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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on 27 Feb 2026 has been entered.
Response to Amendment
Status of the Claims
Receipt of Applicant’s response, filed 27 Feb 2026 has been entered.
Claims 1, 2, 4, 6-11, 13-20, 23, 24, 26 and 28 remain pending in the application.
Claims 1, 13-16, and 28 are amended.
Claims 3, 5, 12, 21, 22, 25, and 27 are cancelled.
Claims 10 and 11 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are under consideration to the extent of the elected species, i.e., cKK-E12 as the cationic lipid, DOPE as the helper lipid, cholesterol as the cholesterol lipid, DMG-PEG2K as the PEG-modified lipid and trehalose as the sugar.
Rejections Withdrawn
Double Patenting
The double patenting rejection over application 17/625,507 has been withdrawn due to the cancellation of the claims in the reference application
Rejections Maintained-in modified form
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The rejection below was applied previously and has been updated to address the claim amendments.
Claims 1, 2, 4, 6-9, 13-18, 24, 26 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022).
Derosa teaches an improved process for lipid nanoparticle formulation and mRNA encapsulation (abstract). Derosa teaches that the process comprises a step of mixing a mRNA solution and a lipid solution ([0004]), rendering obvious the mixing of a lipid solution with an mRNA solution in step (a) of claims 1 and 28. Derosa teaches that subsequent to formulation and encapsulation that the lipid nanoparticles are purified and/or concentrated ([0100]). Derosa teaches purification techniques such as tangential flow filtration where buffer is exchanged with an alternative buffer such as PBS ([0126]). The purification and buffer exchange taught by Derosa renders obvious the formation of the mRNA-LNP in a drug product formulation solution as in step (b) of claims 1 and 28. Derosa teaches heating of the solutions and teaches that in some embodiments that the mRNA solution and the lipid solution are heated prior to mixing ([0090]), rendering obvious the heating prior to mixing as in claim 28 and Derosa also teaches that solutions may be mixed at ambient temperature but then heated to the pre-determined temperature after the mixing ([0090]). As heating may occur after the mixing of the mRNA and lipid solutions, this renders obvious the heating of the mRNA-LNP in the drug product formulation solution of step (c) in claims 1 and 28. Derosa teaches that an increase in temperature during nanoparticle encapsulation process results in increased yield and/or encapsulation efficiency ([0113]), rendering obvious the greater encapsulation efficiency limitation of claim 1. Derosa provides an example where nanoparticles were formed with heating and without heating and shows that encapsulation at ambient temperature was from 71-76% whereas encapsulation at 65°C resulted in encapsulation from 81-96% (Table 1 [0122]), rendering obvious that the heating step provides encapsulation efficiency of at least 5%, 10% and 25% as in claims 14-16 and 28. Derosa teaches that the mRNA encodes at least one polypeptide ([0037]), rendering obvious the mRNA limitation of claims 1 and 28.
Derosa teaches that the lipid solution contains a mixture of desired lipids including cationic lipids, helper lipids (such as non-cationic lipids and/or cholesterol lipids) and/or PEGylated lipids ([0066]). Derosa teaches that the cationic lipid may be cKK-E12 ([0018]), that the non-cationic lipid may be DOPE ([0019]), that the cholesterol lipid may be cholesterol ([0020]) and that the PEG-modified lipid may contain a PEG chain of up to 5kDa in length covalently attached to a lipid with alkyl chain of C6-C20 length ([0020]) and specifically teaches DMG-PEG2K ([0087]). Thus, Derosa renders obvious the elected lipid components as in claims 2, 4, 6 and 7. As described above, Derosa teaches that the helper lipids may or may not include cholesterol lipids ([0066]) rendering obvious that the lipid component of the solution would not contain cholesterol as in instant claim 9. Regarding the temperature of claims 14 and 28, Derosa teaches that the predetermined temperature greater than ambient temperature may be about 60-70 °C ([0089]). Derosa teaches an example formulation where the mixture of lipids was prepared in an ethanolic solution and the mRNA solution was prepared in an aqueous buffered solution that contained citrate and was at a pH of 4.5 ([0116]), rendering obvious the ethanol and citrate buffer as in claims 17 and 18 and the pH of the mRNA solution of less than 5.0 as in claim 26. As described above, Derosa teaches the purification and exchange of buffer for an alternative composition such as PBS ([0126]), rendering obvious that both ethanol and citrate are absent from the drug product formulation solution as in claim 24. Regarding claim 8, Derosa teaches that the lipids may be mixed at any ratio suitable for encapsulating mRNAs ([0066]) and that the selection of molar ratio of the cationic, non-cationic and PEG modified lipids is based upon the characteristics of the selected lipid and the nature of the mRNA to be encapsulated and that the molar ratios may be adjusted accordingly.
Derosa does not expressly teach a process of encapsulating mRNA including mixing a lipid and mRNA solution, exchanging an LNP formation solution for a drug product formulation solution and heating of the mRNA-LNP in the drug product formulation solution with sufficient specificity to rise to the level of anticipation.
However, 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 have a process of encapsulating mRNA including mixing a lipid solution comprising cKK-E12, DOPE, cholesterol and DMG-PEG2K and an mRNA solution where the mRNA encodes a polypeptide and purifying and buffer exchanging the resulting solution and subsequently heating the solution to about 60-70°C. Derosa teaches mixing a lipid and an mRNA solution to encapsulate mRNA and subsequent heating and that heating improves encapsulation efficiency. One of ordinary skill in the art would have been motivated to form lipid nanoparticles with encapsulated mRNA by mixing the mRNA and lipid solutions and subsequently heating as heating is known to improve efficiency. Each of the individual lipid components, heating temperature and solution components of ethanol and citrate buffer are taught by Derosa as suitable for forming such encapsulated mRNA nanoparticles. Thus, one of ordinary skill in the art would have a reasonable expectation of successfully forming lipid nanoparticles with encapsulated mRNA with the specific components of the instant claims as taught by Derosa since the modification of the prior art represents nothing more than the predictable use of prior art elements according to their established functions.
Regarding the specific time of heating between 10 and 20 minutes, Derosa does not explicitly teach this time frame, however, in view of the teachings of Derosa that heating improves efficiency of lipid nanoparticles encapsulating mRNA, the heating is an art-recognized result effective variable such that determining encapsulation parameters such as the heating time between 10 and 20 minutes would be a matter of optimization through routine experimentation. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Derosa renders obvious the process of heating to improve encapsulation efficiency of nanoparticles. While Derosa does not teach how long to heat the solution the heat would necessarily have to be applied for a set amount of time. It would be well within the scope of one of ordinary skill to determine an optimal heating time in order to reach a desired encapsulation efficiency.
Regarding the specific molar ratios of cationic:helper:cholesterol:PEG-modfified lipid of about 20-50:25-35:20-50:1-5 as in claim 8, Derosa does not explicitly teach this molar ratio range, however, in view of the teachings of Derosa that the molar ratio of the lipids may be adjusted and that the ratio depends on the characteristics of the selected lipids and the nature of the mRNA to be encapsulated, the molar ratio of the lipids in the nanoparticles is an art-recognized result effective variable such that determining the molar ratio of the cationic:helper:cholesterol:PEG-modfified lipid is from about 20-50:25-35:20-50:1-5 would be a matter of optimization through routine experimentation. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Derosa renders obvious the concept that the molar ratio of the lipid components may be adjusted depending on the selected lipids and mRNA for the composition. Thus, it would have been obvious to and within the skill of one of ordinary skill in the art to determine the optimal molar ratio for the lipid components in order to encapsulate mRNA and form nanoparticles.
Accordingly, the instant claims are rendered prima facie obvious over the teachings of Derosa.
Response to Arguments
Applicant's arguments filed 27 Feb 2026 have been fully considered but they are not persuasive. The applicant argues that Derosa does not teach the heating time as a result effective variable for routine experimentation (pages 8 and 9 of remarks). The applicant argues that Derosa does not disclose heating after formation of the mRNA-LNPs and after exchanging solutions but only discloses heating while forming mRNA-LNPs before any exchange of solutions (pages 9 and 10 of remarks). Applicant argues that Derosa is explicit that exchanging solutions is subsequent to formulation and encapsulation ([0100]) and thus the heating of Derosa would occur before any solution exchange for purification/concentration (page 11 of remarks). Applicant argues that the heating of the instant claims is different from Derosa in that Derosa heats as part of forming mRNA-LNPs whereas the claimed process heats already formed mRNA-LNPs (page 11 of remarks). Applicant asserts unexpected results from heating after mRNA-LNP formation as shown in examples 1-3 (pages 11 and 12 of remarks).
The examiner does not find the above arguments persuasive. Regarding the amount of time that heat is applied, as it is obvious from Derosa to heat the composition, the heat must necessarily be applied for an amount of time. In other words, it is obvious from Derosa to apply heat for enhancing encapsulation efficiency and thus one of ordinary skill would recognize the necessity to optimize the application of the heat for improved encapsulation. The heat cannot be applied without an amount of time and thus the length of time would be a necessary part of optimizing the heating step. Further, as indicated by Schubert et al. (International Journal of Pharmaceutics 298 (2005) 242–254) heat flow in lipids and changes occurring from heating is time dependent (e.g. Fig 3, 5, 6, 8) and one of ordinary skill would readily recognize that the length of time that heat is applied would dictate the affects to the lipids. The applicant may provide evidence that the claimed heating time of between 10-20 minutes is unexpected and not routine experimentation.
Regarding the timing of the heating step, the examiner notes that Derosa teaches that the heating may occur after the mRNA and lipid solutions are mixed ([0090]), which is open ended about when the heating may occur. As noted by the applicant, Derosa indicates that purification occurs subsequent to formulation and encapsulation ([0100]) but this doesn’t preclude further preclude any further processing, such as heating, of the mixture after purification and buffer exchange. The encapsulation occurs upon the mixing of mRNA and lipid whether or not the mixture is heated and the purification may occur after mixing, which involves encapsulation, and then may be followed by heating. In other words, the open ended teaching of Derosa that the heating occurs after mixing is sufficient to render obvious heating after the encapsulation. The applicant disagrees with the examiners position that the selection of any order of performing process steps is prima facie obviousness in the absence of new or unexpected results by arguing that the heating after forming mRNA-LNPs in their drug formulation solution is heating of a different type of solution than heating before the mRNA-LNPs are in their drug formulation (page 11 of remarks). The examiner, however, maintains that the distinction asserted by the applicant has not been sufficiently established to overcome the heating and purification steps taught by Derosa which render the claims prima facie obvious. The applicant points to examples from the instant specification which indicate increased encapsulation after heating the drug product formulation as compared to the encapsulation prior to heating (Tables 1-3), but this data is not persuasive in overcoming the obviousness of each of the steps of the method. The examiner notes that the data in the examples of the instant specification refer to specific combinations of a cationic lipid, PEG-modified lipid, cholesterol and DOPE in specific ratios and this is not commensurate in scope with the claims. Claims 1 and 28 do not require any of these lipid components or amounts to be present but instead merely requires “one or more lipids.” Similarly, the examples were heated to a specific temperature of 65°C for a specific time of 15 minutes ([0165]) but the instant claims are broader than what has been demonstrated. The applicant has not demonstrated that the results presented in the examples would be applicable to the broader claims. Additionally, it is not clear that the results presented by the applicant are truly unexpected. The results presented by Derosa in Table 1 where mRNA lipid particles formed with heating and from lipid components of cKK-E12, DOPE, cholesterol and DMG-PEG2K ([0118]) resulted in a high encapsulation ranging from 85-96%. The best performing formulation in Table 1 of the instant specification was test 7 with an encapsulation after heating of 91%. Alternative formulations had final encapsulations ranging as low as 52.7%. Thus, the encapsulation demonstrated by the applicant is less than what is demonstrated in the prior art and the encapsulation results do not appear to be unexpected. Based on the data in the instant specification in comparison with the data of Derosa it is not clear that the order of the heating steps provides an unexpected result but rather appears to only indicate that heating enhances encapsulation (which is already known from Derosa) and the timing of the heating is not a significant factor. Perhaps the claimed method works better under specific conditions or with specific lipid components but the instant claims are broad and a clear comparison of the claimed method with the method of the closest prior art has not been established. As each of the method steps are known in the art, the claims remain obvious as described above as the applicant has not presented unexpected results sufficient to overcome the obviousness and establish the importance to the order of the claimed method steps.
Claims 19, 20 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022) as applied to claims 1, 2, 4, 6, 7-9, 13-18, 24, 26 and 28 above and view of Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315).
The teachings of Derosa are described supra.
Derosa does not teach the inclusion of a cryoprotectant or trehalose. These deficiencies are made up for in the teachings of Ball.
Ball teaches that lipidoid nanoparticles show promise for delivering mRNA into various cell types in vitro and in vivo and that stability of the particles for long-term storage is an important factor for consideration in translating the vehicles into clinical settings (page 305 Introduction). Ball teaches that freeze-drying (lyophilization) is the most commonly used long-term storage method (page 306 left column middle). Ball teaches that trehalose is widely used as a cryoprotectant to improve the stability of proteins and nanoparticles at low temperatures (page 308). Ball showed that LNPs with 20% trehalose showed significantly less decrease in potency post-freeze-thaw than LNPs with 0% sugar (page 308 right column bottom, Figure 2). Ball teaches that damage done to LNPs post freeze-thaw is lessened with the addition of cryoprotectants such as trehalose and that similar stability retention post-freeze thaw has been shown for polymeric nanoparticles using 5-20% trehalose (page 313 left column top).
Therefore, 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 have included a cryoprotectant such as trehalose from 5-20% in the lipid nanoparticles formation process of Derosa. An important factor in achieving clinical use of mRNA nanoparticles is the ability to achieve long-term storage and while freeze drying is commonly used for storage, the addition of cryoprotectants such as trehalose can aid in limiting potency loss post-freeze-thaw, as taught by Bell. Thus, it would have been obvious to one of ordinary skill in the art to include a cryoprotectant such as trehalose in the lipid nanoparticles for improved long term storage capabilities. Trehalose has been described by Ball to have beneficial stability retention in nanoparticles from 5-20% thus rendering this an obvious range for trehalose in nanoparticle compositions and rendering obvious the about 10% of claim 23%.
Therefore, the invention as a whole was 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.
Claim 8 was rejected above as obvious over the teachings of Derosa et al. Claim 8 is alternatively rejected below.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022) as applied to claims 1, 2, 4, 6-9, 13-18, 24, 26 and 28 above and view of Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
The teachings of Derosa are described supra.
Derosa does not teach the molar ratio limitation as in claim 8. This deficiency is made up for in the teachings of Derosa ‘196.
Derosa ‘196 teaches lipid nanoparticles that encapsulates mRNA ([0006]). Derosa ‘196 teaches that the nanoparticles may comprise one or more cationic lipids ([0015]) and one or more helper lipids such as DOPE and cholesterol ([0016]) and one or more PEG-modified lipids ([0017]) such as DMG-PEG-2000 ([0018]). Derosa ’196 teaches that the cationic lipid may comprise molar ratios such as about 5% to about 50% ([0058]) and the PEG-modified phospholipid may comprise a molar ratio from about 1% to about 15% ([0061]) and the non-cationic lipid may comprise a molar ratio such as about 10-70% of the total lipid present in the nanoparticle ([0063]).
Therefore, 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 have the cationic lipid of ckk-E12, the non-cationic lipid DOPE, cholesterol and the PEG-modified lipid DMD-PEG2K in a ratio of 5-50:10-70:10-70:1-15. This ratio would have been obvious as these amounts for each of the lipids are known for use in lipid nanoparticles that encapsulate mRNA based on the teachings of Derosa ‘196. Derosa teaches that the molar ratio of lipid components may vary depending on the lipids used in the nanoparticle and as similar components with molar ratio amounts listed above are known for constructing lipid nanoparticles, one of ordinary skill would have a reasonable expectation of successfully forming the nanoparticles within this molar ratio range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Therefore, the invention as a whole was 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 67-81 of copending Application No. 18/910,694 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 7, 11-15, 18-20, 26, 27 and 29-32 of copending Application No. 18/762,242 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 44 of copending Application No. 18/753,746 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 48-58, 60, 61, and 63-69 of copending Application No. 18/328,206 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 8, 11, 12, 15, 16, 22, 24, 26, 28, 29, 34 and 35 of copending Application No. 17/450,628 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 13, 18, 20, 22, 25, 30, 31, 33, 36, 37, 54, 61, 64, 66-70 and 74 of copending Application No. 17/450,629 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
This is a provisional nonstatutory double patenting rejection.
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,064,515 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 2 of U.S. Patent No. 12,053,551 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-16 of U.S. Patent No. 12,144,871 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
Claims 1, 2, 4, 6-9, 13-20, 23, 24, 26 and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,357,726 in view of Derosa et al. (WO 2016/004318, published 07 Jan 2016, listed in IDS filed 11 Jun 2022), Ball et al. (International Journal of Nanomedicine 30 Dec 2016, 12 305–315) and Derosa et al. (WO 2014/144196, published 18 Sept 2014, referred to as Derosa ‘196).
The claims of the ‘694 application recite a process of encapsulating mRNA in lipid nanoparticles by mixing an mRNA solution and a lipid solution in the presence of a polymer and removing the polymer.
The claims of the ‘242 application recite a process of encapsulating mRNA in lipid nanoparticles by mixing preformed lipid nanoparticles and mRNA (claim 1) and heating after mixing to about 65°C (claims 13-15).
The claim of the ‘746 application recites a method of manufacturing a composition comprising lipid nanoparticles encapsulating mRNA comprising steps of mixing empty lipid nanoparticles with mRNA to form mRNA-LNPs.
The claims of the ‘206 application recite a process of encapsulating mRNA in lipid nanoparticles comprising providing a lipid mixture comprising a cationic lipid, a non-cationic lipid, a PEG modified lipid and a cholesterol based lipid dissolved in ethanol and mixing with an aqueous solution comprising mRNA at a pH of 3.5-6.5 and heating the lipid nanoparticle and mRNA solution at a temperature of about or greater than 50°C.
The claims of the ‘628 application recite a process of encapsulating mRNA in LNPs comprising comprising mixing an mRNA solution comprising one or more mRNAs with a lipid solution comprising one or more cationic lipids, non-cationic lipids and PEG-modified lipids to form mRNA encapsulated within the LNPs.
The claims of the ‘628 application recite a large scale manufacturing process of encapsulating mRNA in LNPs comprising the step of mixing an mRNA solution comprising mRNAs with a lipid soluton comprising one or more cationoic lipids, non-cationic lipids and PEG_modified lids to form mRNA encapsulated within LNPs.
The claims of the ‘515 patent recite a process of encapsulating mRNA in lipid nanoparticles comprising mixing pre-formed lipid nanoparticles and mRNA such that the lipid nanoparticles encapsulating mRNA are formed and the lipid nanoparticles comprise lipids such as cationic lipids, DOPE, cholesterol and DMP PEG. The ‘515 patent further recites heating the mixture above ambient temperature after mixing the lipid nanoparties and mRNA (claim 6).
The claims of the ‘551 patent recite a method of manufacturing a composition comprising lipid nanoparticles encapsulating mRNA comprisings steps of mixing empty LNPs with mRNA.
The claims of the ‘871 patent recite a a process of encapsulating messenger mRNA in lipid nanoparticles comprising mixing an mRNA solution and a lipid solution comprising one or more cationic lipids, non-catioinic lipidsand PEG-modified lipids.
The claims of the ‘726 patent recite a process of encapsulating mRNA in lipid nanoparticles comprising steps of mixing a solution of pre-formed lipid nanoparticles and mRNA such that lipid nanoparticles encapsulating mRNA are formed. The ‘726 patent further recites heating the lipid nanoparticles and mRNA to a temperature greater than ambient after mixing (claim 8).
The claims of the applications and patents above differ from the instant claims in exchanging the LNP formation solution to provide mRNA-LNP in a drug product formulation solution (step (b)) and heating the mRNA-LNPs (step c) where the heating step provides greater encapsulation efficiency. The reference applications/patents also differ in the specific lipids for the lipid nanoparticles and the inclusion of a cryoprotectant/trehalose. These deficiencies are made up for in the teachings of Derosa, Ball and Derosa ‘196.
The teachings of Derosa, Ball and Derosa ‘196 are described supra.
It would have been obvious to incorporate a heating step after forming the mRNA-LNP solutions as heating is known to increase encapsulation efficiency and that heating may be done after mixing mRNA and LNPs based on the teachings of Derosa. The specific heating time of instant claim 13 is obvious through a process of routine experimentation as the encapsulation efficiency is known to vary with heating and one of ordinary skill would seek to determine the optimal heating conditions for encapsulation. Purfication and buffer exchange is also a known step for such mRNA-LNP compositions from the teachings of Derosa, rendering obvious the solution exchange step (b). Each of the elected lipid species (cKK-E12, DOPE, cholesterol, DMG-PEG2K) are known for forming lipid nanoparticles from the teachings of Derosa, providing a reasonable expectation of success in using them to form lipid nanoparticles. Cryoprotectants such as trehalose are known to improve lyophilization stability for lipid nanoparticles from the teachings of Ball, providing motivation to include a cryoprotectant such as trehalose for improved stability. It would have been obvious to have the cationic lipid of ckk-E12, the non-cationic lipid DOPE, cholesterol and the PEG-modified lipid DMD-PEG2K in a ratio of 5-50:10-70:10-70:1-15 as these amounts for each of the lipids are known for use in lipid nanoparticles that encapsulate mRNA based on the teachings of Derosa ‘196, providing a reasonable expectation of success in utilizing this ratio composition. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
Response to Arguments
Applicant's arguments filed 27 Feb 2026 have been fully considered but they are not persuasive. The applicant applies the same arguments toward the prior art Derosa presented supra in the 35 USC 103 rejection to the double patenting rejections. These arguments have been addressed supra and the same reasoning by the examiner applies in response to double patenting rejections.
Conclusion
No claim is allowed.
Correspondence
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/E.C.M./Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600