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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-10 (Group I) in the reply filed on 01/13/2026 is acknowledged.
Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest effective filing date to which the application is entitled is 05/13/2022.
Drawings
The Examiner acknowledges that Applicant’s petition to filed color drawings (filed 05/11/2023) was granted on 09/18/2023. The drawings filed 05/11/2023 are acceptable.
Claim Objections
Claims 1-3 are objected to because of the following informalities:
Instant claims 1-3 all recite “SEQ ID NO.” (bolded and underlined emphasis added), which is inconsistent with the recitation of “SEQ ID NO:” (bolded and underlined emphasis added) required under 37 C.F.R. 1.831(c). See MPEP § 2412.04. It would be remedial to amend the recitation of “SEQ ID NO.” (bolded and underlined emphasis added) to instead recite “SEQ ID NO:” (bolded and underlined emphasis added) in order to comport with the conventional recitation of SEQ ID NOs.
Additionally, instant claim 1 includes a typographical error at line 6. The semicolon preceding the “and” at the end of line 6 is spaced incorrectly, thereby failing to comport with standard grammatical and/or linguistic conventions. The indicated semicolon should immediately succeed “miR-1,” followed by a space prior to reciting “and.” It would be remedial to amend the instant claim to comport with standard grammatical and/or linguistic conventions.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-10 are 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.
Claim 1 is drawn to a synthetic modified mRNA (modRNA) system for delivery of at least one cell cycle regulator gene to cardiac cells, said system comprising at least a first modRNA and a second modRNA. The rejected claims thus encompass a modRNA system comprising up to an unlimited number of modRNAs delivering up to an unlimited number of cell cycle regulator genes to cardiac cells. Dependent claims 2-10 all directly depend from independent claim 1 and do not limit the number of modRNAs or cell cycle regulator genes delivered by the same. While dependent claim 6 recites “the at least one cell cycle regulator gene comprises CCND2,” this recitation does not limit the number of cell cycle regulator genes to be delivered. Thus, dependent claims 2-10 inherit the rejection of independent claim 1, which is set forth in greater detail below.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes modRNAs for L7Ae, luciferase, CCND2, GFP, nuclear GFP (nGFP), and CCND2-nGFP (paragraph [0077]; see section ”EXAMPLES”). No description is provided of a modRNA system comprising up to an unlimited number of modRNA constructs delivering up to an unlimited number of cell cycle regulator genes to cardiac cells, as is encompassed by the instant claim language.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of a limited number of modRNA species (i.e. L7Ae, luciferase, CCND2, GFP, nuclear GFP (nGFP), and CCND2-nGFP as in paragraph [0077]) rather than of a modRNA system comprising up to an unlimited number of modRNA constructs delivering up to an unlimited number of cell cycle regulator genes to cardiac cells, as is encompassed by the instant claim language. The disclosed results are thus not necessarily predictive of a modRNA system comprising up to an unlimited number of modRNA constructs delivering up to an unlimited number of cell cycle regulator genes to cardiac cells, as is encompassed by the instant claim language. Therefore, it is impossible for one to extrapolate from the examples described herein those modRNA systems comprising up to an unlimited number of modRNA constructs delivering up to an unlimited number of cell cycle regulator genes to cardiac cells that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a modRNA system comprising up to an unlimited number of modRNA constructs delivering up to an unlimited number of cell cycle regulator genes to cardiac cells.
Therefore, the skilled artisan would have reasonably concluded that Applicants were not in possession of the claimed invention for claims 1-10.
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 1-10 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.
Instant claim 1 recites “a synthetic modified mRNA (modRNA) system…wherein the modRNA system comprises a composition comprising at least a first modRNA and a second modRNA; wherein the first modRNA comprises…an mRNA sequence complementary to SEQ ID NO[:] 3…and wherein the second modRNA comprises…an mRNA sequence complementary to SEQ ID NO[:] 1.” However, the instantly claimed SEQ ID NOs themselves correspond to the sequences encoding the archaeal large ribosomal subunit L7Ae (see paragraphs [0021] and [0029] of the instant specification) and to Cyclin D2 (CCND2; see paragraphs [0004], [0006], [0010], [0018], and [0028] of the instant specification), as disclosed in the instant specification. This disclosure is consistent with BLASTN results obtained from querying these sequences. As shown in Appendices I and II, SEQ ID NOs: 3 and 1 correspond to GenBank MW331570.1 and M90813.1, respectively. Both of these sequences are annotated as sequences that directly encode their associated protein products. As taught by Columbia University (Lecture #13-RNA and Protein Synthesis), the coding strand sequence of a gene is identical to the transcribed RNA that is translated into the product; whereas, the transcribed template strand is complementary to the RNA transcribed therefrom (see especially section (I)(C)). Given that both instant SEQ ID NOs: 3 and 1 are annotated as coding sequences, it is not clear how complementary sequences would produce L7Ae or Cyclin D2, as those of ordinary skill in the art are aware that complementary nucleotide sequences necessarily have different sequences that must therefore encode different products, or even no products at all.
Given that the instant invention, as disclosed in the specification, is drawn to modRNAs comprising mRNA sequences that must express the products of SEQ ID NOs: 3 and 1 (see paragraphs [0004], [0006], [0010], [0018], [0028], and [0033] of the instant specification), which respectively correspond to the archaeal large ribosomal subunit L7Ae (see paragraphs [0021] and [0029] of the instant specification) and to Cyclin D2 (CCND2; see paragraphs [0004], [0006], [0010], [0018], and [0028] of the instant specification), the recitation of the instant claim language is indefinite, as sequences complementary to SEQ ID NOs: 3 and 1 cannot encode the products of SEQ ID NOs: 3 and 1. Accordingly, for purposes of examination, the Examiner has interpreted the recitation of modRNAs comprising mRNA sequences complementary to the claimed sequences to require modRNAs comprising sequences encoding the products of SEQ ID NOs: 3 and 1 (see paragraphs [0004], [0006], [0010], [0018], [0028], and [0033] of the instant specification), which is consistent with the disclosure of the instant specification.
Dependent claims 2-10 all directly depend from independent claim 1 and do not resolve the basis of the indefiniteness rejection set forth above. Dependent claims 2 and 3 explicitly recite “mRNA sequence complementary to” SEQ ID NOs: 3 and 1, which is indefinite for the same reasons set forth above regarding independent claim 1. Thus, dependent claims 2-10 inherit the indefiniteness rejection of independent claim 1.
It would be remedial to amend the instant claim language such that one of ordinary skill in the art would be clearly apprised of what sequences are included in the instantly claimed modRNA system.
Furthermore, claim 1 recites the limitation "the microRNA" in lines 6 and 7. There is insufficient antecedent basis for this limitation in the claim. Dependent claims 2-10 all directly depend from instant claim 1 and do not establish sufficient antecedent basis for the limitation “the microRNA.” Thus, dependent claims 2-10 inherit the indefiniteness rejection of instant claim 1. It would be remedial to amend the instant claim language such that there is sufficient antecedent basis for all claim terms, including the instantly claimed microRNA recognition sequences.
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) in view of US 2002/0166134 A1 (hereinafter Field) and WO 2021/096911 A1 (hereinafter Icahn).
With regard to claim 1, which recites “a synthetic modified mRNA (modRNA) system for delivery of at least one cell cycle regulator gene to cardiac cells, wherein the modRNA system comprises a composition comprising at least a first modRNA and a second modRNA;
wherein the first modRNA comprises:
an mRNA sequence complementary to SEQ ID NO[:] 3;
a recognition sequence for the microRNA miR-1 ;and [sic]
a recognition sequence for the microRNA miR-208; and
wherein the second modRNA comprises:
a kink-turn motif; and
an mRNA sequence complementary to SEQ ID NO[:] 1,”
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 III, 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). As set forth above (see section Claim Objections), the Examiner has interpreted the language of instant claim 1 to require that the modRNA claimed herein encodes the products of the claimed sequences see paragraphs [0004], [0006], [0010], [0018], [0028], and [0033] of the instant specification). 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 CCDN2 and comprises a kink-turn motif, Zangi does not disclose the sequence encoding CCDN2, 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 IV, SEQ ID NO: 3 of Field comprises instant SEQ ID NO: 1. Thus, it is considered that Zangi and Field collectively disclose the instantly claimed modRNA system.
With regard to 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 complementary to 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 (see section Claim Objections). Thus, it is considered that Zangi discloses the additional limitations of instant claim 2.
With regard to claim 3, which recites “the kink-turn motif [of the modRNA system of claim 1] is located 5’ to the mRNA sequence complementary to 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 (see section Claim Objections). Thus, it is considered that Zangi discloses the additional limitations of 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 claim 6, which recites “the at least one 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, 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 further to modify the modRNAs disclosed in Zangi such that every Uridine residue is replaced with N1-methylpseudouridines to predictably express CCND1 specifically in cardiomyocytes, 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 CCND1 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.
Claims 1-3 are objected to.
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-Th 8-5, F 8-12.
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