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
Claims 1 – 2, 5 – 6, 31, 37, 39, 42, 45, 49, 69, 73, 80, 84, 86, 128, 131, 133, 147, and 149 are pending in this application and are examined on the merits herein. Applicant’s amendment, submitted September 18, 2023, is entered, wherein claims 1 – 2, 5 – 6, 31, 37, 39, 42, 45, 49, 69, 73, 80, 84, 86, 128, 131 and 149 are amended and claims 3 – 4, 7 – 30, 32 – 36, 38, 40 – 41, 43 – 44, 46 – 48, 50 – 68, 70 – 72, 74 – 79, 81 – 83, 85, 87 – 127, 129 – 130, 132, 134 – 136, 148, and 150 – 151 are canceled.
Priority
This application is a national stage application of PCT/US2021/053182, filed October 1, 2021, which claim benefit of domestic application 63/086,095, filed October 1, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/31/2023 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 2 and 6 are objected to because of the following informalities:
Claim 2, line 1, “a” immediately after “exerts” should read “the”.
Claim 6, lines 3 – 4, recites “i.” and “ii.”. According to MPEP § 608.01(m), each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claim except for abbreviation. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995).
Claim 131, line 3, “claim 129” should read “claim 128” because claim 129 has been canceled.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 80 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 80 recites the limitation "the collecting of the solubilized mRNA" in lines 1 – 2. There is insufficient antecedent basis for this limitation in the claim. Claim 80 depends from claim 31, which depends from claim 1, however, claim 1 never recites “the collecting of the solubilized mRNA”. It is unclear which “collecting of the solubilized mRNA” the claim is referring to.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 – 2, 5 – 6, 31, 37, 39, 42, 45, 69, 73, 80, 84, 86, 128, and 131 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Derosa et al. (WO2018/157141A1) with evidence provided by IQVIA (IQVIA Laboratories “How To” Guide, 2025, Reference included with PTO-892).
Independent claim 1 is directed to a method for purifying mRNA, wherein the method comprises the steps of (a) precipitating mRNA from a solution comprising one or more protein and/or short abortive transcript contaminants from manufacturing the mRNA to provide a suspension comprising precipitated mRNA; (b) loading the suspension comprising the precipitated mRNA into a filtering centrifuge comprising a filter wherein the precipitated mRNA is retained by the filter; (c) washing the retained precipitated mRNA by adding a wash buffer to the filtering centrifuge; and (d) recovering the retained precipitated mRNA from the filter, wherein the filtering centrifuge is operated during loading step (b) and washing step (c) at a centrifuge speed that exerts a gravitational (g) force of less than 1300 g. Dependent claim 2 is directed to the method, wherein the centrifuge speed exerts a gravitational (g) force of between about 300 g and about 1300 g. Dependent claim 5 is directed to the method, wherein the filtering centrifuge is operated at the same centrifuge speed during loading step (b) and washing step (c). Dependent claim 6 is directed to the method, wherein the recovering step comprises the steps of solubilizing the retained precipitated mRNA and collecting the solubilized mRNA. Dependent claim 31 is directed to the method, wherein step (a) further comprises adding at least one filtration aid to the suspension. Dependent claim 37 is directed to the method, wherein the suspension comprises at least 10 g of mRNA. Dependent claim 39 is directed to the method, wherein the filter comprises a porous substrate. Dependent claim 42 is directed to the method, wherein the filter has an average pore size of about 0.01 micron to about 200 microns. Dependent claim 45 is directed to the method, wherein a volume of the wash buffer is between about 0.5 L/g mRNA and about 8 L/g mRNA. Dependent claim 69 is directed to the method, wherein the recovering step occurs while the filtering centrifuge is in operation or not in operation. Dependent claim 73 is directed to the method, wherein the solubilizing step comprises dissolving the mRNA in an aqueous medium. Dependent claim 80 is directed to the method, wherein the collecting step comprises one or more steps of separating the filtration aid from the solubilized mRNA. Dependent claim 84 is directed to the method, wherein the filtering centrifuge is a continuous centrifuge. Dependent claim 86 is directed to the method, wherein the mRNA suspension is loaded into the filtering centrifuge at a rate of about 1 liter/min to about 60 liter/min. Independent claim 128 is directed to a purified mRNA obtained by the method. Independent claim 131 is directed to a method for treating a disease or disorder comprising administering to a subject in need thereof.
Derosa et al. teach methods for large-scale purification of mRNA (Abstract). In particular, the invention provides methods of purifying mRNA based on filtering centrifuge, resulting in unprecedented large-scale production of mRNA with high purity and integrity (para. [0005]). Such a method uses a filtering centrifuge platform in conjunction with alternate precipitation and processing methods to successfully, capture, wash, and collect mRNA manufactured at a scale capable of meeting most clinical and commercial needs (para. [0123]). The method includes steps of providing a suspension comprising precipitated mRNA; and centrifuging the suspension in a centrifuge comprising a porous substrate, such as a removable porous substrate, and the precipitated mRNA is captured on the porous substrate (para. [0006]). The provided suspension comprises prematurely aborted RNA sequences and/or enzyme reagents used in in vitro synthesis (para. [0042]). In an embodiment, the method is for purifying at least about 10 grams mRNA (para. [0007]). In example 8, the mRNA was purified using a horizontal centrifuge with the loading rate of 2.0 L/min (para. [0300]). The precipitated mRNA composition includes at least one dispersant, wherein the dispersant is a filtration aid (para. [0152]). In embodiments, a porous substrate is a filter paper or a filter cloth (para. [0012]). A porous substrate used in any of the methods described herein may feature variety of filter pore sizes and types. For example, a centrifuge filter can have an average pore size of about 0.01 micron to about 200 microns (para. [0220]). In some embodiments, the centrifuge is a continuous centrifuge (para. [0029]). The speed of the centrifuging of the mRNA suspension is between about 2000 RPM and about 4000 RPM, for example 2500 RPM (para. [0164]). In some embodiments, a method further comprises a step of washing the purified mRNA composition with a solvent (para. [0021]). In some embodiments, a washing occurs via centrifugation at a speed between about 100 RPM to about 3000 RPM (para. [0022]). The elution wash volume used for centrifuge mRNA purification is 1.0 L per 2 grams of mRNA (Table 1). In some embodiments, the method further comprises a step of solubilizing the purified mRNA in an aqueous medium, thereby obtaining a solution comprising purified mRNA (para. [0026]). Moreover, the invention features a method for treating a disease or disorder comprising administering to a subject in need thereof any composition comprising purified mRNA as described (para. [0071]).
According to IQVIA, an average centrifuge rotor radius is 5 – 15 cm (page 2). The gravitational force of 2500 RPM for 15 cm rotor radius is 1048 g after calculation, which addresses the limitation of the centrifuge speed recited in claims 1 – 2.
For these reasons, Derosa et al. with evidence provided by IQVIA anticipate the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 2, 5 – 6, 31, 37, 39, 42, 45, 49, 69, 73, 80, 84, 86, 128, 131, and 133 is/are rejected under 35 U.S.C. 103 as being unpatentable over Derosa et al. (WO2018/157141A1) with evidence provided by IQVIA (IQVIA Laboratories “How To” Guide, 2025, Reference included with PTO-892). Claims 1 – 2, 5 – 6, 31, 37, 39, 42, 45, 69, 73, 80, 84, 128, and 131 are rejected here because they have been rejected by the primary reference under 102.
Regarding claims 1 – 2, 5 – 6, 31, 37, 39, 42, 45, 49, 69, 73, 80, 84, 86, 128, 131, and 133, Derosa et al. teach an invention relates to methods for large-scale purification of mRNA (Abstract). In particular, the invention provides methods of purifying mRNA based on filtering centrifuge, resulting in unprecedented large-scale production of mRNA with high purity and integrity (para. [0005]). Such method uses a filtering centrifuge platform in conjunction with alternate precipitation and processing methods to successfully, capture, wash, and collect mRNA manufactured at a scale capable of meeting most clinical and commercial needs (para. [0123]). The method includes steps of providing a suspension comprising precipitated mRNA; and centrifuging the suspension in a centrifuge comprising a porous substrate, such as a removable porous substrate, and the precipitated mRNA is captured on the porous substrate (para. [0006]). The provided suspension comprises prematurely aborted RNA sequences and/or enzyme reagents used in in vitro synthesis (para. [0042]). In an embodiment, the method is for purifying at least about 10 grams mRNA (para. [0007]). In example 8, the mRNA was purified using a horizontal centrifuge with the loading rate of 2.0 L/min (para. [0300]). The precipitated mRNA composition includes at least one dispersant, wherein the dispersant is a filtration aid (para. [0152]). In embodiments, a porous substrate is a filter paper or a filter cloth (para. [0012]). A porous substrate used in any of the methods described herein may feature variety of filter pore sizes and types. For example, a centrifuge filter can have an average pore size of about 0.01 micron to about 200 microns (para. [0220]). In some embodiments, the centrifuge is a continuous centrifuge (para. [0029]). The speed of the centrifuging of the mRNA suspension is between about 2000 RPM and about 4000 RPM, for example 2500 RPM (para. [0164]). The surface area of a vertical filtering centrifuge and horizontal filtering centrifuge are 438 cm2 and 1400 cm2 (para. [0261]). In some embodiments, a method further comprises a step of washing the purified mRNA composition with a solvent (para. [0021]). In some embodiments, a washing occurs via centrifugation at a speed between about 100 RPM to about 3000 RPM (para. [0022]). The elution wash volume used for centrifuge mRNA purification is 1.0 L per 2 grams of mRNA in 5 minutes elution time (Table 1). In some embodiments, the method further comprises a step of solubilizing the purified mRNA in an aqueous medium, thereby obtaining a solution comprising purified mRNA (para. [0026]). Moreover, the invention features a method for treating a disease or disorder comprising administering to a subject in need thereof any composition comprising purified mRNA as described (para. [0071]).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the loading parameter as taught by Derosa et al. to achieve the claimed method because Derosa et al. teach the loading rate of mRNA, the loading rate of the wash, and the filter surface area. After calculation, the loading rate of elution wash is 4.57 L/min/m2 and 14.3 L/min/m2. One would have performed routine experimentation to discover the best loading rate at different stages for optimal mRNA purification. According to IQVIA, an average centrifuge rotor radius is 5 – 15 cm (page 2). The gravitational force of 2500 RPM for 15 cm rotor radius is 1048 g after calculation, which addresses the limitation of the centrifuge speed recited in claims 1 – 2. Therefore, one of the ordinary skill in the art before the effective filing date of the claimed invention to modify the loading parameter as taught by Derosa et al. to achieve the claimed method because Derosa et al. teach the loading parameters of the claimed method.
Claims 147 and 149 are rejected under 35 U.S.C. 103 as being unpatentable over Derosa et al. (WO2018/157141A1) with evidence provided by IQVIA (IQVIA Laboratories “How To” Guide, 2025, Reference included with PTO-892) as applied to claims 1 – 2, 5 – 6, 31, 37, 39, 42, 45, 49, 69, 73, 80, 84, 86, 128, 131, and 133 above, and further in view of Schmitz (Analytical Biochemistry, 2006, Vol. 354, Issue 2, page 311 – 313, Reference included with PTO-892).
Regarding claims 147 and 149, the references teach the limitations discussed above. Derosa et al. teach that about 250 g of filtration aid is used (para. [0291]). Derosa et al. further teach that the dried mRNA precipitate is stored in a sterile bottle at -20 ⁰C for long-term storage.
However, these references do not teach the composition comprising amphiphilic polymer, wherein the amphiphilic polymer comprises PEG-6000.
Schmitz teaches the purification of nucleic acids by selective precipitation with polyethylene glycol 6000 (PEG6000) (Title). Schmitz discloses that selective precipitation of the product with PEG6000 provides comparable results and such procedure is both cheaper and quicker (page 311, Left Col, para. 1). Moreover, plasmid DNA template can be easily removed from the in vitro transcripts in this procedure, offering two advantages: (i) the DNA can be reused for further transcriptions and (ii) the employment of DNase can be avoided, as residual contamination of the transcripts by template DNA is barely detectable (page 313, Right Col., para. 2). Different amounts of PEG6000 are used depends on the products being purified, for example, 34 μL of 50% PEG6000 is used for PCR products with lengths of 120 – 400 bp (page 311, Right Col., para. 2).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine mRNA and filtration aid as taught by Derosa et al. with PEG6000 in view of Schmitz because Schmitz teaches that using PEG6000 to precipitate nucleic acid is cheaper and quicker. One would have been motivated to combine mRNA and filtration aid as taught by Derosa et al. with PEG6000 in view of Schmitz because of the benefits disclosed by Schmitz. For the relative concentration of mRNA, PEG6000, and filtration aid, one would have performed routine experimentation to discover the best relative concentration for optimal precipitation of the mRNA. Moreover, Derosa et al. do not teach the addition of RNase. It is expected that the composition or method does not contain any RNase. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine mRNA and filtration aid as taught by Derosa et al. with PEG6000 in view of Schmitz because Derosa et al. teach some of the claimed components and Schmitz teaches that PEG6000 is an alternative for precipitating nucleic acid.
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, 37, 39, and 69 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2 and 6 – 7 of U.S. Patent No. 12410422B2 with evidence provided by IQVIA (IQVIA Laboratories “How To” Guide, 2025, Reference included with PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘422B2 anticipate the claimed invention.
a. Independent claim 1 is directed to a method for purifying mRNA, wherein the method comprises the steps of (a) precipitating mRNA from a solution comprising one or more protein and/or short abortive transcript contaminants from manufacturing the mRNA to provide a suspension comprising precipitated mRNA; (b) loading the suspension comprising the precipitated mRNA into a filtering centrifuge comprising a filter wherein the precipitated mRNA is retained by the filter; (c) washing the retained precipitated mRNA by adding a wash buffer to the filtering centrifuge; and (d) recovering the retained precipitated mRNA from the filter, wherein the filtering centrifuge is operated during loading step (b) and washing step (c) at a centrifuge speed that exerts a gravitational (g) force of less than 1300 g. Dependent claim 2 is directed to the method, wherein the centrifuge speed exerts a gravitational (g) force of between about 300 g and about 1300 g. Dependent claim 37 is directed to the method, wherein the suspension comprises at least 10 g of mRNA. Dependent claim 39 is directed to the method, wherein the filter comprises a porous substrate. Dependent claim 69 is directed to the method, wherein the recovering step occurs while the filtering centrifuge is in operation or not in operation.
‘422B2 teaches a composition comprising at least 10 grams of dried purified mRNA, wherein said mRNA is obtained by a method for large-scale purification of mRNA, comprising the steps of providing a suspension comprising precipitated mRNA manufactured by in vitro synthesis; centrifuging the suspension at a speed of about 1000 to 5000 RPM in a centrifuge comprising a porous substrate such that the precipitated mRNA is captured on the porous substrate, and contaminants are removed from the precipitated to provide captured purified mRNA; washing the captured purified mRNA composition with a solvent; and drying the captured purified mRNA, thereby obtaining dried purified mRNA in the form of a solid, wherein the purified mRNA is substantially free of prematurely aborted RNA sequences, DNA templates, and one or more enzyme reagents used in the in vitro synthesis (claim 1). The suspension comprises precipitated manufactured by in vitro synthesis comprises at least about 1 kg (claim 2). The washing and drying of the captured purified mRNA occurs via centrifugation (claims 6 – 7).
According to IQVIA, an average centrifuge rotor radius is 5 – 15 cm (page 2). The gravitational force of 2500 RPM for 15 cm rotor radius is 1048 g after calculation, which addresses the limitation of the centrifuge speed recited in claims 1 – 2.
For these reasons above, ‘422B2 anticipates the claimed invention.
Claims 1 – 2, 31, 37, 39, and 128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 29, 56, and 94 of copending Application No. 17/871,121 in view of Derosa et al. (WO2018/157141A1) with evidence provided by IQVIA (IQVIA Laboratories “How To” Guide, 2025, Reference included with PTO-892).
b. Regarding claims 1 – 2, 31, 37, 39, and 128, ‘121 teaches a method of purifying mRNA comprising (a) precipitating the mRNA in a suspension comprising a high molar salt solution and an amphiphilic polymer to provide precipitated mRNA; (b) capturing the precipitated mRNA; (c) washing the precipitated mRNA with a wash solution; and (d) solubilizing the precipitated mRNA to obtain a purified mRNA composition (claim 1). The amphiphilic polymer is a PEG (claim 4). ‘121 teaches that the capturing step occurs on a microfiltration (claim 29). In the method of purifying mRNA, a filter aid is used (claim 36). The precipitated mRNA is about 1 kg (claim 56). Finally, ‘121 teaches a purified mRNA composition that is substantially free of contaminants comprising abortive RNA species (claim 94).
However, ‘121 does not teach the use of filtering centrifuge and the centrifuge speed.
Derosa et al. teach an invention relates to methods for large-scale purification of mRNA (Abstract). In particular, the invention provides methods of purifying mRNA based on filtering centrifuge, resulting in unprecedented large-scale production of mRNA with high purity and integrity (para. [0005]). Such method uses a filtering centrifuge platform in conjunction with alternate precipitation and processing methods to successfully, capture, wash, and collect mRNA manufactured at a scale capable of meeting most clinical and commercial needs (para. [0123]). The method includes steps of providing a suspension comprising precipitated mRNA; and centrifuging the suspension in a centrifuge comprising a porous substrate, such as a removable porous substrate, and the precipitated mRNA is captured on the porous substrate (para. [0006]). The provided suspension comprises prematurely aborted RNA sequences and/or enzyme reagents used in in vitro synthesis (para. [0042]). The speed of the centrifuging of the mRNA suspension is between about 2000 RPM and about 4000 RPM, for example 2500 RPM (para. [0164]). In some embodiments, a method further comprises a step of washing the purified mRNA composition with a solvent (para. [0021]). In some embodiments, a washing occurs via centrifugation at a speed between about 100 RPM to about 3000 RPM (para. [0022]).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of purifying mRNA as taught by ‘121 with the step of filtering centrifugation in view of Derosa et al. because both references teach the purification of mRNA and Derosa et al. demonstrate that incorporating centrifugation into the process yield the same result, which is purification of mRNA. One would have been motivated to combine the method of purifying mRNA as taught by ‘121 with the step of filtering centrifugation in view of Derosa et al. because the combination will yield predictable results. According to IQVIA, an average centrifuge rotor radius is 5 – 15 cm (page 2). The gravitational force of 2500 RPM for 15 cm rotor radius is 1048 g after calculation, which addresses the limitation of the centrifuge speed recited in claims 1 – 2. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to combine the method of purifying mRNA as taught by ‘121 with the step of filtering centrifugation in view of Derosa et al. because it is known in the art that incorporating centrifugation into the process will also result in purified mRNA.
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 2, 31, 37, 39, 128, and 131 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 8 – 9, 13, 21, 27, 111, and 113 of copending Application No. 17/130,114 (reference application) with evidence provided by IQVIA (IQVIA Laboratories “How To” Guide, 2025, Reference included with PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘114 anticipate the claimed invention.
c. Independent claim 1 is directed to a method for purifying mRNA, wherein the method comprises the steps of (a) precipitating mRNA from a solution comprising one or more protein and/or short abortive transcript contaminants from manufacturing the mRNA to provide a suspension comprising precipitated mRNA; (b) loading the suspension comprising the precipitated mRNA into a filtering centrifuge comprising a filter wherein the precipitated mRNA is retained by the filter; (c) washing the retained precipitated mRNA by adding a wash buffer to the filtering centrifuge; and (d) recovering the retained precipitated mRNA from the filter, wherein the filtering centrifuge is operated during loading step (b) and washing step (c) at a centrifuge speed that exerts a gravitational (g) force of less than 1300 g. Dependent claim 2 is directed to the method, wherein the centrifuge speed exerts a gravitational (g) force of between about 300 g and about 1300 g. Dependent claim 31 is directed to the method, wherein step (a) further comprises adding at least one filtration aid to the suspension. Dependent claim 37 is directed to the method, wherein the suspension comprises at least 10 g of mRNA. Dependent claim 39 is directed to the method, wherein the filter comprises a porous substrate. Independent claim 128 is directed to a purified mRNA obtained by the method. Independent claim 131 is directed to a method for treating a disease or disorder comprising administering to a subject in need thereof.
‘114 teaches a method of purifying mRNA comprising steps of providing a suspension comprising precipitated mRNA; and centrifuging the suspension in a centrifuge comprising a porous substrate such that the precipitated mRNA is captured on the porous substrate, thereby purifying contaminants from the mRNA (claim 1). The method comprising purifying at least 1 kg mRNA, wherein the purified mRNA is substantially free of prematurely aborted RNA sequences and/or enzyme reagents (claim 2). The method further comprising a step of first producing the suspension of precipitated mRNA by providing a solution comprising mRNA and adding to the solution one or more agents that promote precipitation of mRNA (claim 8). The suspension comprises precipitated mRNA and at least one filtration aid that is a dispersant (claim 9). The speed of the centrifuging step is about 2500 RPM (claim 13). The method further comprises a step of washing the purified mRNA composition with a solvent and a step of drying the captured mRNA (claims 21 and 27). ‘114 further teaches a composition comprising purified mRNA and the method of treating a disease or disorder comprising administering to a subject in need thereof (claims 111 and 113).
According to IQVIA, an average centrifuge rotor radius is 5 – 15 cm (page 2). The gravitational force of 2500 RPM for 15 cm rotor radius is 1048 g after calculation, which addresses the limitation of the centrifuge speed recited in claims 1 – 2.
For these reasons above, ‘114 with evidence provided by IQVIA anticipate the claimed invention.
This is a provisional nonstatutory double patenting rejection.
Claims 1 – 2, 31, 37, 39, 69, and 128 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 3, 5 – 6, and 14 of U.S. Patent No. 10975369B2 with evidence provided by IQVIA (IQVIA Laboratories “How To” Guide, 2025, Reference included with PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘369B2 anticipate the claimed invention.
d. Independent claim 1 is directed to a method for purifying mRNA, wherein the method comprises the steps of (a) precipitating mRNA from a solution comprising one or more protein and/or short abortive transcript contaminants from manufacturing the mRNA to provide a suspension comprising precipitated mRNA; (b) loading the suspension comprising the precipitated mRNA into a filtering centrifuge comprising a filter wherein the precipitated mRNA is retained by the filter; (c) washing the retained precipitated mRNA by adding a wash buffer to the filtering centrifuge; and (d) recovering the retained precipitated mRNA from the filter, wherein the filtering centrifuge is operated during loading step (b) and washing step (c) at a centrifuge speed that exerts a gravitational (g) force of less than 1300 g. Dependent claim 2 is directed to the method, wherein the centrifuge speed exerts a gravitational (g) force of between about 300 g and about 1300 g. Dependent claim 31 is directed to the method, wherein step (a) further comprises adding at least one filtration aid to the suspension. Dependent claim 37 is directed to the method, wherein the suspension comprises at least 10 g of mRNA. Dependent claim 39 is directed to the method, wherein the filter comprises a porous substrate. Dependent claim 69 is directed to the method, wherein the recovering step occurs while the filtering centrifuge is in operation or not in operation. Independent claim 128 is directed to a purified mRNA obtained by the method.
‘369B2 teaches a method for large-scale purification of mRNA, comprising steps of providing a suspension comprising at least about 10 grams of precipitated mRNA manufactured by in vitro synthesis and centrifuging the suspension at a speed of about 1000 to 5000 RPM in a centrifuge comprising a porous substrate such that the precipitated mRNA is captured on the porous substrate and contaminants are removed from the precipitated mRNA to provide a purified mRNA, wherein the purified mRNA yield is substantially free of one or more enzyme reagents used in in vitro synthesis (claim 1). The method further comprises a step of first producing the suspension of precipitated mRNA by providing a solution comprising mRNA and adding to the solution one or more agents that promote precipitation of mRNA one or more agents that promote precipitation of mRNA (claim 2). The suspension comprising the precipitated mRNA comprises at least one filtration aid that is a dispersant (claim 3). The method further comprises a step of washing the purified mRNA composition with a solvent and drying the purified mRNA (claims 5 – 6). The method comprises purifying at least about 1 kg mRNA (claim 14).
According to IQVIA, an average centrifuge rotor radius is 5 – 15 cm (page 2). The gravitational force of 2500 RPM for 15 cm rotor radius is 1048 g after calculation, which addresses the limitation of the centrifuge speed recited in claims 1 – 2.
For these reasons above, ‘369B2 with evidence provided by IQVIA anticipate the claimed invention.
Conclusion
No claim is found to be allowable.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693