DETAILED ACTION
Status of the Claims
Claims 1-19 and 25 are pending in the instant application. Claims 15-19 have been withdrawn based upon Restriction/Election as discussed below. Claims 1-14 and 25 are being examined on the merits in the instant application.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Restriction/Election
Applicant's election without traverse of Group I, currently claims 1-14 and 25, in the reply filed on 12/23/2025 is acknowledged.
The requirement is deemed proper and is therefore made FINAL.
Claims 15-19 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/23/2025.
Priority
The U.S. effective filing date has been determined to be 05/31/2022, the filing date of PCT/CA2022/050868. Applicant's claim for a foreign priority date of, 06/01/2021, the filing date of the U.S. Provisional Application No. 63/195,269 is acknowledged, the examiner finds no support for the genus sphingolipid (instant claim 1, line 2; instant claim 2, item (ii)); sphingomyelin is disclosed but is narrower in scope that sphingolipid.
Information Disclosure Statement
The information disclosure statements submitted on 11/27/2023; 01/09/25025; and 09/22/2025 were filed before the mailing date of the first office action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-14 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over PAYNE (US 2018/0170866; published June 2018) in view of Sato et al. (“Hydrophobic scaffolds of pH-sensitive cationic lipids contribute to miscibility with phospholipids and improve the efficiency of delivering short interfering RNA by small-sized lipid nanoparticles, ” 2020, ELSEVIER; pp. 341-350) and RAMSAY (US 2016/0022580; published January, 2016).
Applicants Claims
Applicant claims a lipid nanoparticle comprising encapsulated mRNA and 30 to 60 mol% of a sphingolipid, and at least one of a sterol and a hydrophilic polymer- lipid conjugate, the lipid nanoparticle comprising a core having an electron dense region and an aqueous portion surrounded at least partially by a lipid layer comprising at least a bilayer and the lipid nanoparticle exhibiting at least a 2-fold increase in gene expression in the liver, spleen and/or bone marrow at 4 or 24 hours post-injection as compared to a lipid nanoparticle encapsulating the mRNA with a formulation of ionizable, cationic lipid/DSPC/cholesterol/PEG-lipid or ionizable, cationic lipid/egg sphingolipid/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol, wherein the gene expression is measured in an animal model by detection of green fluorescent protein (GFP) or luciferase (instant claim 1).
Applicant claims lipid nanoparticle for hepatic or extrahepatic delivery of mRNA, the lipid nanoparticle comprising: (i) encapsulated mRNA; (ii) a sphingolipid content of from 30 mol% to 60 mol% of total lipid present in the lipid nanoparticle; (iii) a cationic lipid content of from 5 mol% to 50 mol% of the total lipid; (iv) a sterol selected from cholesterol or a derivative thereof; and (v) a hydrophilic polymer-lipid conjugate that is present at 0.5 mol% to 5 mol%, or at 0.5 mol% to 3 mol% of the total lipid, the lipid nanoparticle having a core comprising an electron dense region and an aqueous portion surrounded at least partially by a lipid layer comprising at least a bilayer.
Determination of the scope
and content of the prior art (MPEP 2141.01)
PAYNE teaches ionizable cationic lipid for RNA delivery (title, see whole document), and particularly lipid nanoparticles for mRNA delivery ([0098]-[0100])(instant claims 1-2, mRNA). PAYNE teaches that: “A compound of formula I includes a pharmaceutically acceptable salt thereof, in a lipid composition, comprising a nanoparticle or a bilayer of lipid molecules.” [emphasis added](instant claim 2, "a lipid layer comprising at least a bilayer.") PAYNE teaches that: "The description provides lipid particles comprising one or more therapeutic RNA molecules encapsulated within the lipid particles." ([0129]). And including cationic lipids ([0138]-[0143]), neutral helper lipids including non-cationic lipids such as sphingomyelin and egg sphingomyelin (ESM), among others ([0144])(instant claim 8, an amino lipid; instant claim 13), and “In some embodiments, the non-cationic lipid comprises from 10 mol% to 60 mol%,” [emphasis added]([0148])(instant claim 1, lines 1-2; instant claim 2 item ii; instant claim 4), and particularly teaches that: “A composition containing a cationic lipid compound may be 30-70% cationic lipid compound, 0-60% cholesterol, 0-30% phospholipid and 1-10% polyethylene glycol (PEG).” [emphasis added]([0156])(instant claim 1, lines 2-3; instant claim 2, items iii and iv; instant claim 10; instant claim 11, 12), and including lipid conjugates such as PEG-lipids ([0158]), and particularly “In some embodiments, the lipid conjugate (e.g., PEG-lipid) comprises from 0.1 mol% to 2 mol%,” [emphasis added]([0168])(instant claim 2, item v). "In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.' (MPEP §2144.05-1). In the instant case PAYNE clearly teaches overlapping amounts with those of instant claim 2 and therefore the subject matter therein is considered prima facie obvious.
PAYNE teaches that: “The cationic lipid may have a measured pKa (in the formulation milieu) in the range of approximately 5.5 to approximately 7.5, more preferably between approximately 6.0 and approximately 7.0.” ([0143])(instant claim 9).
PAYNE teaches that: “Compositions of this disclosure may be administered
in an aqueous solution […].” ([0177])(instant claim 1, an aqueous region; instant claim 6, the lipid nanoparticles are (i) enveloped by the aqueous portion).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of PAYNE is that PAYNE does not expressly teach: (1) the lipid nanoparticles comprise a core having an electron dense region; (2) wherein the electron dense region is denser than the aqueous portion as visualized by cryo-EM microscopy; (3) “the lipid nanoparticle exhibiting at least a 2-fold increase in gene expression in the liver, spleen and/or bone marrow at 4 or 24 hours post-injection as compared to a lipid nanoparticle encapsulating the mRNA with a formulation of ionizable, cationic lipid/DSPC/cholesterol/PEG-lipid or ionizable, cationic lipid/egg sphingolipid/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol, wherein the gene expression is measured in an animal model by detection of green fluorescent protein (GFP) or luciferase” (instant claim 1); or (4) “wherein the mRNA stability of the lipid nanoparticle is improved relative to the formulation of lipid/DSPC/cholesterol/PEG lipid ionizable, cationic lipid/DSPC/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol as measured by quantifying degradation in an in vitro assay by determining band intensity using a denaturing agarose gel after incubation of the lipid nanoparticle with fetal bovine serum for 2, 4 or 24 hours, wherein the mRNA stability improvement is measured by determining a normalized absorption ratio for peaks at λ 260 nm and λ 280 nm (λ 260 nm/ λ 280 nm) for the lipid nanoparticle, and wherein the normalized absorption ratio is least 0.5, 1.0, 1.5 or 2% greater than that of the cationic lipid/DSPC/cholesterol/PEG- lipid at 50/10/38.5/1.5, mol:mol at any one of the 2, 4 or 24 hours.” (instant claim 14).
PAYNE does not clearly teach "the lipid particle having a core comprising an electron dense region and an aqueous portion," however RAMSAY teaches lipid nanoparticles for transfection (title, see whole document), and particularly “Liposomes have been used successfully to encapsulate and deliver a wide range of chemicals including nucleic acids, proteins and. small molecule drugs, to cells.” (abstract), nucleic acids including mRNA “Alternatively applications include delivery of DNA or mRNA sequences that code for therapeutically useful polypeptides.” ([0225], claim 26). RAMSAY teaches that: “The lipid nanoparticles of the invention can also be characterized by electron microscopy. The particles of the invention having a substantially solid core have an electron dense core as seen by electron microscopy. Electron dense is defined such that area-averaged electron density of the interior 50% of the projected area of a solid core particle (as seen in a 2-D cryo EM image) is not less than x % (x=20%, 40%, 60%) of the maximum electron density at the periphery of the particle. Electron density is calculated as the absolute value of the difference in image intensity of the region of interest from the background intensity in a region containing no nanoparticle.” (instant claims 1-14 and 25, an electron dense core region).
Sato et al. teaches that: “Despite the fact that small-sized lipid nanoparticles (LNPs) are important for improved tissue penetration and efficient drug delivery, their poor stability and intracellular trafficking significantly hinders their use as potent small-sized LNPs. It has been reported that both the diffusion of lipid components from LNPs and the adsorption of proteins on the surface of LNPs are responsible for their decreased potency. To overcome this issue, we focused on the chemical structure of hydrophobic scaffolds of pH-sensitive cationic lipids with various lengths and shapes. LNPs composed of a pH-sensitive cationic lipid with long, linear scaffolds induced gene silencing in a dose-dependent manner, while LNPs with a classical scaffold length (C18) failed. Replacing the helper lipid from cholesterol to egg sphingomyelin (ESM) resulted in the formation of smaller LNPs with a diameter of ~22 nm and enhanced gene silencing activity. Most of the ESMs were located in the outer layer and functioned to stabilize the LNPs. Long, linear scaffolds contributed to immiscibility with phosphocholine-containing lipids including ESM. This contribution was dependent on the scaffold length of pH-sensitive cationic lipids. Although phosphocholine-containing lipids usually inhibit membrane fusion-mediated endosomal escape, long, linear scaffolds contributed to avoiding the inhibitory effect and to enhance the potency of the LNPs. These findings provide useful information needed for the rational design of pH-sensitive cationic lipid structures and the selection of appropriate helper lipids and will facilitate the development of highly potent small-sized LNPs.” [emphasis added](abstract, see whole document).
Regarding the claimed properties (instant claims 1 and 14), PAYNE does not expressly teach that: (3) “the lipid nanoparticle exhibiting at least a 2-fold increase in gene expression in the liver, spleen and/or bone marrow at 4 or 24 hours post-injection as compared to a lipid nanoparticle encapsulating the mRNA with a formulation of ionizable, cationic lipid/DSPC/cholesterol/PEG-lipid or ionizable, cationic lipid/egg sphingolipid/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol, wherein the gene expression is measured in an animal model by detection of green fluorescent protein (GFP) or luciferase” (instant claim 1); or (4) “wherein the mRNA stability of the lipid nanoparticle is improved relative to the formulation of lipid/DSPC/cholesterol/PEG lipid ionizable, cationic lipid/DSPC/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol as measured by quantifying degradation in an in vitro assay by determining band intensity using a denaturing agarose gel after incubation of the lipid nanoparticle with fetal bovine serum for 2, 4 or 24 hours, wherein the mRNA stability improvement is measured by determining a normalized absorption ratio for peaks at λ 260 nm and λ 280 nm (λ 260 nm/ λ 280 nm) for the lipid nanoparticle, and wherein the normalized absorption ratio is least 0.5, 1.0, 1.5 or 2% greater than that of the cationic lipid/DSPC/cholesterol/PEG- lipid at 50/10/38.5/1.5, mol:mol at any one of the 2, 4 or 24 hours.” (instant claim 14). However the lipid nanoparticles are substantially identical in structure and are used for the very same purpose (delivery of encapsulated mRNA), and therefore would have more likely than not also consisted of (3) “the lipid nanoparticle exhibiting at least a 2-fold increase in gene expression in the liver, spleen and/or bone marrow at 4 or 24 hours post-injection as compared to a lipid nanoparticle encapsulating the mRNA with a formulation of ionizable, cationic lipid/DSPC/cholesterol/PEG-lipid or ionizable, cationic lipid/egg sphingolipid/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol, wherein the gene expression is measured in an animal model by detection of green fluorescent protein (GFP) or luciferase” (instant claim 1); or (4) “wherein the mRNA stability of the lipid nanoparticle is improved relative to the formulation of lipid/DSPC/cholesterol/PEG lipid ionizable, cationic lipid/DSPC/cholesterol/PEG-lipid at 50/10/38.5/1.5, mol:mol as measured by quantifying degradation in an in vitro assay by determining band intensity using a denaturing agarose gel after incubation of the lipid nanoparticle with fetal bovine serum for 2, 4 or 24 hours, wherein the mRNA stability improvement is measured by determining a normalized absorption ratio for peaks at λ 260 nm and λ 280 nm (λ 260 nm/ λ 280 nm) for the lipid nanoparticle, and wherein the normalized absorption ratio is least 0.5, 1.0, 1.5 or 2% greater than that of the cationic lipid/DSPC/cholesterol/PEG- lipid at 50/10/38.5/1.5, mol:mol at any one of the 2, 4 or 24 hours.” (instant claim 14)(MPEP §2112).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce a lipid nanoparticle comprising (i) encapsulated mRNA; (ii) a sphingolipid content of from 30 mol% to 60 mol% of total lipid present in the lipid nanoparticle; (iii) a cationic lipid content of from 5 mol% to 50 mol% of the total lipid; (iv) a sterol selected from cholesterol or a derivative thereof; and (v) a hydrophilic polymer-lipid conjugate that is present at 0.5 mol% to 5 mol%, or at 0.5 mol% to 3 mol% of the total lipid, the lipid nanoparticle having a core comprising an electron dense region and an aqueous portion surrounded at least partially by a lipid layer comprising at least a bilayer, as per the broad disclosure of PAYNE and the teaching of Sato et al. that “egg sphingomyelin (ESM) resulted in the formation of smaller LNPs with a diameter of ~22 nm and enhanced gene silencing activity” (abstract), in order to produce a lipid nanoparticle with enhanced gene activity upon administration; and to produce a lipid nanoparticle with a solid core as suggested by RAMSAY.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention it would have been within the ordinary level of skill in the art to produce lipid nanoparticles for mRNA delivery including known constituent chemical ingredients and method steps with a reasonable expectation of success. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
Conclusion
Claims 1-14 and 25 are pending and have been examined on the merits. Claim 1-14 and 25 are rejected under 35 U.S.C. 103. No claims allowed at this time.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619