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 .
Applicant’s response of 04/30/2026 has been received and entered into the application file.
Claims 1-3, and 6 were amended in the claim set filed 04/30/2026.
Claims 1-20 are pending, of which claims 11-20 were previously withdrawn.
Accordingly, claims 1-10 are pending and under consideration.
Status of Prior Objections/Rejections
RE: Election/Restrictions
Applicant’s previous election without traverse of claims 1-10 (Group I) in the reply filed on 01/13/2026 is acknowledged.
Claims 11-20 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/13/2026.
Accordingly, claims 1-10 are pending and under consideration.
RE: Claim Objections
►Claims 1-3 were previously objected to for various informalities.
The amendments to the instant claim set filed 04/30/2026 have obviated the basis of the objections of record. The objections of record are hereby withdrawn.
RE: Claim Rejections - 35 USC § 112(a)
►Claims 1-10 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The amendments to the instant claim set filed 04/30/2026 have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 112(b)
►Claims 1-10 were previously 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 amendments to the instant claim set filed 04/30/2026 have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 103
►Claims 1-10 were previously rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/053414 A1 (hereinafter Zangi) in view of US 2002/0166134 A1 (hereinafter Field) and WO 2021/096911 A1 (hereinafter Icahn).
Applicant has traversed the rejection of record, asserting that Zangi discloses a second modRNA that encodes CCND2 only in passing and further that Zangi does not disclose working examples of modRNA systems including CCND2. Applicant further asserts that Zangi directly teaches against the virus-mediated delivery and other delivery mechanisms of Field. Finally, Applicant states that Field utilizes the myosin heavy chain promoter, which is excluded from the instant claim set.
In response, it is found persuasive that Field utilizes the α-myosin heavy chain promoter, which is excluded from the instant claim set. However, it is not found persuasive that Zangi does not motivate the use of CCND2 in a second modRNA. As Applicant has asserted, Zangi does directly teach against the virus-mediated delivery and other delivery mechanisms of Field. Zangi discloses therapeutic delivery of an entirely alternative system (paragraphs [0011], [0052], and [0056]), a modRNA-based expression regulatory system, wherein said expression regulatory system comprising a first modRNA that encodes a microRNA recognition element that specifically binds a target cell miR and a translation suppressor protein; and a second modRNA that encodes a protein of interest and comprises a suppressor protein interaction motif that binds the translation suppressor protein of the first modRNA (i.e. a kink-turn motif), thereby expressing the protein of interest in a cardiomyocyte-specific fashion (abstract; paragraphs [0008], [0009], [0011], and [0012]). While Zangi does not disclose working examples with CCND2, as Applicant has asserted, Zangi does disclose that cyclin D2 has previously been demonstrated to have the ability to reactivate adult cardiomyocyte proliferation in transgenic mouse models (paragraphs [0066] and [0085]). Thus, while Zangi does not disclose working examples involving CCND2, Zangi discloses that the prior art teaches the utility of CCND2, thereby providing sufficient motivation for someone of ordinary skill in the art to practice the invention of Zangi with CCND2 as a cell cycle inducer protein provided by a second modRNA that encodes said CCND2 and comprises a kink-turn motif (paragraphs [0004] and [0017]; Table 1). As previously set forth, Zangi is silent as to the sequence of said CCND2, and Field is applied solely to provide the sequence of CCND2 (paragraphs [0012] and [0035]).
However, as set forth above, it is found persuasive that Field utilizes the α-myosin heavy chain promoter, which is excluded from the instant claim set. Therefore, new grounds of rejection necessitated by amendment are set forth below.
New/Maintained Grounds of Objection/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 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/053414 A1 (hereinafter Zangi; of record) in view of US 2002/0166134 A1 (hereinafter Field; of record), WO 2021/096911 A1 (hereinafter Icahn), and Mϋller et al., 2007 (hereinafter Mϋller).
With regard to amended claim 1, which recites “a synthetic modified mRNA (modRNA) system for delivery of a cell cycle regulator gene to cardiac cells, wherein the modRNA system comprises a composition comprising a first modRNA and a second modRNA;
wherein the first modRNA comprises:
an mRNA sequence encoding the product of SEQ ID NO: 3;
a recognition sequence for the microRNA miR-1; and
a recognition sequence for the microRNA miR-208; and
wherein the second modRNA comprises:
a kink-turn motif; and
an mRNA sequence encoding the product of SEQ ID NO: 1;
wherein the system is not delivered using a viral vector; and
wherein the mRNA sequence encoding the product of SEQ ID NO: 1 is not fused to an α-myosin heavy chain promoter,” as previously set forth, Zangi discloses a modRNA-based expression regulatory system for cardiomyocyte-specific expression of a protein of interest (such as a cell cycle inducer), said expression regulatory system comprising a first modRNA that encodes a microRNA recognition element that specifically binds a target cell miR and a translation suppressor protein; and a second modRNA that encodes a protein of interest and comprises a suppressor protein interaction motif that binds the translation suppressor protein of the first modRNA (i.e. a kink-turn motif), thereby expressing the protein of interest in a cardiomyocyte-specific fashion (abstract; paragraphs [0008], [0009], [0011], and [0012]). Zangi further discloses that SEQ ID NO: 4 taught therein comprises an ORF encoding miR 1 and miR208a recognition elements and L7AE, which is an archaeal ribosomal protein that regulates the translation of a designed gene of interest modRNA (Table 1; paragraphs [0017] and [0073]). Per Zangi, the modRNAs taught therein facilitate reactivation of cardiomyocyte regeneration, which is important following post-myocardial infarction or in heart failure settings (paragraph [0011]). As shown in the alignment of Appendix I, the modRNA of Zangi comprising SEQ ID NO: 4 taught therein comprises instant SEQ ID NO: 3, which is also disclosed to encode L7AE per Table 1 of the instant specification. The L7AE modRNA of Zangi is further disclosed to comprise miR1 and miR208 recognition elements (Figure 19B). It is thus considered that the L7AE modRNA of Zangi reads on the instantly claimed first modRNA.
Additionally, as set forth above, Zangi further discloses a second modRNA that encodes a protein of interest and comprises a suppressor protein interaction motif that binds the translation suppressor protein of the first modRNA (i.e. a kink-turn motif), thereby expressing the protein of interest in a cardiomyocyte-specific fashion (abstract; paragraphs [0008], [0009], [0011], and [0012]). Zangi specifically discloses that a suitable cell cycle inducer protein envisioned for use in the modRNA system taught therein is Cyclin D2 (paragraph [0017]). Per the instant specification, SEQ ID NO: 1 comprises the open reading frame of Cyclin D2 (CCND2) (paragraph [0004]; Table 1). Thus, while Zangi discloses a second modRNA that encodes CCND2 and comprises a kink-turn motif, Zangi does not disclose the sequence encoding CCND2, which corresponds to instant SEQ ID NO: 1.
However, this deficiency is cured by US 2002/0166134 A1 (hereinafter Field), which discloses SEQ ID NO: 3, a nucleic acid sequence encoding human Cyclin D2 (paragraphs [0012] and [0035]). As shown in the alignment of Appendix II, SEQ ID NO: 3 of Field comprises instant SEQ ID NO: 1.
Regarding the amended limitations concerning system delivery and promoter choice, Zangi discloses that viral vector delivery shows promise, but its applications are limited due to its length of expression and inability to regulate gene expression in a quantifiable dose manner (paragraph [0061]). To overcome these limitations and achieve therapeutic effect, Zangi discloses that direct delivery (i.e. via myocardial injection) of modRNA has emerged as an effective and safe tool for somatic gene transfer, specifically for gene delivery to the heart, all without eliciting immune response or compromising the genome (paragraphs [0059] and [0064]-[0066]). Thus, it is considered that Zangi discloses non-viral delivery of modRNA systems to the heart, as instantly claimed.
Finally, while the CCND2 sequence taught by Field is linked to an α-myosin heavy chain promoter, the α-myosin heavy chain promoter is not the only promoter known to drive cardiac gene expression. Mϋller discloses multiple promoters known to drive cardiac gene expression in vivo, including hypoxia-response elements + mSV40 promoter, CMV-enhanced 1.5 kb myosin light chain-2v promoter, and the 1.7 kb myosin light chain-2v promoter, amongst other candidate promoters (Table 1). Therefore, for purposes of achieving cardiac-specific gene expression, one of ordinary skill in the art would have been motivated by the disclosure of Mϋller to select and test multiple cardiac-specific promoters in order to determine the most efficient and effective promoter for expressing the products of modRNA system disclosed in Zangi in cardiac cells.
Thus, it is considered that Zangi, Field, and Mϋller collectively disclose the instantly claimed modRNA system.
With regard to amended claim 2, which recites “the recognition sequence for miR-1 and the recognition sequence for miR-208 [of the modRNA system of claim 1] are located 3’ to the mRNA sequence encoding the product of SEQ ID NO: 3,” as set forth above, the L7AE modRNA of Zangi is disclosed to comprise miR1 and miR208 recognition elements in addition to the sequence encoding L7AE (Figure 19B). As shown in Figure 19B, the miR1 and miR208 recognition elements of Zangi are located 3’ to the sequence encoding L7AE, as instantly claimed. Thus, it is considered that Zangi discloses the additional limitations of amended instant claim 2.
With regard to amended claim 3, which recites “the kink-turn motif [of the modRNA system of claim 1] is located 5’ to the mRNA sequence encoding the product of SEQ ID NO: 1,” as set forth above, the modRNA of Zangi that encodes a protein of interest such as cell cycle inducer CCND2 comprises a kink-turn motif (Figure 19B; paragraph [0017]). As shown in Figure 19B, the kink-turn motif of Zangi is located 5’ to the sequence encoding the protein of interest (such as CCND2 per paragraph [0017]), as instantly claimed. Thus, it is considered that Zangi discloses the additional limitations of amended instant claim 3.
With regard to claim 4, which recites “both the first modRNA and the second modRNA [of the modRNA system of claim 1] comprise N1-methylpseudouridine residues in place of one or more uridine residues,” Zangi further discloses that the modRNAs taught therein comprise modified residues such as N1-methylpseudouridine, which stabilizes the modRNA, enhances transcription from the same, and reduces the immune response elicited from exogenous RNA (paragraphs [0052], [0063], [0086], and [0099]). Thus, it is considered that Zangi discloses the additional limitations of instant claim 4.
With regard to claim 5, which recites “both the first modRNA and the second modRNA [of the modRNA system of claim 1] comprise N1-methylpseudouridine residues in place of all uridine residues,” while Zangi discloses incorporation of modified residues such as N1-methylpseudouridine into the modRNAs taught therein (paragraphs [0052], [0063], [0086], and [0099]), they do not explicitly disclose that all uridine residues are replaced by N1-methylpseudouridine. However, this deficiency is cured by Icahn, which also discloses a modRNA composition for treating heart failure (abstract). Icahn explicitly discloses that 100% of the Uridine residues of the modRNAs taught therein are replaced with N1-methylpseudouridines (paragraph [00159]). Thus, it is considered that Icahn discloses the additional limitations of instant claim 5.
With regard to amended claim 6, which recites “the cell cycle regulator gene [of the modRNA system of claim 1] comprises CCND2,” as set forth above, Zangi further a second modRNA that encodes a protein of interest and comprises a suppressor protein interaction motif that binds the translation suppressor protein of the first modRNA (i.e. a kink-turn motif), thereby expressing the protein of interest in a cardiomyocyte-specific fashion (abstract; paragraphs [0008], [0009], [0011], and [0012]). Zangi specifically discloses that a suitable cell cycle inducer protein envisioned for use in the modRNA system taught therein is Cyclin D2 (paragraph [0017]). Thus, it is considered that Zangi discloses the additional limitations of instant claim 6.
With regard to claim 7, which recites “the cardiac cells [targeted by the modRNA system of claim 1] comprise cardiac fibroblasts, cardiomyocytes, endothelial cells, other cardiac cells, or any combination thereof,” as set forth above, Zangi discloses a modRNA-based expression regulatory system for cardiomyocyte-specific expression of a protein of interest, such as a cell cycle inducer (abstract; paragraphs [0008], [0009], [0011], and [0012]). Thus, it is considered that Zangi discloses the additional limitations of instant claim 7.
With regard to claim 8, which recites “the first modRNA and the second modRNA [of the modRNA system of claim 1] are nonimmunogenic,” Zangi further discloses that the modRNA system taught therein is a safe, transient, local, and non-immunogenic platform for gene transfer (paragraphs [0004], [0060], and [0086]). Thus, it is considered that Zangi discloses the additional limitations of instant claim 8.
With regard to claim 9, which recites “the modRNA system of claim 1, wherein the modRNA system is inactive in non-cardiac cells,” as set forth above, Zangi discloses a modRNA-based expression regulatory system for cardiomyocyte-specific expression of a protein of interest, such as a cell cycle inducer (abstract; paragraphs [0008], [0009], [0011], and [0012]). Zangi repeatedly discloses that the modRNA system taught therein facilitates cardiomyocyte-specific expression such that the modRNAs are exclusively translated in cardiomyocytes (paragraphs [0011]-[0013]). Thus, it is considered that Zangi discloses the additional limitations of instant claim 9.
With regard to claim 10, which recites “the composition [of the modRNA system of claim 1] comprises 1.5 μg of the first modRNA and 3 μg of the second modRNA,” Zangi discloses varying the amounts of first and second modRNA administered to achieve a therapeutic effect at paragraphs [00117] and [00118]. While Zangi does not explicitly disclose the instantly claimed amounts of first and second modRNAs, this disclosure does establish that varying these amounts is within the realm of routine experimentation by someone of ordinary skill in the art. Per MPEP 2144.05.I.A, “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)). Given that the disclosure of Zangi establishes that it is within the realm of routine experimentation by someone of ordinary skill in the art to optimize the amounts of modRNAs delivered, it is considered that Zangi would motivate someone of ordinary skill in the art to practice such routine experimentation to arrive at the claimed amounts of instant claim 10.
Given that Zangi discloses a modRNA-based expression regulatory system for cardiomyocyte-specific expression of a protein of interest (such as a cell cycle inducer), said expression regulatory system comprising a first modRNA that encodes a microRNA recognition element that specifically binds a target cell miR and a translation suppressor protein (i.e. L7AE); and a second modRNA that encodes a protein of interest (i.e. CCND2) and comprises a suppressor protein interaction motif that binds the translation suppressor protein of the first modRNA (i.e. a kink-turn motif), thereby expressing the protein of interest in a cardiomyocyte-specific fashion; that Field discloses SEQ ID NO: 3, a nucleic acid sequence encoding human CCND2; that Mϋller discloses multiple cardiac-specific promoters suitable for therapeutic gene delivery; and that Icahn discloses a modRNA composition for treating heart failure wherein 100% of the Uridine residues of the modRNAs taught therein are replaced with N1-methylpseudouridines, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to express cell cycle protein CCND2 from the second modRNA disclosed in Zangi using the sequence disclosed in Field and a promoter disclosed in Mϋller, and further to modify the modRNAs disclosed in Zangi such that every Uridine residue is replaced with N1-methylpseudouridines to predictably express CCND2 specifically in cardiomyocytes from a cardiac-specific promoter, thereby reactivating cardiomyocyte regeneration, which is important following post-myocardial infarction or in other heart failure settings. One would have been motivated to make such a modification in order to receive the expected benefit of expressing CCND2 specifically in cardiomyocytes, thereby reactivating cardiomyocyte regeneration, which is important following post-myocardial infarction or in other heart failure settings.
Conclusion
No claims are 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 Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
Prosecution Insights