DETAILED ACTIONNotice 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/28/25 has been entered.
Application Status
Claims 61, 62, 64-70, 72, 74, and 76-79 are pending and under examination. No claims have been added or amended.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicants’ amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 103 – MODIFIED
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.
Claim(s) 61, 62, 64-70, 72, 74, and 76-79 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bancel of record (Bancel, S., US20130259924A1) in view of Venditti of record (Venditti, F., US20160040150A1), priority to Feb 11 2016 and Yin (Yin, Hao, et al. "Non-viral vectors for gene-based therapy." Nature reviews genetics 15.8 (2014): 541-555.)
Regarding claim 61, Bancel teaches methods comprising administering modified mRNAs and their encoded proteins or complexes to a subject in need thereof [0780]. Bancel teaches mRNA of the invention designed to encode polypeptides of interest selected from any of several target categories including, but not limited to, biologics, antibodies, vaccines, therapeutic proteins or peptides, cell penetrating peptides, secreted proteins, plasma membrane proteins, cytoplasmic or cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease [0152]. Bancel teaches one such mRNA, SEQ ID NO: 1517 methylmalonyl-CoA mutase (MUT) sequence with 100% identity to Applicant’s SEQ ID NO: 5601 (Table 6, [0288]; See alignment in OA appendix of record). Bancel teaches in Example 161 the modified mRNA SEQ ID NO: 1658 which contains SEQ ID 1517 ORF and teaches confirmation of peptide fragments identified for the evaluated MUT proteins in Table 205 [1910]. Bancel teaches the plasmid containing the mRNA construct may be purified by HPLC, i.e. high performance liquid chromatography [0261]. Bancel teaches in another embodiment the mRNA containing pharmaceutically acceptable excipient includes lipid nanoparticles [0554-0555]. Bancel further teaches the mRNA construct formulated with a lipidoid for systemic intravenous administration [0560]. Bancel further teaches the mRNA molecule includes a 5′UTR, a 3′UTR, a 5′cap and a poly-A tail [0096].
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Although Bancel teaches the HPLC purified mRNA with SEQ ID NO: 1517 which expresses methylmalonyl-CoA mutase (MUT) and the use of lipid nanoparticles within the method of administering modified mRNAs and their encoded proteins or complexes to a subject in need thereof, Bancel does not apply the construct specifically for the treatment of methylmalonic acidemia (MMA).
However, Venditti teaches a method of treating methylmalonic acidemia (MMA) in a subject mediated by methylmalonyl-CoA mutase delivery, comprising administering a therapeutic amount of a synthetic methylmalonyl-CoA mutase (MUT) polynucleotide ([0007] and claims 9 and 11). Venditti teaches an adeno-associated viral (AAV) gene therapy vector encoding synMUT under the control of a liver-specific promoter (AAV2/8-HCR-hAAT-synMUT-RBG) successfully rescued the neonatal lethal phenotype displayed by methylmalonyl-CoA mutase-deficient mice (abstract).
Yin teaches mRNA for therapeutic protein expression in vivo as an alternative to DNA-based gene therapy owing to its unique advantages (abstract). Yin teaches synthetic lipid ‘vehicles’ tend to have lower immunogenicity than viral vectors, where patients do not have pre-existing immunity as is the case with some viral systems, and where non-viral vectors also have the potential to deliver larger genetic payloads and are typically easier to synthesize than viral vectors (pg 541 col 1 para 2).
Although Venditti teaches viral mediated delivery of the methylmalonyl-CoA mutase (MUT) protein to treat subjects with methylmalonic acidemia, it would have been predictable and obvious to one skilled in the art before the effective filing date of the claimed invention that MUT could be effectively delivered within Bancel’s method of administering methylmalonyl-CoA mutase mRNA/lipid composition to treat a subject with methylmalonic acidemia (MMA). It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that Bancel’s HPLC purified mRNA construct with SEQ ID NO: 1517 as delivered by a pharmaceutically acceptable lipid nanoparticle could increase the level of MUT in a subject because Bancel teaches these components can be combined within the method of administering modified mRNAs and their encoded proteins to a subject. The skilled artisan would further expect that Bancel’s mRNA lipid composition of methylmalony-CoA mutase coding mRNA of SEQ ID NO: 1517 with 100% identity to instant SEQ ID NO: 5601 could predictably treat a subject with MMA because Venditti expressly teaches the therapeutic benefit of treating an MMA subject with a nucleic acid encoding methylmalonyl-CoA mutase. Yin further teaches the advantages of mRNA delivery within lipid vehicles such that the skilled artisan would be motivated to administer Bancel’s mRNA lipid composition to a subject with MMA for increased therapeutic benefit.
Regarding claim 62 and 79, Bancel teaches the mRNA construct formulated with the lipidoid PEG-DMG [0560].
Regarding claim 64, Bancel teaches the total daily usage of the compositions of the present invention may be decided by the attending physician within the scope of sound medical judgment where the specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder [0780]. Bancel teaches 100 ug of mRNA lipid compositions administered to a rodent [1307]. Although Bancel does not specifically teach the methylmalony-CoA mutase coding mRNA administered at 100 ug daily to a rodent, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention for Bancel to administer 100ug of the methylmalony-CoA mutase coding mRNA construct with SEQ ID NO: 1517. It would have merely amounted to a simple substitution of a known elements to yield predictable results. The skilled artisan would have expected that an mRNA lipid composition of methylmalony-CoA mutase coding mRNA of SEQ ID NO: 1517 could be effectively delivered within the lipid coding package because Bancel teaches the mRNA lipid composition can be delivered at 100 ug. The skilled artisan would have been motivated to administer the methylmalony-CoA mutase coding mRNA of SEQ ID NO: 1517 in a lipid composition at 100 ug in order to express methylmalony-CoA mutase in a subject in need. Note that the optimization of doses/concentrations would have been prima facie obvious to one of ordinary skill in the art at the time of filing: “[W[here the general conditions of a claim are disclosed in the prior art, 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) (see MPEP 2144.05). As set forth at MPEP 2144.05 II. A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.” Therefore, claim 65 is obvious and is properly rejected under 35 U.S.C. 103.
Regarding claims 65-68, Bancel teaches modifications to the mRNA such as the chemically modified 5’ cap structure ARCA-CAP [0226].
Regarding claim 69, Bancel teaches the cap structures within the method can contain a phosphorothioate linkage [0223]. Although, Bancel does not specifically state the ARCA-CAP is modified with a phosphorothioate linkage, it would be obvious to the skilled artisan that ARCA-CAP would be modified in Bancel’s method with a phosphorothioate linkage because Bancel teaches the use of a group of 5’ caps including ARCA-CAP and that the caps within that group can be modified with a phosphorothioate linkage.
Regarding claim 70, Bancel teaches the chemically modified nucleotide includes 5-methyl-uridine [0510].
Regarding claim 72, the teachings of Bancel as applied above for claim 61 are incorporated here. I.e., the method of claim 61, wherein mRNA comprises a sequence at least 97% identical to SEQ ID NO: 5601.
Regarding claim 74, Bancel teaches the chemically modified nucleotide includes 5-methoxy-uridine (mo5U) [0510].
Regarding claim 76, Bancel teaches the target polynucleotide sequence sequences within the method may be codon optimized.
Regarding claim 77 and 78, Bancel teaches a combination therapy method of delivering the mRNA constructs of the invention to encode for a protein that boosts a mammalian subject's immunity to be used in combination with a protein that induces antibody-dependent cellular toxicity such as trastuzumab in the treatment of breast cancer patients [0813]. Although Bancel doesn’t specifically teach the MUT encoding mRNA in the example, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Bancel’s MUT encoded polypeptide in the combination therapy method of boosting immunity in a subject with breast cancer. It would have merely amounted to a simple substitution of prior art elements according to known methods to yield predictable results. The skilled artisan would have had a reasonable expectation that the MUT encoded polypeptide could be used in the combination immune boosting therapy with the antibody-dependent cellular toxicity inducing trastuzumab in a breast cancer subject because Bancel teaches the mRNA encoding polynucleotide compositions of the invention can be used within the combination therapy method. The skilled artisan would be motivated to use the methylmalonyl-CoA mutase encoded polypeptide with trastuzumab in the combination therapy method so as to boost immunity to the construct and thus overcome resistance to trastuzumab [0813].
Response to Arguments
Applicants argue (Remarks pg 5-7) that the ORF of Bancel's SEQ 1658 is only 78% identical to the ORF of Bancel's SEQ 1517, however as described in the §103 rejection above, the presently claimed instant SEQ ID NO: 5601 from independent claim 61 has 100% identity to Bancel’s MUT (SEQ ID NO: 1517), as seen in table 6 and the attached alignment appendix. Applicants further argue that Venditti teaches expression of the mRNA in the liver using a liver-specific promoter which emphasizes the therapeutic benefit of treating MMA subjects with MUT which requires the expression to be under the control of a liver-specific promoter. Applicants’ arguments have been thoroughly reviewed and found unpersuasive. Examiner notes that the features upon which applicant relies are not recited in the rejected claim(s). Venditti’s success at applying MUT gene therapy to treat subjects with MMA through virally mediated delivery to the liver does not undermine the predictability of MUT gene delivery in Bancel’s method using SEQ ID NO: 1517 to effectively treat MMA with MUT, as Venditti establishes MMA expression is an effective treatment for MUT and Yin describes non-viral lipid delivery method, alternative to DNA-based gene therapy, has unique advantages and is well known in the art.
Examiner notes that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
All claims are rejected.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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