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 instant application is a national stage entry under 35 U.S.C. § 371 of PCT/EP2022/064237 (filed 05/25/2022). Acknowledgement is made of Applicants’ claim for priority to foreign application EP21175871.9 (filed 05/26/2021).
Response to Amendment
The amendment filed on 06/22/2026 has been received and entered into the application file; claims 11 and 15-16 have been canceled and claim 21 has been added.
Claims 10, 12-14, and 17-21 are now pending and examined herein.
Status of Prior Rejections/Response to Arguments
RE: Rejection of the following under 35 U.S.C. 103:
claims 10-19 over Eshoo and Duncan in view of Gregoire; and
claim 20 over Eshoo and Duncan in view of Gregoire, as evidenced by Qiagen®:
The cancellation of claims 11 and 15-16 technically renders the rejections thereof moot; the subject matter of the cancelled claims has been incorporated into independent claim 10.
The arguments set forth by Applicants in the response filed on 06/22/2026 are directed to (i) the Eshoo and Duncan (hereinafter Eshoo) disclosure; (ii) the Gregoire disclosure; and (iii) the specific combination of the Eshoo and Gregoire disclosures.
Regarding Eshoo: Applicants assert Eshoo teaches synthetic DNA oligonucleotides, and repeatedly characterizes the nucleic acid as synthetic oligonucleotides; Applicants further assert highly purified synthetic oligonucleotides do not present the same technical environment as an in vitro transcribed (IVT)-RNA reaction mixture containing residual divalent metal ions from enzymatic transcription.
Respectfully, these arguments are found unpersuasive. Eshoo explicitly teaches the nucleic acid may be a polynucleotide, including single-stranded RNA molecules, which may be enzymatically modified (pars. 0009, 0023).
Regarding Gregoire: Applicants assert Gregoire is directed primarily to polynucleotide delivery and expression (e.g., kidney-specific delivery) and does not address the problem of RNA aggregate formation upon freezing; Applicants further assert the disclosure does not teach preparing a composition that contains IVT CAP-1 RNA, divalent metal ions, and a metal binding chelator in the claimed equimolar-or-higher stoichiometric relationship, nor selecting that relationship specifically to address aggregation of IVT CAP-1 RNA during freezing.
Respectfully, these arguments are found unpersuasive. In response to Applicants’ argument Gregoire does not address the problem of RNA aggregate formation upon freezing, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As set forth in the non-final Office action dated 02/20/2026, Gregoire teaches a renal IVT mRNA polynucleotide comprising a 5’-CAP1 structure, disclosing a specific formulation thereof comprising metal cations; e.g., Zn2+, Ca2+, Cu2+, Mg2+ (pars. 0021, 0023-0024, 0414). Gregoire is relied upon for the RNA molecule of the claimed invention; as such, it is not necessary for Gregoire to disclose the metal binding chelator nor selecting the claimed equimolar-or-higher stoichiometric relationship of the chelator and divalent metal cations specifically to address aggregation of IVT CAP-1 RNA during freezing.
Regarding the combination of references: Applicants assert that even if one were to combine the teachings of Eshoo and Gregoire, the combination does not teach each and every limitation and, at most, would suggest certain nucleic acids, including RNA, may be stored or formulated; this is contrasted with the claimed method, which requires preparing a composition containing IVT CAP-1 RNA, divalent metal ions, and a metal binding chelator, wherein the chelator is present in an amount equimolar to, or higher than, the divalent metal ion concentration, then freezing the composition to reduce and/or prevent RNA aggregate formation.
Respectfully, this argument is found unpersuasive. As a first matter, Applicants’ argument relies on language solely recited in preamble recitations in claim 10. When reading the preamble in the context of the entire claim, the recitation for reducing and/or preventing formation of RNA aggregates in a composition is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02. As a second matter, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) and MPEP 2144(IV).
Additionally, Eshoo explicitly teaches a method for storing nucleic acid comprising mixing a solution comprising a chelator (e.g., EDTA) with e.g., an RNA molecule (pars. 0013, 0023, 0031, 0033). Regarding the arguments directed to the stoichiometry relationship of the chelator to the divalent metal ions, as set forth in the non-final Office action dated 02/20/2026, Eshoo teaches many enzymes (e.g., nucleases) require a metal ion for activity, but that metal ions themselves can attack and degrade biological molecules, e.g., nucleic acids (par. 0030); chelators form complexes with metal ions so they can't participate or interact normally with other elements, ions or molecules (par. 0030); and that chelators can be used to sequester the metal ions to maintain the integrity of a nucleic acid in solution (par. 0030). Therefore, it would have been obvious to a person having ordinary skill in the art to have formulated the storage solution so the concentration of chelator is equimolar to or higher than equimolar to the concentration of divalent metal ions in order to provide sufficient chelator to sequester any metal ions to prevent degradation of the nucleic acid and maintain its integrity.
Applicants’ assert a person of ordinary skill in the art would not have combined the references as Eshoo and Gregoire intend to solve different problems. Respectfully, it is submitted a requirement of motivation to modify or combine is not the standard for a proper rejection under 35 U.S.C. 103. In the recent Supreme Court decision in KSR International Co v Teleflex Inc the court stated, “Rigid application of “teaching, suggestion, or motivation” test, under which patent claim is proved obvious only if prior art, nature of problem addressed by inventor, or knowledge of person having ordinary skill in art reveals some motivation or suggestion to combine prior art teachings, is inconsistent with expansive and flexible “functional approach” to resolution of obviousness issue, under which scope and content of prior art are determined, differences between prior art and claims at issue are ascertained, level of ordinary skill in pertinent art is resolved, and secondary considerations such as commercial success, long felt but unsolved needs, and failure of others may be considered if doing so would prove instructive; rigid TSM approach is therefore rejected.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at page 1386. In the instant case, the ‘substitution rationale’ is relied upon. This rationale requires a finding that the substituted components and their functions were known in the art, and a person having ordinary skill in the art could have substituted one element for another and the results of said substitution would have been predictable; see MPEP 2143(I)(B).
Lastly, in response to Applicants’ argument that the Examiner’s conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicants’ disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Therefore, the remaining rejections of record are maintained. New grounds of rejection necessitated by the entry of claim 21 are additionally set forth below.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 10, 12-14, and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Eshoo and Duncan (US 2012/171685) in view of Gregoire (US 2019/0054112).
Eshoo and Duncan (hereinafter Eshoo) teaches buffers for the stabilization of nucleic acid molecules (Abstract).
Gregoire teaches compositions and methods for the preparation, manufacture, and therapeutic use of renal polynucleotides (Abstract).
Regarding claims 10, 12-14, 17-19: Eshoo teaches a method for storing nucleic acid comprising mixing a storage solution comprising a chelator and the nucleic acid, e.g., synthetic oligonucleotide, polynucleotide, wherein the storage solution is stored at -20°C to freeze the solution; the solution may be thawed again (par. 0013); the chelator may be EDTA, BAPTA, DTPA, TPEN (par. 0031), and the nucleic acid may be RNA (par. 0023, 0033). This reads on:
the preparing a composition comprising RNA and a metal binding chelator and freezing the composition limitations recited in claim 10.
Eshoo does not teach the remaining limitations recited in claim 10.
Regarding the in vitro transcribed RNA having a 5’ CAP-1 structure limitation:
Gregoire teaches a nucleic acid molecule encoding one or more renal peptide(s) of interest (par. 0021), disclosing an embodiment wherein the nucleic acid is a renal in vitro transcribed (IVT), modified mRNA polynucleotide (pars. 0023-0024). Gregoire teaches an embodiment wherein the modification comprises a 5’-Cap1 structure (par. 0118); formulations of the renal polynucleotide may further comprise metal cations, e.g., Zn2+, Ca2+, Cu2+, Mg2+ (par. 0141). Thus, the renal polynucleotide of Gregoire reads on:
the wherein the RNA is in vitro transcribed and has a 5’ CAP-1 structure limitation recited in claim 10.
It would have been prima facie obvious to have modified the method of Eshoo by substituting the RNA with the renal polynucleotide of Gregoire. This conclusion of obviousness is based on the ‘substitution rationale’. The use of the renal polynucleotide in place of the RNA is a predictable use of prior art elements according to their established functions as nucleic acid molecules, leading to the predictable result of storing the molecule; further, as Gregoire teaches the renal polynucleotide may be stored between -20°C and -80°C (par. 0422), one skilled in the art would have more than a reasonable expectation of success. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results; see MPEP 2143(I)(B).
Regarding the equimolar or higher than equimolar limitations:
Eshoo teaches chelators form complexes with metal ions so they can't participate or interact normally with other elements, ions or molecules (par. 0030). Many enzymes (e.g., nucleases) require a metal ion for activity; additionally, metal ions themselves can attack and degrade biological molecules, e.g., nucleic acids (par. 0030). Thus, a chelator can be used to sequester the metal ions from interacting with enzyme polypeptides, therefore eliminating, inhibiting, or minimizing enzyme activity, or to maintain the integrity of a nucleic acid in solution (par. 0030).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the method of Eshoo by formulating the storage solution so the concentration of chelator is equimolar to or higher than equimolar to the concentration of divalent metal ions. This conclusion is based on the ‘teaching, suggestion, or motivation rationale’; one would be motivated to do so in order to provide sufficient chelator to sequester any metal ions in order to prevent degradation of the nucleic acid and maintain its integrity. Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical; see MPEP 2144.05(II)(A).
As the modified method carries out the same active steps, the effect of reducing and/or preventing the formation of RNA aggregates is necessarily achieved.
In addition to rendering obvious the remaining divalent metal ions and wherein the metal binding chelator is present in the composition at a concentration that is equimolar or higher than equimolar compared to a concentration of the divalent metal ions in the composition limitations recited in claim 10, the modified method of Eshoo as set forth above also reads on:
the wherein the metal binding chelator is capable of binding divalent metal ions limitation recited in claim 12;
the wherein the divalent metal ions are selected from: Ca2+ ions, Cu²+ ions, Fe²+ ions, Zn2+ ions, and Mg2+ ions limitations recited in claim 13;
the wherein the divalent metal ions are Mg2+ ions limitation recited in claim 14;
the wherein the metal binding chelator is BAPTA (1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), EDTA (ethylenediaminetetraacetic acid), DPTА (diethylenetriaminepentaacetic acid), or TPEN (N'- Tetrakis(2-pyridylmethyl)ethylenediamine) limitations recited in claim 17;
the wherein freezing the composition comprises freezing the composition at a temperature of -20°C or less limitation recited in claim 18; and
the further comprising thawing the composition limitation recited in claim 19.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Eshoo and Duncan (US 2012/171685) in view of Gregoire (US 2019/0054112), as evidenced by Qiagen® (“Supplementary Protocol”; 2019).
The teachings of Eshoo and Gregoire are set forth above.
Regarding claim 20: Following the above discussion, the modified method of Eshoo does not explicitly teach thawing the storage solution comprising the renal polynucleotide at a temperature from about 20°C to 30°C, as required by the limitation recited in claim 20. However, regarding the thawing temperature, as per MPEP 716.02, any differences between the claimed invention and the prior art may be expected to result in some difference in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d1091.231 USPQ 375 (Fed. Cir. 1986). Furthermore, the ordinary artisan would have known the prior art recognized room temperature (~25°C) as an appropriate temperature for thawing biological material, e.g., nucleic acids, as evidenced by the supplementary protocol taught by Qiagen® (pg. 2; pars. 2, 4).
Thus, the modified method of Eshoo renders obvious the limitation recited in claim 20.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Eshoo and Duncan (US 2012/171685) in view of Gregoire (US 2019/0054112), further in view of Lei, et al. (Calcif Tissue Int. 2013) and Haas, et al. (WO 2019/077053), as evidenced by Wypych (“Ecological Properties: ethylenediaminetetraacetic acid.” 2024).
The teachings of Eshoo and Gregoire are set forth above.
Lei, et al. (hereinafter Lei) teaches the use of chelating agents in calcified aortic tissue (Abstract).
Haas, et al. (hereinafter Haas) teaches methods for the preparation of RNA lipoplex particles (Abstract).
Regarding claim 21: Following the above discussion, the modified method of Eshoo does not teach the concentration of EDTA as at least 6 mM, as required by the limitations of the instant claim.
However, Lei investigates the ability of common chelating agents, including EDTA, to remove calcium from hydroxyapatite and calcified tissues without damaging the tissue architecture (pg. 427; col. 1, par. 1). Three series of concentration (1, 5, and 10 mg/mL) of chelating agent solutions were prepared in order to optimize the concentration needed for efficient demineralization (pg. 428; col. 2, par. 3); thus, Lei evidences it is standard in the art to optimize the chelator concentration for in vitro applications. As evidenced by Wypych, the molecular weight of EDTA is 292.28 g/mol (pg. 1); 1, 5, and 10 mg/mL EDTA is approximately 3.4, 17.1, and 34.2 mM EDTA, respectively.
Additionally, Haas teaches RNA lipoplex formation in the presence of increasing concentrations of chelator EDTA up to 18 mM (pg. 85; lines 18-20); thus, Haas further evidences optimization of chelator concentration is standard in the art. Hass further discloses the formation of RNA lipoplexes in the presence of high concentrations of EDTA (up to 18 mM) results in particle characteristics equivalent to preparation in the presence of lower concentrations, further stating the presence of EDTA concentrations of up to 20 mM during RNA lipoplex formation is considered advantageous (pg. 85; lines 22-29). Thus, it is reasonable to conclude Haas teaches EDTA concentrations of up to 20 mM can be safely used with RNA molecules.
Therefore, as Lei evidences the art recognized the concentration of chelating agent EDTA for in vitro applications as a result effective variable, it would have been routinely optimized by one having ordinary skill in the art. Additionally, as Lei teaches the use of EDTA up to 34.2 mM in aortic tissue (pg. 427), and as Hass teaches the use of EDTA up to 20 mM in RNA lipoplexes (pg. 85), the skilled artisan would have more than a reasonable expectation of success in the routine optimization of EDTA for IVT CAP-1 RNA in a concentration of at least up to 20 mM. Furthermore, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. See MPEP 2144.05(II)(A).
This renders obvious the wherein the metal binding chelator is EDTA and wherein the EDTA is present in the composition at a concentration of at least 6 mM limitation recited in claim 21.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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