprising NaCl at about 2.0 mg/mL to about 4.0 mg/mL, at pH of about 7.0 to about 8.5, as taught by Sullivan and obtained a combination with TRIS protonated form using the teachings of PubChem pdf and calculation of Bhagavan. One motivated in obtaining a perfectly buffered condition closed to physiological conditions for the formulation of a vaccine to be used in human subjects and capable to be stored frozen, could have performed these calculations and optimization with a reasonable expectation of success and would arrived at the claimed invention.
Therefore, the combination of references Sullivan, PubChem pdf and Bhagavan renders elements of claims 1 and 32 obvious.
Regarding claim 33, the combination of references Sullivan, PubChem and Bhagavan does not teach elements of claim 33, i.e., a composition wherein:
“(i) integrity of the RNA after thawing the frozen composition is at least
50% compared to integrity of the RNA before the composition was frozen;
(ii) the size (Zaverage), size distribution, and/or polydispersity index (PDI)
of the LNPs after thawing the frozen composition is equal to the size (Zaverage), size distribution, and/or PDI of the LNPs before the composition was frozen; or
(iii) both (i) and (ii).”
However, Smith teaches novel lipids and compositions comprised within lipid stabilized nanoparticles, as well as additional lipids such as phospholipids, structural lipids, and PEG lipids to be included in these nanoparticles for delivery of therapeutics RNAs and/or prophylactics agents (see abstract).
Smith teaches that the formulation is an aqueous formulation or a lyophilized or frozen formulation (see [0007]). Smith teaches that the formulation and a pharmaceutically acceptable carrier can be stored frozen (see [0079]).
Smith teaches LNPs comprising cationic ionizable lipids with different formulas (see [00243]-[00244]). Smith teaches that the LNP may include one or more PEG or Peg-modified lipids ([00245]). Smith teaches that the LNPs can comprise one or more structural lipids ([00246]), and phospholipids ([00247]-[00248]).
Smith also discloses that the nucleic acid for delivery, can be an RNA, with structure identical to those disclosed by Sullivan, i.e., having a 5’ cap1 or 5’ cap 2 ([00300]-[00303]). Smith teaches that the RNA can be an mRNA, with a 5’ UTR, 3’ UTR and other elements ([00304]-[00307]), such as a poly-A region ([00372], [00377]-[00378]).
In sum, Smith discloses the same lipids as disclosed by Sullivan, being part of LNPs, used as carrier for the same types of RNA.
Smith also teaches that the encapsulation efficiency, stability and integrity of a formulation can be preserved when adding an excipient polymer such as Poloxamer-188 (P188) (see [00548]-[00549]). Smith teaches the stability of frozen formulations with or without P188. Smith teaches characteristics of the formulations using three conditions shown in the table in [00554]. However, Smith teaches that the stability of a formulation comprising only 20 mM Tris buffer, with 8% w/v sucrose, with or without P188, with or without NaCl, exhibited similar stability before and after freeze/thaw cycles (see [00553]- [00555], and Figures 14A and 14B).
Figure 14A shows the diameters in nm, i.e., sizes of LNPs, in three buffers, from 0 to 20 freeze/thaw cycles. Smith teaches that the LNPs do not significantly change in size.
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have modified the LNPs as taught by Sullivan, to obtain stabilized LNPs as taught by Smith, using the buffers taught by Smith (20 mM Tris buffer, 8% w/v sucrose) as taught by Smith. One with ordinary skills in the art, motivated in obtaining the same level of stability and maintaining the size of LNPs before and after freezing, would have considered the teachings of Smith and could have adjusted the sucrose concentration accordingly with a reasonable expectation of success and would arrived at the claimed invention.
The following rejections are made in view of the Species election made by Applicant in the response dated 04/13/2026: “Species A: the cationically ionizable lipid that (4) has the structure of I-3”:
Claim 13(iv) is rejected under 35 U.S.C. § 103 as being unpatentable over Sullivan (Sullivan, S.M. et al. US Patent No. 11,744,887 B2, dated September 5, 2023, benefitting from priority from Provisional Applications Nos. 63/073,900 and 62/987,191 filed Sep.2,2020 and Mar.9,2020), in view of PubChem pdf (Tris(hydroxymethyl)aminomethane-CID6503; created 03/26/2005) and Bhagavan (Bhagavan, N.V. “Water, Acids, Bases, and Buffers”. Medical Biochemistry (Fourth edition) Chapter 1, (2002), pp: 1-16), as applied to claim 1 above, and in further view of Besin (Besin, G. et al. US 2019/0314291 A1, published October 17, 2019).
It is noted that Sullivan, as evidenced by PubChem pdf and Bhagavan, anticipates claim 1. Therefore, the elements of claim 1 are rendered obvious by Sullivan.
Regarding claims 1 and 13(iv), Sullivan teaches compositions comprising nucleic acid molecules encoding viral replication proteins and antigenic coronavirus proteins or fragments thereof (see title and abstract). Sullivan teaches compositions comprising TRIS buffer at a pH of about 7.0 to about 8.5 (see column 41, lines 3-7).
Sullivan teaches ionizable cationic lipid in the formulations (see column 6, lines 1-8; column 137, line 24). Sullivan teaches that when a liposome is used to carry a nucleic acid such as RNA, the nucleic acid will be contained within the liposomal compartment in an aqueous phase (see column 139, lines 1-4). Therefore, Examiner interprets that the lipids were dispersed into an aqueous phase before forming liposomes and entrapping some of the aqueous phase.
Sullivan teaches that the composition comprises RNAs (see column 1, lines 54-59; column 4, lines 3, 10-11, 24-25; column 5, lines 54-67).
Sullivan teaches that in some embodiments the TRIS buffer is at a concentration of about 7 mg/mL to about 15 mg/mL and also comprising NaCl at about 2.0 mg/mL to about 4.0 mg/mL. Therefore, Sullivan teaches composition comprising a TRIS buffer that also comprises a monovalent anion in the composition at lower concentration compared to the buffer substance in the composition (see column 41, lines 8-11).
Sullivan is silent on inorganic phosphate anions, citrate anions or anions of EDTA.
Regarding the claim reciting “(Tris) and its protonated form”, Bhagavan teaches that the Henderson-Hasselbalch equation can be used to calculate the protonated forms of physiological fluids and buffers (see page 5, right column). Applying the Henderson-Hasselbalch equation:
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or, for clarity:
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As evidenced by PubChem pdf, at a pH range of 7 to 9, the pKa of TRIS is 8.3 at 20 ºC and 7.82 at 37 ºC.
Therefore, Examiner interprets that the mean temperature of 28 ºC is closed to ambient temperature, and the mean pKa is 8.06.
At pH 8.0, 8.0 = 8.06 + log ([unprotonated]/[protonated]) gives :
0.06 = log ([unprotonated]/[protonated]).
According to Bhagavan, Table 1-3 (see page 6), when the Log([unprotonated]/[protonated]) which is equivalent to (pH-pKa), is 0.00, the solution is a buffer that is neutral with 50/50 (a ratio of 1:1) of both forms.
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This means that at pH 8.0, the ratio of unprotonated TRIS to protonated TRIS is about 0.06, higher then 0.00, but lower than 0.18. Therefore, the ratio is between 60/40 and 50/50; roughly the level of unprotonated TRIS in solution is about 54% and protonated TRIS is about 46%. Both molecules types coexist in a solution of TRIS at pH 8.0 at room temperature.
Therefore, it would have been obvious to one with ordinary skills in the art to have combined obtained a composition with TRIS buffer at 7 mg/mL to about 15 mg/mL and also comprising NaCl at about 2.0 mg/mL to about 4.0 mg/mL, at pH of about 7.0 to about 8.5, as taught by Sullivan and obtained a combination with TRIS protonated form using the teachings of PubChem pdf and calculations of Bhagavan. One with ordinary skills in the art motivated in obtaining a perfectly buffered solution, closed to physiological conditions for the formulation of a vaccine to be used in human subjects, could have performed these calculations and optimizations with a reasonable expectation of success and would arrived at the claimed invention.
Regarding claim 13(iv), the combination of references Sullivan, PubChem and Bhagavan does not teach a cationically ionizable lipid that has the structure of I-3, as shown below:
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However, Besin discloses a structure identical to the structure I-3, as one of the proposed ionizable amino lipids (see page 143, [0525], third structure).
Besin also teaches LNPs compositions allowing enhanced delivery of nucleic acids such as therapeutic and/or prophylactic RNAs to immune cells (see title and abstract).
Besin teaches that in one embodiment, the agent (e.g., mRNA) associated with/encapsulated by the lipid nanoparticle encodes a protein that is an antigen, such as a vaccine antigen (e.g., viral antigen, bacterial antigen, tumor antigen) (page 276, [1554]).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention, to have substituted the ionizable lipid used in the LNPs taught by Sullivan/PubChem pdf/Bhagavan, with an ionizable lipid such as one with I-3 structure, as taught by Besin. One with ordinary skills in the art, motivated in improving the delivery of mRNA vaccines to immune cells would have considered and would have used a known structure optimized for the delivery of viral antigens taught by Besin, with a reasonable expectation of success, and would have arrived at the claimed invention.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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