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 .
Status of Application
Applicants' arguments/remarks filed 04/14/2026 are acknowledged. Claims 2-3, 11, 17, 23, 27-28, 31-33, 35-36 and 47 are currently amended. Claims 1 and 29-30 are newly canceled. Claim 48-49 are newly added. Claims 2-3, 11, 17, 23, 27-28, 31-33, 35-36, 47 and 48-49 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment, filed 04/14/2026 and with respect to Applicant’s arguments/remarks:
the 35 U.S.C. § 112(b) rejection of Claims 31, 32 and 33 has been withdrawn in view of the amendments;
the 35 U.S.C. § 102(a)(1) rejection of Claims 1, 2, 3, 11, 17, 28 and 29 by Rohloff et al. or Eliaz et al. has been withdrawn in view of the cancelation of claim 1 and the amendments.
the 35 U.S.C. § 102(a)(2) rejection of Claims 1, 2 3, 11, 28 and 29 by Dane has been withdrawn in view of the cancelation of claim 1 and the amendments.
the 35 U.S.C. § 102(a)(2) rejection of Claims 1, 2, 3, 11 17, 27-28 and 29-32 by Navarro y Garcia et al. has been withdrawn in view of the cancelation of claim 1 and the amendments.
the 35 U.S.C. § 102(a)(2) rejection of Claims 1, 2, 3, 28, 29, 30, 32, 33 and 36 by Nel et al. has been withdrawn in view of the cancelation of claim 1 and the amendments.
the 35 U.S.C. § 102(a)(2) rejection of Claims 1, 2, 3, 23, 28, 29 and 32 by Robillard et al. has been withdrawn in view of the cancelation of claim 1 and the amendments.
the 35 U.S.C. § 102(a)(2) rejection of Claims 1, 2, 3, 23, 28, 29, 30, 32, 33, 35 and 36 by Navarro et al. has been withdrawn in view of the cancelation of claim 1 and the amendments.
the 35 U.S.C. § 103 rejection of Claims 35 and 47 over Dane and Smith et al. has been withdrawn in view of the cancellation of claim 1 and the amendments;
Modified Rejections
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.
(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.
Claim(s) 2, 3, 28, 32, 33 and 36 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Nel et al. (US 20250195639 A1).
Claims 2 and 28
Nel et al. teach nanoparticles (Abs) comprising one or more cationic lipids selected from the group consisting of dilinoleylmethyl-4 dimethyl aminobutyrate (DLin-MC3-DMA) and 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) (0233); 1.25% Pluronic L121 (PEO10PPO68.3PEO10) is included in the nanoparticles. (0539).
Nanoparticles for the delivery of one or more nucleic acid(s) (e.g., DNA or mRNA. (0488).
N/P is 4:1, Table 41. (0547).
With regard to claim 3,
Nel et al. teach a helper lipid selected from 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) (0235); a structural lipid cholesterol (0236); and a PEG-lipid (0237). The immunogenic nanoparticle according to any one of embodiments 221-226, wherein said lipidic nanoparticle comprises an ionizable (e.g., a cationic) lipid, a helper lipid, a PEG-lipid, and cholesterol. (0238). Embodiment 228: The immunogenic nanoparticle of embodiment 227, wherein said lipidic nanoparticle comprises cholesterol, distearoylphosphatidylcholine (DSPC), PEG-Lipid and DODAP. (0239). DODAP is an ionizable lipid.
With regard to claims 32-33 and 36,
Table 40 shows the hydrodynamic size, PDI, Zeta potential and encapsulation efficiency of illustrative mRNA-LNPs. (0506).
PNG
media_image1.png
131
392
media_image1.png
Greyscale
Claim(s) 2-3, 23, 28, 32-33, 35-36 and 48-49 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Navarro et al. (WO 2021123332 A1).
Claim(s) 2-3, 23, 28 and 48-49
Navarro et al. teach Lipid Nanoparticles for Delivery of Nucleic Acids. (Title). The application relates to cationic lipids and to compositions comprising said cationic lipids. (Abs). Lipid nanoparticles formed from cationic lipids with other lipid components, such as neutral lipids, cholesterol, PEGylated lipids, and oligonucleotides have been used to block degradation of the RNAs in plasma and facilitate the cellular uptake of the oligonucleotides. (pg. 2, lines 22-23). The hydrophilic polymer moiety P in the polymer conjugated lipid according to formula (II) may be a polyethylene glycol ("PEG") moiety. (pg. 55, lines 42-43). In another embodiment, the hydrophilic polymer moiety P in the polymer conjugated lipid may also be a substantially hydrophilic polymer which is different from the above describes hydrophilic polymer moieties, i.e. the hydrophilic polymer moiety P in the polymer conjugated lipid may be based on poly(propylene oxide) PPO. (pg. 56, lines 6-8). PPO at low molecular weight <700 g/mol is hydrophilic. The polymer conjugated lipid in the composition or in the lipid nanoparticles may be about 0.1mol%-7mol%. (pg. 64, lines 15-23).
Table F: Formulations incl. mol-percentages for excipients of preferred compositions of the invention (table split into two tabulars) (pg. 70).
PNG
media_image2.png
113
271
media_image2.png
Greyscale
PNG
media_image3.png
26
264
media_image3.png
Greyscale
PNG
media_image4.png
27
270
media_image4.png
Greyscale
the composition comprises an mRNA compound, (pg. 102, line 4), RNA or DNA sequences, (pg. 104, lines 5-14).
The lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. (pg. 76, lines 16-21). Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5. (pg. 76, lines 26-30).
With regard to claim 32,
Lipid nanoparticle particle diameter size was from about 90 nm to about 140 nm as determined by quasi-elastic light scattering using a Malvern Zetasizer Nano (Malvern Instruments Ltd.; Malvern, UK). (pg. 167, lines 22-24).
With regard to claim 33,
PNG
media_image5.png
173
607
media_image5.png
Greyscale
(pg. 177, lines 15-18).
With regard to claim 35,
Lipid to mRNA mol ratio) preferably is 17.5 and the total lipid/mRNA mass ratio preferably is 40. (pg. 168, lines 7-8).
With regard to claim 36,
Encapsulation Efficiency (EE%) are mostly 54-96%, except 3 samples are lower than 50%. (Table Ex-4, pg. 169-170).
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 non-obviousness.
Claim(s) 2, 3, 11, 17 and 28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated over Rohloff et al. (AU 2004291162 B2) in view of Navarro et al. (WO 2021123332 A1).
Claim(s) 2, 3, 11, 17, 28
Rohloff et al. teach a liquid composition in an osmotic drug delivery system and a dosage form in an osmotic drug delivery system is disclosed comprising an amphiphilic molecule, a non-aqueous liquid solvent, and a pharmaceutically active agent. (Abs). The bioadhesive compositions can be in form of, e.g., a spray, a solution, a dispersion, a suspension, an emulsion, powders, gels including hydrogels, pastes, ointments, creams, drenches, delivery devices, suppositories, enemas, implants, aerosols, microcapsules, microspheres, nanoparticles, liposomes. (0103). It comprises block copolymers surfactants compound of formula I like Pluronic® surfactant F-127 (PEO100PPO65PEO100) (0014) or other Pluronic®: PEOx-PPOy-PEOx like PLURONIC L92 (PEO14PPO50PEO14) PLURONIC L121 (PEO10PPO68PEO10), PLURONIC L81 (PEO6PPO42PEO6), or formula II like Pluronic®-R (PPOyPEOxPPOy) like PLURONIC® 31R1 surfactant (PPO26PEO8PPO26), PLURONIC® l7R4 surfactant (PPO14PEO24PPO14) (0079), cationic lipid (0007), structural lipids like DSPC and PEG-lipid (0014) and structural lipid like cholesterol (0106, 0109).
Certain pharmaceutically acceptable excipients can be added in much larger concentrations without having any substantially negative influence on the biopharmaceutical properties of the composition. Thus, the concentration of such excipients can be at least about 5%, 8%, 9%, 10%, 15% or 20% by weight. (0097).
The pharmaceutically active agent includes, but is not limited to a protein, peptide, small molecule drug, lipid dmg ornμcleic acid dmg (e.g., DNA, RNA, antisense, ribozyme, DNAzyme. (0092).
Rohloff et al. to not teach a nucleic acid wherein the nucleic acid comprises a DNA or an RNA:
wherein the N/P ratio of the LNP is from 0.1 to 4.
Navarro et al. teach The lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. (pg. 76, lines 16-21). Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5. (pg. 76, lines 26-30).
It would have been obvious for one of skill in the art before the effective filing date of the invention to prepare lipid nanoparticle of lipids in combination with polymer, taught by Rohloff et al. and the N/P ratios can be in the range of about 1 to about 50, taught by Navarro et al. since they have proven it would be possible to do so.
Claim(s) 2, 3, 11, 17, 28 is/are rejected under 35 U.S.C. 102(a)(2) as being unpatentable over Eliaz et al. (CN 1897918 A) in view of Navarro et al. (WO 2021123332 A1).
Claim(s) 2, 3, 11, 17, 28
Eliaz et al. teach The liquid medicaments combination and dosage form during the process of infiltrative medicaments transmitting. It includes amphiphilic molecule, non-aqueous liquid flux and pharmic activator. (Abs). The bio-adhesive composition may be as follows: for example, spray, solution, dispersion, suspension, emulsion, powder, a gel, paste, ointment, cream, drenches, delivery device of the hydrogels, suppositories, enemas, implants, aerosols, microcapsules, microspheres, nanoparticles, liposomes. (0103). The composition includes cationic lipid (0007); helper lipid like DSPC, PEG-lipid (0014); structural lipid, cholesterol (0106); and compound of formula I: PEOxPPOyPEOx like PLURONIC L92 (PEO14PPO50PEO14) PLURONIC L121 (PEO10PPO68PEO10), PLURONIC L81 (PEO6PPO42PEO6), or formula II like Pluronic®-R (PPOyPEOxPPOy) like PLURONIC® 31R1 surfactant (PPO26PEO8PPO26), PLURONIC® l7R4 surfactant (PPO14PEO24PPO14) (0079)
Certain pharmaceutically acceptable excipients can be added very large concentration, but does not substantially has a negative effect on the biological and pharmaceutical properties of the composition. Therefore, the concentration of the excipient can be at least about 5%, 8%, 9%, 10%, 15%, or 20% by weight. (0097).
In another embodiment, the pharmaceutically active agent is selected from the group consisting
of protein, peptide, small molecule drug, lipid drug or nucleic acid drug (e.g., DNA, RNA, antisense, ribozyme, DNAzyme, etc.). (0016).
Eliaz et al. to not teach a nucleic acid wherein the nucleic acid comprises a DNA or an RNA:
wherein the N/P ratio of the LNP is from 0.1 to 4.
Navarro et al. teach The lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. (pg. 76, lines 16-21). Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5. (pg. 76, lines 26-30).
It would have been obvious for one of skill in the art before the effective filing date of the invention to prepare lipid nanoparticle of lipids in combination with polymer, taught by Eliaz et al. and the N/P ratios can be in the range of about 1 to about 50, taught by Navarro et al. since they have proven it would be possible to do so.
Claim(s) 2, 3, 11 and 28 is/are rejected under 35 U.S.C. 102(a)(2) as being unpatentable over Dane (US 20240425454 A1) in view of Navarro et al. (WO 2021123332 A1).
Claims 2 and 28
Dane teaches cationic and/or ionizable lipid compounds that can be used, in combination with other lipid molecules, to form lipid nanoparticles for delivery of a polynucleotide to a subject. (0001). Polymers like pluronics, comprising Pluronic L121 (PEO10PPO68.3PEO10), 1.25%, are included in the nanoparticles. (0234).
The term “polynucleotide” as used herein refers to a polymer containing at least two deoxyribonucleotides or ribonucleotides in either single- or double-stranded form and includes DNA, RNA, and hybrids thereof. (0045).
Dane do not teach a nucleic acid wherein the nucleic acid comprises a DNA or an RNA:
wherein the N/P ratio of the LNP is from 0.1 to 4.
Navarro et al. teach the lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. (pg. 76, lines 16-21). Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5. (pg. 76, lines 26-30).
It would have been obvious for one of skill in the art before the effective filing date of the invention to prepare lipid nanoparticle of lipids in combination with polymer, taught by Dane and the N/P ratios can be in the range of about 1 to about 50, taught by Navarro et al. since they have proven it would be possible to do so.
With regard to claim 3,
Dane teaches LNPs are commonly formed from ionizable cationic lipids and other lipid components such as neutral lipids, sterols such as cholesterol and PEGylated lipids. (0003). Neutral lipids include DSPC, DOPE. (0043). Cationic and/or ionizable lipid of Formula I or I-A to I-N or II-A to II-N, may be selected from DLin-DMA, DLin-MC3-DMA and DLin-KC2-DMA. (0174). The LNP additionally comprises one or more of a PEG-lipid, a sterol structural lipid and/or a neutral lipid. (0188).
With regard to claim 11,
Dane teaches the lipid component of the LNP formulation comprises about:
25 mol % to about 60 mol % compound of Formula I or I-A to I-N or II-A to II-N,
2 mol % to about 25 mol % phospholipid (neutral lipid),
18.5 mol % to about 60 mol % structural lipid (sterol), and
0.2 mol % to about 10 mol % of PEGylated lipid, provided that the total mol % does not exceed 100%. (0224).
Polymers like pluronics, comprising Pluronic L121 (PEO10PPO68.3PEO10), 1.25%, are included in the nanoparticles. (0234). With 1.25% Pluronic L121, the molar percentages of lipids are not changed much from the ranges above.
Claim(s) 2, 3, 23, 28 and 32 is/are rejected under 35 U.S.C. 102(a)(2) as being unpatentable over Robillard et al. (WO 2014081299 A1) in view of Navarro et al. (WO 2021123332 A1).
Claim(s) 2, 3, 23 and 28,
Robillard et al. teach liposome, (Abs), typically with sizes between about 0.1 to 10 microns, (pg. 93, line 5), which contain cationic lipid (pg. 68, line 2), like DOTAP, DMRIE, DORIE, DOTMA, DC-Choi or a neutral lipid derivatized with polylysine to form a cationic lipid, (pg. 85, lines 11-22) or a pH sensitive or ionizable lipid like DOPE (pg. 79, line 13); PEG-lipid (pg. 79, line 21); cholesterol (pg. 84, line 15); and phospholipids such as phosphatidylcholine (PC), (pg. 82, line 6). Phosphatidylcholine is a zwitterionic or neutral helper lipid. One preferred lipid is
distearoylphosphatidylethanolamine (DSPE), however those of skill in the art will appreciate the wide variety of lipids that fall within this description. (pg. 83, lines 10-13). In one embodiment, each liposome contains an outer liposome surface having a coating of chemically releasable hydrophilic polymer chains MM, and hydrophobic polymers TA on the liposome outer surface. (pg. 67, lines 27-29). The hydrophobic polymer is preferably a chain of polypropylene oxide, (PPO). (pg. 68, line 3). The hydrophobic polymer would constitute 50% x 5%, or 2.5 mole percent, of the surface lipids. (pg. 72, lines 25-26).
In one embodiment, each liposome contains an outer liposome surface having a coating of chemically releasable hydrophilic polymer chains MM, and hydrophobic polymers TA on the liposome outer surface. The polymers TA are initially shielded by the hydrophilic polymer coating MM, then exposed for fusion with the target membrane when the hydrophilic polymer coating is chemically released. (pg. 67, lines 27-32). The hydrophobic polymer is preferably a chain of polypropylene oxide. The polymer chains have a preferred molecular weight of between of between 100-5,000 daltons, more preferably between 500-3,000 daltons. In one preferred
embodiment, the hydrophobic polymer is polypropylene oxide (PPO) having a molecular weight between 500-3,000 daltons. (pg. 68, lines 1-9).
With reference to Scheme 2, the liposome is composed of vesicle-forming lipids, such as lipids A, which each include hydrophilic head groups, and (pg. 69, lines 31-32) typically two diacyl hydrophobic lipid chains. Preferred diacyl-chain lipids for use in the present invention include diacyl glycerol, phosphatidyl ethanolamine (PE), diacylaminopropanediols, such as
disteroylaminopropanediol (DS), and phosphatidylglycerol (PG). These lipids are preferred for use as the vesicle-forming lipid A, the major liposome component, and for use in the polymer-lipid diblock conjugates (D) and lipids with directly linked hydrophilic polymer chains (B), which together are preferably included in the liposome outer layer at a mole ratio between about 1-20 mol%. (pg. 70, lines 1-9). Hydrophobic chain TA is bound at its distal end to hydrophilic
polymer chain MM. (pg. 71, lines 1-2).
PNG
media_image6.png
375
579
media_image6.png
Greyscale
The percent of hydrophobic chains, i.e., the percentage of diblock lipid conjugates in the liposomes, typically ranges between about 5-100% of the total surface lipids containing conjugated hydrophilic polymers. Thus, for example, in a liposome formulation containing 5 mole percent hydrophilic polymer liposome-surface lipids, and 50% diblock lipid conjugates, the
hydrophobic polymer would constitute 50% x 5% = 2.5 mole%, of the surface lipids. (pg. 72, lines 20-26).
With reference to Scheme 2, preferred formulations are those with
lipid A: 0.5 - 10 mol%
DOPE: 50-100 mol%, (a pH sensitive or ionizable lipid and a helper lipid)
Cholesterol (Choi) and/or cholesterolhemisuccinate (CHEMS): total 0-50 mol%. (pg. 107, lines 6-8 and pg. 108, line 1). (Lipid A which each include hydrophilic head groups, typically two diacyl hydrophobic lipid chains. Preferred diacyl-chain lipids for use in the present invention include diacyl glycerol, phosphatidyl ethanolamine (PE), diacylaminopropanediols, such as disteroylaminopropanediol (DS), and phosphatidylglycerol (PG). These lipids are preferred for use as the vesicle-forming. (pg. 69 line 31-32-pg. 70, lines 1-6), and Cholesteryl hemisuccinate (CHEMS) is an ionizable lipid. And with hydrophobic polymer PPO, 2.5 mol%, helper lipids could be reduced to 48mol%. Lipid A includes phosphatidyl ethanolamine (PE), diacylaminopropanediols, such as disteroylaminopropanediol (DS), and phosphatidylglycerol (PG), (pg. 70, line 3-4), are ionizable lipids.
Particular preferred formulations include: DOPE/CHEMS/DSPE-TCO-mPEG 60:40:3 molar ratio, (pg. 108, line 9), in which the total mols is 103 moles and DOPE/CHEMS are both ionizable lipids, and CHEMS could include Cholesterol.
The invention pertains to reactive (activatable) liposomes, and particularly to liposomal compositions designed for improved target delivery of an entrapped agent. (pg. 1, lines 9-11). Targeting agents include DNA, RNA, PNA and LNA. (pg. 87, lines 28-29).
Robillard do not teach a nucleic acid wherein the nucleic acid comprises a DNA or an RNA:
wherein the N/P ratio of the LNP is from 0.1 to 4.
Navarro et al. teach the lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. (pg. 76, lines 16-21). Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5. (pg. 76, lines 26-30).
It would have been obvious for one of skill in the art before the effective filing date of the invention to prepare lipid nanoparticle of lipids in combination with polymer, taught by Robillard et al. and the N/P ratios can be in the range of about 1 to about 50, taught by Navarro et al. since they have proven it would be possible to do so.
With regard to claim 32,
The liposomes of the invention are preferably prepared to have substantially homogeneous sizes in a selected size range, typically between about 0.01 to 0.5 microns, more preferably between 0.03-0.40 microns. (pg. 94, lines 26-29).
Claim(s) 2, 3, 11, 17, 27-28 and 31-32, is/are rejected under 35 U.S.C. 102(a)(2) as being unpatentable over Navarro y Garcia et al. (US 20230136944 A1) in view of Navarro et al. (WO 2021123332 A1).
Claim(s) 3, 27, 28 and 31
Navarro y Garcia et al. teach DNA/RNA molecule, or a complex thereof with at least one nanoparticle. (Abs). Liposome comprises or consists of at least one cationic lipid such as DOTAP, DOTMA, or DMRIE; DOGS, DC-Chol or BGTC. Liposome may also comprise a helper lipid DOPE or cholesterol. Said liposome may comprise at least 2, 3, 4, 5 lipids such as described above: a DOTMA/DOPE or DOTAP/cholesterol liposome. Optionally, said liposome may also comprise at least one PEG-lipid. Liposomes also containing at least one PEG are liposomes composed of DODAC, DOPE and PEG ceramide conjugates; PEG-C-DMA, 1,2-dilinoleylloxy-N-N-dimethyl-3-aminopropane (DLin DMA), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol in a ratio of 2:40:10:48 mole percent; liposomes composed of β-L-arginyl-2,3-L-diaminopropionic acid-N-palmityl-N-oleyl-amide trihydrochloride, 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (DphyPE) and the PEGylated lipid DSPE-PEG; liposomes composed of phosphatidylcholine (soybean, hydrogenated) (HSPC), cholesterol, DSPE-PEG2000 and DOTAP, (0051). A helper lipid is preferred DOPE. (0176). Surfactants comprise Pluronic® F68, F127, L64, L61 (PEO-PPO-PEO) or Pluronic®-R 10R4, 17R2, 17R4, 25R2 or 25R4 (PPO-PEO-PPO) (0213).
The HLB values of L61 and P85 are less than 18.
The quantities of lipid nanoparticles were adjusted to maintain a constant N/P ratio with N/P=36 (N: DOTAP/DOPE amine group; P: phosphate group of the corresponding nucleic acid). (0313).
PNG
media_image7.png
178
711
media_image7.png
Greyscale
PNG
media_image8.png
384
579
media_image8.png
Greyscale
PNG
media_image9.png
323
460
media_image9.png
Greyscale
PNG
media_image10.png
492
678
media_image10.png
Greyscale
Navarro y Garcia et al. do not teach a nucleic acid vvherein the nucleic acid comprises a DNA or an RNA, wherein the N/P ratio of the LNP is from 0.1 to 4.
Navarro et al. teach The lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. (pg. 76, lines 16-21). Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5. (pg. 76, lines 26-30).
It would have been obvious for one of skill in the art before the effective filing date of the invention to prepare lipid nanoparticle of lipids in combination with polymer like (PEOx-PPOv-PEOz), taught by Navarro y Garcia et al. and the N/P ratios can be in the range of about 1 to about 50, taught by Navarro et al. since they have proven it would be possible to do so.
With regard to claims 2, 11 and 17,
Navarro y Garcia et al. teach The nanoemulsion comprises 10-55 mole % of co-surfactant relative to the whole (amphiphilic lipid/cationic surfactant (lipid)/co-surfactant/optional helper lipid). (0206 & 0215).
Navarro y Garcia et al. teach The nanoemulsion comprises 15 to 70 mol% of at least one cationic surfactant (lipid) relative to the whole (amphiphilic lipid/cationic surfactant (lipid)/co-surfactant/optional helper lipid). (0173). Phospholipids are preferred amphiphilic lipids, (0184), such as DSPC, DOPE, which are helper lipids.
Navarro y Garcia et al. teach liposome with molar ratio of PEG-lipid: cationic lipid DLin DMA:helper lipid DSPC:cholesterol 2:40:10:48. (0051).
To include 10-55 mole % of co-surfactant, Pluronic®: for example:
20% of Pluronic®, then the mol% of Pluronic®:PEG-lipid:cationic lipid DLin DMA:helper lipid DSPC:cholesterol are: 20:1.6:32:8:48 to 2:30:10:38.4.
With regard to claim 32,
The droplets of the nanoemulsion before complexing with the htiRNA hybrid(s) (non-complexed droplets) generally have a diameter of between 20 and 200 nm. This diameter can particularly be measured by Dynamic Light Scattering (DLS) on ZetaSizer apparatus, Malvern. (0251).
Claim(s) 1 and 35 and 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nel et al. (US 20250195639 A1) or Navarro et al. (WO 2021123332 A1) in view of Smith et al. (US 20200069599A1).
The teachings of Nel et al. or Navarro et al. are described in claim 28 above.
Claim 35,
Nel et al. or Navarro et al. do not teach the w/w ratio of the lipid component to the nucleic acid is from about 2:1 to about 50:1.
Smith et al. teach weight of nucleic acid and of lipid components in the table below:
10.9 +5.15 +2.7+1.35 = 20.1 mg/1mg of mRNA.
It would have been obvious for one of skill in the art before the effective filing date of the invention to prepare lipid nanoparticle of lipids in combination with polymer taught by Nel et al. or Navarro et al., to have the w/w ratio of the lipid component to the nucleic acid is 20:1, taught by Dane, since they have proven this would be a good ratio for LNP to encapsulate nucleic acid.
PNG
media_image11.png
269
376
media_image11.png
Greyscale
Claim 47,
Nel et al. or Navarro et al. do not teach weight percentage PEO of less than 20% when the polymer component comprises a compound of formula I;
Smith et al. teach the amphiphilic polymer , or the first , second , third , or fourth amphiphilic polymer is present at a concentration ranging between about 0.1 % w/v and about 3 % w/v , or between about 0.1 % w/w and about 3 % w/w. (0075). For Pluronic L121: MW 4400, since total Pluronic L121 (PEO10PPO68.3PEO10) has less than 3% w/w in total lipid, the PEO alone has less than 20% w/w in total lipid composition. Similarly, the second LNP formulation has substantially no increase in LNP mean size as compared to the first LNP formulation . For example , the second LNP formulation has an increase in LNP mean size of about 20 % or less (e.g. , about 15 % , about 10 % , about 5 % or less ) as compared to the first LNP formulation, then less than 20% PEO in the LNP formulation.
It would have been obvious for one of skill in the art before the effective filing date of the invention to prepare lipid nanoparticle of lipids in combination with polymer taught by Nel et al. or Navarro et al. and the weight percentage of polymer is 20% or less in LNP and the weight percentage of PEO is less than 20% in LNP, taught by Smith et al. since they have proven it would be possible to do so.
Response to Arguments
Rejections Under 35 U.S.C. § 102
Applicant argues that Navarro or Nel does not teach NIP ratio of the LNP is from 0.1 to 4 as recited in amended claim 28.
Applicant's arguments have been fully considered but they are not persuasive since Navarro et al. teach the lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5 that Applicant’s claim range overlaps entirely inside a broader range disclosed in the prior art Navarro, so a person of ordinary skill in the art would find it routine to select or "optimize" a value within that overlapping space. And Nel teaches N/P is 4:1. a single specific value 4 matching the applicant’s claim limitation, so the claim is anticipated.
Applicant argues that Rohloff, Eliaz, Dane and Robillard do not teach NIP ratio of the LNP is from 0.1 to 4" as recited in amended claim 28.
Applicant's arguments have been fully considered but they are persuasive so the 102 rejection is modified to 103 rejection, in which Navarro et al. teach the lipid nanoparticles comprise the mRNA compound at an amount such as to achieve a lipid to mRNA weight ratio in the range of from about 4 to about 8. (pg. 76, lines 16-21). Further, the amount of the cationic lipid may be selected taking the amount of the nucleic acid cargo such as the mRNA compound into account. In one embodiment, the N/P ratio can be in the range of about 1 to about 50. In another embodiment, the range is about 1 to about 20, about 1 to about 10, about 1 to about 5. (pg. 76, lines 26-30). As explained above that Applicant’s claim range overlaps entirely inside a broader range disclosed in the prior art Navarro, so a person of ordinary skill in the art would find it routine to select or "optimize" a value within that overlapping space.
Rejections under 35 U.S.C. §103
Applicant argues that Dane and Smith, either alone or in combination, fail to teach or suggest
"wherein the NIP ratio of the LNP is from 0.1 to 4" as recited in amended claim 28, Applicant
respectfully submits that amended claim 28 and its dependent claims are not obvious over Dane
in view of Smith.
Applicant's arguments have been fully considered but they are not persuasive as explained above, so the rejection is maintained.
Conclusion
Applicants' 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 extension fee 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 date of this final action.
Correspondence
No claim is allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGOC-ANH THI NGUYEN whose telephone number is (571)270-0867. The examiner can normally be reached Monday - Friday 8:00 am.
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, Robert A Wax can be reached on 571-272-0623. 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.
/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights