DETAILED ACTION
This Office Action is in response to Applicant’s Amendment and Remarks filed on 14 November 2025 in which claims 1 and 2 were amended to change the scope and breadth of the claims.
Claims 1-7 are pending in the current application. Claims 5-7 remain withdrawn as being drawn to a non-elected invention. Claims 1-4 are examined on the merits herein.
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 .
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3 and 4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The recitation “R2 is OH, R3 is OH” in claim 1 renders the claim, and dependent claims 3 and 4 herein indefinite. The 5’-terminal ribose would contain two chemically unstable peroxy moieties if R2 and R3 were defined as “OH”. For purposes of examination, the claims are interpreted as if “R2 is H and R3 is H”.
Claim 1 also recites a definition for R4, however, R4 is not a variable recited in the compound.
Response to Arguments
Applicant's arguments filed 14 July 2014 have been fully considered but they are not persuasive.
Applicant contends a definition for R2 has now been provided.
The argument is not found persuasive, since the definition provided for R2 would result in a chemically unstable peroxy moiety.
The rejection is hereby maintained.
Modified Rejections
The following are new ground(s) or modified rejections necessitated by Applicant's amendment, filed on 07 November 2025, where the limitations in pending claim 1 as amended now have been changed. Therefore, rejections from the previous Office Action, dated 14 July 2025, have been modified and are listed below.
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.
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.
Claim(s) 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Hogrefe et al. (WO 2017/053297, cited in previous Office Action) in view of Jemielity et al. (WO2017/130151, cited in previous Office Action).
Hogrefe et al. teach preparing 5’-capped RNAs having the general formula: m7Gppp[N2’OMe]n[N]m, wherein N is any natural, modified or unnatural nucleoside, “n” can be any integer from 0 to 4 and “m” can be an integer from 1 to 9 (abstract). In certain embodiments, the initiating capped oligonucleotide primer is a trimer, and includes m7GpppA(2’OMe)pG (p.25-26, para [00111], Table 1):
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. Hogrefe et al. teach “the presence of the m7Gppp fragment on the 5’-end is essential for mRNA maturation, it protects the mRNA from degradation by exonucleases, facilitates transport of mRNAs from the nucleus to the cytoplasm and plays a key role in assembly of the translation initiation complex” (para [0006]). “Another element of eukaryotic mRNA is the presence of 2’-O-methyl nucleoside residues at transcript position 1 (Cap 1), and in some cases, at transcript positions 1 and 2 (Cap 2). The 2’-O methylation of mRNA is required for higher efficacy of mRNA translation in vivo…and further improves nuclease stability of the 5’-capped mRNA.” (para [0008]).
While Hogrefe et al. teach m7GpppA(2’OMe)pG, also referred to as m7GpppAmpG, Hogrefe et al. do not expressly disclose wherein present X3 is -S- (elected species m7Gppp5’sAmpG, present claim 2).
Jemielity et al. teach 5’-phosphorothiolate mRNA 5’-end cap analogs comprising a compound of formula 1:
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, wherein B includes formula 3, adenine:
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, and L1 and L2 are independently selected from the group consisting of O and S, wherein at least one of L1 and L2 is not O (p.5-6). Jemielity teach compound 22: m7Gppp5’SG:
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(p.5-6; claim 2). Jemielity et al. teach the 5’-phosphorothiolate moiety increases mRNA stability and biosynthesis efficiency of protein encoded by that mRNA in the cells (p.4:28-32). Jemielity et al. teach preparing analogs wherein at least one of oxygen atoms in position 5’ was replaced by a sulfur atom (p.4:15-17). Jemielity et al. teach the relative translation efficiency of m27,2’-OGpppSG was 2.23 ± 0.31 relative to m7GpppG (table 6).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify m7GpppAmpG of Hogrefe et al. to include a 5’-phosphorothiolate moiety to give m7Gppp5’sAmpG, because Jemielity found replacing oxygen with sulfur at either 5’-positions increased the compound’s stability and translation efficiency relative to m7GpppG.
In the same field of invention, Hogrefe et al. and Jemielity et al. describe preparing mRNA 5’-cap analogs having improved stability relative to m7GpppG. While Hogrefe et al. recognize incorporation of a 2’-OMe at the second nucleotide improves stability, m7Gppp[N2’OMe]m[N]m, Jemielity et al. recognize substitution of an oxygen for a sulfur atom at either 5’-positions improved stability and translation efficiency.
Thus, one having ordinary skill in the art would have had a reasonable expectation of success in substituting an -O- for an -S- to obtain a 5’-cap suitable for incorporation into mRNA.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Response to Arguments
Applicant's arguments filed 14 November 2025 have been fully considered but they are not persuasive.
Applicant contends one of ordinary skill in the art would not have been motivated to modify the teachings of Hogrefe with the teachings of Jemielity. Applicant argues Hogrefe is concerned with the efficient, co-transcriptional synthesis of RNA with Cap1 or Cap2 structures, wherein the oligonucleotide primers are trimers or longer. Applicant argues Jemielity is concerned with dinucleotide caps, and does not teach replacing an oxygen for a sulfur in trinucleotide caps. Applicant further argues one having ordinary skill in the art would not have combined the two references together because they are each concerned with providing solutions to different technical problems.
The above arguments are not found persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, both references are concerned with preparing 5’-cap analogs that are useful for the in vitro synthesis of 5’-capped RNA molecules. Hogrefe acknowledges 2’-O-methylation improves nuclease stability (para [0008]). And while Jemielity is concerned with targeting or inhibiting DcpS, Jemielity also expressly teaches the mRNAs modified at the 5’-end with analogs containing 5’-phosphorothiolate moiety have an increased stability and translational activity in cellular conditions (abstract). Thus, both prior art references are concerned with using the 5’-cap analogs for the in vitro synthesis of 5’-capped RNA molecules.
Applicant further contends dinucleotides have opposite effects on translational properties as trinucleotides.
Applicant has not provided any specific examples or explanation of any specific properties. For example, there is no explanation as to which compounds were tested, and for what they were tested.
Applicant also argues modifying Hogrefe’s already DcpS-resistant ARCA primer with modifications taught by Jemielity that increase resistance to DcpS would either be redundant, or exacerbate the risk of cellular toxicity, thereby teaching away from the combination.
The above argument is not found persuasive. It’s not clear how Applicant is arguing the references are directed towards solving fundamentally different problems, and yet redundant at the same time.
Both references are concerned with preparing 5’-capped RNAs that are stable to in vitro transcription. One having ordinary skill in the art would have looked to different analogs for how stability has been improved upon.
The rejection is hereby maintained.
Claim(s) 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Hogrefe et al. (cited above) in view of Kuhn et al. (WO 2019/175356, cited above).
Hogrefe et al. teach as discussed above, including specifically m7GpppA(2’OMe)pG, which can also be written as m7GpppAmpG:
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. Furthermore, Hogrefe et al. teach the compounds have better capping efficiency than with the ARCA analog m7G3’OMepppG (Anti-Reverse Cap Analogs (ARCA)), (Example 17).
While Hogrefe et al. teach m7GpppAmpG, Hogrefe et al. do not expressly disclose wherein present X2 is -S-, i.e. m7GppSpAmpG.
Kuhn et al. teach preparing 5’-cap trinucleotide compounds, wherein the 5’-cap compounds contain at least one phosphorothioate, phosphorselenoate and/or boranophosphate moiety in the phosphate bridge between the first and second nucleotide, and wherein the second nucleotide is blocked at its 2’-position (abstract, title, p.1:5-17). The aforementioned chemical modifications improve the stability of RNA having these 5’-cap compounds and translation efficiency (Example 4, p.120).
Kuhn et al. teach a compound of formula (I):
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, wherein R2 and R3 are independently selected from the group consisting of H, halo, OH, and optionally substituted alkoxy; R4 and R6 are independently selected from the group consisting of O and S; and R5 is selected from the group consisting of S, Se, and BH3 (p.69-70; claim 1).
Kuhn et al. exemplify
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(fig. 2): m7,2-OMeGppspGpG.
It would have been obvious to prepare a 5’-cap where R1 is CH3; R2 and R3 are H; X2 is S; X1, X5, X3, X4 are oxygen; and Base1 is G or A, because Kuhn et al. teach 5’-cap trinucleotide compounds containing at least one phosphorothioate, phosphoroselenoate and/or boranophosphate moiety between the first and second nucleotide showed improved mRNA stability and translation efficiency.
It also would have been obvious to substitute G in m27,3-OGppspGmpG with A to give m7GppspAmpG with a reasonable expectation of success in preparing an RNA molecule having a stable 5’-trinucleotide cap.
Starting from Hogrefe et al., one having ordinary skill in the art would have looked to the teachings of Kuhn, because they are both concerned with improving the translation efficiency compared to known ARCA analogs. While the compounds exemplified in Kuhn are blocked at the 2’-position, Kuhn is still relevant for teaching it need not be blocked. Hogrefe et al. also demonstrate one having ordinary skill in the art would have had a reasonable expectation of success using compounds without blocking at the 2’-position and 3’-position for in vitro RNA transcription.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Response to Arguments
Applicant's arguments filed 14 November 2025 have been fully considered but they are not persuasive.
With respect to Kuhn, Applicant contends the presently claimed compounds possess a surprising and advantageous property not taught by Kuhn. Applicant contends Kuhn’s invention is directed to ARCA-type trinucleotides, wherein the second nucleotide is blocked at its 2’-position. The blocking of the 2’- or 3’-OH groups of the 7-methylguanosine is an essential feature in the compounds taught by Kuhn, to prevent reverse incorporation and enhance stability. Applicant argues the presently amended claims define R2 is OH and R3 is OH (i.e. R2 and R3 is H). Applicant argues the claimed compounds as amended are fundamentally different from Kuhn’s ARCA-based compounds. And Applicant argues one having ordinary skill in the art would not have been motivated to arrive at the claimed invention.
The above arguments are not found persuasive because Kuhn expressly teaches a genus of compounds which would include the presently claimed compounds where R2 and R3 are H (i.e. hydroxyl groups). Furthermore, Hogrefe et al. is now cited in combination with Kuhn for expressly teaching 5’-cap trinucleotide analogs wherein R2 and R3 are H.
Starting from Hogrefe et al., one having ordinary skill in the art would have looked to the teachings of Kuhn, because they are both concerned with improving the translation efficiency compared to established ARCA analogs. While the compounds exemplified in Kuhn are blocked at the 2’-position, Kuhn is still relevant for teaching it need not be blocked. Hogrefe et al. also demonstrate one having ordinary skill in the art would have had a reasonable expectation of success using compounds without blocking at the 2’-position and 3’-position for in vitro RNA transcription.
The rejection is hereby maintained.
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 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of copending Application No. 17/798,099 in view of Hogrefe et al. (cited above).
The claims of the reference application are directed towards a compound of formula:
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(claim 1).
The difference between the claims of the reference application and the present application, is the reference application has defined R5 as a benzyl or substituted benzyl group. The present claims do not require a benzylated adenosine moiety.
Hogrefe et al. teach in certain embodiments, the initiating capped oligonucleotide primer is a trimer, and includes m7GpppA(2’OMe)pG (p.25-26, para [00111], Table 1):
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.
It would have been obvious to modify the compound of the reference application wherein the adenine base is not benzylated, because Hogrefe et al. teach trinucleotide compounds which function as a 5’cap for RNA having an unmodified adenine base.
Thus, the present claims are prima facie obvious over the claims of the reference application in view of Hogrefe et al.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 14 November 2025 have been fully considered but they are not persuasive.
Applicant contends the claims of the current compound are not exactly the same as the compounds of the reference Application.
The above arguments are not found persuasive because Hogrefe et al. teach trinucleotide compounds which function as a 5’cap for RNA having an unmodified adenine base.
The rejection is hereby maintained.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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 BAHAR A CRAIGO whose telephone number is (571)270-1326. The examiner can normally be reached M-F: Noon-8pm ET.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699