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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/17/2026 has been entered.
Information Disclosure Statement
The submitted information disclosure statements (IDS) were filed on 03/17/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of Application
Applicants' arguments/remarks filed 03/17/2026 are acknowledged. Claims 148, 154, 156, 157, 160, 164-166 and 175 are currently amended. Claims 155 and 173 are newly canceled. Claims 148-152, 154, 156-161, 163-172 and 174-176 are examined on the merits within and are currently pending.
Withdrawn Rejections
With applicants' amendment filed 03/17/2026 and with respect to the arguments/remarks:
The rejection of Claims 153 and 173 under 35 U.S.C. § 103 has been withdrawn due to the cancelation of these claims.
Modified Rejections
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) 148, 149, 150-152, 154, 157-160, 166-170 and 174-176 is/are rejected under 35 U.S.C. §103 as being unpatentable over Karve et al. (WO 2018089801 A1) in view of Westesen et al. (Westesen et al. Physicochemical characterization of lipid nanoparticles and
evaluation of their drug loading capacity and sustained release potential. Journal of Controlled Release 48 (1997) 223–236).
Claims 148 and 174,
Karve et al. teach
An improved process for lipid nanoparticle formulation and mRNA encapsulation. In some embodiments, the present invention provides a process of encapsulating messenger RNA (mRNA) in lipid nanoparticles comprising a step of mixing a solution of pre-formed lipid nanoparticles and mRNA. (Abs).
In some embodiments, a suitable mRNA solution may have a pH ranging from
about 3.5-6.5. In some embodiments, a suitable mRNA solution may have a pH of or no
greater than about 6.5, (0121). In some embodiments, one or both of the solution containing
the mRNA and the solution containing the pre-formed lipid nanoparticles include only
residual citrate during the mixing addition of mRNA to the pre-formed lipid nanoparticles.
In some embodiments, one or both of the solution containing the mRNA and the
solution containing the pre-formed lipid nanoparticles contains less than about l0mM (e.g.,
less than about 9mM, about 8mM, about 7mM, about 6mM, about 5mM, about 4mM, about
3mM, about 2mM, or about l mM) of citrate present during the addition of mRNA to the preformed lipid nanoparticles. In some embodiments, the solution comprising the lipid nanoparticles encapsulating mRNA does not require any further downstream processing (e.g., buffer exchange and/or further purification steps) after the preformed lipid nanoparticles and mRNA are mixed to form that solution. (0028). In some embodiments, the empty (i.e., empty of mRNA) lipid nanoparticles without mRNA are formed by mixing a lipid solution containing dissolved lipids in a solvent, and an aqueous/buffer solution. In some embodiments, the solvent can be ethanol. In some embodiments, the aqueous solution can be a citrate buffer. (0159). Citrate buffer is highly effective for maintaining pH levels in the acidic range, typically between pH 3.0 and 6.2. Any desired lipids may be mixed at any ratios suitable for encapsulating mRNAs. In some embodiments, a suitable lipid solution contains a mixture of desired lipids including cationic lipids, helper lipids ( e.g. non cationic lipids and/or cholesterol lipids) and/or PEGylated lipids. In some embodiments, a suitable lipid solution contains a mixture of desired lipids including one or more cationic lipids, one or more helper lipids (e.g. non cationic lipids and/or cholesterol lipids) and one or more PEGylated lipids. (0128). Helper lipids are structural lipids. A cationic lipid is a type of ionizable lipid. Phospholipids include DSPC, DOPC, DOPE, DPPC, DPPG, POPC, DMPE, DSPE or SOPE. (0148).
(ii) An empty pre-formed lipid nanoparticle formulation used in making this novel nanoparticle formulation can be stably frozen in 10% trehalose solution, (0172), which means empty pre-formed lipid nanoparticles can be stored for long period in between 1 hour to about years.
A process of encapsulating messenger RNA (mRNA) in lipid nanoparticles comprising a step of mixing a solution comprising pre-formed lipid nanoparticles and a solution comprising mRNA such that lipid nanoparticles encapsulating mRNA are formed. (0009).
Even though Karve et al. teach an empty pre-formed lipid nanoparticle formulation used in making this novel nanoparticle formulation can be stably frozen in 10% trehalose solution and it means that empty pre-formed lipid nanoparticle formulation is in storage before loading, still Karve et al. do not teach the empty-LNP solution is stored for about 1 hour to about 5 years before loading.
Westesen et al. teach the cold stored solidified hard fat nanoparticles transform into a more stable poly morph than their bulk material within a comparatively short time of storage. (pg. 232, right col., 2nd par.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to prepare a loaded lipid nanoparticle solution by preparing empty preformed lipid nanoparticle, which can be stored by freezing in trehalose solution and then when needed to prepare loaded lipid nanoparticle mixing mRNA with empty preformed lipid nanoparticle, taught by Karve et al. and empty preformed lipid nanoparticle should be stored for a short time to stabilize LNPs before loading, since they have provided successful method to prepare them with better encapsulation percentages than preparing loaded lipid nanoparticles by mixing lipids with mRNA.
With regard to claims 149 and 174,
Karve et al. teach process for lipid nanoparticle formulation and mRNA encapsulation comprising a step of mixing a solution of preformed lipid nanoparticles and mRNA solution, (Abs), which is processing the empty LNP solution and loading step, forming a loaded LNP solution of loaded LNP.
With regard to claims 150-152, 157 and 160,
Karve et al. teach one or both of the solution containing the mRNA and the solution containing the pre-formed lipid nanoparticles are buffer exchanged to remove one or both of nonaqueous solvents, such as ethanol, and citrate prior to the mixing addition of the mRNA to the pre-formed LNP. After the preformed LNPs and mRNA are mixed to form the solution comprising the LNPs encapsulating mRNA, further downstream requires processing including buffer exchange and/or further purification steps. (0028). Processing the empty-LNP solution comprises pH adjusting. A suitable formulation or encapsulation solution may also contain a buffering agent or salt. Exemplary buffering agent may include sodium citrate, sodium acetate, potassium phosphate and sodium phosphate. (0172) and (0119). Suitable mRNA solution may have a pH ranging from about 3.5-6.5, (0121), so the pH of mRNA and the empty-LNP solutions should be adjusted to within the range of 3.5-6.0. A second buffer is needed to adjust for loading or encapsulation step. Purified and/or concentrated lipid nanoparticles may be formulated in a desired buffer such as, for example, PBS, (0180). Citrate buffer is highly effective for maintaining pH levels in the acidic range, typically between pH 3.0 and 6.2.
With regard to claim 154,
Karve et al. teach diafiltration is a fractionation process whereby small undesired particles are passed through a filter while larger desired nanoparticles are maintained in the retentate without changing the concentration of those nanoparticles in solution. Diafiltration is often used to remove salts or reaction buffers from a solution. Diafiltration may be either continuous or discontinuous. In continuous diafiltration, a diafiltration solution is added to the sample feed at the same rate that filtrate is generated. In discontinuous diafiltration, the solution is first diluted and then concentrated back to the starting concentration. Discontinuous diafiltration may be repeated until a desired concentration of nanoparticles is reached. (0179). Diafiltration is a filtration technique that separates molecules in a solution based on their size.
With regard to Claims 158-159,
Karve et al. teach in the empty (i.e., empty of mRNA) lipid nanoparticles without mRNA are formed by mixing a lipid solution containing dissolved lipids in a solvent, and an aqueous/buffer solution. In some embodiments, the solvent can be ethanol. In some embodiments, the aqueous solution can be a citrate buffer. (0159). The ethanol lipid solution and the aqueous buffered solution of mRNA were prepared separately. A solution of mixture of lipids was prepared by dissolving lipids in ethanol.
With regard to claims 166,
Karve et al. teach the pH of a suitable mRNA solution may have a pH ranging from about 3.5-6.5, which is the pH post loading. (0121).
With regard to claims 167, Karve et al. teach polyethylene glycol (PEG)-modified
phospholipids and derivatized lipids such as derivatized ceramides (PEG-CER), including NOctanoyl-Sphingosine-1-[Succinyl(Methoxy Polyethylene Glycol)-2000] (C8 PEG-2000
ceramide). (0151).
With regard to claims 168,
Karve et al. teach lipids may be mixed at any ratios suitable for encapsulating mRNAs like cholesterol (0128), (which is known as a structure lipid).
With regard to claims 169,
Karve et al. teach the one or more non-cationic lipids are selected from DSPC (l,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (l,2-dipalmitoyl-snglycero-3-phosphocholine ), DOPE (l ,2-dioleyl-sn-glycero-3-phosphoethanolamine ), DOPC
(l,2-dioleyl-sn-glycero-3-phosphotidylcholine). (Claim 15, pg. 82).
With regard to claims 170,
Karve et al. teach the one or more cationic lipids are amino lipids. Amino lipids suitable for use in the invention include those described in WO2017180917,
which is hereby incorporated by reference. Exemplary aminolipids in WO2017180917
include those described at paragraph (0744) such as DLin-MC3-DMA (MC3) (which is an ionizable amino lipid). (0015).
With regard to claims 175, Karve et al. teach typically, a suitable mRNA solution may also contain a buffering agent and/or salt. Generally, buffering agents can include sodium acetate, pH range 3.5-6.5. (0119 and 0121). Since the preparation of lipid nanoparticle encapsulating mRNA, includes adding mRNA solution in buffer acetate, so the empty-LNP solution should comprise an acetate buffer, with pH range 3.5-6.5.
With regard to claims 176, Karve et al. teach empty lipid nanoparticles can result in a final formulation that does not require any downstream purification or processing and can be stably stored in frozen form. (0173). Lipid Nanoparticles (LNPs) for applications like mRNA vaccines are typically stored at frozen temperatures ranging from -20°C to -80°C, with -80°C being common for ultra-cold storage requirements to ensure stability. (Ball et al. Achieving long-term stability of lipid nanoparticles: examining the effect of pH, temperature, and lyophilization. Int J Nanomedicine. 2016 Dec 30;12:305–315).
Claim(s) 148, 161 and 171 is/are rejected under 35 U.S.C. 103 as being unpatentable over Karve et al. (WO 2018089801 A1) in view of Westesen et al. (Westesen et al. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. Journal of Controlled Release 48 (1997) 223–236), as described in claim 148 above, and further in view of Hansson et al. (WO 2019089818 Al).
The teachings of Karve et al. and Westesen et al. are described in claims 148 above.
Claim 161,
Karve et al. and Westesen et al. do not teach percentage ranges of different lipids in the empty LNP compositions.
Hanson et al. teach the term "lipid component" is that component of a nanoparticle that includes one or more lipids. For example, the lipid component may include one or more cationic/ionizable, PEGylated, structural, or other lipids, such as phospholipids. (088):
about 30-60 mol% ionizable lipid;
about 0-30 mol% phospholipid;
about 18.5-48.5 mol% structural lipid;
and about 0.0-10 mol% PEG lipid. (0124).
Claim 171,
Karve et al. and Westesen et al. do not teach the ionizable lipid below.
Hansson et al. teach the ionizable lipid (claim 1, pg. 40).
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to prepare a loaded lipid nanoparticle solution by preparing empty preformed lipid nanoparticle, which can be stored by freezing in trehalose solution and then when needed to prepare loaded lipid nanoparticle mixing mRNA with empty preformed lipid nanoparticle, taught by Karve et al. and empty preformed lipid nanoparticle should be stored for a short time to stabilize LNPs before loading, taught by Westesen et al., with the lipid above taught by Hanson et al. since they have provided successful methods to prepare them with better encapsulation percentages than preparing loaded lipid nanoparticles by mixing lipids with mRNA.
Claim(s) 148 and 156, 163 is/are rejected under 35 U.S.C. 103 as being unpatentable over Karve et al. (WO 2018/089801 Al) in view of Westesen et al. (Westesen et al. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. Journal of Controlled Release 48 (1997) 223–236) and further in view of Monoharan et al. (US 20180065918 A1).
The teachings of Karve et al. and Westesen et al. are described in claim 148 above.
Karve et al. teach sodium acetate buffer, but do not specify pH 5.
Karve et al. teach in some embodiments, the previous invention provides a process of encapsulating messenger RNA (mRNA) in lipid nanoparticles by mixing an mRNA solution and a lipid solution, wherein the mRNA solution and/or the lipid solution are heated to a pre-determined temperature greater than ambient temperature prior to mixing, to form lipid nanoparticles that encapsulate mRNA. (0155).
Karve et al. and Westesen et al. do not teach processing the loaded LNP solution, thereby forming a lipid nanoparticle formulation.
Claim 156,
Manoharan et al. teach a liposome is prepared by providing a solution of a lipid described herein mixed in a solution with cholesterol, PEG, ethanol, and acetate buffer to provide a mixture of about pH 5. (0587),
Claim 163,
Manoharan et al. teach the mixture is then extruded through at least one filter, and dialyzed against PBS at pH 7.4 for about 90 minutes at RT. (0587). This is processing the loaded-LNP solution forming lipid nanoparticle formulation.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to prepare a loaded lipid nanoparticle solution by preparing empty preformed lipid nanoparticle, which can be stored by freezing in trehalose solution and then when needed to prepare loaded lipid nanoparticle mixing mRNA with empty preformed lipid nanoparticle, taught by Karve et al. and empty preformed lipid nanoparticle should be stored for a short time to stabilize LNPs before loading, taught by Westesen et al. and a residence time between the mixing and the processing step, is about 20 minutes and to have the aqueous buffer solution with a pH of about 5.0, and processing the loaded-LNP solution forming lipid nanoparticle formulation, taught by Monoharan et al., since they have proven it would be feasible to do so.
Claim(s) 148, 163 and 164, 165 is/are rejected under 35 U.S.C. 103 as being unpatentable over Karve et al. (WO 2018/089801 Al) in view of Westesen et al. (Westesen et al. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. Journal of Controlled Release 48 (1997) 223–236), as described in claim 148 above, and further in view of Monoharan et al. (US 20180065918 A1), Suk et al., (Suk et al., PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016 April 1; 99(Pt A): 28–51), Uster et al. (Uster et al., Insertion of poly(ethylene glycol) derivatized phospholipid into pre-formed liposomes results in prolonged in vivo circulation time. FEBS Letters 386 (1996) 243 246) and Nakamura et al., (Nakamura et al., Comparative studies of polyethylene glycol-modified liposomes prepared using different PEG-modification methods. Biochimica et Biophysica Acta 1818 (2012) 2801–2807).
The teachings of Karve et al., Westesen et al. and Monoharan et al. are described in claims 148, 163 above.
Karve et al., Westesen et al. and Monoharan et al. do not teach the loaded-LNP solution comprises adding a polyethylene glycol lipid (PEG lipid) to the loaded LNP.
Claims 164 and 165,
Suk et al. teach PEG-containing lipids added during the self-assembly process will insert into the bilayer with the hydrophilic PEG chains extending toward the aqueous phase. For liposomes, this means that PEG can partition to the inner and outer sides of the lipid bilayer. PEG on the liposome interior does not contribute to the PEG surface coating, and may interfere with drug loading. To overcome this limitation, PEG can also be incorporated by post-insertion or post-conjugation methods. PEG density on the liposome surface can be controlled by changing the ratio of PEG-lipids to unmodified lipids, the type of PEG-lipid conjugate, and the molecular weight of PEG used for self-assembly. The presence of PEG on the liposome surface can prevent aggregation of liposomes, though incorporating too much PEG can compromise liposome formation and stability. Yu and coworkers reported that when the PEG-lipid conjugate content was increased to 12 mol%, both the drug loading and in vivo vaginal distribution was reduced. (pg. 33, 2nd par.).
Uster et al. teach insertion of poly(ethylene glycol) derivatized phospholipid into pre-formed liposomes results in prolonged in vivo circulation time. (Title). The lipid matrix of was mixed in solvent and dried under high vacuum overnight to remove residual solvent. The hydrated multilamellar vesicles were extruded through polycarbonate membranes to a final mean selected diameter range. For leakage studies, 100 mM purified 5,6-carboxyfluorescein was entrapped inside the liposomes. The liposome dispersion was equilibrated with a concentrated MPEG1900-DSPE to give a final theoretical 3 mol% of MPEG1900-DSPE to total lipid liposome. (pg. 243, right col., section 2.2. Liposome preparation and MPEG1900-DSPE lipid insertion).
Nakamura et al. teach to address the issue of excess polyethylene glycol (PEG)-lipid degradation observed when PEG-modified liposomes are prepared using the pH-gradient method, a concept using a novel PEG-modification method, called the post-modification method. PEG-lipid degradation could be markedly inhibited in the post-modification method, which could be used without any manufacturing process difficulties, especially with high PEG-lipid content. In addition, a higher blood circulation capability was observed in the post-modification method. The novel post-modification method was advantageous compared to the pre-modification method, can achieve a higher preservation stability of PEG-lipid, a greater ease of manufacturing, and a higher blood circulation capability, especially in the manufacturing of pH-gradient liposomal products. (Abs). 2.2.2. DXR liposomes prepared using the post-modification method: Bare liposomes (non-PEGylated liposomes) composed of HSPC and Chol were dissolved in ethanol to yield crude liposomes, by extruding through membrane of selected sizes and then PEG-lipid solution was added to the liposome suspension to yield PEGylated liposomes with the desired PEG-lipid mol% (0.25, 0.5, 0.75, 1.0, and 2.0 mol%). (pg. 2802, left col., section 2.2.2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to prepare a loaded lipid nanoparticle solution by preparing empty preformed lipid nanoparticle, which can be stored by freezing in trehalose solution and then when needed to prepare loaded lipid nanoparticle mixing mRNA with empty preformed lipid nanoparticle, taught by Karve et al. and empty preformed lipid nanoparticle should be stored for a short time to stabilize LNPs before loading, taught by Westesen et al. and a residence time between the mixing and the processing step, is about 20 minutes and to have the aqueous buffer solution with a pH of about 5.0, and processing the loaded-LNP solution forming lipid nanoparticle formulation, taught by Monoharan et al., and to add more PEG-lipid by post PEGylated method taught by Suk et al., Uster et al., and Nakamura et al., since they have proven it would be advantageous to do so.
Claim(s) 148 and 172 is/are rejected under 35 U.S.C. 103 as being unpatentable over Karve et al. (WO 2018/089801 Al) in view of Westesen et al. (Westesen et al. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. Journal of Controlled Release 48 (1997) 223–236) and further in view of Almarsson et al. (WO 2018170322).
The teachings of Karve et al. and Westesen et al. are described in claim 148 above.
Karve et al. and Westesen et al. do not teach compounds of claim 172.
Almarsson et al. teach the compounds of claim 172 (0006) (pg. 2).
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention, to prepare a loaded lipid nanoparticle solution by preparing empty preformed lipid nanoparticle, which can be stored by freezing in trehalose solution and then when needed to prepare loaded lipid nanoparticle mixing mRNA with empty preformed lipid nanoparticle, taught by Karve et al. and empty preformed lipid nanoparticle should be stored for a short time to stabilize LNPs before loading, taught by Westesen et al. and to use the ionizable lipid compound 2 and 3 above, taught by Almarsson et al. since they have proven it would be feasible to do so.
Response to Arguments
Rejection under 35 U.S.C. § 103,
Applicant argues that Applicant has amended claim 148 to recite that "the aqueous buffer solution" of step (i) has a pH of 5.0 to 7.0. The cited combination of references does not teach, suggest, or provide a reasonable expectation of success for a method as claimed, comprising mixing a lipid solution comprising an ionizable lipid, a phospholipid, a PEG lipid, and a structural lipid with an aqueous buffer solution that has a pH of 5.0 to 7.0,
Applicant's arguments have been fully considered but they are not persuasive, since Karve et al. teach in some embodiments, one or both of the solution containing the mRNA and the solution containing the pre-formed lipid nanoparticles include only residual citrate during the mixing addition of mRNA to the pre-formed lipid nanoparticles. In some embodiments, one or both of the solution containing the mRNA and the solution containing the pre-formed lipid nanoparticles contains less than about l0mM (e.g., less than about 9mM, about 8mM, about 7mM, about 6mM, about 5mM, about 4mM, about 3mM, about 2mM, or about l mM) of citrate present during the addition of mRNA to the preformed lipid nanoparticles. In some embodiments, the solution comprising the lipid nanoparticles encapsulating mRNA does not require any further downstream processing (e.g., buffer exchange and/or further purification steps) after the preformed lipid nanoparticles and mRNA are mixed to form that solution. (0028). In some embodiments, the empty (i.e., empty of mRNA) lipid nanoparticles without mRNA are formed by mixing a lipid solution containing dissolved lipids in a solvent, and an aqueous/buffer solution. In some embodiments, the solvent can be ethanol. In some embodiments, the aqueous solution can be a citrate buffer. Citrate buffer is highly effective for maintaining pH levels in the acidic range, typically between pH 3.0 and 6.2. This pH range is overlapping with instant claim 148 limitation of pH range 5.0-7.0.
Applicant argues that the rejections rely on Karve for allegedly disclosing a lipid mixing step in which empty lipid nanoparticles (without mRNA) are formed by mixing a lipid solution containing dissolved lipids in a solvent with an aqueous buffer solution. See, e.g., Office Action, at 4. According to the rejection, the cited lipid mixture includes "cationic lipids, helper lipids (e.g., non-cationic lipids and/or cholesterol lipids) and/or PEGylated lipids." Id (citing Karve, ,i [0128]). The rejection cites Karve for disclosing that the aqueous buffer solution can be a citrate buffer. Id ( citing Karve, [0159]). However, the Office Action does not cite any disclosure in Karve of a pH for this mixing step, which results in formation of an empty LNP. Indeed, in formulating the rejection of claim 155, the Office Action cited passages of Karve relating to preparation of an mRNA-loaded LNP where a pH of 4.5 was used. See, e.g., Office Action, pages 5-6 (citing Karve, [0192]).
Applicant's arguments have been fully considered but they are not persuasive, as explained above, since general knowledge of citrate buffer range is between 3.0-6.2, which is overlapping with the applicant claim 1, limitation of pH range 5.0-7.0. pH 4.5 was only a specific pH in the Example 1, among the pH range Karve teaches of pH range 3.0-6.2.
Applicant argues that the rejection of claim 156 relied on Manoharan for disclosing a pH that can be used to form its liposome complexes. From the quoted language, Applicant believes the Examiner is citing paragraph [0587] of Manoharan, which states:
In one embodiment, a liposome is prepared by providing a solution of a lipid
described herein mixed in a solution with cholesterol, PEG, ethanol, and a 25 mM
acetate buffer to provide a mixture of about pH 5. The mixture is gently vortexed,
and to the mixture is added sucrose. The mixture is then vortexed again until the
sucrose is dissolved. To this mixture is added a solution of siRNA in acetate buffer,
vortexing lightly for about 20 minutes. The mixture is then extruded (e.g., at least
about 10 times, e.g., 11 times or more) through at least one filter (e.g., two 200 nm
filters) at 40° C., and dialyzed against PBS at pH 7.4 for about 90 minutes at RT.
Applicant acknowledges that Manoharan states in paragraph [0589] that "methods of forming
association complexes such as liposomes above can be used to form association complexes free of a therapeutic agent, such as a nucleic acid .... " However, Manoharan does not disclose a
method as claimed, and the Office Action has not provided the required rationale for the asserted
combination of Karve and Manoharan. Manoharan does not disclose a method of forming empty LNPs from a lipid solution as claimed, that comprises an ionizable lipid, a phospholipid, a PEG lipid, and a structural lipid. The Office Action has not articulated any reason why a person of ordinary skill would have been motivated to use the pH disclosed in Manoharan in a method according to Karve, let alone provided a basis for a reasonable expectation of success for doing so. Accordingly, the Office Action has failed to make out a prima facie case of obviousness for the subject matter of the pending claims.
Applicant's arguments have been fully considered but they are not persuasive, since Manoharan’s teachings are also preparing a loaded lipid nanoparticles. Manoharan teach in (0587) the process to make the liposome without the active ingredient at pH 5, and the active ingredient can be added or not. As Karve teaches a suitable mRNA solution may have a pH ranging from about 3.5-6.5, the pH range to prepare lipid nanoparticles is to be suitable for nucleic acid pH range.
Applicant argues that combining Karve and Manoharan with one or more or all of the other cited references (Westesen, Hansson, Suk, Uster, Nakamura, and Almarsson) still does not make out a prima facie case of obviousness for the subject matter of the pending claims as a whole. Indeed, Westesen only was alleged to be relevant to step (ii) of claim 148 (which Applicant does not address or concede), and none of Hansson, Suk, Uster, Nakamura, and Almarsson were alleged to be relevant to the subject matter of claim 148. Applicant therefore respectfully requests reconsideration and withdrawal of the pending rejections.
Applicant's arguments have been fully considered but they are not persuasive, since the basis for 103 rejection is that no one reference has to teach all the claim limitations for an obviousness rejection and therefore several references are combined to render the claims obvious. One with ordinary skill in the art can learn from and select specific parts of several prior arts’ teachings before the effective filing date of the invention to achieve better outcome results even though some prior arts may teach more and may teach different things. One with skill in the art, is known for solving the same problem, is represented with design choices, may modify the teachings of the prior arts until they can achieve better outcome results.
Conclusion
No claim is allowed
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/NGOC-ANH THI NGUYEN/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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