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 .
Amendments
In the reply filed 12/16/2025, Applicant has amended Claims 35, 44, 58, 61, 66, 68, 74, and 76, cancelled Claims 65 and 67, and added new claims, Claims 80-81.
Claims 35, 37, 40, 44-45, 51, 57-64, 66, 68-81 are under consideration.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/16/2025 was filed after the mailing date of the non-final Office action on 9/16/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objection to Specification
The prior objection to the disclosure for embedded hyperlink is withdrawn in light of Applicant’s amendment.
Withdrawn Claim Objections
The prior objection to Claim 44 for a typographical error is withdrawn in light of Applicant’s amendment.
Withdrawn 35 USC § 103
The prior rejection of Claims 35, 37, 40, 44, 51, 57-60, 62, and 69-78 under 35 U.S.C. 103 as being unpatentable over Backman et al. (WO 2022/187424, filed 3/03/2022, published 9/09/2022, see IDS filed 4/01/2025) is withdrawn in light of Applicant’s amendment of Claims 35 and 76 to limit the ribose bases to being N4-acetylcytidine or 5-hydroxymethyluridine, which are limitations Backman does not teach.
The prior rejection of Claims 45, 61, 63, 64, and 79 under 35 U.S.C. 103 as being unpatentable over Backman et al. (WO 2022/187424, filed 3/03/2022, published 9/09/2022, see IDS filed 4/01/2025), in view of Goldsborough et al., (US 6,867,290, patented 3/15/2005) is withdrawn in light of Applicant’s amendment of Claims 35 and 76.
New 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 35, 37, 40, 44, 51, 57-60, 62, 66, 68-78, and 80-81 are rejected under 35 U.S.C. 103 as being unpatentable over Backman et al. (WO 2022/187424, filed 3/03/2022, published 9/09/2022, see IDS filed 4/01/2025) in view of Dhar et al. (WO 2022/235838, filed 5/4/2022, published 11/10/2022, prior art of record)
With respect to claims 35 and 76, Backman teaches a polyribonucleotide (e.g., mRNA) encoding a fusion polypeptide, wherein the fusion polypeptide comprises (a) one or more antigens comprising an epitope of a target protein, and (b) a C3d-binding polypeptide from an Ig-binding protein (Sbi) of Staph. aureus (Abstract, Summary [0003-0010, 0064], Detailed Description [0199], mRNA encoding polypeptides and formulations thereof, pgs. 58-60, Examples 1-3, pg. 67-69, see Claims 1-27 of Bachman, and see also Fig. 1A). Furthermore, Backman teaches the polyribonucleotide comprises one or more modified ribonucleotides comprising modified nucleobase or modified ribose (p. 29, [0193]).
However, although Backman teaches that the cytidine or uridine ribose base can also be modified (p. 29, 1st para.), they are silent with respect to the ribose base being N4-acetylcytidine or 5-hydroxymethyluridine.
Nevertheless, those following the guidance of Backman et al. would have been aware of the inventor’s related publication of Dhar et al (WO2022), who shares all of the same inventors with Backman et al.
Specifically, Dhar teaches a modified polyribonucleotide comprising up to 100% modification with N4-acetylcytidine or 5-hydroxymethyluridine modified base (Abstract, Examples 1 & 2).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare the modified polyribonucleotide comprising a modified cytidine or uridine base as taught by Backman, and combine a N4-acetylcytidine or 5-hydroxymethyluridine modified base as taught by Dhar with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Dhar because the modifications reduce to innate immunogenicity caused by the RNA itself [0003-0005].
In regard to the at least 5% modification as per Claims 66 and 68, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
In regard to claim 37, Backman teaches the fusion comprises one or both of domains III and IV of the Sbi (see Fig. 1A).
In regard to claims 40 and 57, Backman teaches the one or more antigens are viral antigens such as those from SARS-CoV-2 (Example 1, [0360]).
In regard to claim 44, Backman teaches the one or more of the modified ribonucleotide bases include nucleoside analogues such as 2-aminoadenosine [0193].
In regard to claim 51, Backman teaches the polyribonucleotide is in an expression vector [0093, 0195], see Claim 43 of Backman). Note that Applicant’s specification does not define “expression vector”, and this phrase has been broadly interpreted by the Examiner as a polyribonucleotide capable of expression in a cell.
In regard to claims 58-59, and 80-81, Backman teaches the domains II and IV of the Sbi from S. aureus are SEQ ID NOs: 9 and 10, respectively (Table 1, p. 45), which are 100% identical to instant SEQ ID NOs: 3 and 4, respectively, and combine to form SEQ ID NO:5.
In regard to claim 60, since as all ribonucleotides, with exception to those in the 5’ CAP, have a 5’ monophosphate as part of their phosphodiester bond, the one or more modified ribonucleotides of Backman would naturally comprise a 5’ monophosphate.
In regard to claim 62, Backman teaches the polyribonucleotide comprises a 5’ CAP structure [0195], and is silent to a 2’-O-acetylated ribose.
In regard to claim 69, Backman teaches the polypeptide comprises more than one antigen [0015-0016, 0214, 0216, 0218, 0288, 0496].
In regard to claims 70 and 72-73, Backman teaches the polypeptide comprises more than one antigen from the same pathogen (e.g., SARS-CoV-2) with either a second antigen being variants or fragments from the same target antigen as per claim 72, or different target antigens (e.g., spike protein, envelope protein, membrane protein, nucleocapsid) as per claim 73 [0016, 0079-0080, 0214, 0218, 0504].
In regard to claim 71, Backman teaches the polypeptide comprises more than one antigen from different pathogens [0015-0016, 0079-0080, 0214-0216, 0498].
In regard to claim 74, Backman teaches the polynucleotide encodes a fusion protein with the antigen disposed N-terminal to the Sbi (Table 3, p. 55).
In regard to claim 75, Backman teaches the polynucleotide encodes a secretion signal ([0254], Table 1, SEQ ID NO:1, see Example 3, [0367]).
In regard to claims 77 and 78, Backman teaches the polynucleotide is in a pharmaceutical composition with a pharmaceutically acceptable excipient [0097-0098], and is considered a vaccine (Example 2, [0363]).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 12/16/2025 are acknowledged.
First, Applicant argues that there was no motivation to have arrived at the claimed invention and that the Examiner had to piece together disclosures from three refences to make the case of obviousness. Applicant argues that Backman is silent to the claimed modified ribonucleotides, and Goldsborough fails to make up for this deficiency as they are also silent to these particular modified ribonucleotides, and Dhar is silent to fusions between an antigen and Sbi protein.
Second, Applicant argues that because Backman already demonstrates a 15-fold increase in the IgG titer after vaccination with the Sbi fusion, there was no motivation to further modify the polyribonucleotide. Furthermore, Applicant argues that because Backman teaches some modified polyribonucleotide can be modified, and provided modified nucleotides other than those claimed, Backman would have taught away from the claimed modifications.
Third, Applicant argues that the claimed combination of modified nucleotides yielded unexpected results. Specifically, Applicant argues that Examples 6 & 7, as demonstrated in Figs. 18 & 19 demonstrated that the modification improved immune responses.
Applicant's arguments have been fully considered but they are not persuasive.
In response to Applicant's first argument, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In instant case, the primary reference of Backman teaches the polyribonucleotide encoding the Sbi fusion, while the secondary reference of Dhar teaches that modifying the polyribonucleotide to include N4-acetylcytidine or 5-hydroxymethlyuridine would have reduced the immunogenicity in response to the RNA itself (not to be confused with the immunogenicity caused by the polypeptide antigens encoded by the RNA) [0003].
In response to Applicant's second argument, Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). In instant case, as acknowledged by Applicant, Backman discloses the use of modified nucleosides, which were well known for decreasing RNA degradation, reducing immunogenicity, and increasing expression.
In response to Applicant's arguments that Backman teaches away from the claimed invention by disclosing nucleoside modifications other than those claimed, MPEP 2141.02 (VI) states that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
In response to Applicant's third argument, as per the purported unexpected results. As a first matter, the cited figures demonstrated increases in serum antibody levels in response to ac4C modified RNA in a lipid nanoparticle (LNP), which is not commensurate in scope with the claims. As a second matter, Applicant does not proved comparative data for the effects of unmodified RNA. Applicant is reminded that a showing of unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements regarding unusually low immune response or unexpected biological activity that were unsupported by comparative data held insufficient to overcome prima facie case of obviousness). As a final matter, Dhar teaches that “N4-acetylcytidine and 5-hydroxymethyluridine residues can interact synergistically in polyribonucleotides to reduce immunogenicity, increase cell viability, and/or increase expression of proteins”, and as acknowledged by Applicant, Backman demonstrates a 15 fold increase in IgG titer with the Sbi fusion protein. Thus, the increase in serum IgG levels with the modified polyribonucleotide encoding the Sbi fusion amounts to an affirmation that the claimed subject matter functions as it was intended to function. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claims 45, 61, 63, 64, and 79 are rejected under 35 U.S.C. 103 as being unpatentable over Backman et al. (WO 2022/187424, filed 3/03/2022, published 9/09/2022, see IDS filed 4/01/2025), in view of Dhar et al. (WO 2022/235838, filed 5/4/2022, published 11/10/2022, prior art of record), as applied to claim 35, in further view of Goldsborough et al., (US 6,867,290, patented 3/15/2005, prior art of record).
As discussed previously, Backman in view of Dhar suggest a modified polyribonucleotide encoding a fusion protein comprising (a) one or more antigens, and (b) a Sbi C3d binding domain, wherein the modified polyribonucleotide comprise a N4-acetylcytidine or 5-hydroxymethyluridine.
However, although Backman teaches that the ribose sugar can also be modified at the 2’ position (p. 29, 1st para.), they are silent with respect to the ribose sugar being 2’-O-acteylated.
In regard to claim 45, Goldsborough teach polyribonucleotides encoding a protein (e.g, mRNA) comprising a ribose sugar being 2’-O-acetylated (Abstract, Summary of the Invention, Examples 1-33, see also Claims 1-15 of Goldsborough).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to prepare the modified polyribonucleotide comprising a modified ribose as taught by Backman, and combine a 2’-O-acetylation of the ribose as taught by Goldsborough with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Goldsborough because acetylation stabilizes the mRNA molecule and increases resistance to ribonucleases degradation (col 20, 2nd para., col 31, 4th & 5th para., cols 44-46, Example 33).
In regard to claims 61 and 79, Goldsborough teaches that greater than 25% of the ribose rings are covalently modified at the 2’-OH position (Summary of Invention, 1st & 2nd para., but see also Claims 9-15 of Goldsborough), thus at least one of the modified ribonucleotides of encoding the fusion protein of Backman would have an adenine, guanine, cytosine, or uracil base. In regard to the at least 5% modification as per Claim 79, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
In regard to claim 63, Backman teaches the RNA comprises a 5’ CAP structure [0195]. Furthermore, Goldsborough teaches that “In the case of mRNA which has a common 5’ CAP structure it would be expected that the CAP is also modified” (col 24, lines 48-50). Accordingly, it would have been obvious that the 5’ CAP structure would comprise a 2’-O-acetylated ribose.
In regard to claim 64, as stated supra, Goldsborough teaches that between 25-99% of the 2’-OH positions are modified; thus, there would have been at least one ribonucleotide without a 2’-O-ribose acetylation.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 12/16/2025 are acknowledged and have been addressed above.
Terminal Disclaimer
The terminal disclaimer filed on 12/16/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent Nos. 11,771,758 and 12,343,392 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Withdrawn Double Patenting
The prior rejection of Claims 35, 37, 40, 45, 51, 57-61, 63-64, 69-79 on the grounds of nonstatutory double patenting over claims 1-27 of U.S. Patent No. 11,771,758 (Backman et al., Patented 10/03/2023) in view of Goldsborough et al., (US 6,867,290, patented 3/15/2005) is withdrawn in light of the terminal disclaimer filed.
The prior rejection of Claims 35, 37, 40, 44, 51, 57-60, 62, and 66, 68-78 on the grounds of nonstatutory double patenting over claims 1-27 of U.S. Patent No. 11,771,758 (Backman et al., Patented 10/03/2023) in view of Dhar et al. (WO 2022/235838, filed 5/4/2022, published 11/10/2022) is withdrawn in light of the terminal disclaimer filed.
The prior rejection of Claims 35, 37, 40, 45, 51, 57-61, 63-64, 69-79 on the grounds of nonstatutory double patenting over claims 1-28 of U.S. Patent No. 12,343,392 (Backman et al., Patented 7/01/2025) in view of Goldsborough et al., (US 6,867,290, patented 3/15/2005) is withdrawn in light of the terminal disclaimer filed.
The prior rejection of Claims 35, 37, 40, 44, 51, 57-60, 62, and 66, 68-78 on the grounds of nonstatutory double patenting over claims 1-28 of U.S. Patent No. 12,343,392 (Backman et al., Patented 7/01/2025), in view of Dhar et al. (WO 2022/235838, filed 5/4/2022, published 11/10/2022) is withdrawn in light of the terminal disclaimer filed.
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
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/ARTHUR S LEONARD/Examiner, Art Unit 1631