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 Claims 15-19 have been withdrawn based upon Restriction/Election. 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 .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
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.
Claim Rejections – 35 USC §103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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); RAMSAY (US 2016/0022580; published January, 2016) WHEELER (WO 96/40964 A2; published December, 1996).
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, wherein the lipid nanoparticles in the preparation have an average particle size diameter of between 40 and 120 nm based on number weighting (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, wherein the lipid nanoparticles in the preparation have an average particle size diameter of between 40 and 120 nm based on number weighting (instant claim 2).
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).
PAYNE teaches that: “The lipid particles typically have a mean diameter of from 30 nm to 150 nm, from 40 nm to 150 run, from 50 run to 150 run, from 60 run to 130 run, from 70 run to 110 run, or from 70 to 90 run.” ([130]). "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 claims 1 and 2 (“wherein the lipid nanoparticles in the preparation have an average particle size diameter between 40 nm and 120 nm based on number weighting.”) and therefore the subject matter therein is considered prima facie obvious.
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).
WHEELER teaches lipid-nucleic acid particulate complexes (title, abstract, see whole document), and particularly that: “This invention relates to lipid-nucleic acid particles which are useful for the introduction of nucleic acids into cells, and methods of making and using them.” (p. 1, lines 1-2). And that: “In one embodiment, a plasmid is combined with cationic lipids in a detergent solution to provide a coated plasmid-lipid complex. The complex is then contacted with non-cationic lipids to provide a solution of detergent, a plasmid-lipid complex and non-cationic lipids, and the detergent is then removed to provide a solution of serum-stable plasmid-lipid particles, in which the plasmid is encapsulated in a lipid bilayer. The particles thus formed have a size of about 50 to 150 nm.” (p. 3, line 28 through p. 4, line 1). WHEELER teaches nucleic acid includes mRNA, among others (p. 13, lines 17-19). WHEELER teaches that: “In particularly preferred embodiments, the non-cationic lipid will be 1,2-sn-dioleoylphosphatidylethanolamine, or egg sphingomyelin (ESM).” (p. 25-26).
WHEELER teaches that: “The particles [made] by the methods of this invention have a size of about 50 to about 150 nm, with a majority of the particles being about 65 to 85 nm.” (p. 23, lines 21-22). And that: “As Figure 33 indicates, complexes containing ESM provide protection of DNA from DNase I degradation.” (p. 67, lines 24-25), and that: “The transfection study showed excellent transfection efficiency with ESM-containing complexes and with DOPE-containing complexes (not shown).” (p. 68, lines 14-15).
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.
Response to Arguments:
Applicant's arguments filed 04/06/2026 have been fully considered but they are not persuasive.
Applicant’s argument that “the present specification provides evidence demonstrating that the described LNP formulations exhibit a ~2-fold increase in mRNA expression in liver, spleen, and/or bone marrow at 4 and 24 hours post injection. As discussed in greater detail below, this evidence demonstrates that the inventive LNP formulations can perform significantly better than the gold standard Onpattro™-type baseline (50/10/38.5/1.5 mol% ionizable lipid/helper lipid/cholesterol/PEG-lipid).” (paragraph bridging pp. 6-7). And that: “Figure 5D reproduced below shows the unexpected improvements in cells positive for the marker protein (eGFP+) measured in hepatocytes (liver cells) as the sphingolipid content of the LNP is increased from 10 mo1% to 50 mol%” (p. 7, 4th paragraph). Applicant goes on to point to Figures 7D, 8D, 9D (pp. 8-9). And argues that: “The present specification further describes structural characteristics of the claimed lipid nanoparticles that distinguish them from those disclosed in the cited prior art. In particular, cryogenic transmission electron microscopy (cryo-TEM) analysis indicates that the lipid nanoparticles of the present disclosure can exhibit a morphology that differs from that typically observed in conventional LNP systems.” (p. 9, 2nd paragraph).
In response the examiner agues that the results are not commensurate with the claims because this is one specific Example not supportive of the broad claim, for example, egg sphingomyelin (ESM) is not commensurate with “a sphingolipid” (“a class of lipids comprising a backbone of sphingoid bases” – Specification, p. 10, 5th paragraph; [0055], as published). The examiner further cites Hannun et al. (“Sphingolipids and their metabolism in physiology and disease,” 2018, Nature Reviews – Molecular Cell Biology, Vol. 19, pp. 175-191, and Supplementary Information – S2) teaching that “Sphingolipids represent one of the major classes of eukaryotic lipids. […] Biochemical and chemical approaches in the first part of the 20th century resulted in elucidation of the chemical structure of sphingosine, one of the major sphingoid bases, which are the founding blocks of all sphingolipids (distinguishing sphingolipids from other lipids). […]” (p. 175, col. 2, 1st paragraph). And that: “The main bioactive sphingolipids (Table 1; Supplementary information S2 (table)) that have received the most attention are ceramide, sphingosine and S1P.” (p. 175, col. 1, 2nd paragraph; Supplementary Information - S2, Table). Thus, “a sphingolipid” is much broader than what is demonstrated. The examiner further cites Applicant’s non-patent literature document Chander et al. (“Lipid nanoparticle mRNA systems containing high levels of sphingomyelin engenders higher protein expression in hepatic and extra-hepatic tissues,” 2023, Molecular Therapy Methods and Clinical Development, Vol. 30, pp. 235-245, and Supplemental Information pp. 1-4) showing the specific combination of lipids used (Dlin-MC3-DMA, Cholesterol, ESM/DSPC, and PEG-DMG). The claimed preparation of lipid nanoparticles only requires “encapsulated mRNA and 30 to 60 mol% of a sphingolipid, and at least one of a sterol and a hydrophilic polymer-lipid conjugate”. Which is not close to being commensurate with the data shown with specific lipid composition components (Dlin-MC3-DMA, Cholesterol, ESM/DSPC, and PEG-DMG)(MPEP §716.02(d)). Also, see MPEP §716.02(e) which requires comparison with the closest prior art or closer rather than “the gold standard Onpattro™-type baseline”.
Additionally, the examiner cites WHEELER (with common inventor Cullis Ro Pieter) clearly teaching that : “The particles [made] by the methods of this invention have a size of about 50 to about 150 nm, with a majority of the particles being about 65 to 85 nm.” (p. 23, lines 21-22). And that: “As Figure 33 indicates, complexes containing ESM provide protection of DNA from DNase I degradation.” [emphasis added](p. 67, lines 24-25), and that: “The transfection study showed excellent transfection efficiency with ESM-containing complexes and with DOPE-containing complexes (not shown).” [emphasis added](p. 68, lines 14-15).
Applicant argues that: “RAMSAY merely describes an area-averaged measurement of electron density of a solid core particle, rather than identifying or characterizing any distinct internal regions within the particle and expressly refers to the particle as being ‘solid core.'’ Consistent with this description, RAMSAY also specifies that the particles do "not have extended aqueous regions on the interior" (paragraph [0188]).” And that: “The inventors have found that as the sphingolipid content is increased, the core adopts a morphology with both an electron dense region and an aqueous portion. The present specification depicts the transition in Figure 2A and 2B:” (p. 10, paragraphs 3-4).
In response the examiner argues that 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. It would have been prima facie obvious to produce a lipid particle consistent with the full range of non-cationic lipids such as sphingomyelin and egg sphingomyelin (ESM) (from 10 mol% to 60 mol%), and the result would have, more likely than not, been the same (MPEP 2112.01).
Applicant argues that: “As to Sato et al., the Office relies on this reference as teaching that ''egg sphingomyelin (ESM) resulted in the formation of smaller LNPs with a diameter of ~22 nm and enhanced gene silencing activity." (Office Action, page 13) However, the particles of the present disclosure have a size in the range of 40 nm to 120 nm, which is substantially larger than the 22 nm particle size disclosed in Sato et al.” (p. 11, 3rd paragraph). And “Thus, Sato et al. identifies small particles as critical for achieving the desired biological performance and in doing so teaches that reducing particle size is necessary for improved biodistribution and tissue penetration. A person of ordinary skill in the art reading Sato et al. would therefore be directed toward minimizing particle size of sphingolipid-containing lipid nanoparticles to improve biodistribution, not increasing particle size to the substantially larger range of 40-120 nm as required by the present claims. Accordingly, Sato et al. teaches away from the claimed particle size range.” (p. 12, 2nd paragraph).
In response the examiner argues that: (1) PAYNE already teaches the particle size, as discussed above, and WHEELER (with common inventor Cullis Ro Pieter) clearly teaching that : “The particles [made] by the methods of this invention have a size of about 50 to about 150 nm, with a majority of the particles being about 65 to 85 nm.” (p. 23, lines 21-22). And that: “As Figure 33 indicates, complexes containing ESM provide protection of DNA from DNase I degradation.” [emphasis added](p. 67, lines 24-25), and that: “The transfection study showed excellent transfection efficiency with ESM-containing complexes and with DOPE-containing complexes (not shown).” [emphasis added](p. 68, lines 14-15). The rejected claims are directed to broadly claimed “A preparation of lipid nanoparticles comprising encapsulated mRNA and 30 to 60 mol% of a sphingolipid, and at least one of a sterol and a hydrophilic polymer-lipid conjugate […]” Applicant further claims a functional result of a species – “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” – where both WHEELER and Sato et al. suggests enhance gene silencing (with siRNA nucleic acid), and WHEELER suggest enhanced stability (“ESM provide protection of DNA from DNase I degradation.”) and enhanced transfection (“excellent transfection efficiency with ESM-containing complexes”) with lipid particles “of about 50 to about 150 nm, with a majority of the particles being about 65 to 85 nm.” Furthermore, it would have been prima facie to select within the scope and range of the disclosure of PAYNE which clearly teaches "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]).
Applicant argues that: “In summary, the Office does not address the unexpected results and the sphingolipid dependent nanoparticle morphology described in the present specification. The cited references neither teach nor suggest that increasing sphingolipid content to 30-60 mol% in particles having a size of about 40-120 nm would produced the claimed morphology, much less with a 2:2 fold enhancement in organ-specific mRNA expression. These results constitute objective evidence of non-obviousness that should be considered in evaluating the pending claims.” (p. 12, 4th paragraph).
As discussed above the claims are clearly not commensurate with Applicants showing of results, and the prior art fairly suggest including ESM would have resulted in improved properties where both WHEELER and Sato et al. suggests enhance gene silencing (with siRNA nucleic acid), and WHEELER suggest enhanced stability (“ESM provide protection of DNA from DNase I degradation.”) and enhanced transfection (“excellent transfection efficiency with ESM-containing complexes”) with lipid particles “of about 50 to about 150 nm, with a majority of the particles being about 65 to 85 nm.” Furthermore, it would have been prima facie to select within the scope and range of the disclosure of PAYNE, as discussed above.
Although the record may establish evidence of secondary considerations which are indicia of nonobviousness, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). Applicant is reminded that the submission of objective evidence of patentability does not mandate a conclusion of patentability in and of itself. In re Chupp, 816 F.2d 643, 2 USPQ2d 1437 (Fed. Cir. 1987).
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.
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 IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
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