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 .
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on 1/12/2026 is acknowledged. The traversal is on the ground(s) that Groups I-Ill relate to a single general inventive concept under PCT Rule 13.1. Applicant argues that claim 15 is amended to specify that "the cationic polymer comprises oligolysine comprising 16 lysine residues" and that Hu et al. does not teach or suggest that the nanoparticle may comprise a cationic polymer that comprises oligolysine comprising 16 lysine residues (i.e., K16). This is not found persuasive because lack of unity can still be shown in view of Grant-Serroukh et al. (US 2021/0170046), which teaches components a-e of the amended claims. For example, a liposome is taught for the non-viral delivery of a nucleic acid to a cell, comprising a cationic lipid, a phospholipid and a peptide and, optionally, cholesterol, wherein: a) the cationic lipid is selected from DTDTMA (ditetradecyl trimethyl ammonium), DHDTMA (dihexadecyl trimethyl ammonium) or DOTMA (2,3-dioleyloxypropyl-1-trimentyl ammonium); and b) the phospholipid is DOPE (phosphatidyl ethanolamine or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine); and [0018] c) the peptide has the amino acid sequence K16RVRRXSXGACYGLPHKFCG
The requirement is still deemed proper and is therefore made FINAL.
Status of Claims
Claims 15-22, 24 and 26-33 are pending, of which claims 30 and 33 are withdrawn from consideration at this time as being directed to a non-elected invention. Claims 15-22, 24, 26-29, 31 and 32 encompass the elected invention and are examined herein on the merits for patentability.
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) 15-21, 24 and 26-29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Grant-Serroukh et al. (US 2021/0170046).
Grant-Serroukh discloses a liposome comprising a cationic lipid, a phospholipid and a peptide and optionally consisting of from 20 to 50% by molarity cholesterol, based on the total amount of lipids, for use in non-viral gene delivery systems, for example, in the formation of lipopolyplex transfection vectors for the delivery of mRNA to cells.
In a first aspect, the present invention provides a liposome for the non-viral delivery of a nucleic acid to a cell, comprising a cationic lipid, a phospholipid and a peptide and, optionally, cholesterol, wherein: a) the cationic lipid is selected from DTDTMA (ditetradecyl trimethyl ammonium), DHDTMA (dihexadecyl trimethyl ammonium) or DOTMA (2,3-dioleyloxypropyl-1-trimentyl ammonium); and b) the phospholipid is DOPE (phosphatidyl ethanolamine or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine); and c) the peptide has the amino acid sequence K16RVRRXSXGACYGLPHKFCG (SEQ ID NO: 2) (paragraph 0015).
The peptide A is a polycationic nucleic acid-binding component (paragraph 0049).
The polycationic nucleic acid-binding component typically comprises anoligolysine having from 3 to 35, for example, from 2 to 25, for example, form 10 to 20 lysine residues, for example, from 13 to 19, for example, from 14 to 18, for example, from 15 to 17 residues, for example, 16 residues i.e. [K]16, “K” denoting lysine (paragraph 0054).
The nucleic acid component (d) may be any suitable nucleic acid. It may be DNA or RNA or a chemically modified nucleic acid mimetic, for example a PNA molecule. It may, for example, code for a protein that has a utility in the target cell. Advantageously, the nucleic acid is cellular messenger RNA (mRNA) (paragraph 0078).
The transfection complex is suitable for use as a medicament or a vaccine (paragraph 0073).
The lipid-peptide nanoparticles of the invention can deliver mRNA in vivo without substantial interference from serum proteins and other biological challenges (paragraph 0139).
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.
Claim(s) 15-21, 24, 26-29, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Grant-Serroukh et al. (US 2021/0170046) in view of Verovskaya et al. (US 2024/0000966).
Grant-Serroukh teaches a liposome comprising a cationic lipid, a phospholipid and a peptide and optionally consisting of from 20 to 50% by molarity cholesterol, based on the total amount of lipids, for use in non-viral gene delivery systems, for example, in the formation of lipopolyplex transfection vectors for the delivery of mRNA to cells.
In a first aspect, the present invention provides a liposome for the non-viral delivery of a nucleic acid to a cell, comprising a cationic lipid, a phospholipid and a peptide and, optionally, cholesterol, wherein: a) the cationic lipid is selected from DTDTMA (ditetradecyl trimethyl ammonium), DHDTMA (dihexadecyl trimethyl ammonium) or DOTMA (2,3-dioleyloxypropyl-1-trimentyl ammonium); and b) the phospholipid is DOPE (phosphatidyl ethanolamine or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine); and c) the peptide has the amino acid sequence K16RVRRXSXGACYGLPHKFCG (SEQ ID NO: 2) (paragraph 0015).
The peptide A is a polycationic nucleic acid-binding component (paragraph 0049).
The polycationic nucleic acid-binding component typically comprises anoligolysine having from 3 to 35, for example, from 2 to 25, for example, form 10 to 20 lysine residues, for example, from 13 to 19, for example, from 14 to 18, for example, from 15 to 17 residues, for example, 16 residues i.e. [K]16, “K” denoting lysine (paragraph 0054).
The nucleic acid component (d) may be any suitable nucleic acid. It may be DNA or RNA or a chemically modified nucleic acid mimetic, for example a PNA molecule. It may, for example, code for a protein that has a utility in the target cell. Advantageously, the nucleic acid is cellular messenger RNA (mRNA) (paragraph 0078).
The transfection complex is suitable for use as a medicament or a vaccine (paragraph 0073).
The lipid-peptide nanoparticles of the invention can deliver mRNA in vivo without substantial interference from serum proteins and other biological challenges (paragraph 0139).
Grant-Serroukh does not specifically recite a PEG lipid or the polydispersity of the nanoparticles.
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 et al. (US 2021/0170046) 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 liposome 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, including in liposome form.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618