DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Receipt is acknowledged of an amendment, filed 3/10/2026, in which claims 1, 7-12, 14-20, 72 and 74 were cancelled, claim 32 was amended, and claims 80-98 were newly added. Claims 32, 62, 63 and 78-98 are pending and under consideration.
Any rejection of record in the previous office actions not addressed herein is withdrawn. New grounds of rejection are presented herein that were not necessitated by applicant’s amendment of the claims since the office action mailed 12/10/2025. Therefore, this action is not final.
Information Disclosure Statement
Receipt of an information disclosure statement is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Double Patenting (Warning)
Applicant is advised that should claim 97 be found allowable, claim 98 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Although the claims have different claim dependencies, the claims cover the same scope.
Claim Rejections - 35 USC § 112
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 97 and 98 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. This is a new rejection, necessitated by the addition of new claims 97 and 98 in the reply filed 3/10/2026.
Claim 97 is vague and indefinite in that the metes and bounds of the phrase “at least about 100 nucleotides in length” are unclear. The phrase is unclear in that the lower bound of the range is not clearly defined. It is unclear whether there must be at least 100 nucleotides or whether lower values are encompassed. It would be remedial to replace the phrase “at least about 100” with the phrase “at least 100.”
Claim 98 is vague and indefinite in that the metes and bounds of the phrase “at least about 100 nucleotides in length” are unclear. The phrase is unclear in that the lower bound of the range is not clearly defined. It is unclear whether there must be at least 100 nucleotides or whether lower values are encompassed. It would be remedial to replace the phrase “at least about 100” with the phrase “at least 100.”
Response to Arguments - 35 USC § 112
The rejection of claims 7-10 and 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
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.
Claims 32, 62, 63, 78, 79, 90 and 94-96 are rejected under 35 U.S.C. 103 as being unpatentable over Martini et al (US Patent Application Publication No. 2018/0271795 A1, cited as reference 18 on the IDS filed 4/2/2024; see the entire reference). This is a new rejection.
Regarding claim 32, Martini teaches a polynucleotide sequence of SEQ ID NO: 734, in the form of mRNA which comprises an open reading frame (ORF) encoding a methylmalonyl-CoA mutase (e.g., paragraphs [0002], [0024], [0055]-[0057], [0365] and [1689]; Fig. 11; SEQ ID NO: 734). Alignment of instant SEQ ID NO: 7 and SEQ ID NO: 734 of Martini is shown in attached Appendix I. When considering that all positions reciting “T” will actually be “U” in the RNA, the alignment shows that the two sequences have 96% identity (2163/2244 nucleotides match). The sequence of SEQ ID NO: 734 of Martini encodes a protein of 99% identity to instant SEQ ID NO: 1. See the attached alignment in Appendix II. The protein encoded by SEQ ID NO: 734 contains an I671V substitution relative to instant SEQ ID NO: 1. See the asterisk marking the single amino acid change in Appendix II. The alignment in Appendix I shows the prior art codon of GTG for valine in place of the codon ATC for isoleucine (see the box).
Regarding claim 62, Martini teaches a pharmaceutical composition comprising the mRNA and a pharmaceutically acceptable excipient (e.g., paragraph [1689]).
Regarding claim 63, Martini teaches a lipid nanoparticle (LNP) comprising the mRNA (e.g., paragraph [1689]).
Regarding claim 78, Martini teaches a method of treating methylmalonic acidemia in a human subject in need thereof, comprising administering the mRNA encoding an MCM polypeptide (e.g., Abstract; paragraphs [1403]-[1407]).
Regarding claim 79, Martini teaches a method of treating methylmalonic acidemia in a human subject in need thereof, comprising administering the mRNA encoding an MCM polypeptide (e.g., Abstract; paragraphs [1403]-[1407]). Martini teaches the method reduces the level of methylmalonic acid present in the subject (e.g., paragraphs [0060] and [1403]).
Regarding claim 94, Martini teaches the mRNA comprising a 5’ terminal cap and poly-A region (e.g., paragraphs [0411], [0582] and [0601]).
Regarding claim 95, Martini teaches an N7-methyl-guanylate residue as the 5’-terminal cap linked to the 5’ end of the mRNA, which is 2’-O-methylated (e.g., paragraph [0582]-[0583]). Martini teaches the poly-A region is 100 residues in length (e.g., paragraph [0601]).
Regarding claim 96, Martini teaches the mRNA, where the bases of the mRNA are chemically modified, and where the mRNA is fully modified throughout the entire sequence (e.g., paragraphs [0369]-[0371]). Martini teaches modification with a number of modifications, including 1-methylpseudouridine (m1Ψ), where the polynucleotide can be uniformly modified with this residue (e.g., paragraphs [0369]-[0371]).
Martini does not teach the mRNA of SEQ ID NO: 734, where the codon for amino acid 671 is for isoleucine.
Martini teaches the following codons code for the amino acid isoleucine: ATT, ATC and ATA (e.g., Table 2 at page 17). Martini teaches that the encoded MCM polypeptides may encode a variant with a V671I substitution while retaining functional activity, because the mutation is function-neutral (e.g., paragraphs [0054], [0254] and [0407]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the mRNA sequence of Martini to include a codon for valine at nucleotides 2013-2015, because Martini teaches that a V671I substitution can be introduced into the ORF and retain functional activity. One could have predictably made such a substitution using any of the codons for isoleucine taught by Martini, because Martini teaches it is within the ordinary skill in the art to make such a substitution to predictably provide a polynucleotide encoding a functional MCM polypeptide.
Regarding claim 90, Martini teaches that the disclosure provides polynucleotide sequences that encode sequence-optimized nucleic acids encoding a methylmalonyl-CoA mutase (MCM) polypeptide (e.g., paragraphs [0247]-[0249]). Martini teaches that the polynucleotide, such as mRNA, increases MCM expression levels in cells when introduced into those cells by at least 20% (e.g., paragraph [0252]). Martini teaches that sequence optimization methods are known in the art and can be useful to achieve one or more desired results, including to match codon frequencies in target and host organisms to ensure proper folding, bias GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons or base runs that impair gene construction or expression, customize transcriptional and translational control regions, for example (e.g., paragraph [0294]). Martini teaches that sequence optimization tools, algorithms and services are known in the art (e.g., paragraph [0294]). Furthermore, each codon capable of coding for a given amino acid was known in the art and presented in Table 2 of Martini (e.g., paragraph [0294], pages 17-18). Further, Martini teaches varying the minimum number of uracil residues and maximal levels of G/C content (e.g., paragraphs [0306]-[0326]). Martini provides a method for assessing the codon optimized sequence using in vitro cell based assays and in vivo assay using a known mouse model (e.g., Examples 14-24).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sequence of SEQ ID NO: 734 by a known codon optimization process, including varying the levels of uracil and G/C to arrive at a sequence 100% identical to instant SEQ ID NO: 7. Martini teaches that there was a recognized need to optimize the coding sequence of mRNA encoding MCM (MUT of claims) in order to provide a variety of benefits, including increased expression. Further, Martini teaches there were a number of known tools, algorithms and services available to achieve such optimization. Moreover, Martini teaches that there are a finite number of codons to code for each amino acid position. Thus, optimization the sequence of SEQ ID NO: 734 while encoding the same polypeptide with the V671I substitution would have a finite number of identified, predictable potential solutions. The effect of the optimization can readily be assessed in vitro or in vivo according to known methods to predictably identify optimized sequences.
Claims 80-89 and 91-93 are rejected under 35 U.S.C. 103 as being unpatentable over Martini et al (US Patent Application Publication No. 2018/0271795 A1, cited as reference 18 on the IDS filed 4/2/2024; see the entire reference) as applied to claims 32, 62, 63, 78, 79, 94-96 and 90 above, and further in view of Jain et al (WO 2020/263985 A1; see the entire reference). This is a new rejection.
The teachings of Martini are described above and applied as before.
Martini does not teach that the mRNA comprises the 5’UTR of SEQ ID NO: 78, and the 3’ UTR of SEQ ID NO: 136, or the sequence of SEQ ID NO: 10.
Jain teaches an mRNA comprising a 5’ cap, a 5’UTR, an ORF encoding a polypeptide, and a 3’-UTR, where the 5’UTR is SEQ ID NO: 120, and the 3’UTR is SEQ ID NO: 170 (e.g., page 27, 1st and 2nd full paragraphs). SEQ ID NO: 120 is named RNAseP-P2 (e.g., Table 8 at page 74; Table 21 at pages 334-335). SEQ ID NO: 120 is identical to instant SEQ ID NO: 78. See the attached alignment in Appendix III. SEQ ID NO: 170 is named Sod2_3 (e.g., Table 21 at pages 334-335). SEQ ID NO: 170 is identical to instant SEQ ID NO: 136. See the attached alignment in Appendix IV. The mRNA identified as P2_Sod2_3 contains the 5’UTR of SEQ ID NO: 120 and the 3’UTR of SEQ ID NO: 170 (e.g., Table 21 at pages 334-335). Jain teaches that an mRNA encoding enzyme_B had the highest increase in enzyme expression and activity as compared to other combinations of 5’UTR and 3’UTR sequences (e.g., page 335, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Martini to include the 5’UTR and 3’UTR sequences of Jain in the mRNA as taught by Marini, because Martini teaches mRNA encoding an enzyme, and Jain teaches it is within the ordinary skill in the art to use a 5’UTR of SEQ ID NO: 120 (instant SEQ ID NO: 78) and a 3’ UTR of SEQ ID NO: 170 (instant SEQ ID NO: 136) in an mRNA encoding an enzyme.
One would have been motivated to make such a modification in order to receive the expected benefit of providing an mRNA capable of expressing higher levels of the enzyme relative to other 5’UTR and 3’UTR combinations as taught by Jain.
Regarding claims 93, 97 and 98, each of the elements of the claim are rendered obvious by the teachings of Martini as discussed above, except Martini does not teach the sequence of SEQ ID NO: 10. However, by including the 5’UTR and 3’UTR sequences to the 5’ and 3’ends, respectively, of the optimized coding sequence, one would have arrived at the claimed invention. Instant SEQ ID NO: 10. See the additional alignment information below.
SEQ ID NO: 120 of Jain (Sbjct) aligns with nucleotides 1-76 of instant SEQ ID NO: 10 (Query) with 100% identity.
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168
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SEQ ID NO: 734 of Martini aligns with nucleotides 77-2326 of SEQ ID NO: 10. See the alignment in Appendix V. As discussed above, it would have been obvious to try to modify the sequence of Martini to arrive at the sequence of SEQ ID NO: 7, which corresponds the same positions in SEQ ID NO: 10.
SEQ ID NO: 170 of Jain (Sbjct) aligns with nucleotides 2327-2567 of SEQ ID NO: 10 (Query).
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Response to Arguments - 35 USC § 103
The rejection of claims 1, 7, 11, 12, 14, 16-19, 20, 72 and 74 under 35 U.S.C. 103 as being unpatentable over Martini (US 2018/0271795 A1), as evidenced by Biocceleration1 and Biocceleration 2 is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
The rejection of claims 8-10 under 35 U.S.C. 103 as being unpatentable over Martini (US 2018/0271795 A1) in view of Fu et al (WO 2020/227510 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
The rejection of claim 15 under 35 U.S.C. 103 as being unpatentable over Martini (US 2018/0271795 A1) in view of Rajendran (WO 2019/104160) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
With regard to the new rejections based on the application of the Martini reference (US 2018/0271795 A1) under 35 U.S.C. 103, Applicant's arguments filed 3/10/2026 have been fully considered but they are not persuasive.
The response notes that the ORF having SEQ ID NO: 734 of Martini does not encode the polypeptide of SEQ ID NO: 1.
This argument is not found persuasive, because the only difference between the polypeptide encoded by SEQ ID NO: 734 and the instant polypeptide of SEQ ID NO: 7 is that SEQ ID NO: 734 contains Valine (V) at position 671, whereas SEQ ID NO: 7 contains isoleucine (I) at position 671. However, Martini teaches that the encoded MCM polypeptide (MUT polypeptide of the claims) can contain a V671I mutation, and that mutation is function-neutral (e.g., paragraphs [0054] and [0254]). Additionally, Martini teaches the codons of isoleucine at Table 2. One could have predictably substituted the codon for valine with a codon for isoleucine to arrive at the sequence encoding the functional-neutral V671I mutation, thereby encoding the protein of instant SEQ ID NO: 1.
The response asserts that the prior art does not teach the nucleotide sequences of SEQ ID NOS: 78 and 136.
This deficiency has been met by relying on the combined teachings of Martini and Jain (WO 2020/263985 A1) as set forth above.
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 32, 62, 63, 78-98 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-50 of copending Application No. 18/560,498 (hereinafter the ‘498 application). This is a new rejection.
Although the claims at issue are not identical, they are not patentably distinct from each other. Claim 6 of the ‘498 application requires the provision of a lipid nanoparticle comprising mRNA comprising a 5’ UTR comprising the nucleotide sequence of SEQ ID NO: 78 (identical to instant SEQ ID NO: 78), and an open reading frame (ORF) encoding the polypeptide of SEQ ID NO: 1 (identical to instant SEQ ID NO: 1), where the ORF is at least 96% identical to the nucleotide sequence of SEQ ID NO: 7, where the lipid nanoparticle is formulated for administration to a human subject in need thereof. Thus, claim 6 of the ‘498 application anticipates instant claims 32, 62, 63, 80, 82, 84 90 and 91. Further, claim 6 of the ‘498 application is drawn to the administration to treat methylmalonic acidemia in a human subject in need thereof. Thus, claim 6 of the ‘498 application also anticipates instant claims 78, 79, 86 and 88. Claim 7 of the ’498 application requires the provision of a lipid nanoparticle comprising mRNA comprising a 5’ UTR comprising the nucleotide sequence of SEQ ID NO: 78, an open reading frame (ORF) encoding the polypeptide of SEQ ID NO: 1 (identical to instant SEQ ID NO: 1), where the ORF is at least 96% identical to the nucleotide sequence of SEQ ID NO: 7, and a 3’ UTR comprising the nucleotide sequence of SEQ ID NO: 136 (identical to instant SEQ ID NO: 136). Claim 7 of the ‘498 application requires the mRNA to comprise the nucleic acid sequence of SEQ ID NO: 10 (identical to instant SEQ ID NO: 10). Thus, claims 7 and 8 of the ‘498 application anticipate instant claims 32, 62, 63 and 78-93. Further, claims 9 and 10 of the ‘498 application are dependent claims that require a 5’ terminal cap (claim 9), where the 5’ terminal cap comprises a guanine nucleotide containing an N7 methylation and the 5’-terminal nucleotide of the mRNA contains a 2’-O-methyl. Accordingly, instant claims 94 and 95 are anticipated by claims 9 and 10 of the ’498 application, respectively. Dependent claim 13 of the ‘498 application requires all uracils to be N1-methylpseudouracils. Accordingly, claim 13 anticipates instant claim 96. Dependent claim 14 of the ‘498 application states, “the mRNA comprises a 5' terminal cap comprising a guanine cap nucleotide containing an N7 methylation and the 5'- terminal nucleotide of the mRNA contains a 2'-0-methyl, wherein the mRNA comprises the nucleotide sequence of SEQ ID NO:10, wherein the mRNA comprises poly-A region at least about 100 nucleotides in length, and wherein all of the uracils of the mRNA are N1-methylpseudouracils.” Claim 14 of the ‘498 application anticipates instant claims 97-98.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 32, 62, 63 and 78-96 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16 and 18 of U.S. Patent No. 11,504,337 B2 (hereinafter the ‘337 patent) in view of Martini et al (US Patent Application Publication No. 2018/0271795 A1, cited as reference 18 on the IDS filed 4/2/2024) and Jain et al (WO 2020/263985 A1; see the entire reference). This is a new rejection.
Claim 1 of the ‘337 patent is drawn to a lipid nanoparticle composition comprising a messenger RNA (mRNA) that comprises an open reading frame (ORF) encoding a methylmalonyl-CoA mutase (MCM) polypeptide. Dependent claims 16 and 18 each depend from claim 1 and specify that the ORF encodes the polypeptide of SEQ ID NO: 208, which is identical to instant SEQ ID NO: 1.
The claims of the ‘337 patent do not require the specific nucleic acid sequences or pharmaceutically acceptable excipient as claimed, or the method of administering to a human subject to treat methylmalonic aidemia. However, one would have turned to the teachings of the prior art for sequences that could be used to provide a fully defined mRNA with 5’ UTR, coding sequence, and 3’ UTR. The teachings of Martini et al and Jane et al make up for these deficiencies and provide the necessary sequence.
Regarding claim 32, Martini teaches a polynucleotide sequence of SEQ ID NO: 734, in the form of mRNA which comprises an open reading frame (ORF) encoding a methylmalonyl-CoA mutase (e.g., paragraphs [0002], [0024], [0055]-[0057], [0365] and [1689]; Fig. 11; SEQ ID NO: 734). Alignment of instant SEQ ID NO: 7 and SEQ ID NO: 734 of Martini is shown in attached Appendix I. When considering that all positions reciting “T” will actually be “U” in the RNA, the alignment shows that the two sequences have 96% identity (2163/2244 nucleotides match). The sequence of SEQ ID NO: 734 of Martini encodes a protein of 99% identity to instant SEQ ID NO: 1. See the attached alignment in Appendix II. The protein encoded by SEQ ID NO: 734 contains an I671V substitution relative to instant SEQ ID NO: 1. See the asterisk marking the single amino acid change in Appendix II. The alignment in Appendix I shows the prior art codon of GTG for valine in place of the codon ATC for isoleucine (see the box).
Regarding claim 62, Martini teaches a pharmaceutical composition comprising the mRNA and a pharmaceutically acceptable excipient (e.g., paragraph [1689]).
Regarding claim 63, Martini teaches a lipid nanoparticle (LNP) comprising the mRNA (e.g., paragraph [1689]).
Regarding claim 78, Martini teaches a method of treating methylmalonic acidemia in a human subject in need thereof, comprising administering the mRNA encoding an MCM polypeptide (e.g., Abstract; paragraphs [1403]-[1407]).
Regarding claim 79, Martini teaches a method of treating methylmalonic acidemia in a human subject in need thereof, comprising administering the mRNA encoding an MCM polypeptide (e.g., Abstract; paragraphs [1403]-[1407]). Martini teaches the method reduces the level of methylmalonic acid present in the subject (e.g., paragraphs [0060] and [1403]).
Regarding claim 94, Martini teaches the mRNA comprising a 5’ terminal cap and poly-A region (e.g., paragraphs [0411], [0582] and [0601]).
Regarding claim 95, Martini teaches an N7-methyl-guanylate residue as the 5’-terminal cap linked to the 5’ end of the mRNA, which is 2’-O-methylated (e.g., paragraph [0582]-[0583]). Martini teaches the poly-A region is 100 residues in length (e.g., paragraph [0601]).
Regarding claim 96, Martini teaches the mRNA, where the bases of the mRNA are chemically modified, and where the mRNA is fully modified throughout the entire sequence (e.g., paragraphs [0369]-[0371]). Martini teaches modification with a number of modifications, including 1-methylpseudouridine (m1Ψ), where the polynucleotide can be uniformly modified with this residue (e.g., paragraphs [0369]-[0371]).
Martini does not teach the mRNA of SEQ ID NO: 734, where the codon for amino acid 671 is for isoleucine.
Martini teaches the following codons code for the amino acid isoleucine: ATT, ATC and ATA (e.g., Table 2 at page 17). Martini teaches that the encoded MCM polypeptides may encode a variant with a V671I substitution while retaining functional activity, because the mutation is function-neutral (e.g., paragraphs [0054], [0254] and [0407]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the mRNA sequence of Martini to include a codon for valine at nucleotides 2013-2015, because Martini teaches that a V671I substitution can be introduced into the ORF and retain functional activity. One could have predictably made such a substitution using any of the codons for isoleucine taught by Martini, because Martini teach it is within the ordinary skill in the art to make such a substitution to predictably provide a polynucleotide encoding a functional MCM polypeptide. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the coding sequence of Martini as the sequence of mRNA encoding the methylmalonyl-CoA mutase (MCM) polypeptide of the ‘337 patent to obtain the predictable result of providing a specific coding sequence for the claimed polypeptide.
Regarding claim 90, Martini teaches that the disclosure provides polynucleotide sequences that encode sequence-optimized nucleic acids encoding a methylmalonyl-CoA mutase (MCM) polypeptide (e.g., paragraphs [0247]-[0249]). Martini teaches that the polynucleotide, such as mRNA, increases MCM expression levels in cells when introduced into those cells by at least 20% (e.g., paragraph [0252]). Martini teaches that sequence optimization methods are known in the art and can be useful to achieve one or more desired results, including to match codon frequencies in target and host organisms to ensure proper folding, bias GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons or base runs that impair gene construction or expression, customize transcriptional and translational control regions, for example (e.g., paragraph [0294]). Martini teaches that sequence optimization tools, algorithms and services are known in the art (e.g., paragraph [0294]). Furthermore, each codon capable of coding for a given amino acid was known in the art and presented in Table 2 of Martini (e.g., paragraph [0294], pages 17-18). Further, Martini teaches varying the minimum number of uracil residues and maximal levels of G/C content (e.g., paragraphs [0306]-[0326]). Martini provides a method for assessing the codon optimized sequence using in vitro cell based assays and in vivo assay using a known mouse model (e.g., Examples 14-24).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sequence of SEQ ID NO: 734 by a known codon optimization process, including varying the levels of uracil and G/C to arrive at a sequence 100% identical to instant SEQ ID NO: 7. Martini teaches that there was a recognized need to optimize the coding sequence of mRNA encoding MCM (MUT of claims) in order to provide a variety of benefits, including increased expression. Further, Martini teaches there were a number of known tools, algorithms and services available to achieve such optimization. Moreover, Martini teaches that there are a finite number of codons to code for each amino acid position. Thus, optimization the sequence of SEQ ID NO: 734 while encoding the same polypeptide with the V671I substitution would have a finite number of identified, predictable potential solutions. The effect of the optimization can readily be assessed in vitro or in vivo according to known methods to predictably identify optimized sequences. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the coding sequence of Martini as the sequence of mRNA encoding the methylmalonyl-CoA mutase (MCM) polypeptide of the ‘337 patent to obtain the predictable result of providing a specific coding sequence for the claimed polypeptide.
Martini does not teach that the mRNA comprises the 5’UTR of SEQ ID NO: 78, and the 3’ UTR of SEQ ID NO: 136, or the sequence of SEQ ID NO: 10.
Jain teaches an mRNA comprising a 5’ cap, a 5’UTR, an ORF encoding a polypeptide, and a 3’-UTR, where the 5’UTR is SEQ ID NO: 120, and the 3’UTR is SEQ ID NO: 170 (e.g., page 27, 1st and 2nd full paragraphs). SEQ ID NO: 120 is named RNAseP-P2 (e.g., Table 8 at page 74; Table 21 at pages 334-335). SEQ ID NO: 120 is identical to instant SEQ ID NO: 78. See the attached alignment in Appendix III. SEQ ID NO: 170 is named Sod2_3 (e.g., Table 21 at pages 334-335). SEQ ID NO: 170 is identical to instant SEQ ID NO: 136. See the attached alignment in Appendix IV. The mRNA identified as P2_Sod2_3 contains the 5’UTR of SEQ ID NO: 120 and the 3’UTR of SEQ ID NO: 170 (e.g., Table 21 at pages 334-335). Jain teaches that an mRNA encoding enzyme_B had the highest increase in enzyme expression and activity as compared to other combinations of 5’UTR and 3’UTR sequences (e.g., page 335, 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Martini to include the 5’UTR and 3’UTR sequences of Jain in the mRNA as taught by Marini, because Martini teaches mRNA encoding an enzyme, and Jain teaches it is within the ordinary skill in the art to use a 5’UTR of SEQ ID NO: 120 (instant SEQ ID NO: 78) and a 3’ UTR of SEQ ID NO: 170 (instant SEQ ID NO: 136) in an mRNA encoding an enzyme. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the UTRs and coding sequence of Martini and Jane as the sequence of mRNA encoding the methylmalonyl-CoA mutase (MCM) polypeptide of the ‘337 patent to obtain the predictable result of providing a specific coding sequence for the claimed polypeptide.
One would have been motivated to make such a modification in order to receive the expected benefit of providing an mRNA capable of expressing higher levels of the enzyme relative to other 5’UTR and 3’UTR combinations as taught by Jain.
Regarding claims 93, 97 and 98, each of the elements of the claim are rendered obvious by the teachings of Martini as discussed above, except Martini does not teach the sequence of SEQ ID NO: 10. However, by including the 5’UTR and 3’UTR sequences to the 5’ and 3’ends, respectively, of the optimized coding sequence, one would have arrived at the claimed invention. Instant SEQ ID NO: 10. See the additional alignment information above.
Response to Arguments - Double Patenting
The rejection of claims 1, 7-12 and 14-20 on the ground of nonstatutory double patenting as being unpatentable over claims 9, 18, 26 and 30 of US Patent No. 12,151,995 B2 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
Upon further consideration, the rejection of claims 32, 62 and 63 on the ground of nonstatutory double patenting as being unpatentable over claims 9, 18, 26 and 30 of US Patent No. 12,151,995 B2 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the patent are not directed to an mRNA. The claims of the ‘995 patent are patentably distinct from the instant claims.
The rejection of claims 1, 7-12, 14-20, 72 and 74 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 13 of US Patent No. 11,504,337 B2 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
With respect to the rejection of claims 32, 62, 63 and 78-96 on the ground of nonstatutory double patenting as being unpatentable over claims 16 and 18 of U.S. Patent No. 11,504,337 B2 (hereinafter the ‘337 patent) in view of Martini et al and Jain et al, Applicant's arguments filed 3/10/2026 have been fully considered but they are not persuasive. The response notes the cancellation of claims 1, 7-12, 14-20, 72 and 74. However, pending claims 32, 62, 63 and 78-96 are not patentably distinct from the claims of the ‘337 patent for the reasons given above.
The rejection of claims 1, 7-12 and 14-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 10, 15, 18-21, 29 and 30 of US Patent No. 10,857,105 B2 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
The rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 10, 15, 18-21, 29 and 30 of US Patent No. 10,857,105 B2 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the ‘105 patent are not directed to mRNA encoding methylmaloyl-CoA mutase.
The rejection of claims 1, 7-12 and 14-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of US Patent No. 11,001,861 B2 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
Upon further consideration, the rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of US Patent No. 11,001,861 B2 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the patent are directed to an mRNA encoding galactose-1-phosphate uridyltransferase (GALT) polypeptide, which is structurally, biologically and functionally distinct from the mRNA of the instant claims. The claims of the ‘861 patent are patentably distinct from the instant claims.
The provisional rejection of claims 1, 7-12, 14-20 and 72 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 116-119, 132, 150, 151, 169 and 174 of copending Application No. 19/275692 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
The provisional rejection of claims 32, 62, 63 and 78 pm the ground of nonstatutory double patenting as being unpatentable over claims 1, 116-119, 132, 150, 151, 169 and 174 of copending Application No. 19/275692 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the ‘692 application are not directed to an mRNA encoding methylmalonyl-CoA mutase.
The provisional rejection of claims 1, 7-12 and 14-20 on the ground of nonstatutory double patenting as being unpatentable over claims 6, 88, 89, 93-96 and 98 of copending Application No. 18/985208 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
The provisional rejection of claims 32, 62 and 63 on the ground of nonstatutory double patenting as being unpatentable over claims 6, 88, 89, 93-96 and 98 of copending Application No. 18/985208 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the ‘208 application are not directed to an mRNA encoding methylmalonyl-CoA mutase.
The provisional rejection of claims 1, 7-12, 14-20 and 72 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10, 13, 14 and 30 of copending Application No. 18/282643 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
Upon further consideration, the provisional rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10, 13, 14 and 30 of copending Application No. 18/282643 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the conflicting application are directed to an mRNA encoding glucose-6-phosphatse (G6PC) polypeptide, which is structurally, biologically and functionally distinct from the mRNA of the instant claims. The claims of the ‘643 application are patentably distinct from the instant claims.
The provisional rejection of claims 1, 7-12, 14-20 and 72 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10, 15, 16 and 40 of copending Application No. 18/282639 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
Upon further consideration, the provisional rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10, 15, 16 and 40 of copending Application No. 18/282639 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the conflicting application are directed to an mRNA encoding phenylalanine hydroxylase (PAH) polypeptide, which is structurally, biologically and functionally distinct from the mRNA of the instant claims. The claims of the ‘639 application are patentably distinct from the instant claims.
The provisional rejection of claims 1, 7-12, 14-20 and 72 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10, 13, 14 and 31 of copending Application No. 18/282640 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
Upon further consideration, the provisional rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-10, 13, 14 and 31 of copending Application No. 18/282640 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the conflicting application are directed to an mRNA encoding propionyl-CoA carboxylase alpha (PCCA) polypeptide, which is structurally, biologically and functionally distinct from the mRNA of the instant claims. The claims of the ‘640 application are patentably distinct from the instant claims.
The provisional rejection of claims 1, 7-12, 14-20 and 72 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 98 of copending Application No. 18/282647 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
Upon further consideration, the provisional rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 98 of copending Application No. 18/282647 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the conflicting application are directed to an mRNA encoding ornithine transcarbamylase (OTC) polypeptide, which is structurally, biologically and functionally distinct from the mRNA of the instant claims. The claims of the ‘647 application are patentably distinct from the instant claims.
The provisional rejection of claims 1, 7-12, 14-20 and 72 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 22 and 23 of copending Application No. 17/928684 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
The provisional rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 22 and 23 of copending Application No. 17/928684 in view of Martini et al (US 2018/0271795 A1) has been withdrawn. The claims of the ‘684 application are not directed to an mRNA encoding methylmalonyl-CoA mutase.
The provisional rejection of claims 1, 7-12, 14-20 and 72 on the ground of nonstatutory double patenting as being unpatentable over claim 16 of copending Application No. 17/989941 in view of Martini et al (US 2018/0271795 A1) is moot in view of Applicant’s cancellation of the claims in the reply filed 3/10/2026.
The provisional rejection of claims 32, 62, 63 and 78 on the ground of nonstatutory double patenting as being unpatentable over claim 16 of copending Application No. 17/989941 in view of Martini et al (US 2018/0271795 A1) is moot in view of the abandonment of the ‘941 application.
Conclusion
No claim is allowed.
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Jennifer Dunston
Supervisory Patent Examiner
Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637
Prosecution Insights