DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being exam/ined under the first inventor to file provisions of the AIA .
Acknowledgement of Receipt
Applicant’s Response, filed 5/19/2026, in reply to the Office Action mailed 2/3/2026, is acknowledged and has been entered. Claim 15 has been amended. Claims 15-22, 24 and 26-33 are pending, of which claims 30 and 33 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 15-22, 24, 26-29, 31 and 32 are encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. New grounds for rejection are set forth herein, necessitated by claim amendment.
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.
Claim(s) 15, 16, 18-21, 24, 26-29 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grant-Serroukh (Lipid Nanoparticles for mRNA mediated Cancer Therapy, 2018, Thesis, University College London).
Grant-Serroukh discloses that lipid-peptide nanoparticles have shown great promise in the delivery of both pDNA and siRNA, but their function as vehicles for mRNA delivery has not yet been determined. Due to the intrinsic differences in composition and structure of pDNA and siRNA as compared to mRNA, including size and charge density, it is likely that an optimal formulation for mRNA delivery will differ substantially from those developed for other nucleic acids. Typical lipid-peptide formulations consist of three components: 1) a cationic lipid, which is able to interact via electrostatic interactions to complex with the nucleic acid; 2) a phospholipid, which provides structure to the lipid bilayer. Additionally, the phospholipid may have structural properties allowing for endosomal escape; 3) a peptide sequence, which can allow for targeting to cell-specific receptors, aiding cell binding and uptake. The peptide also carries a strong positive charge which allows for tight binding and protection of the mRNA. The interaction of these components with the nucleic acid results in the formation of small, self-assembled complexes, about 130 nm in size, which have a strong positive charge (page 85).
The cationic lipids used to form liposomes were either ditetradecyl trimethyl ammonium propane (DTDTMA), dihexadecenyl trimethyl ammonium propane (DHDTMA) or dioctadecenyl trimethyl ammonium propane (DOTMA) which, indicative of the length of their alkyl chains, are referred to in this thesis as C14, C16 and C18 respectively. These cationic lipids were mixed with one of the following phospholipids: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine distearoyl-sn-glycero-3-phosphocholine (DOPE), 1,2 (DSPC) or 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC) at a 1:1 molar ratio. Where specified, cholesterol purchased from Merck (Poole, UK) was added to the cationic and phospholipid mixture prior to forming the liposomes.
The peptides used were 27 (K16RVRRGACRGDCLG) which is an integrin-targeting peptide with an RGD motif, peptide 28 (K16GACYGLPHKFCG, identified via display but with an unknown target), as well as three derivatives of peptide 28: peptide 31 (K16XSXGACYGLPHKFCG), peptide 32 (K16RVRRGACYGLPHKFCG), and peptide 35 (K16RVRRXSXGACYGLPHKFCG). The sequence highlighted in red indicates a cleavable linker, whilst the green sequence indicates a small, hydrophobic linker (page 68).
Table 3.1 shows formulation parameters used in lipid-peptide nanocomplex optimisation for mRNA delivery.
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Different parameters that may influence transfection efficiency were studied in order to optimise the lipid-peptide nanocomplex. The characteristics that seem to be associated with good transfection efficiency were the presence of the phospholipid DOPE and peptide 35. The fusogenic effect of DOPE is well known and these results are in agreement with other reports showing that the addition of DOPE in lipid nanoparticles enhances transfection. Peptides with a cleavable linker, particularly peptide 35 gave more favourable levels of transfection. This is in line with results seen in lipid-peptide vectors used for plasmid DNA and siRNA delivery where the incorporation of RVRR linkers led to better transfection. The addition of cholesterol to the formulation led to an increase in transfection efficiency, with the optimal molar concentration of cholesterol for mRNA delivery determined to be 30%. The improvement in transfection efficiency seen with cholesterol-complexes seemed to be a result of increased protein expression within transfected cells rather than a result of an increase in the percentage of cells transfected (page 122).
The particle sizes of the optimal lipid-peptide formulation (C14-DOPE-30% cholesterol-35), measured by dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) were first compared (Figure 4-1). The particles were small and monodisperse, with mean sizes of 133 ± 2.3 nm and 97 ± 9.6 nm as measured by DLS and NTA respectively (Figure 4-1 and Table 4-2) (page 133).
On the basis of the characterisation studies, we can propose models for the mRNA loaded lipid-peptide nanocomplex. The peptide component tightly packages the mRNA, forming condensed particles where the mRNA is shielded, as shown by the quenching of Ribogreen fluorescence when the complex self-assembles (Figure 4-2). This condensed particle is clearly visualised in TEM images (Figure 4-4 and Figure 4-5). Both the TEM and AFM images show the presence of a component localised on the surface of the particles. Additionally, the TEM images show a ring (thickness ~ 5 nm) surrounding the particles. The SAXS data revealed the lipid bilayer to have a size of 45 Å (4.5 nm) which corroborates the suggestion that the rings visualised by TEM are the lipid bilayer. Within the AFM image, this components seems quite fibrous indicating that at the surface there is either peptide and or mRNA (or both). Surface charge measurements (Table 4-2) show that the liposomes alone are positively charged, but become negative upon the addition of mRNA. This suggests that the mRNA associates at the surface of the liposomes during the self-assembling process. When increasing amounts of liposome are added the positive charge is restored which implies that excess lipids may rearrange on the surface, possibly forming a multi-lamellar structure such as that depicted in Figure 4-11a. The lack of sharp, definitive peaks within the DSC data alludes to the structure of the complexes being quite disordered as depicted in the schematic diagram in Figure 4-11b, although these data should be interpreted with caution due to limitations in sample concentration. Other lipid peptide systems used for DNA delivery have described the nanoparticle structure as disordered, and hypothesised the lipids to be coating the surface with no particular order not forming monolayer, bilayer or multilamellar structures. Without clear, conclusive structural analysis data it is difficult to deduce the exact molecular arrangements and either structure cannot be ruled out (page 151-152).
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Figure 4-11 shows a schematic diagrams showing possible structures for the lipid-peptide nanocomplex. Structures could either be a) ordered with defined lipid arrangements or b) disordered with a random lipid and peptide arrangement.
Both siRNA and mRNA nanocomplexes are taught (page 170). PDI of 0.19 is shown in Table 4.4.
In general the properties of mRNA are perhaps best suited to applications in cancer vaccinations. The ability to modulate the in vivo degradation time of mRNA through chemical modifications as well as the transient nature of the molecule is an attractive 36 37 feature for vaccines where insufficient immune response will not yield therapeutic action but excess immune stimulation can be detrimental to the patient (page 36).
With regard to the amended limitation wherein the nanoparticle does not comprise a liposome, it is submitted that while the lipid-peptide nanoparticles were originally prepared from liposomes, resulting multilamellar or disordered structures were prepared upon addition of mRNA according to pages 151 and Figure 4-11.
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.
Claim(s) 15-21, 24, 26-29 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Grant-Serroukh (Lipid Nanoparticles for mRNA mediated Cancer Therapy, 2018, Thesis, University College London) in view of Verovskaya et al. (US 2024/0000966).
Grant-Serroukh teaches lipid-peptide nanoparticles for the delivery of both pDNA and siRNA, as set forth above.
Grant-Serroukh does not specifically recite a PEG lipid or polydispersity of the nanoparticles of 0.15.
Verovskaya teaches a lipid composition is described, which includes at least one ionizable lipid comprising a charge (N), at least one peptide, and a nucleic acid molecule comprising a charge (P). In aspects, methods are provided for delivery of a payload to an immune cell using a lipid composition comprising at least one ionizable lipid, at least one endosomal release peptide, and a payload (abstract).
In one embodiment, delivering a payload to a spleen cell in a subject, including: (i) providing a lipid complex comprising at least one ionizable lipid, at least one peptide where the peptide comprises LLELLESL (SEQ ID NO: 1), and at least one payload molecule; and (ii) administering the lipid complex to a subject is taught. In some embodiments, the lipid complex further comprises at least one neutral lipid (paragraph 0005).
In some embodiments the payload comprises an RNA molecule, including mRNA (paragraph 0010).
In some embodiments, the nucleic acid payload of the lipid complex compositions is a single-stranded molecule. In some embodiments, the payload may include donor DNA. In still other embodiments, the DNA payload may be a plasmid DNA or linear DNA (paragraph 0139).
In some embodiments, the ionizable lipid includes a lipid according to Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) (paragraph 0015).
The ionizable lipid may be selected from, for example, the group consisting of DOTMA, DOTAP, etc. (paragraph 0164).
In some embodiments, the at least one neutral lipid includes cholesterol, sterol, dioleoylphosphatidylethanolamine (DOPE), etc. (paragraph 0016).
In other embodiments, the lipid complex includes liposomes. In some embodiments, the lipid complex includes lipid nanoparticles. In some embodiments, the lipid complex includes a lipid nanoparticle population, wherein the nanoparticle has a diameter from about 20 nm to about 1 μm (paragraph 0017).
Exemplary transfection enhancing peptides for use in the lipid composition are provided herein. In some embodiments, such peptides comprise the sequence LLELLESL (SEQ ID NO: 1) and optionally comprise a polycationic nucleic acid binding moiety (paragraph 0145).
As described herein, suitable polycationic nucleic acid binding moieties include without limitation polyamines and polybasic peptides containing, for example, poly-arginine, poly-lysine, poly-histidine, and/or poly-ornithine sequences with, for example, lengths of about 8 to about 20 residues (paragraph 0146).
In some embodiments, in addition to the peptide comprising one or more of SEQ ID NO: 1-5 or to the peptide that has at least 80% sequence identity to any one of SEQ ID NO: 6-24, formulations may include additional transfection enhancing agents such as a cell surface ligand peptide and/or a nuclear localization agent such as a nuclear receptor ligand peptide (paragraph 0154).
In other embodiments, any of SEQ ID NO: 28, 30, 32, 34, and 36 may further comprise lysine residues (e.g., K2, K4, K6, K8, K10, K12, K14, K16, K18, K20) at the N or C terminus (paragraph 0156).
The lipid compositions provided herein can also include a stabilizing agent, such as a stabilizing lipid. Stabilizing lipids can be neutral lipids, or they can be charged. Stabilizing lipids that can advantageously be used in the formulations provided herein include, but are not limited to, polyethylene glycol (PEG)-modified lipids (paragraph 0283)
The lipid complex compositions provided herein may be relatively homogenous. A polydispersity index may be used to indicate the homogeneity of a nanoparticle composition, e.g., the particle size distribution of the lipid nanoparticles. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A lipid nanoparticle may have a polydispersity index from about 0 to about 0.25 (paragraph 0134).
As demonstrated herein, use of the peptide combined with the ionizable lipid in the provided composition results in effective and efficient delivery/uptake of the payload nucleic acids, even with the low levels of lipid and/or nucleic acid in the compositions. This improved efficiency allows for administration of less of a formulation (for example, lower mRNA and/or lipid levels) to achieve the therapeutic effect, for example, a specific immune response (paragraph 0063).
The humoral and cellular immunogenicity of an antigen administered via an antigen-encoding mRNA formulated with lipid compositions was evaluated to demonstrate potential for such formulations for vaccine applications (paragraph 0330).
It would have been obvious to one of ordinary skill in the art at the time of the invention to incorporate a PEG-modified lipid in the lipid compositions taught by Grant-Serroukh when the teaching of Grant-Serroukh is taken in view of Verovskaya. Each of Grant-Serroukh and Verovskaya are directed to lipid nanoparticles for use in nucleic acid delivery systems. One would have been motivated to incorporate a PEG-modified lipid in the nanoparticles because Verovskaya teaches that PEG-modified lipids act as a
stabilizing agent in a lipid complex, see paragraph 0283, such that stabilizing lipids that can advantageously be used in the formulations include, but are not limited to, polyethylene glycol (PEG)-modified lipids. It would have been further obvious to one of ordinary skill in the art to provide homogeneous nanoparticles because Verovskaya teaches that lipid complex compositions may be relatively homogenous, a polydispersity index generally indicates a narrow particle size distribution, and a lipid nanoparticle may have a polydispersity index from about 0 to about 0.25 (paragraph 0134).
Claim(s) 15-22, 24, 26-29, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Grant-Serroukh (Lipid Nanoparticles for mRNA mediated Cancer Therapy, 2018, Thesis, University College London), in view of Verovskaya et al. (US 2024/0000966), in further view of Hoffmann et al. (US 2022/0402977).
The rejection over Grant-Serroukh in view of Verovskaya is applied as above.
With regard to claim 22, Grant-Serroukh and Verovskaya do not specifically recite closed linear DNA.
Hoffmann teaches compositions (e.g., vaccine compositions). In some embodiments, the composition comprises: a nucleic acid composition comprising a polynucleotide encoding a fusion protein, wherein the fusion protein comprises an antigenic polypeptide (AP) and an endosomal sorting complex required for transport (ESCRT)-recruiting domain (ERD), and wherein a plurality of fusion proteins are capable of self-assembling into an enveloped nanoparticle (ENP) secreted from a cell in which the fusion proteins are expressed, thereby generating a population of ENPs (paragraph 007).
In some embodiments, the nucleic acid composition is complexed or associated with one or more lipids or lipid-based carriers, thereby forming liposomes, LNPs (paragraph 0031).
The one or more vectors can be a DNA vaccine. The DNA vaccine can be a plasmid-based DNA vaccine, a minicircle-based DNA vaccine, a bacmid-based DNA vaccine, a minigene-based DNA vaccine, a ministring DNA (linear covalently closed DNA vector) vaccine, a closed-ended linear duplex DNA (CELiD or ceDNA) vaccine, etc. (paragraph 0033).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide closed linear DNA as the nucleic acid in the nanoparticle complexes taught by Grant-Serroukh and Verovskaya when the teachings of Grant-Serroukh and Verovskaya are taken in view of Hoffmann. While Grant-Serroukh and Verovskaya teach that DNA and linear DNA may be used as the nucleic acid component in the liposome complexes, respectively, closed linear DNA is not specifically recited. However one of ordinary skill in the art would have been motivated to provide ceDNA, with a reasonable expectation of success, because Hoffmann teaches that ceDNA is known to be a suitable linear DNA form which is suitable for use in a nucleic-acid based vaccine composition.
Conclusion
No claims are allowed at this time.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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