DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application, filed July 22, 2025, is a continuation of 16/875418, filed May 15, 2020, now issued as U.S. patent 11,453,877, which claims the benefit of U.S. provisional applications 62/891781, filed August 26, 2019, and 62/848412, filed May 15, 2019.
Status of the Application
Applicant’s communication, received February 13, 2026, wherein claims 1, 4, 8, 12, and 65 are amended, claims 9, 10, 26, 28, and 66 are canceled, and new claims 97-105 are added, is acknowledged.
Claims 1, 4, 8, 12, 24, 29, 36-37, 44, 56, 65, 78, and 97-105 are pending and examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 1, 4, 8-10, 12, 24, 26, 28-29, 36-37, 44, 56, 65-66, and 78 under 35 USC § 112(b) as indefinite, has been fully considered and found to be persuasive to remove the rejection because claim 1 is amended to define the required salt concentration in step a), claim 65 is amended to define the required salt concentration in step b), and because claims 9-10, 26, 28 are canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 1, 4, 24, and 28 under 35 USC § 102 as anticipated by Schmitz, has been fully considered and found to be persuasive to remove the rejection because claim 1 is amended to require the wash solution comprises polyethylene glycol, which Schmitz does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 1, 4, 8, 24, 28, 29, and 56 under 35 USC § 103 as unpatentable over Schmitz in view of DeRosa, has been fully considered and found to be persuasive to remove the rejection because claim 1 is amended to require the wash solution comprises polyethylene glycol, which the combination of Schmitz and DeRosa does not teach, and because claim 28 is canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 9-10, 12, and 26 under 35 USC § 103 as unpatentable over Schmitz in view of DeRosa and Reinhardt, has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is amended to require the wash solution comprises polyethylene glycol, which the combination of Schmitz, DeRosa, and Reinhardt does not teach, and because claims 9-10 and 26 are canceled. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 36 and 37 under 35 USC § 103 as unpatentable over Schmitz in view of DeRosa and Horn, has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is amended to require the wash solution comprises polyethylene glycol, which the combination of Schmitz, DeRosa, and Horn does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 36 and 37 under 35 USC § 103 as unpatentable over Schmitz in view of DeRosa and Horn, has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is amended to require the wash solution comprises polyethylene glycol, which the combination of Schmitz, DeRosa, and Horn does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 65 and 66 under 35 USC § 103 as unpatentable over DeRosa in view of Schmitz, has been fully considered and found to be persuasive to remove the rejection because independent claim 65 is amended to require the wash solution comprises polyethylene glycol, which the combination of DeRosa and Schmitz does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claim 78 under 35 USC § 103 as unpatentable over DeRosa in view of Schmitz and Horn, has been fully considered and found to be persuasive to remove the rejection because independent claim 65 is amended to require the wash solution comprises polyethylene glycol, which the combination of DeRosa, Schmitz, and Horn does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the rejection of claims 1 and 44 under 35 USC § 103 as unpatentable over Schmitz, has been fully considered and found to be persuasive to remove the rejection because independent claim 1 is amended to require the wash solution comprises polyethylene glycol, which Schmitz does not teach. Therefore the rejection is withdrawn.
Applicant’s amendment, received February 13, 2026, with respect to the nonstatutory double patenting rejections of the present claims over the claims of U.S. Patents 11,453,877, 11,174,500, 12,084,702, 9,850,269, 10,155,785, 11,059,841, 11,884,692, 12,060,381, 10,808,241, 11,976,272, and over co-pending U.S. patent applications 18/794053 and 17/344,535, has been fully considered and found to be persuasive to remove the rejections because independent claims 1 and 65 are amended to require the wash solution comprises polyethylene glycol, which the above patents and copending patent applications, together with the previously cited additional references, do not teach. Therefore the rejections are withdrawn.
The following are new grounds of rejection, necessitated by Applicant’s amendments received February 13, 2026.
Applicant’s arguments regarding the wash solution comprising 70-100% w/v polyethylene glycol are moot in view of the new grounds of rejection below. Applicant’s arguments regarding Horn (U.S. Patent 5,576,196; cited in IDS received October 31, 2022) are addressed following the rejections below that rely on Horn.
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:
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.
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, 4, 12, 24, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Schmitz (Schmitz, A.; Riesner, D. Analytical Biochemistry 2006, vol. 354, pp. 311-313; cited in IDS received October 31, 2022) in view of Lis (Lis, J. T.; Schleif, R. Nucleic Acids Research 1975, vol. 2, pp. 383-390; cited in PTO-892), Himmelreich (U.S. pre-grant publication no. US 20110224419 A1; cited in PTO-892), and Begum (Begum, S. K.; et al. Journal of Molecular Liquids 2013, vol. 177, pp. 11-18; cited in PTO-892).
Schmitz teaches methods for purification of plasmid DNA and PCR products, providing examples for (i) the separation of RNA in vitro transcripts from plasmid DNA template and (ii) enrichment of viroid RNA from plant total RNA (p. 311, left column, first paragraph, lines 13-19). In the example of enrichment of in vitro transcripts, Schmitz teaches when the DNA template is linearized plasmid DNA and the RNA transcript comprises less than 500 nt, the template may be selectively removed by adding 3.7 μL of 500mM EDTA, 15.9 μL of 50% PEG6000, and 13.2 μL of 5 M NaCl to a transcription reaction of 100 μL (p. 312, right column, Purification of in vitro transcripts section, lines 1-5).
Schmitz teaches that after mixing the DNA is sedimented by centrifugation as described above and, following a wash with 70% ethanol and solubilization in buffer A, may be reused for further transcriptions (p. 311, right column, Purification of in vitro transcripts section, line 6 to p. 312, left column, line 2).
Schmitz then teaches the RNA transcript is precipitated by adding 57 μL of 50% PEG6000 and 6.5 μL of 5M NaCl to the supernatant of the first precipitation, followed by mixing, centrifuging, and washing with 70% ethanol as described above, and then the RNA is dissolved in in buffer B (p. (p. 312, left column, lines 2-6). In this instance, PEG6000 is an amphiphilic polymer and a 5 M NaCl is a solution of at least 1 M salt. In addition, pelleting the precipitated mRNA by centrifugation is interpreted as capturing the precipitated mRNA, and 70% ethanol is interpreted as an aqueous solution. In addition, the supernatant after sedimentation of DNA by centrifugation is reasonably considered as a suspension, because removal of all particulates by centrifugation is unlikely. Moreover, after precipitating the RNA transcript using PEG6000 and NaCl, the supernatant is reasonably considered as a suspension.
Schmitz further teaches that the concentration of PEG and NaCl may be adjusted to precipitate nucleic acids of different sizes. For example, Schmitz teaches an example for fractionating nucleic acids from plant material, wherein a specific concentration of 50% PEG and 5M NaCl is added to the plant extract and subsequent sedimentation removes DNA and high molecular weight RNA. Addition of more PEG and 5M NaCl allows for precipitation of RNAs of intermediate size (p. 312, left column, second paragraph, lines 1-17). Although the final concentration of NaCl in each of these steps is less than 1M, this example demonstrates that the concentration of NaCl may be increased to precipitate smaller nucleic acids.
Finally, Schmitz teaches that when used in concentrations of up to 20% and in combination with 500 mM NaCl, PEG6000 precipitates nucleic acids down to a length of 120nt quantitatively, whereas species below 50 nt and nucleoside triphosphates, on the other hand, remain in the supernatant (p. 312, right column, Results and Discussion section, first paragraph, lines 1-5). Schmitz shows that the % of nucleic acid precipitation of a 140 nt transcript reaches as high as 90% with 19% PEG, increasing as nucleic acid concentration increases (p. 312, Figure 1). Therefore, although Schmitz does not teach a specific yield of the transcript isolated using their method, the teachings from Schmitz supports an expectation that practicing the method of Schmitz would provide a high yield of mRNA.
Schmitz does not teach a wash solution comprising polyethylene glycol (PEG) at a concentration of 70-100% weight/volume to purify the precipitated mRNA, and wherein the wash solution is free of alcohol, as required by claim 1. Finally, Schmitz does not teach a yield of purified mRNA of about 70% to about 99%, as required by claim 44.
Lis teaches that DNA molecules of differing molecular mass are separable by selective precipitation with polyethylene glycol (PEG) (p. 383, Abstract, lines 1-2). Lis evaluates the effect of several variables on DNA precipitation with PEG, including the effect of PEG concentration (pp. 385-387, Results, Effect of PEG concentration section) and the effect of salt concentration (p. 387, Effect of salt concentration section, lines 1-9). Lis teaches that at salt concentrations of 0.55 M and 1.1 M, DNA in the size range of 46,500 to 700 and 46,500 to 375 base pairs, respectively were precipitated by 6.5% PEG. Lis teaches that Precipitation by 12% PEG at these salt concentrations showed much less variation; DNA from 46,500 to 125 and 46,500 to 80 base pairs were precipitated at salt concentrations of 0.55 M and 1.1 M, respectively (p. 387, Effect of salt concentration section, lines 5-9).
Himmelreich teaches a method for the isolation and purification of nucleic acids by elution of nucleic acids from nucleic acid-containing sample (cover page, Abstract, lines 1-3). Himmelreich teaches wash buffers for washing nucleic acids immobilized on surfaces which are substantially free of alcohol, such as ethanol (p. 1, [0007], lines 1-4). Himmelreich teaches wash buffers comprising solvents selected form a group that includes tetraethylene glycol (abbreviated by Himmelreich as TEG) (p. 1, [0011], lines 1-4 and 12). Himmelreich teaches in a preferred variant of their method, the wash buffer is tetraethylene glycol in a concentration of 45 to 80% by volume (p. 2, [0037], lines 1-4). As evidenced by the instant specification, tetraethylene glycol is one type of polyethylene glycol (PEG) (p. 7, [0032], lines 1-2).
Himmelreich further teaches embodiments in which tetraethylene glycol is included in a wash buffer. As one example, Himmelreich teaches a first wash buffer (WB10) with 48.5% by volume tetraethylene glycol and 2.5 M GuHCl, and a second wash buffer (WB6) with 69.8% by volume tetraethylene glycol, 100 mM NaCl, and 10 mM Tris-Cl pH 7.5 used for nucleic acid purification in a Biosprint® 96 DNA Blood Protocol (p. 4, [0105]-[0110]). Himmelreich teaches protocol with WB10 followed by WB6 showed an increased yield of DNA compared with the control (document p. 3, see Figure 4). WB6 is free of alcohol. In addition, WB6 is interpreted herein as an aqueous wash solution, because it comprises tetraethylene glycol and includes NaCl and Tris-Cl at pH 7.5.
Begum teaches the density of tetraethylene glycol at 298.15 K, which is interpreted as approximately room temperature, is 1.121 g/cm3 (p. 12, left column, Table 1). This measurement is equivalent to the density in g/mL.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the ethanol wash solution in the method taught by Schmitz for a wash buffer containing tetraethylene glycol, as taught by Himmelreich. One of ordinary skill in the art would have been motivated to substitute the ethanol wash solution in the method taught by Schmitz for a wash buffer containing tetraethylene glycol, as taught by Himmelreich because Himmelreich teaches their wash buffers comprising tetraethylene glycol as an alternative to wash buffers comprising alcohols, and because Himmelreich shows that the DNA yield using their buffer in place of a commercial wash buffer in a standard nucleic acid purification protocol may provide improved yield compared with the commercial wash buffer.
Regarding the concentration of PEG in the wash buffer, Himmelreich discloses their suggested concentrations of tetraethylene glycol in % by volume, not % wt/vol. In this instance, % by volume is interpreted as % vol/vol. The embodied wash solution with a concentration of 69.8% by volume tetraethylene glycol, based on a tetraethylene glycol density of 1.121 g/mL, as taught by Begum, would have a % wt/vol concentration of about 78.2% (determined based on the mass (in grams) of tetraethylene glycol in 100 mL of solution). The suggested concentration of 80% by volume tetraethylene glycol, based on a density of 1.121 g/ml, would have a % wt/vol concentration of 89.7%, which is interpreted as about 90%.
Moreover, if there is doubt about the meaning of “by volume” taught by Himmelreich, one of ordinary skill in the art would have considered reasonable meanings of % by volume, and in doing so, would have contemplated the wash solution of Himmelreich with tetraethylene glycol measured in % vol/vol as one interpretation of “by volume,” as interpreted above.
Regarding the salt concentration of at least 1M recited in claim 1 step a), Schmitz teaches adding a solution of 5M NaCl and PEG to precipitate the nucleic acid. The method of Schmitz thus satisfies the requirement that the suspension comprises at least a 1 M high molar salt solution and an amphiphilic polymer to provide precipitated mRNA.
However, if this step a) of claim 1 is intended to require a final concentration of at least 1 M salt solution, because Schmitz teaches that higher concentrations of PEG and NaCl may be used to precipitate different size nucleic acids, including DNA and RNA, and because Lis teaches that salt concentrations up to 1.1 M may be used for precipitating DNA, one of ordinary skill in the art would have reasonably considered final NaCl concentrations of at least 1M, because said concentrations may be effective for precipitating nucleic acids, including RNA, of different sizes (for example, smaller sized RNA).
Regarding the yield of purified mRNA as from about 70% to about 99%, as recited in claim 44, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to perform the method of mRNA isolation and purification obvious over Schmitz in view of Himmelreich and obtain a yield of about 70% to about 99% mRNA. One of ordinary skill in the art would have been motivated to perform the method of mRNA isolation and purification taught by Schmitz and obtain a yield of about 70% to about 99% of mRNA because Schmitz teaches that percent of a nucleic acid precipitation of a 140 nt transcript reaches as high as 90% with 19% PEG, and increases with increasing concentration of nucleic acid. Therefore, in view of Schmitz, one of ordinary skill in the art would have expected greater than 70% precipitation of mRNA at a concentration of greater than 10 ng/μL, and in order to optimize the yield of mRNA from this method, would have recognized that adjusting the concentration of nucleic acid when performing precipitation may reasonably provide a yield of mRNA between about 70% and 99%.
Therefore the invention taken as a whole is prima facie obvious.
Claims 97-100 are rejected under 35 U.S.C. 103 as being unpatentable over Schmitz (Schmitz, A.; Riesner, D. Analytical Biochemistry 2006, vol. 354, pp. 311-313; cited in IDS received October 31, 2022) in view of Lis (Lis, J. T.; Schleif, R. Nucleic Acids Research 1975, vol. 2, pp. 383-390; cited in PTO-892), Himmelreich (U.S. pre-grant publication no. US 2011/0224419 A1; cited in PTO-892), and Begum (Begum, S. K.; et al. Journal of Molecular Liquids 2013, vol. 177, pp. 11-18; cited in PTO-892) as applied to claims 1 and 12 above, and further in view of Tomé (Tomé, L. I. N.; et al. Journal of Physical Chemistry B 2014, vol. 8, pp. 4615-4629; cited in PTO-892).
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejection under 35 U.S.C. § 103.
Schmitz, Lis, Himmelreich, and Begum do not teach wherein the molecular weight of the PEG is 200 g/mol to 600 g/mol, as recited in claims 97 and 99, or wherein the wherein the PEG comprises PEG 200, PEG 300, or PEG 400, as recited in claims 98 and 100.
Tomé teaches that PEG-200 is a mixture of isomeric polymers which have 4 ethylene oxide (abbreviated by Tomé as EO) units and an average molecular mass of 200. Tomé teaches most abundant component is tetraethylene glycol, which has a molecular weight of 194 (p. 4616, left column, lines 1-4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200. One of ordinary skill in the art would have been motivated to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200 because Schmitz, Lis, Himmelreich, and Begum render obvious the method of claim 1 using tetraethylene glycol in the wash buffer, as described in the above rejection, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol. In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Himmelreich teaches washing of nucleic acids with a composition comprising tetraethylene glycol, and because Tomé teaches that PEG 200 has a similar molecular weight as tetraethylene glycol and includes tetraethylene glycol as its most abundant component, one of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be effective when practicing the method obvious over Schmitz, Lis, Himmelreich, and Begum.
Therefore the invention taken as a whole is prima facie obvious.
Claims 8, 29, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Schmitz (Schmitz, A.; Riesner, D. Analytical Biochemistry 2006, vol. 354, pp. 311-313; cited in IDS received October 31, 2022) in view of Lis (Lis, J. T.; Schleif, R. Nucleic Acids Research 1975, vol. 2, pp. 383-390; cited in PTO-892), Himmelreich (U.S. pre-grant publication no. US 2011/0224419 A1; cited in PTO-892), and Begum (Begum, S. K.; et al. Journal of Molecular Liquids 2013, vol. 177, pp. 11-18; cited in PTO-892) as applied to claim 1 above, and further in view of DeRosa (U.S. pre-grant publication no. US 20150376220 A1; cited in IDS received October 31, 2022).
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejection under 35 U.S.C. § 103.
Schmitz, Lis, Himmelreich, and Begum do not teach wherein a high molar salt comprises guanidinium thiocyanate, as recited in claim 8, capture on a microfiltration or ultrafiltration filter, as recited in claim 29, or the scale of mRNA recited in claim 56.
DeRosa teaches and claims a method of purifying messenger RNA (mRNA), comprising
(a) precipitating mRNA from an impure preparation; and (b) subjecting the impure preparation comprising precipitated mRNA to a purification process involving membrane filtration such that the precipitated mRNA is captured by a membrane; and (c) eluting the captured precipitated mRNA from the mem brane by re-solubilizing the mRNA, thereby resulting in
a purified mRNA solution (p. 20, left column, claim 1). DeRosa further claims the step of precipitating mRNA comprises treating the impure preparation with a solution comprising a reagent selected from the group consisting of lithium chloride, potassium chloride, guanidinium chloride, guanidinium thiocyanate, guanidinium isothiocyanate, ammonium acetate and combinations thereof (p. 20, left column, claim 4). Finally, DeRosa teaches and claims wherein the mRNA is purified at a scale of or greater than 1 gram, 10 gram, 100 gram, 1 kg,
10 kg, or 100 kg per batch (p. 20, right column, claim 28).
DeRosa teaches that a filter used in their method has an average pore size of or greater than 0.10 μm, 0.20 μm, 0.22 μm, 0.24 μm, 0.26 μm, 0.28 μm, 0.30 μm, 0.40 μm, 0.5 μm, or 1.0 μm, and in a particular embodiments, a suitable membrane has an average pore size of about 0.22 μm (pp. 7-8, [0104], lines 6-9). As defined in the instant specification, the microfiltration filter has a pore size of between 0.05 μm and 1.0 μm (p. 12, [0060], lines 2-3). Therefore, the filter suggested by DeRosa is reasonably considered as a microfiltration filter required by claim 29.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to perform the capturing of RNA in the method obvious over on a microfiltration filter, as taught by DeRosa, when practicing the method obvious over Schmitz in view of Lis, Himmelreich, and Begum. One of ordinary skill in the art would have been motivated to perform the capturing of RNA on a microfiltration filter when practicing the method obvious over Schmitz in view of Lis, Himmelreich, and Begum because DeRosa teaches filtration as an effective method of removing soluble and insoluble impurities from precipitated mRNA.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because each of Schmitz, Lis, and DeRosa teach precipitation as a method of isolating mRNA, and because DeRosa teaches capturing of mRNA on a filter instead of by centrifugation, one of ordinary kill in the art would have recognized capturing mRNA on a filter as a viable alternative to centrifugation, and would have reasonably expected substitution of centrifugation for capture on a filter would enable successful capture of the precipitated mRNA when practicing the method obvious over Schmitz in view of Lis, Himmelreich, and Begum.
Regarding the limitation that the high molar salt solution comprises guanidinium thiocyanate, as an alternative to sodium chloride in the step of precipitating mRNA (p. 1, [0006], lines 1-8), one of ordinary skill in the art would have contemplated substituting the sodium chloride salt taught by Schmitz and Lis for guanidinium thiocyanate taught by DeRosa, because guanidinium thiocyanate may also be effective for precipitating mRNA, as taught by DeRosa.
Finally, in view of DeRosa teaching their method may be purified at a scale of or greater than, for example, 1 gram, one of ordinary skill in the art would have contemplated performing the method obvious over Schmitz in view of Lis, Himmelreich, Begum, and DeRosa to isolate greater than, for example, 1 gram of mRNA.
Therefore the invention taken as a whole is prima facie obvious.
Claims 36 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Schmitz (Schmitz, A.; Riesner, D. Analytical Biochemistry 2006, vol. 354, pp. 311-313; cited in IDS received October 31, 2022) in view of Lis (Lis, J. T.; Schleif, R. Nucleic Acids Research 1975, vol. 2, pp. 383-390; cited in PTO-892), Himmelreich (U.S. pre-grant publication no. US 2011/0224419 A1; cited in PTO-892), and Begum (Begum, S. K.; et al. Journal of Molecular Liquids 2013, vol. 177, pp. 11-18; cited in PTO-892) as applied to claim 1 above, and further in view of DeRosa (U.S. pre-grant publication no. US 20150376220 A1; cited in IDS received October 31, 2022) and Horn (U.S. Patent 5,576,196; cited in IDS received October 31, 2022).
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
DeRosa teaches as described in the above rejection under 35 U.S.C. § 103.
Schmitz, Lis, Himmelreich, Begum, and DeRosa do not teach wherein a filter aid is used, as required by claim 36, and wherein the filter aid is cellulose-based, or comprises diatomaceous earth and/or volcanic ash, as recited in claim 37.
Horn teaches a method of separating the RNA by filtration, comprising the step of filtering a sample containing RNA through a diatomaceous earth material to produce a filtrate with a reduced concentration of RNA (cover page, Abstract, lines 1-7). Horn teaches that filter aids that are composed of a diatomaceous earth material in combination with other materials are regarded as falling within the scope of the present invention and that diatomaceous earth can be combined with a cellulose fiber are envisioned (column, 6, lines 26-34).
Horn further teaches that their process may be applicable to the separation of different forms of RNA in a mixture of biological material, stating that as a purification process that selectively removes host contaminant RNA has tremendous value, when the object of the separation is the recovery of a particular form of RNA (column 7, lines 4-10) (emphasis added). Horn teaches that a mixture of biological material having a first and second form of soluble RNA may be filtered through a diatomaceous earth material to produce a filtrate comprising the first form of RNA and a product comprising the second form of RNA that collects in the diatomaceous earth material. Horn teaches that one may collect the filtrate or, alternatively, elute the second form of RNA from the diatomaceous earth material if that is the preferred form (column 7, lines 11-20).
Finally, with respect to the diatomaceous earth filtration step, Horn teaches that the diatomaceous earth material filtration step will be optimized by balancing elements against the additional factor that the diatomaceous earth material acts to bind RNA. Horn teaches that parameters, such as flow rate, clarity, grade and amount of filter aid for filtration, grade and
amount of filter aid for precoat, length of cycle, filtration rate, throughput, and permeability, etc., will depend on the reduction in the concentration of RNA to be achieved, and approximation of the degree of reduction can be gained by running conventional filtration tests. Horn teaches the
amount of RNA in the filtrate can be determined in a number of ways, for example, by routine biochemical analyses (column 8, lines 31-44).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the method obvious over Schmitz in view of Lis, Himmelreich, and Begum to use a filter with a filter aid comprising diatomaceous earth during filtration. Because each of Schmitz, Lis, and DeRosa teach precipitation as a method of isolating mRNA, and because DeRosa teaches capturing of mRNA on a filter instead of by centrifugation, one of ordinary kill in the art would have recognized capturing mRNA on a filter as a viable alternative to centrifugation, and would have reasonably expected substitution of centrifugation for capture on a filter would enable successful capture of the precipitated mRNA when practicing the method obvious over Schmitz in view of Lis, Himmelreich, and Begum.
Moreover, one of ordinary skill in the art would have contemplated filtration in the presence of a filter aid, such as diatomaceous earth, because Horn teaches a filter aid improves adsorption, separates RNA from contaminants, and may permit isolation of a specific RNA species. Accordingly, the use of filtration with a filter aid may reasonably improve the yield and/or purity of RNA from the method obvious over Schmitz in view of Lis, Himmelreich, and Begum.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: Regarding the previous rejection of claims 36-37 over Schmitz in view of DeRosa and Horn, Applicant argues that Horn teaches a method of purification of plasmid DNA from E. coli cells aimed at reducing contaminating RNA See, e.g., Horn, col. 2, lines 66-67, and a skilled person would not have considered the teaching of Horn when designing a method of purifying messenger RNA (Applicant’s remarks, pp. 10-11).
Applicant’s arguments have been fully considered but they are not found persuasive. Horn teaches the use of diatomaceous earth for separating different forms of RNA, as described above. Accordingly, one of ordinary skill in the would have contemplated use of diatomaceous earth filter aid for improving isolation of a specific RNA species or removing unwanted contaminants from the RNA sample.
Accordingly, the present rejection of claims 36-37 is maintained.
Claims 65 and 102 are rejected under 35 U.S.C. 103 as being unpatentable over DeRosa (U.S. pre-grant publication no. US 20150376220 A1; cited in IDS received October 31, 2022) in view of Schmitz (Schmitz, A.; Riesner, D. Analytical Biochemistry 2006, vol. 354, pp. 311-313; cited in IDS received October 31, 2022), Lis (Lis, J. T.; Schleif, R. Nucleic Acids Research 1975, vol. 2, pp. 383-390; cited in PTO-892), Himmelreich (U.S. pre-grant publication no. US 2011/0224419 A1; cited in PTO-892), and Begum (Begum, S. K.; et al. Journal of Molecular Liquids 2013, vol. 177, pp. 11-18; cited in PTO-892).
DeRosa teaches as described in the above rejection under 35 U.S.C. § 103. In addition, DeRosa teaches their method of purifying mRNA may be applied to mRNAs produced by in vitro transcription (IVT). DeRosa teaches that IVT is typically performed with a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may include DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7 or SP6 RNA polymerase) (p. 5, [0080], lines 4-9). DeRosa teaches that presence of these reagents is undesirable in the final product according to several embodiments and may thus be referred to as impurities and a preparation containing one or more of these impurities may be referred to as an impure preparation (p. 5, [0080], lines 10-15).
DeRosa does not teach adding an amphiphilic polymer for precipitating the mRNA in a suspension, as required by claim 65.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the method of DeRosa with the method taught by Schmitz and precipitate the mRNA produced by IVT by addition of an amphiphilic polymer, such as PEG. One of ordinary skill in the art would have been motivated to modify the method of DeRosa with the method of Schmitz and precipitate the mRNA produced by IVT by addition of an amphiphilic polymer, such as PEG, because DeRosa teaches a method of IVT, teaches the present of IVT reagents in the final mRNA product is undesirable, and finally teaches a method of purification of mRNA that involves precipitation, and because Schmitz teaches that addition of PEG in the presence of at least a 1M salt solution may fractionate RNA transcripts from DNA templates. Thus one of ordinary skill in the art would have recognized the method of Schmitz as effective for removing DNA templates from mRNA, as required by claim 65 step d).
Regarding the requirement in step b) that at least a 1M salt solution is provided to the suspension, Schmitz teaches providing a 5M salt solution, which satisfies this requirement in step b) of this method. However, if step b) is intended to require a final concentration of 1M salt, then one of ordinary skill in the art, in view of Lis, would have recognized higher concentrations of salt are effective for precipitating nucleic acids, and that the concentration of PEG and/or salt may be adjusted to optimize the size of nucleic acids precipitated from solution.
Regarding the requirement that the purified full-length mRNA in the aqueous solution provided from step (d) is substantially free of (i) the DNA template comprising a promoter and (ii) the RNA polymerase, because Schmitz teaches removal of DNA template, and because DeRosa teaches that these components are not in the reaction are undesirable in the final product and teaches an example in which no residual enzyme was present after the purification by precipitation method taught by DeRosa (p. 14, [0152], lines 7-10), one of ordinary skill in the art would have performed the method obvious over DeRosa in view of Schmitz with a reasonable expectation of removing both DNA template and polymerase from the mRNA.
Regarding step d) requiring washing the precipitated full-length mRNA of step c) with an aqueous solvent free of alcohol comprising polyethylene glycol (PEG) at a concentration of 70-100% weight/volume to obtain a purified full-length mRNA in an aqueous solution free of alcohol, because Himmelreich teaches the benefits of a wash buffer comprising the PEG species tetraethylene glycol, one of ordinary skill in the art would have contemplated the wash buffer comprising tetraethylene glycol in place of the wash buffers comprising alcohol taught by DeRosa and Schmitz, because said wash buffers may also be effective when isolating mRNA when used in combination with the method obvious over DeRosa and Schmitz.
Regarding the concentration of tetraethylene glycol of required by claim 102, Himmelreich suggests a concentration of tetraethylene glycol up to 80% by volume. Begum teaches the density of tetraethylene glycol at room temperature is 1.121 g/mL. Himmelreich teaches their suggested concentrations of tetraethylene glycol in % by volume, not % wt/vol. In this instance, % by volume is interpreted as % vol/vol. The embodied wash solution with a concentration of 69.8% by volume tetraethylene glycol, based on a tetraethylene glycol density of 1.125 g/mol as taught by Begum, would have a % wt/vol concentration of about 78.2% (determined based on the mass (in grams) of tetraethylene glycol in 100 mL of solution). The suggested concentration of 80% by volume tetraethylene glycol, based on a density of 1.121 g/mL, would thus have a % wt/vol concentration of about 90%.
Moreover, if there is doubt about the meaning of “by volume” taught by Himmelreich, one of ordinary skill in the art would have considered reasonable meanings of % by volume, and in doing so, would have contemplated the wash solution of Himmelreich with tetraethylene glycol measured in % vol/vol as one interpretation of “by volume,” as interpreted above. Accordingly, one of ordinary skill in the art would have considered wash buffers that include 90% wt/vol tetraethylene glycol.
Therefore the invention taken as a whole is prima facie obvious.
Claim 78 is rejected under 35 U.S.C. 103 as being unpatentable over DeRosa (U.S. pre-grant publication no. US 20150376220 A1; cited in IDS received October 31, 2022) in view of Schmitz (Schmitz, A.; Riesner, D. Analytical Biochemistry 2006, vol. 354, pp. 311-313; cited in IDS received October 31, 2022), Lis (Lis, J. T.; Schleif, R. Nucleic Acids Research 1975, vol. 2, pp. 383-390; cited in PTO-892), Himmelreich (U.S. pre-grant publication no. US 2011/0224419 A1; cited in PTO-892), and Begum (Begum, S. K.; et al. Journal of Molecular Liquids 2013, vol. 177, pp. 11-18; cited in PTO-892), as applied to claim 65 above, and further in view of Horn (U.S. Patent 5,576,196; cited in IDS received October 31, 2022).
DeRosa, Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
DeRosa, Schmitz, Lis, Himmelreich, and Begum do not teach wherein the suspension further comprises a filter aid at a mass ratio with the precipitated mRNA of 2:1; 5:1; 10:1 or 15:1.
Horn teaches as described in the above rejections under 35 U.S.C. § 103.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the method obvious over DeRosa in view of Schmitz, Lis, Himmelreich, and Begum and add a filter aid comprising diatomaceous earth during filtration, because filtration in the presence of a filter aid such as diatomaceous earth improves adsorption and RNA from impurities and may reasonably improve the yield of RNA from the method obvious over DeRosa in view of Schmitz, Lis, Himmelreich, and Begum. In this instance, because diatomaceous earth is known to bind RNA during filtration, one of ordinary skill in the art would have reasonably contemplated addition of diatomaceous earth as a filter aid during filtering, because the addition of diatomaceous earth may improve the isolation and purification of RNA.
Regarding the specific mass of diatomaceous earth filtration aid compared with the mass of precipitated mRNA, in view of Horn teaching that a variety of parameters effect the filtration step and that the degree of reduction of RNA can be gained by running conventional filtration tests, one of ordinary skill in the art would have determined the optimal amount of diatomaceous earth filter aid by routine experimentation.
MPEP 2144.05 II at A states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).” In this instance, because Horn expressly suggests optimization of the filtration step, by experimentation, one of ordinary skill in the art would have considered the parameters disclosed by Horn and identified optimal filtration conditions based on the conditions of the specific process being performed.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s arguments: Regarding the previous rejection of claims 36-37 over DeRosa in view of Schmitz and Horn, Applicant argues that Horn teaches a method of purification of plasmid DNA from E. coli cells aimed at reducing contaminating RNA See, e.g., Horn, col. 2, lines 66-67, and a skilled person would not have considered the teaching of Horn when designing a method of purifying messenger RNA Applicant’s remarks, pp. 10-11).
For the same reasons described above with respect to the teachings of Horn, the present rejection of claim 78 is maintained.
Claims 103-104 are rejected under 35 U.S.C. 103 as being unpatentable over DeRosa (U.S. pre-grant publication no. US 20150376220 A1; cited in IDS received October 31, 2022) in view of Schmitz (Schmitz, A.; Riesner, D. Analytical Biochemistry 2006, vol. 354, pp. 311-313; cited in IDS received October 31, 2022), Lis (Lis, J. T.; Schleif, R. Nucleic Acids Research 1975, vol. 2, pp. 383-390; cited in PTO-892), Himmelreich (U.S. pre-grant publication no. US 2011/0224419 A1; cited in PTO-892), and Begum (Begum, S. K.; et al. Journal of Molecular Liquids 2013, vol. 177, pp. 11-18; cited in PTO-892) as applied to claim 65 above, and further in view of Tomé (Tomé, L. I. N.; et al. Journal of Physical Chemistry B 2014, vol. 8, pp. 4615-4629; cited in PTO-892).
DeRosa, Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
DeRosa, Schmitz, Lis, Himmelreich, and Begum do not teach wherein the molecular weight of the PEG is 200 g/mol to 600 g/mol, as recited in claim 103, or wherein the wherein the PEG comprises PEG 200, PEG 300, or PEG 400, as recited in claim 104.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the wash comprising tetraethylene glycol in the method obvious over DeRosa, Schmitz, Lis, Himmelreich, and Begum with PEG 200. One of ordinary skill in the art would have been motivated to substitute the wash solution comprising tetraethylene glycol in the method obvious over DeRosa, Schmitz, Lis, Himmelreich, and Begum with PEG 200 because DeRosa, Schmitz, Lis Himmelreich, and Begum render obvious the method of claim 65 using tetraethylene glycol in the wash buffer, as described in the above rejection, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Himmelreich teaches washing of nucleic acids with a composition comprising tetraethylene glycol, and because Tomé teaches that PEG 200 has a similar molecular weight as tetraethylene glycol and includes tetraethylene glycol as its most abundant component, one of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be effective when practicing the method obvious over DeRosa, Schmitz, Lis, Himmelreich, and Begum.
Therefore the invention taken as a whole is prima facie obvious.
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, 8, 12, 24, and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-8 of U.S. Patent No. 11,453,877 (reference patent, herein referred to as ‘877) in view of Himmelreich and Begum.
The present application and ‘877 are each assigned to Translate Bio, Inc. and include Jonathan Abysalh, Frank DeRosa, Cameron Smith, and Jorel Vargas as inventors.
Claim 1 of ‘877 claims a method of purifying messenger RNA (mRNA) comprising:
a) precipitating the mRNA in a suspension comprising at least a 1M salt solution and an amphiphilic polymer; b) capturing the mRNA on a filter; and c) washing the mRNA of step b) with a triethylene glycol monomethyl ether (MTEG) solution to obtain a purified mRNA composition substantially free of contaminants. Claim 2 of ‘877 depends from claim 1 and requires the precipitated mRNA comprises at least 100 mg, 1 g, 10 g, 100 g, 1 kg, 10 kg, 100 kg, one metric ton, or ten metric tons, of mRNA or any amount there between. Claim 3 of ‘877 depends from claim 1 and requires the salt solution comprises guanidinium thiocyanate (GSCN). Claim 7 of ‘877 depends from claim 1 and requires the amphiphilic polymer comprises MTEG. Claim 8 of ‘877 depends from claim 1 and requires the suspension comprises precipitated mRNA, a high molar salt solution, and MTEG, and thus the suspension of claim 1 as satisfying present claim 1.
Claim 5 of ‘877 claims a method of purifying messenger RNA (mRNA) comprising:
a) precipitating the mRNA in a guanidinium thiocyanate (GSCN) solution comprising MTEG; b) centrifuging the solution of step a) to create an mRNA pellet; c) resuspending the mRNA pellet in a buffer; d) capturing the mRNA on a filter; e) washing the mRNA of step d) with a MTEG solution; and f) solubilizing the washed mRNA of step e) to obtain an mRNA composition substantially free of contaminants.
Claim 1 of ‘877 does not explicitly recite step d) of present claim 1, which requires solubilizing the precipitated mRNA from step c) to obtain a purified mRNA composition. However, because step f) of claim 5 of ‘877 recites solubilizing the washed mRNA to obtain an mRNA composition substantially free of contaminants, one of ordinary skill in the art would have recognized that the mRNA precipitated in step c) of claim 1 of ‘877 may be solubilized obtain an RNA composition substantially free of contaminants (which is interpreted as equivalent to the purified mRNA composition recited in present claim 1).
Claim 1 of ‘877 recites each step of present claim 1, except for the step of washing with a wash solution comprising polyethylene glycol (PEG) at a concentration of 70-100% weight/volume.
Himmelreich and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to modify the method claimed by ‘877 and substitute the wash solution comprising MTEG, as claimed by ‘877, for a wash solution comprising tetraethylene glycol, as taught by Himmelreich, because such a wash solution would also be expected to be effective when practicing the method claimed by ‘877.
As described above, the suggested tetraethylene glycol concentration of 80% by volume would render obvious a concentration of tetraethylene glycol of 90% wt/vol.
Claims 97 and 98 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-8 of U.S. Patent No. 11,453,877 (reference patent, herein referred to as ‘877) in view of Himmelreich and Begum, as applied to 1 above, and further in view of Tomé.
The claims of ‘877 claim as described in the above nonstatutory double patenting rejections.
Himmelreich and Begum teach as described in the above rejections under 35 U.S.C. § 103. As described in the above non-statutory double patenting rejection, these claims, together with Himmelreich and Begum, render obvious the limitations of present claims 1, 4, 8, 12, 24, and 56.
None of the claims of ‘877, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol, as recited in claim 97, or wherein the PEG comprises PEG 200, PEG 300, or PEG 400, as recited in claim 98.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘877, Himmelreich, and Begum render obvious the method of claim 1 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘877, Himmelreich, and Begum, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 36 and 37 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-8 of U.S. Patent No. 11,453,877 (reference patent, herein referred to as ‘877) in view of Himmelreich and Begum, as applied to 1 above, and further in view of Horn.
The claims of ‘877 claim as described in the above nonstatutory double patenting rejections.
Himmelreich and Begum teach as described in the above rejections under 35 U.S.C. § 103.
As described in the above non-statutory double patenting rejection, these claims, together with Himmelreich and Begum, render obvious the limitations of present claims 1, 4, 8, 12, and 56.
None of the claims of ‘877, Himmelreich, or Begum teach use of a filter aid, as required by claim 36, and wherein the filter aid is cellulose-based, or comprises diatomaceous earth and/or volcanic ash, as required by claim 37.
Horn teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method obvious over the claims of ‘877 in view of Himmelreich and Begum and use a filter aid of diatomaceous earth, because Horn teaches that filtration in the presence of a filter aid such as diatomaceous earth improves adsorption and RNA from impurities, and thus may reasonably improve the yield and purify of RNA from the method obvious over the claims of ‘877, Himmelreich, and Begum.
Claims 29, 65, and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-8 of ‘877 in view of Himmelreich and Begum, as applied to claim 1 above, and further in view of DeRosa (U.S. pre-grant publication no. US 20150376220 A1; cited in IDS received October 31, 2022).
The claims of ‘877 claim as described in the above nonstatutory double patenting rejections.
Himmelreich and Begum teach as described in the above rejections under 35 U.S.C. § 103.
As described in the above non-statutory double patenting rejection, these claims, together with Himmelreich and Begum, render obvious the limitations of present claims 1, 4, 8, 12, 24, and 56.
The claims of ‘877 do not claim wherein the capturing the precipitated mRNA occurs on a microfiltration or ultrafiltration filter as required by claim 29. In addition, the claims of ‘877 do not claim the method of claim 1, wherein the wash solution is aqueous, as recited in claim 24. Finally, the claims of ‘877 do not claim the method of manufacturing mRNA in the steps recited in claim 65.
Himmelreich teaches as described in the above rejections under 35 U.S.C. § 103.
DeRosa teaches as described in the above rejection under 35 U.S.C. § 103. Specifically DeRosa teaches that an average pore size of or greater than 0.10 μm, 0.20 μm, 0.22 μm, 0.24 μm, 0.26 μm, 0.28 μm, 0.30 μm, 0.40 μm, 0.5 μm, or 1.0 μm, and in a particular embodiments, a suitable membrane has an average pore size of about 0.22 μm (pp. 7-8, [0104], lines 6-9). As defined in the instant specification, the microfiltration filter has a pore size of between 0.05 μm and 1.0 μm (p. 12, [0060], lines 2-3). Therefore, the filter suggested by DeRosa is reasonably considered as a microfiltration filter.
Finally, DeRosa teaches their method may be applied to mRNAs produced by in vitro transcription (IVT). DeRosa teaches that IVT is typically performed with a linear or circular DNA template containing a promoter, a pool of ribonucleotide triphosphates, a buffer system that may include DTT and magnesium ions, and an appropriate RNA polymerase (e.g., T3, T7 or SP6 RNA polymerase) (p. 5, [0080], lines 4-9). DeRosa teaches that presence of these reagents is
undesirable in the final product according to several embodiments and may thus be referred to as impurities and a preparation containing one or more of these impurities may be referred to as an impure preparation (p. 5, [0080], lines 10-15).
It would therefore have been prima facie obvious to one of ordinary skill to capture the mRNA in step b) of claim 1 of ‘877 on a microfiltration filter because DeRosa teaches a similar method of isolating mRNA by capturing a precipitated mRNA on a filter, and further suggests a microfiltration filter for capturing the mRNA. Therefore, one of ordinary skill in the art would have contemplated using the microfiltration filter taught by DeRosa when practicing the method obvious over the claims of ‘877 in view of Himmelreich.
In addition, it would have been prima facie obvious to one of ordinary skill to apply the method claimed by ‘877 to purify mRNA synthesized by IVT because the method claimed by ‘877 may be used to purify mRNA, and because DeRosa teaches mRNA prepared by IVT by mixing a DNA template comprising a promoter and (ii) an RNA polymerase to generate an impure preparation comprising full-length RNA, such as SP6 polymerase, and thus one of ordinary skill in the art would have recognized that mRNA prepared as taught by DeRosa may be reasonably purified using the method obvious over the claims of ‘877 in view of Himmelreich and Begum. In addition, because DeRosa teaches the template and polymerase as impurities, and the claims of ‘877 claim removal of contaminants using the method recited therein, one of ordinary skill in the art would have reasonably expected the template and polymerase from the IVT reaction to be removed using the method obvious over the claims of ‘877 in view of Himmelreich and Begum.
Claim 78 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-8 of ‘877 in view of Himmelreich and Begum, as applied to claims 1 above, and further in view of DeRosa as applied to claim 65 above, and further in view of Horn.
The claims of ‘877 claim as described in the above nonstatutory double patenting rejections.
DeRosa teaches as described in the above rejections under 35 U.S.C. 103 and in the above nonstatutory double patenting rejection.
The claims of ‘877, Himmelreich, and DeRosa do not claim or teach the method of claim 65, wherein the suspension further comprises a filter aid at a mass ratio with the precipitated mRNA of 2:1; 5:1; 10:1 or 15:1, as required by claim 78.
Horn teaches as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to use a filter aid when practicing the method of claim 65 because Horn teaches that filtration in the presence of a filter aid, such as diatomaceous earth, improves adsorption and RNA from impurities, and thus may reasonably improve the yield and purify of RNA from the method obvious over the claims of ‘877 in view of Himmelreich, Begum, and DeRosa. Regarding the specific mass of diatomaceous earth filtration aid compared with the mass of precipitated mRNA, in view of Horn teaching that a variety of parameters effect the filtration step and that the degree of reduction of RNA can be gained by running conventional filtration tests, one of ordinary skill in the art would have determined the optimal amount of diatomaceous earth filter aid by routine experimentation. See MPEP 2144.05 II at A.
Claims 103 and 104 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-8 of ‘877 in view of Himmelreich and Begum as applied to claim 1 above, and further in view of DeRosa as applied to claim 65 above, and further in view of Tomé.
The claims of ‘877 claim as described in the above nonstatutory double patenting rejections.
Himmelreich, Begum, and DeRosa teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘877, Himmelreich, Begum, or DeRosa teach the molecular weight of the PEG is 200 g/mol to 600 g/mol, as recited in claim 103, or wherein the PEG comprises PEG 200, PEG 300, or PEG 400, as recited in claim 104.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘877, Himmelreich, Begum, and DeRosa render obvious the method of claim 65 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘877 in view of Himmelreich, Begum, and DeRosa, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, and 7-8 of ‘877 in view of Himmelreich and Begum as applied to claim 1 above, and further in view of Schmitz.
The claims of ‘877 claim as described in the above nonstatutory double patenting rejections.
Himmelreich and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘877, Himmelreich, or Begum teach the yield of the purified mRNA
is about 70% to about 99%, as required by claim 44.
Schmitz teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to obtain a yield of purified mRNA from about 70% to about 99% with a method obvious over the claims of ‘877, Himmelreich, Begum, and Schmitz, because Schmitz shows that the % of nucleic acid precipitation of a 140 nt transcript reaches as high as 90% with 19% PEG, increasing as nucleic acid concentration increases (p. 312, Figure 1). Therefore, although Schmitz does not disclose a specific yield of the transcript isolated during their method, teachings from Schmitz supports an expectation that practicing the method of precipitation would provide a high yield of mRNA, and that such yield could be increased, if necessary, by adjusting the concentration of mRNA in the solution to be precipitated.
Claims 1, 4, 12, 24, 29, 44, and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, and 13 of U.S. Patent No. 11,174,500 (reference patent, hereafter ‘500) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘500 are each assigned to Translate Bio, Inc. and each include Jonathan Abysalh and Frank DeRosa as inventors.
Claim 1 of ‘500 claims a method for large scale purification of messenger RNA (mRNA), the method comprising the steps of: (a) precipitating mRNA from a solution comprising one or more contaminants from manufacturing the mRNA to provide a suspension comprising precipitated mRNA; (b) subjecting the suspension comprising the precipitated mRNA to a depth filter, wherein the suspension flows in a direction perpendicular to the surface of the filter and precipitated mRNA is retained by the filter, comprising pore sizes ranging from 400 μm to 5 μm;
(c) dissolving the precipitated mRNA retained by the filter in step (b) thereby allowing purified mRNA to pass through the filter; and (d) recovering the purified mRNA from step (c);
wherein each of steps (b), and (c) is conducted using normal flow filtration, and wherein at least 10 grams of mRNA is purified by the method in a single batch.
Claim 9 of ‘500 claims further comprising a step of washing the precipitated mRNA retained on the filter from step (b).
Claim 13 of ‘500 claims the total purified mRNA recovered from the method is recovered in an amount that results in a yield of about 85%.
The claims of ‘500 do not claim the conditions required for precipitating the mRNA in a suspension comprising a high molar salt solution and an amphiphilic polymer to provide precipitated mRNA, as recited in claims 1 and 4, or a wash solution comprising polyethylene glycol, as required by claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘500 with the teachings of Schmitz and Lis and precipitate the mRNA using PEG and sodium chloride using precipitation conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising tetraethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing steps in the method claimed by ‘500.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, and 13 of U.S. Patent No. 11,174,500 (reference patent, hereafter ‘500) in view of Schmitz, Lis, Himmelreich, and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘500 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘500, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘500, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘500, Schmitz, Lis, Himmelreich, and Begum, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 12, 24, 44, and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 17 of U.S. Patent No. 12,084,702 (reference patent, hereafter ‘702) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘702 are each assigned to Translate Bio, Inc. and include Jonathan Abysalh and Frank DeRosa as inventors.
Claim 1 of ‘702 claims a method for purifying messenger RNA (mRNA) manufactured by in vitro transcription (IVT) synthesis, the method comprising the steps of: (a) precipitating mRNA from a solution comprising one or more contaminants from manufacturing the mRNA to provide a suspension comprising precipitated mRNA; (b) subjecting the suspension comprising the precipitated mRNA to a depth filter comprising three or more filter layers of a single three-dimensional matrix, or three or more filter layers of different three-dimensional matrices, wherein each of the three or more layers has a pore size that is smaller than the pore size of the preceding layer in the direction of flow and wherein the precipitated mRNA is retained by the depth filter; (c) dissolving the precipitated mRNA retained by the depth filter in step (b) thereby allowing purified mRNA to pass through the depth filter; and (d) recovering the purified mRNA from step (c); wherein at least 1 gram of mRNA is purified per batch and the depth filter is made of an inert material that allows capture of the precipitated mRNA without clogging or forming a gel layer.
Claim 4 of ‘702 depends from claim 1 and requires a step of washing the precipitated mRNA retained on the depth filter from step (b).
Claim 17 of ‘702 claims a method of purifying a composition comprising 100 grams or more of mRNA manufactured by in vitro transcription (IVT) synthesis, the method comprising:
(a) precipitating the IVT-transcribed mRNA comprising one or more contaminants from the IVT synthesis to generate a suspension; (b) subjecting the suspension comprising the precipitated mRNA and contaminants to filtration through a depth filter, where the precipitated mRNA is retained by the depth filter, wherein the depth filter comprises three or more filter layers of a single three-dimensional matrix, or three or more filter layers of different three-dimensional matrices, wherein each of the three or more layers has a pore size that is smaller than the pore size of the preceding layer in the direction of flow; wherein the depth filter is made of an inert material, and has a surface area of or greater than about 5,000 cm2; and (c) recovering the mRNA from the depth filter in a solution, thereby purifying the mRNA, wherein at least 85% of the mRNA is recovered and the recovered mRNA has integrity of 90% or greater and is substantially free of protein contaminants.
The claims of ‘702 do not claim the conditions required for precipitating the mRNA in a suspension comprising a high molar salt solution and an amphiphilic polymer to provide precipitated mRNA, as recited in claims 1 and 4, or a wash solution comprising polyethylene glycol, as required by claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘702 and precipitate the mRNA using PEG and sodium chloride conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising amphiphilic polymer such as polyethylene glycol as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing steps in the method claimed by ‘702.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 17 of U.S. Patent No. 12,084,702 (reference patent, hereafter ‘702) in view of Schmitz, Lis, Himmelreich, and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘702 claim as described in the above nonstatutory double patenting rejection.
Schmitz and Himmelreich teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘702, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘702, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘702, Schmitz, Lis, Himmelreich, and Begum, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 12, 24, and 56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of co-pending U.S. patent application 18/794053 (reference application, hereafter ‘053) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘053 are each assigned to Translate Bio, Inc. and include Jonathan Abysalh and Frank DeRosa as inventors.
The amended claims received December 12, 2024 are cited in this provisional nonstatutory double patenting rejection.
Claims 1 of ‘053 claims a method for purifying messenger RNA (mRNA) manufactured by in vitro transcription (IVT) synthesis, the method comprising the steps of:(a) precipitating mRNA from a solution comprising one or more contaminants from manufacturing the mRNA to provide a suspension comprising precipitated mRNA;(b) subjecting the suspension comprising the precipitated mRNA to a pleated or wrapped depth filter, wherein the precipitated mRNA is retained by the depth filter;(c) dissolving the precipitated mRNA retained by the depth filter in step (b) thereby allowing purified mRNA to pass through the depth filter; and(d) recovering the purified mRNA from step (c);wherein each of steps (b), and (c) is conducted using normal flow filtration; and wherein at least 1 gram of mRNA is purified per batch and the depth filter captures the precipitated mRNA without clogging or forming a gel layer.
Claim 10 of ‘053 depends from claim 1 and claims the method further comprising a step of washing the precipitated mRNA retained on the depth filter from step (b).
The claims of ‘053 do not claim the conditions required for precipitating the mRNA in a suspension comprising a high molar salt solution and an amphiphilic polymer to provide precipitated mRNA, as recited in claims 1 and 4, or the specific wash conditions recited in claims 9-10, 12, 24, 26, and 28.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘053 and precipitate the mRNA using PEG and sodium chloride conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising polyethylene glycol as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘053.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Claims 97-100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of co-pending U.S. patent application 18/794053 (reference application, hereafter ‘053) in view of Schmitz and Himmelreich, as evidenced by Begum, as applied to claims 1, 4, 12, 24, and 56 above, and further in view of Tomé.
The claims of ‘053 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘053, Schmitz, Lis, or Himmelreich teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘053, Schmitz, Lis, Himmelreich and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘053, Schmitz, Lis, Himmelreich, and Begum in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 8, 12, 24, and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 8 of U.S. Patent No. 9,850,269 (reference patent, hereafter ‘269) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘269 are each assigned to Translate Bio, Inc. and include Frank DeRosa as an inventor.
Claim 1 of ‘269 claims a method of large scale purification of messenger RNA (mRNA), comprising: providing an impure preparation comprising in vitro synthesized mRNA greater than 1 gram and prematurely aborted RNA sequences; treating the impure preparation with a denaturing agent under conditions that facilitate separation of the prematurely aborted RNA sequences from the mRNA; precipitating the mRNA from the treated impure preparation;
subjecting a heterogeneous suspension comprising the precipitated mRNA to tangential flow filtration such that the precipitated mRNA is captured by a filtration membrane; and eluting the captured precipitated mRNA from the membrane by re-solubilizing the mRNA, thereby resulting in a purified mRNA solution.
Claim 2 of ‘269 depends from claim 1 and claims wherein the step of precipitating mRNA comprises treating the impure preparation with a solution comprising a reagent selected from the group consisting of lithium chloride, potassium chloride, guanidinium chloride, guanidinium thiocyanate, guanidinium isothiocyanate, and ammonium acetate, or a combination thereof, and claim 8 claims wherein the in vitro synthesized mRNA is greater than 10 gram, 100 gram, 1 kg, 10 kg, or 100 kg of mRNA.
The claims of ‘269 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer to provide precipitated mRNA, as recited in claims 1 and 4, the step of washing the precipitated mRNA captured in step b) with a wash solution to purify the precipitated mRNA, as recited in present claim 1, or the specific wash conditions recited in claims 9-10, 12, 24, 26, and 28.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘269 and precipitate the mRNA using PEG and sodium chloride conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising polyethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘269.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 8 of U.S. Patent No. 9,850,269 (reference patent, hereafter ‘269) in view of Schmitz, Lis, Himmelreich, and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘269 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘269, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘269, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘269, Schmitz, Lis, Himmelreich and Begum in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 8, 12, 24, and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 8 of U.S. Patent No. 10,155,785 (reference patent, hereafter ‘785) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘785 are each assigned to Translate Bio, Inc. and include Frank DeRosa as an inventor.
Claim 1 of ‘785 claims a method of large scale purification of messenger RNA (mRNA), comprising: providing an impure preparation comprising in vitro synthesized mRNA greater than 1 gram and prematurely aborted RNA sequences; treating the impure preparation with a denaturing agent under conditions that facilitate separation of the prematurely aborted RNA sequences from the mRNA; precipitating the mRNA from the treated impure preparation; subjecting a heterogeneous suspension comprising the precipitated mRNA to tangential flow filtration such that the precipitated mRNA is captured by a filtration membrane; and
eluting the captured precipitated mRNA from the membrane by re-solubilizing the mRNA, thereby resulting in a purified mRNA solution, wherein the mRNA has a coding region that encodes cystic fibrosis conductance regulator protein.
Claim 2 of ‘785 depends from claim 1 and claims the step of precipitating mRNA comprises treating the impure preparation with a solution comprising a reagent selected from the group consisting of lithium chloride, potassium chloride, guanidinium chloride, guanidinium thiocyanate, guanidinium isothiocyanate, and ammonium acetate, or a combination thereof, and claim 8 claims wherein the in vitro synthesized mRNA is greater than 10 gram, 100 gram, 1 kg, 10 kg, or 100 kg.
The claims of ‘785 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer to provide precipitated mRNA, as recited in claims 1 and 4, or the step of washing the precipitated mRNA captured in step b) with a wash solution comprising polyethylene glycol, as recited in present claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘785 and precipitate the mRNA using PEG and sodium chloride conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising polyethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘785.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 8 of U.S. Patent No. 10,155,785 (reference patent, hereafter ‘785) in view of Schmitz, Lis, Himmelreich, and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘785 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘785, Schmitz, Lis, Himmelreich, and Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘785, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘785, Schmitz, Lis, Himmelreich, and Begum in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 8, 12, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 3 of U.S. Patent No. 11,059,841 (reference patent, hereafter ‘841) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘841 are each assigned to Translate Bio, Inc. and include Frank DeRosa as an inventor.
Claim 1 of ‘841 claims a method of purifying messenger RNA (mRNA), comprising
(a) precipitating mRNA from an impure preparation; (b) subjecting the impure preparation comprising precipitated mRNA to a purification process involving membrane filtration such that the precipitated mRNA is captured by a membrane; and (c) eluting the captured precipitated mRNA from the membrane by re-solubilizing the mRNA, thereby resulting in a purified mRNA solution, wherein the purification process involving membrane filtration is tangential flow filtration.
Claim 2 of ‘841 depends from claim 1 and claims the step of precipitating mRNA comprises treating the impure preparation with a solution comprising a reagent selected from the group consisting of lithium chloride, potassium chloride, guanidinium chloride, guanidinium thiocyanate, guanidinium isothiocyanate, ammonium acetate and combinations thereof, and claim 3 claims the reagent is guanidinium thiocyanate.
The claims of ‘841 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer to provide precipitated mRNA, as recited in claims 1 and 4, or the step of washing the precipitated mRNA captured in step b) with a wash solution comprising polyethylene glycol as recited in present claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘841 and precipitate the mRNA using PEG and sodium chloride conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising polyethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘841.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 3 of U.S. Patent No. 11,059,841 (reference patent, hereafter ‘841) in view of Schmitz, Lis, Himmelreich and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘841 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘841, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘841, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘841, Schmitz, Lis, Himmelreich, and Begum in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 8, 12, 24, and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 10, and 15 of U.S. Patent No. 11,884,692 (reference patent, hereafter ‘692) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘692 are each assigned to Translate Bio, Inc. and include Frank DeRosa as an inventor.
Claim 1 of ‘692 claims a method of purifying messenger RNA (mRNA), comprising (a) precipitating mRNA; (b) treating the precipitated mRNA to a membrane filtration process; and
(c) eluting the precipitated mRNA from the membrane by re-solubilizing the mRNA; wherein the membrane filtration process is tangential flow filtration, and wherein the method further comprises a step of dialyzing the purified mRNA solution.
Claim 4 of ‘692 depends from claim 1 and requires the precipitating mRNA comprises treating mRNA with a denaturing agent, salt, surfactant or solvent suitable for precipitating the mRNA, claim 5 claims the denaturing agent is selected from the group consisting of lithium chloride, potassium chloride, guanidinium chloride, guanidinium thiocyanate, guanidinium isothiocyanate, ammonium acetate and combinations thereof, and claim 6 claims the denaturing agent is guanidinium thiocyanate.
Claim 10 of ‘692 depends from claim 1 and claims wherein the method further comprises a step of washing the precipitated mRNA before eluting.
Claim 15 of ‘692 claims wherein the mRNA is purified at a scale of or greater than 1 gram, 5 gram, 10 gram, 100 gram, 1 kg, 10 kg, or 100 kg per batch.
The claims of ‘692 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer as recited in present claim 1, or washing the precipitated mRNA with a wash solution comprising polyethylene glycol, as recited in present claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘692 and precipitate the mRNA using PEG as an amphiphilic polymer and greater than 1 M salt solution, as taught by Schmitz and Lis, and to wash the mRNA using a wash solution comprising polyethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘692.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-6, 10, and 15 of U.S. Patent No. 11,884,692 (reference patent, hereafter ‘692) in view of Schmitz, Lis, Himmelreich, Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘692 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘692, Schmitz, Lis, Himmelreich, and Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘692, Schmitz, Lis, Himmelreich and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘692, Schmitz, Lis, Himmelreich, and Begum in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 8, 12, 24, and 56 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-8, 10, and 18 of U.S. Patent No. 12,060,381 (reference patent, hereafter ‘381) in view of Schmitz, Lis, Himmelreich and Begum.
The present application and ‘381 are each assigned to Translate Bio, Inc. and include Frank DeRosa as an inventor.
Claim 1 of ‘381 depends from claim 1 and claims a method for manufacturing messenger RNA (mRNA) comprising: synthesizing mRNA in vitro; and purifying the in vitro synthesized mRNA, comprising (a) precipitating mRNA; (b) passing precipitated mRNA across or along a membrane; (c) eluting the precipitated mRNA from the membrane, thereby manufacturing mRNA.
Claim 3 of ‘381 claims wherein the precipitating mRNA comprises treating mRNA with a denaturing agent, salt, surfactant or solvent suitable for precipitating the mRNA, claim 6 claims wherein the denaturing agent is selected from the group consisting of lithium chloride, potassium chloride, guanidinium chloride, guanidinium thiocyanate, guanidinium isothiocyanate, ammonium acetate and combinations thereof, claim 7 claims the denaturing agent is guanidinium thiocyanate, and claim 8 claims wherein the precipitating comprises treating with 4M guanidinium thiocyanate.
Claim 10 of ‘381 depends from claim 1 and claims the method further comprises a step of washing the precipitated mRNA before eluting.
Claim 18 of ‘381 depends from claim 1 and claims the mRNA is purified at a scale of or greater than 1 gram, 5 gram, 10 gram, 100 gram, 1 kg, 10 kg, or 100 kg per batch.
The claims of ‘381 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer, as recited in claim 1, or solubilizing the precipitated mRNA to obtain a purified mRNA composition, as recited in claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘381 and precipitate the mRNA using PEG as an amphiphilic polymer and greater than 1 M salt solution, as taught by Schmitz and Lis, and to wash the mRNA using a wash solution comprising polyethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘381.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6-8, 10, and 18 of U.S. Patent No. 12,060,381 (reference patent, hereafter ‘381) in view of Schmitz, Lis, Himmelreich, Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘381 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘381, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘381, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘381, Schmitz, Lis, Himmelreich, and Begum, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 8, 12, 24, and 56 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 28 of co-pending U.S. patent application 17/344,535 (reference application, hereafter ‘535) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘535 are each assigned to Translate Bio, Inc. and include Frank DeRosa as an inventor.
The amended claims received March 18, 2026 are cited in this provisional non-statutory double patenting rejection.
Claim 1 of ‘535 claims a method of purifying messenger RNA (mRNA) at a scale of 1
gram per batch or greater, comprising (a) precipitating mRNA from an impure preparation;
(b) subjecting the impure preparation comprising precipitated mRNA to a purification process involving membrane filtration, wherein the purification process involving membrane filtration is direct flow filtration; (c) capturing the precipitated mRNA on the membrane; (d) washing the captured precipitated mRNA; and (e) eluting the captured precipitated mRNA from the membrane by re-solubilizing the mRNA.
Claim 4 of ‘535 depends from claim 1 and claims the step of precipitating mRNA involves treating the impure preparation with a solution comprising a reagent selected from the group consisting of lithium chloride, potassium chloride, guanidinium chloride, guanidinium thiocyanate, guanidinium isothiocyanate, ammonium acetate and combinations thereof, and claim 5 claims the reagent is guanidinium thiocyanate.
Claim 28 of ‘535 claims the method of claim 1, wherein the mRNA is purified at a scale of or greater than 10 gram, 100 gram, 1 kg, 10 kg, or 100 kg per batch.
The claims of ‘535 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer as recited in claims 1 and 4. In addition, the claims of ‘535 do not claim washing the precipitated mRNA with a wash buffer comprising polyethylene glycol, as recited in claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘535 and precipitate the mRNA using PEG and sodium chloride conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising amphiphilic polymer such as polyethylene glycol as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘535.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not been patented.
Claims 97-100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, and 28 of co-pending U.S. patent application 17/344,535 (reference application, hereafter ‘535) in view of Schmitz, Lis, Himmelreich, and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘535 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘535, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘535, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘535, Schmitz, Lis, Himmelreich, and Begum, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 12, 24, 29, 36, and 44 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8, 10, 18, and 21 of U.S. Patent No. 10,808,241 (reference patent, hereafter ‘241) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘241 are each assigned to Translate Bio, Inc. and include Frank DeRosa and Jonathan Abysalh as inventors.
Claim 1 of ‘241 claims a method of large scale purification of mRNA, comprising steps of: providing a solution comprising at least 250 mg of in vitro synthesized mRNA; adding one or more agents that promote precipitation of the mRNA, thereby obtaining a slurry; stirring the slurry in an agitated filter dryer at a speed between 50 revolutions per minute RPM and 500 revolutions per minute under pressure to the slurry and/or a vacuum to the slurry sufficient to direct the slurry's mother liquor through the filter, thereby obtaining a precipitate-containing composition; and washing the precipitate-containing composition with stiffing and under pressure, thereby yielding a purified mRNA precipitate, wherein the purified mRNA has reduced impurity of enzyme reagents used in in vitro synthesis as compared to the otherwise same mRNA purified by tangential flow filtration and has an integrity greater than about 95% determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis with silver staining.
Claim 2 of ‘241 claims the method purifies at least about 2.5 grams mRNA in one batch, claim 8 claims the one or more agents that promote precipitation of mRNA are a chaotropic salt and an alcohol, and claim 10 claims further comprising a step of solubilizing the purified mRNA precipitate in an aqueous medium, thereby obtaining a solution comprising purified mRNA. Claim 18 of ‘241 claims the total purified mRNA is recovered in an amount that results in a yield of at least about 80%, and claim 21 claims the slurry comprises at least one filtration aid. In this instance, a slurry is interpreted as one example of a suspension recited in the present claims.
The claims of ‘241 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer and high molar salt to provide precipitated mRNA, as recited in claims 1 and 4, or the wash solution comprising polyethylene glycol, as recited in claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘241 and precipitate the mRNA using PEG and sodium chloride using conditions taught by Schmitz and Lis, and further to wash the captured RNA with a wash solution comprising polyethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘241.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8, 10, 18, and 21 of U.S. Patent No. 10,808,241 (reference patent, hereafter ‘241) in view of Schmitz, Lis, Himmelreich, and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘241 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘241, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘241, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claim 1 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘241, Schmitz, Lis, Himmelreich, and Begum, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Claims 1, 4, 12, 24, and 29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 12 of U.S. Patent No. 11,976,272 (reference patent, hereafter ‘272) in view of Schmitz, Lis, Himmelreich, and Begum.
The present application and ‘272 are each assigned to Translate Bio, Inc. and include Frank DeRosa and Jonathan Abysalh as inventors.
Claim 1 of ‘272 claims a method of purifying at least about 1 gram of in vitro transcribed mRNA, comprising steps of: providing a solution comprising the in vitro transcribed mRNA;
adding one or more agents that promote precipitation of the in vitro transcribed mRNA, thereby obtaining a slurry; stirring the slurry prior to and/or while providing pressure to the slurry and/or a vacuum to the slurry sufficient to direct the slurry's mother liquor through a filter, thereby obtaining a precipitate-containing composition; and washing the precipitate-containing composition, thereby yielding a purified mRNA precipitate; wherein the slurry comprises at least one dispersant; wherein at least 1 gram of purified mRNA is obtained, and wherein the purified mRNA has reduced impurity of enzyme reagents used in in vitro transcription as compared to the otherwise same mRNA purified by tangential flow filtration.
Claim 12 of ‘272 claims wherein a washing step comprises contacting the precipitate-containing composition with a first solution comprising a chaotropic salt and an alcohol. In this instance, a slurry is interpreted as one example of a suspension recited in the present claims.
The claims of ‘272 do not claim the conditions required for precipitating the mRNA in a suspension comprising an amphiphilic polymer and high molar salt to provide precipitated mRNA, as recited in claims 1 and 4, solubilizing the precipitated mRNA from step c) to obtain a purified mRNA composition as recited in claim 1, or the wash buffer comprising polyethylene glycol as recited in claim 1.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify the method claimed by ‘272 and precipitate the mRNA using PEG and sodium chloride conditions taught by Schmitz and Lis, to resolubilize the precipitated mRNA after capture of said precipitated mRNA, as taught by Schmitz, and further to wash the captured RNA with a wash solution polyethylene glycol, as taught by Himmelreich, because one of ordinary skill in the art would have recognized the conditions taught by Schmitz, Lis, Himmelreich, and Begum as effective for performing these steps in the method claimed by ‘272.
As evidenced by Begum, the suggested tetraethylene glycol concentration of 80% by volume corresponds to a concentration of about 90% wt/vol.
Claims 97-100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 12 of U.S. Patent No. 11,976,272 (reference patent, hereafter ‘272) in view of Schmitz, Lis, Himmelreich, and Begum as applied to claims 1 and 12 above, and further in view of Tomé.
The claims of ‘272 claim as described in the above nonstatutory double patenting rejection.
Schmitz, Lis, Himmelreich, and Begum teach as described in the above rejections under 35 U.S.C. § 103.
None of the claims of ‘272, Schmitz, Lis, Himmelreich, or Begum teach the molecular weight of the PEG is 200 g/mol to 600 g/mol or the PEG comprising PEG 200, PEG 300, or PEG 400, as recited in claims 97-100.
Tomé teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the tetraethylene glycol in the wash solution of Himmelreich with PEG 200, because the claims of ‘272, Schmitz, Lis, Himmelreich, and Begum render obvious the method of claims 1 and 12 using tetraethylene glycol in the wash buffer, and because Tomé teaches PEG 200 has a molecular weight of 200 and includes, as its most abundant component, tetraethylene glycol.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. One of ordinary skill in the art would have recognized that tetraethylene glycol in the wash solution taught by Himmelreich may be substituted with PEG 200 with a reasonable expectation that the wash solution would be still be effective when practicing the method obvious over the claims of ‘272, Schmitz, Lis, Himmelreich, and Begum, in view of the similarity in both the molecular weight and composition between tetraethylene glycol and PEG 200 taught by Tomé.
Allowable Subject Matter
Claims 101 and 105 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 101 and 105 require the PEG comprises PEG 400.
The closest prior art to claims 101 and 105 is considered the combination of Himmelreich, whose teachings are described in the above rejections under 35 U.S.C. § 103. Himmelreich, who embodies a step of washing with 70% by volume tetraethylene glycol and suggests a concentration of up to 80% by volume tetraethylene glycol, does not teach or suggest the use of PEG 400 in a wash solution, and no prior art of record would have motivated one of ordinary skill in the art to substitute the tetraethylene glycol taught by Himmelreich with PEG 400.
Moreover, Reinhardt (Publication no. WO 2015188994 A1; cited in previous office action) teaches and claims a method for enrichment and/or purification of nucleic acids, wherein the nucleic acids are bound to a solid phase and eluted after one or more washing steps, characterized in that the washing step(s) are carried out with one or more washing solutions containing polyethylene glycol (English translation, document p. 23, claim 1). However, shows a preference for larger PEG groups, with an average molar mass of 6000 g/mol (English translation, document p. 23, claim 3), and does not teach or suggest PEG 400 for washing nucleic acid samples.
Therefore, in view of Himmelreich and Reinhardt, one of ordinary skill in the art would not have been motivated to wash a precipitated nucleic acid solution with wash solution comprising PEG 400, and thus claims 101 and 105 are novel and nonobvious over the prior art of record.
Conclusion
Claims 1, 4, 8, 12, 24, 29, 36-37, 44, 56, 65, 78, 97-100, and 102-104 are rejected.
Claims 101 and 105 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/B.M.B./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
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