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
Response to Amendment
Status of the Claims
Receipt of Applicant’s response, filed 30 Jan 2026 has been entered.
Claims 1-4, 6, 8, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45, 47 and 48 remain pending in the application.
Claims 1, 2, 23, 45 and 48 are amended.
Claims 5, 7, 9-14, 16-17, 19-22, 25-26, 28-30, 32-36, 39-40, 42, and 46 are cancelled.
Claim 47 is withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 1-4, 6, 8, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are under consideration to the extent of the elected species, i.e., that the cationic lipid is cKK-E10, the non-cationic lipid is DOPE, and the PEG modified lipid is DMG-PEG-2000.
Rejections Withdrawn
Rejections Pursuant to 35 USC § 112
The rejections of claims 1-4, 6, 8, 15, 18, 23, 24, 27, 31, 37, 38, 41, and 43-45 pursuant to 35 U.S.C. 112(a) set forth in the Non-Final Office Action mailed 02 February 2023 are hereby withdrawn in light of applicant’s amendment of the claims.
The rejections of claims 1-4, 6, 8, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 pursuant to 35 U.S.C. 112(b) set forth in the Non-Final Office Action mailed 02 February 2023 are hereby withdrawn in light of applicant’s amendment of the claims.
Rejections Pursuant to Double Patenting
The rejection over double patenting with application No. 18/458,767 is withdrawn do to the abandonment of the reference application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 art used in the rejection below was previously applied and the rejection has been updated to better address the current claim amendments.
Claims 1-4, 6, 8, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Karve et al. (US 2018/0153822, published 07 Jun 2018) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification in view of Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990).
Karve teaches a process for lipid nanoparticle formulation and mRNA encapsulation (abstract). Karve teaches that lipid nanoparticles are commonly used to encapsulate mRNA for efficient in vivo delivery of mRNA ([0003]). Karve teaches that the lipids may contain one or more cationic lipids, one or more helper lipids, one or more PEG lipids and one or more cholesterol lipids ([0013], [0031], [0102]). Karve teaches that the cationic lipid may be cKK-E12 ([0014]). Karve teaches that the non-cationic lipid may be DOPE ([0016], [0033]). Karve teaches that the PEG-modified lipid may comprise poly(ethylene) glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chains ([0017], [0034]). Karve teaches an example combination of lipids comprising cKK-E12, DOPE, cholesterol and DMG-PEG2K ([0161]) thus making obvious the lipid nanoparticle comprising DMG-PEG-2000, DOPE and cholesterol as recited in instant claims 1, 3, 38 and 48. Karve teaches the addition of one or more excipients such as trehalose ([0027]) rendering obvious the disaccharide of claims 1, 24 and 48.
Karve teaches that the expression of the mRNA refers to translation of an mRNA into a peptide (e.g., an antigen) or polypetide ([0082], [0005]) rendering obvious the mRNA encoding a peptide or polypeptide of instant claims 1 and 48. Karve teaches that the composition comprises mRNA at 0.1-1.0 mg/mL ([0118]), rendering obvious the mRNA concentration of instant claim 41. 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). Karve teaches that the mRNA solution may contain a buffering agent such as sodium citrate, potassium phosphate or sodium phosphate ([0119]), rendering obvious the pH buffer of claims 1, 15, 18 and 48. Karve teaches that the buffering agent may be present at a variety of concentrations such as from about 0.1 mM to 100 mM or greater than about 50 mM ([0119]), rendering obvious that the buffer may be present at lower or higher amounts and rendering obvious that such buffer ranges are suitable for mRNA solutions. Karve teaches that suitable salts for the mRNA solution include sodium chloride and potassium chloride ([0120]) rendering obvious the inclusion of the salts as in the instant claims. Karve teaches that the salt may be present from 1mM to 500 mM ([0120]). As evidenced by Toppr, the ionic strength is calculated as the sum of each ion’s molar concentration multiplied by the valence squared (page 1 Derivation of Ionic strength formula). Thus, the salt at 1mM to 500mM and a buffer of greater than 50 mM, as taught by Karve, necessarily has an ionic strength of 50 to 550 mM or greater, and thus renders obvious ionic strengths between 150 mM – 750 mM (claims 1, 31 and 48) as suitable for mRNA solutions. The inclusion of salt necessarily provides increased ionic strength in addition to the pH buffer as recited in claims 1 and 48.
Karve teaches the nanoparticles with a narrow particle size range such as about 75-90 nm ([0191]), rendering obvious the 70 – 90 nm of instant claim 37. Regarding instant claim 6, Karve teaches that the cationic lipids may be present at various amounts such as 30-60% by weight or by molar relative to the total amount of lipids ([0152]). Regarding the molar ratio of 10% or greater of instant claim 4, Karve teaches that the non-cationic lipids such as DOPE may constitute at least 10% of the total lipids in a suitable lipid solution by weight or by molar ([0155]). Regarding instant claim 43, Karve teaches that the final formulation can be stably stored in frozen form ([0181]) and teaches example compositions that exhibited stability and functionality after extended storage at -80°C ([0209]), providing a reasonable expectation of maintaining stability at -20°C for at least 3 months or more as recited.
Karve does not teach the cationic lipid of cKK-E10 (the elected species of cationic lipid) or that the mRNA encodes a vaccine antigen (claim 8) or the specific stability after dilution (claim 44) or an N/P ratio between 3-5 (claim 37) or the pH values of claims 1, 2, and 48 or the concentration of the trehalose (disaccharide) (claim 24) or a ratio of the disaccharide to pH buffer between 0.2:1 and 0.5-1 (claim 1). These deficiencies are made up for in the teachings of Dong, Smith and Law.
Dong teaches lipopeptide nanoparticles (LPNs) that could entrap and carry siRNA (page 3955 col 2). Dong teaches nanoparticles formed with cholesterol, DSPC, PEG-lipid, siRNA and a lipopeptide such as cKK-E10 (page 3956 col 1 last paragraph – col 2 second paragraph, Fig. 1). As evidenced by the instant specification, cKK-E10 is a lipidoid ([0094]), thereby meeting the lipidoid of claim 6.
Smith teaches stabilized formulations of lipid nanoparticles comprising an amphiphilic polymer and one or more lipid nanoparticle components (title, [0002]). Smith teaches that the formulation comprises an mRNA ([0035], [0080]). Smith teaches that the mRNA may encode any polypeptide ([00255]). Smith teaches that non-translatable mRNA may be useful as vaccines ([00496]). Smith teaches that the LNP component comprises a cationic/ionizable lipid, a phospholipid (such as DOPE, see [00248]), a structural lipid (e.g. cholesterol) and a PEG lipid (e.g. PEG-DMG, see [00245]) (see [0049]-[0054], [00212], [00520] Table 1). Smith teaches that the LNP may include one or more RNAs and the one or more RNAs, lipids and amounts thereof may be selected to provide a specific N:P ratio from about 2:1 to about 30:1 such as 3:1, 4:1, 5:1 ([00415]), rendering obvious the N/P ratios of claim 37. Smith additionally teaches that the formulations may comprise a sugar such as trehalose between 0% w/w and about 30% w/w ([0029]-[0030]), rendering obvious the amount of disaccharide of 2.5-3.0% as recited in instant claim 24. Smith teaches the formulations have a salt concentration with NaCl from 0-300 mM ([0031]-[0032]), rendering obvious the salt that increases ionic strength in claims 1 and 48 and the NaCl concentrations of claim 15. Smith teaches that the formulations have a pH value ranging between about 4 and about 8 ([0034]), rendering obvious the pH range of claims 1, 2 and 48.
Law teaches stable liposomes for encapsulating macromolecules (abstract). Law teaches that an aqueous solution of low ionic strength (i.e., less than 10 mM of ionic species) may encapsulate more macromolecule but is not stable (col 2 lines 60-68). Law teaches the macromolecules may be encapsulated under low ionic strength conditions to improve encapsulation and subsequently dialyzed against a high ionic strength solution to improve the stability (col 3 lines 1-6). Law teaches that high ionic strength buffers which contain greater than 100 mM of ionic species enable macromolecule encapsulated liposomes to withstand heat stress and remain active (col 3 lines 7-11).
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 formed a high ionic strength stable liquid lipid nanoparticle formulation that is comprised of cKK-E10, DOPE, DMG-PEG2K and cholesterol, 0-30% w/w trehalose, a pH from 4-8, a buffer such as sodium citrate or potassium phosphate, and additionally a salt such as sodium chloride from 0-300 mM and encapsulating mRNA with an N/P ratio at 3:1, 4:1, or 5:1 that encodes a vaccine antigen. Stable nanoparticles for encapsulating mRNA that are formed from multiple lipid components including cationic lipids such as cKK-E12 are taught by Karve and nanoparticles for encapsulation of siRNA formed from multiple ligands such as cKK-E10 are taught by Dong. Thus, it would be obvious to one of ordinary skill in the art that cKK-E10 is a suitable lipid for forming nanoparticles for encapsulating RNA and it would thus provide a reasonable expectation of successfully forming the nanoparticles of Karve by substituting the cKK-E12 as taught by Karve with cKK-E10 as taught by Dong. Regarding the specific ionic strength values (total is between 150-750 mM and the pH buffer is between 30 mM-300 mM or 40-250 mM in claim 27), in light of the teaching of Karve that the mRNA is suitable in buffer concentrations of 0.1 mM to 100 mM or greater than about 50 mM and salt concentrations of 1mM to 500mM and the teaching of Smith where salt is from 0-300 mM and the teaching of Law that the stability of liposomes is improved in high ionic strength solutions (i.e. greater than 100 mM ionic species), it would be obvious to form the liposomal formulations under high ionic strength conditions that meet the limitations of the claims. For instance, it is obvious to form the composition with greater than 100 mM ionic species, for added liposomal stability as taught by Law, which indicates that high ionic strength is beneficial. Further, a variable amount of buffer and salt concentrations are suitable for mRNA, as taught by Karve. Thus, it would be obvious to vary the salt and buffer concentrations such that the overall ionic species is above 100 mM, for improved liposomal stability. An ionic species concentration of at least 100 mM requires a minimum of at least 100 mM ionic strength in the composition and thus renders obvious the ionic strength and concentrations of the instant claims. 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).
Regarding the specific ratio of disaccharide to buffer (between 0.2:1 and 0.5:1), this would be obvious through a process of routine experimentation. Trehalose is obvious to include from the teachings of Karve and Smith renders the range of 0-30% w/w as obvious as it is taught as suitable for liposomal mRNA solutions with similar components, thus rendering obvious the recited percentage of disaccharide of 2.5 -3.0%. A disaccharide:pH buffer ratio of 0.2:1 – 0.5:1 is obvious from the 0 – 30% w/w sugar such as trehalose and the inclusion of pH buffer at 0.1 mM to 100 mM or greater than about 50 mM. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM
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Assuming the percentage of sugar as 2.5% as in the instant claims, which is rendered obvious as described above, this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio.
Further, nanoparticles with multiple lipids that carry mRNA, similar to those of Karve (i.e. containing cationic lipid, DOPE, cholesterol, PEG-DMG), are taught by Smith and N/P ratios of 3:1, 4:1, or 5:1 are suitable for such formulations. Thus, it would be obvious to have an N/P ratio of 3:1, 4:1, or 5:1 as Smith teaches stabilized nanoparticles with similar components and for similar purposes (i.e. mRNA encapsulation). It further would have a been obvious to have the mRNA encode a vaccine antigen as Karve teaches that the mRNA may encode antigens and Smith teaches that the mRNA may be useful as vaccines thus making obvious that the antigen encoding mRNA of Karve may be a vaccine antigen encoding mRNA. Additionally, as Smith teaches lipid nanoparticle formulations with a pH from 4-8, it would be obvious to one of ordinary skill that the liposomal formulations may be prepared with a pH between 4 to 8, with a reasonable expectation of success.
Regarding the recitation of claim 45 that the formulation has reduced pain upon administration in comparison to a formulation without a pH buffer from 30-300 mM and a pH between 7.0-7.5, as evidenced by the instant specification, formulations with certain ionic strengths result in reduced pain upon administration by intramuscular or subcutaneous administration ([0081]). Thus, the reduction in pain is associated with the ionic strength of the composition. As evidenced by the instant specification, suitable ionic strengths for the invention range from 150 mM – 750 mM ([0089]) and as it is obvious to form the liposomal formulations with ionic species greater than 100 mM, the formulations rendered obvious by the cited references necessarily have the ionic strength amounts and necessarily result in reduction in pain upon administration as this is a functional characteristic necessarily present upon administration of the same composition. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
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.
Response to Arguments
Applicant's arguments filed 30 Jan 2026 have been fully considered but they are not persuasive. Applicant states that the office does make a finding that any of the applied references recognize the disaccharide:buffer ratio as a result-effective variable and thus the claimed ratio is not obvious through a process of routine optimization (page 8 of remarks). Applicant states that the references do not disclose any disaccharide:buffer ratio and thus can not be a result-effective variable (page 8 of remarks). Applicant states that Karve and Smith do not teach the results for the individual buffer and sugar components beyond the concentration ranges for the components (page 9 of remarks). The examiner does not find this to be persuasive. The examiner does not assert that adjusting the disaccharide to buffer ratio directly is itself obvious. Rather, adjusting the trehalose content and the pH buffer individually is obvious based on the teachings of the prior art and the ratio of trehalose to pH buffer is a necessary consequence of adjusting the trehalose and pH buffer content. The trehalose and pH buffer are both variable parameters as it is obvious that trehalose may vary from 0-30% and to adjust the pH buffer from 0.1 mM to 100 mM or greater than about 50 mM. The inclusion of trehalose and pH buffer is obvious and it is known that their inclusion is not limited to a specific amount but is instead variable and it is well within the scope of one of ordinary skill, when presented with a variable amount, to determine the amount that is optimal for their desired use. Further, based on the teachings of Law that liposomal stability is increased under high ionic strength conditions, it would be obvious to adjust the pH buffer content with the liposomal stability in mind. The applicant asserts that the example calculation using 2.5% trehalose incorporate subject matter from the claim not taught by the applied references and is unavailable to establish prima facie obviousness. The examiner disagrees with this assessment as the amount of trehalose is obvious to vary from 0-30% and the selection of 2.5% in the calculation (which is encompassed by the 0-30% as taught) was chosen merely as exemplary to highlight the fact that adjusting the trehalose and pH buffer within the ranges taught by art necessarily results in disaccharide to buffer ratios that encompass the claimed ratio and thereby render it obvious. In summary, even though the art does not address the ratio of disaccharide to buffer directly, the claimed ratio is nonetheless obvious as a matter of adjusting the trehalose and pH buffer in the amounts obvious from the art as the ratio is a necessary consequence of having the trehalose and pH buffer present.
Applicant suggests that Smith recognizes the polymer P188 is a result effect variable when the sugar concentration is held constant (page 9 of remarks) but this is not persuasive as this section of Smith is testing P188 and it is reasonable that other parameters such as the sugar would be held constant in this experiment and this does not speak to whether the sugar is considered variable, which Smith elsewhere teaches (e.g. [0030]). Applicant points to example 4 of their specification which exemplifies the disaccharide:buffer ratio and suggests that low trehalose to PBS ratio favored increased encapsulation and decreased LNP size corresponding to higher stability (page 9 of remarks). The examiner notes that the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."). As far as the applicant may be asserting unexpected results from example 4, the examiner notes that the data presented is not persuasive toward this end. For instance, the data is not commensurate in scope with the instant claims as only one disaccharide and buffer were tested in a limited range of concentrations. Further, the claimed ratio is from 0.2:1 to 0.5:1 which includes the entire range of data tested, including the portion with a higher ratio which the applicant described as having less stability. Similarly, the data appears to be merely a trend that occurs with decreasing trehalose content which one of ordinary skill would recognize and optimize for instead of something that is unexpected. Further, the testing demonstrated does not clearly establish the disaccharide:buffer ratio as the effective variable versus just the disaccharide content. The ratio was adjusted by varying the ratio from 3% to 1.69% but data is not presented to show that the same performance is observed at a constant ratio while the trehalose is varied (i.e. adjusting the trehalose and buffer content to keep the ratio constant) or at different ratios while the trehalose is constant (i.e. maintain the trehalose content while varying the buffer content). The single sugar and buffer tested along with what appears to be single data point for each formulation is insufficient to establish a clear role to the disaccharide to buffer ratio. Further, it is worth noting that the formulations attested by the applicant as having poorer stability have the trehalose content at ~2.7-3% which is within the amount claimed (claim 24) and thus it appears that the claims are covering the formulations that are described as having worse stability instead of better stability.
Overall, the examiner is not persuaded by the applicants remarks and maintains the claims as obvious for the reasons provided above.
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 1-4, 6, 8, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 12, 16, 18, 19, 21, 22, 31, 42, 55, 56, 57, 58, 60, 67-97, of U.S. Patent No. 11,771,652 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claims 1, 2, 57 and 58 of the ‘652 patent recites a pharmaceutical composition comprising a nucleic acid molecule encapsulated in a LNP which comprises cKK-E10 at 40%, DMG-PEG2000 at 1.5%, cholesterol at 28.5% and DOPE at 30%. Claim 12 recites a diameter of 30-200 nm. Claims 16, 18, 19, 21, 22, 31, 56, 60, 67-79, and 84-96 recite specifics of the mRNA (e.g., type and amount) that are more specific than the generic recitation of the mRNA in the instant claims. Claim 80 recites a phosphate buffer saline. Claim 81 recites trehalose and claim 82 recites trehalose at 10%. Claims 55 and 83 recite the composition in the form of a kit. Claim 97 recites that the antigen may be a viral antigen.
The claims of the ‘652 patent do not recite, a pH of 7.0-7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claims 1 and 48, an amount of disaccharide from 2.5-3.0% and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM, an N/P ratio of 3:1-5:1 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Smith and Law.
The teachings of Karve, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have the nanoparticle composition of the ‘652 patent at a pH of 4-8 and the mRNA at 0.1-1.0 mg/mL as rendered obvious by Karve and Smith as suitable for mRNA encapsulated nanoparticles. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would be obvious to have trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and buffer and salt concentration values and the ratio of the disaccharide to the buffer of 0.2:1-0.5:1. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘652 patent and Karve, Smith and Law would necessarily meet.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending US Patent No. 12/569,572 (previously application 17/016,860) in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 1 recites a pharmaceutical composition for treating FRDA comprising an mRNA encoding frataxin protein where the mRNA is encapsulated in a liposome and recites polynucleotide sequences and claim 2 recites delivery forms and claim 3 recites an amount of mRNA. Claim 10 recites that the liposome comprises cationic lipids, non-cationic lipids (such as DOPE, see claim 12) and PEG modified lipids and claim 13 includes cholesterol. Claim 14 includes sphingomyelin. Claim 4-9 recite specific characteristics of the mRNA.
The claims of the ‘572 patent do not recite the inclusion of cKK-E10, DMG-PEG-2000, a pH buffer, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), and ionic strength of 150 -750 mM, an N/P ratio of 3-5 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong, Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to use cKK-E10, DMG-PEG2K, and cholesterol in the nanoparticle of the ‘860 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations.It further would be obvious to have trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2:1-0.5:1. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘860 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘860 application and over Karve, Dong, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-17 of U.S. Patent No. 11,559,561 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 14 of the ‘561 patent is directed to a composition for treatment PCD comprising mRNA encoding DNAH5 encapsulated in a liposome wherein the liposome comprises cationic lipids, non-cationic lipids, and PEG-modified lipids. Claim 15 recites specific characteristics of the mRNA and claim 16 recites that the liposome is 100 nm in diameter or less and claim 17 recites an excipient.
The claims of the ‘561 patent do not recite, cKK-E10, DOPE, DMG-PEG2000 or cholesterol or a pH buffer and a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, a sugar (disaccharide) in an amount from 2.5-3.0% and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), and ionic strength of 150 -750 mM, an N/P ratio of 3-5 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong, Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to use cKK-E10, DMG-PEG2K, and cholesterol in the liposome of the ‘561 patent as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong and it would have been obvious to have the composition of the ‘561 patent at a pH of 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would be obvious to have trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsultated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2:1-0.5:1. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘561 patent and Karve, Smith and Law would necessarily meet.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7, 17, 18, 20, 23, 26, 30, 31, 37, 44 and 47 of copending Application No. 17/923,470 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claims 1, 4, 7, 17, and 18 of the ‘470 application recites a codon-optimized mRNA molecule comprising a coding sequence encoding CFTR protein. Claims 20, 23 and 26 recite the form of a pharmaceutical composition. Claim 28 recites that the mRNA is encapsulated within a liposome. Claim 30 recites that the liposome comprises cationic lipids, non-cationic lipids and PEG-modified lipids and claim 31 includes cholesterol (see also claim 37). Claim 44 recites that the liposome has a size less than about 100 nm and claim 47 includes an CFTR potentiator, corrector and/or activator.
The claims of the ‘470 application do not recite the inclusion of cKK-E10, DOPE and DMG-PEG-2000, a pH buffer, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), and ionic strength of 150 -750 mM, an N/P ratio of 3-5 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong, Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to use cKK-E10, DOPE and DMG-PEG2K, in the liposome of the ‘470 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would be obvious to have trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2:1-0.5:1. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘470 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘470 application and over Karve, Dong, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 52 and 54 of copending Application No. 17/923,839 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 52 of the ‘839 application recites a composition for treatment of PCD comprising an mRNA encoding DNAI1 encapsulated in a liposome, wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids and one or more PEG modified lipids. Claim 54 recites coding sequences of the mRNA.
The claims of the ‘839 application do not recite the inclusion of cKK-E10, DOPE, DMG-PEG-2000 and cholesterol in the liposome, a pH buffer, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2:1 – 0.5:1 (instant claim 2), and ionic strength of 150 -400 mM, an N/P ratio of 3-5 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong, Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to use cKK-E10, DOPE and DMG-PEG2K, in the liposome of the ‘839 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would be obvious to have trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘839 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘839 application and over Karve, Dong, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 32, 41-54 of copending Application No. 18/352,615 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 31 recites a composition comprising mRNA encoding heavy and light chains of an antibody where the mRNA is encapsulated in a LNP. Claim 32 recites specific parameters of the mRNA. Claims 41-55 recite parameters of the mRNA.
The claims of the ‘615 application do not recite cKK-E10, DOPE, DMG-PEG-2000 and cholesterol in the LNP, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM, an N/P ratio of 3:1-5:1 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Smith and Law.
The teachings of Karve, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have to used cKK-E10 and DMG-PEG2K, in the liposome of the ‘615 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It further would have been obvious to use trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It would have been obvious to have the pH of the ‘615 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘615 application and over Karve, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 11, 17, 23, 27, 28, 30, 52, 66, 72, 80, 81, 107-109, 117, 131, 147 and 166 of copending Application No. 18/286,029 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 1 recites a lipid nanoparticle comprising an mRNA encapsulated with the nanoparticle and the lipid components of a cationic lipid (greater than 40%), a non-cationic lipid (less than 25%), a PEG-modified lipid component and a cholesterol component. Claims 117 and 131 recite that the non-cationic lipid is DOPE and that the PEG-modified lipid is DMG-PEG2K. Claim 166 recites that the mRNA is at 0.4-0.8 mg/mL
The claims of the ‘029 application do not recite cKK-E10 as a lipid in the LNP, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM and an N/P ratio of 3:1-5:1 (instant claim 37) and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have to used cKK-E10, in the liposome of the ‘029 application as it is a known lipid for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would have been obvious to use trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘029 composition from 4-8 as taught by Smith. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘029 application and over Karve, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 89-98 and 164-171 of copending Application No. 18/602,227 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 89 of the ‘227 application recites a composition comprising mRNA encapsulating lipid nanoparticles with a cationic lipid, a non-cationic lipid and a PEG-modified lipid and a second empty lipid nanoparticle.
The claims of the ‘227 application do not recite cKK-E10, DOPE, DMG-PEG-2000 and cholesterol in the LNP, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM, an N/P ratio of 3:1-5:1 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong, Smith and Law.
The teachings of Karve, Dong Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have to used DOPE, cKK-E10 and DMG-PEG2K, in the liposome of the ‘615 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would have been obvious to use trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘227 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘227 application and over Karve, Dong, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26-40 of copending Application No. 18/753,746 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 26 recites a composition comprising a mixture of lipid nanoparticles encapsulating mRNA and preformed lipid nanoparticles. Claims 32 and 33 recite PEG-modified lipids.
The claims of the ‘746 application do not recite cKK-E10, DOPE, DMG-PEG-2000 and cholesterol in the LNP, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM, an N/P ratio of 3:1-5:1 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have to used DOPE, cKK-E10 and DMG-PEG2K, in the liposome of the ‘615 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would have been obvious to use trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘746 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘746 application and over Karve, Dong, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-59 and 65-70 of copending Application No. 18/782,767 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 46 recites a composition comprising mRNA encapsulated within lipid nanoparticles comprising cKK-E12. Claim 58 recites cholesterol.
The claims of the ‘767 application do not recite cKK-E10, DOPE, DMG-PEG-2000 and cholesterol in the LNP, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM, an N/P ratio of 3:1-5:1 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong, Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have to used cKK-E10 and DMG-PEG2K, in the liposome of the ‘615 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would have been obvious to use trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘839 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘767 application and over Karve, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 82-85 of copending Application No. 18/910,694 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
Claim 82 recites mRNA-LNPs where the mRNA encodes a protein/peptide and the mRNA-LNPs comprise cationic lipids, non-cationic lipids, less than 0.5% PEG-modified lipids and less than 0.05% of amphiphilic polymer.
The claims of the ‘694 application do not recite cKK-E10, DOPE, DMG-PEG-2000 and cholesterol in the LNP, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (sugar, disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM, an N/P ratio of 3:1-5:1 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have to used cKK-E10 and DMG-PEG2K, in the liposome of the ‘694 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would have been obvious to use trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘694 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘694 application and over Karve, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 15, 18, 23, 24, 27, 31, 37, 38, 41, 43-45 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41-59 of copending Application No. 19/027,351 in view of Karve et al. (US 2018/0153822, published 07 Jun 2018), Dong et al. (PNAS, March 18, 2014, vol. 111, no. 11, 3955–3960), Smith et al. (WO 2017/218704, published 21 Dec 2017, as listed on the IDS filed 01 March 2023) and Law et al. (US 4,933,421, published 12 Jun 1990) as evidenced by Toppr (Chemistry Formulas-Ionic Strength Formula) and as evidenced by the instant specification.
The claims of the ‘351 application recite a composition with an mRNA encoding a protein or peptide encapsulated in a lipid nanoparticle where the lipid nanoparticle comprises a PEG-modified lipid, cationic lipid, non-cationic lipid (e.g. DOPE claim 46) and cholesterol. The size of the nanoparticle is less than 75 nm (claim 51).
The claims of the ‘351 application do not recite cKK-E10, DMG-PEG-2000 and in the LNP, a pH of 7.0 to 7.5, the buffer and NaCl of claim 15, the ionic strength an concentration amounts of claim 1, an amount of trehalose (disaccharide) and a ratio disaccharide to buffer of 0.2 – 0.5 (instant claim 2), ionic strength of 150 -750 mM, an N/P ratio of 3:1-5:1 (instant claim 37), an mRNA concentration of 0.05 – 1.0 mg/mL (instant claim 41), and does not recite the reduced pain of claim 45. These deficiencies are made up for in the teachings of Karve, Dong Smith and Law.
The teachings of Karve, Dong, Smith and Law are described supra.
Thus, it would have been obvious to one or ordinary skill in the art to have to used cKK-E10 and DMG-PEG2K, in the liposome of the ‘351 application as these are known lipids for forming nanoparticles for encapsulating mRNA as made obvious by Karve and Dong. It would have been obvious to use a buffer such as a phosphate buffer and 0-300 mM NaCl, as these are known from Karve and Smith for liposomal formulations. It further would have been obvious to use trehalose from 0-30%, as taught by Smith, and to adjust the pH buffer to a high ionic strength in the composition to maintain stability of the encapsulated macromolecule, as taught by Law, thus making obvious the instant ionic strength values and the ratio of the disaccharide to the buffer of 0.2-0.5. For example, assuming an aqueous solution, the concentration of 0-30% w/w trehalose can be approximated as 0-876 mM. Assuming the percentage of sugar as 2.5% as in the instant claims which is rendered obvious as described above this would result in a concentration of approximately 73 mM and further assuming a 100 mM – 300 mM buffer concentration as in the instant claims and which is rendered obvious as described above, this would result in a sugar to buffer ratio ranging from 0.24:1 to 0.73:1 which covers the ratio as instantly claimed and indicating the obviousness of the claimed ratio. It would have been obvious to have the pH of the ‘351 composition from 4-8 as taught by Smith and the mRNA at 0.1-1.0 mg/mL as taught by Karve as suitable for mRNA encapsulated nanoparticles. Regarding the absence of an amphiphilic polymer, the reference claims and the art do not require an amphiphilic polymer and thus the limitation is met. Further, the reduced pain upon administration is a functional property of the composition made obvious by the ‘351 application and over Karve, Smith and Law would necessarily meet.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 30 Jan 2026 have been fully considered but they are not persuasive. Applicant argues against the double patenting rejections for the same reasons given against the prior art applied to the 103 rejection. The examiner notes that the response to these arguments has been given in the response to arguments for the 103 above.
Conclusion
No claims are allowed.
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).
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/E.C.M./Examiner, Art Unit 1619 /ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600
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