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 .
The Response of 20 July 2026 has been entered.
Claims 1, 3-5, 8, 10, 20, 22, 26, 31, 35, 37, 38, 40, 41, 43, 51, 55, 68 and 70 are currently pending.
Election/Restrictions
Applicant’s election without traverse of the invention of Group I, claims 1, 3-5, 8, 10, 20, 22 and 26, and the species of: TATCTGTC as the termination signal and TCTCTGTC as the modified termination sequence in the reply filed on 20 July 2026 is acknowledged.
Claims 31, 35, 37, 38, 40, 41, 43, 51, 55, 68 and 70 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 20 July 2026.
Claims 1, 3-5, 8, 10, 20, 22 and 26 are considered herein with respect to the elected species.
Claim Rejections - 35 USC § 112(b) (indefiniteness)
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.
Claim 1, 3-5, 8, 10, 20, 22 and 26 are rejected under 35 U.S.C. 112(b) 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.
Claim 1 recites “wherein, if required, the one or more replacement nucleic acids are selected to preserve the amino acid sequence of the protein encoded by the protein coding sequence”. It is unclear what condition(s) would make the claimed selection step “required”. For example, Mead et al., Nucleic acids research 13.4 (1985): 1103-1118, teaches altering a termination signal within the coding sequence of a heterologous protein wherein the alteration results in a conservative substitution that does not affect the functionality being assayed (p. 72, under Oligonucleotide mutagenesis of a transcriptional terminator in PTH cDNA). It is unclear whether a selection step as instantly claimed would be considered “required” or not required under such circumstances. The rejection can be overcome by amending the claim to delete “if required”.
Claim 5 recites a step of modifying the DNA sequence to optimize mRNA processing/stability and/or translation/folding, “wherein the modifications are made before the optimized DNA sequence is generated.” Claim 1 recites a modifying step to generate an optimized DNA sequence wherein the step is contingent on the presence of a termination signal (see above re claim 1). Since the modifying step of claim 5 is defined relative to the contingent step of claim 1, it is unclear when the modifying step of claim 1 is not carried out whether the step of claim 5 is required and/or when it is conducted. For purposes of applying prior art below, claim 5 is construed such that the modifying step can be carried out at any point in the method when the modifying step of claim 1 is not carried out.
Claim 20 recites “the synthesized mRNA” in claim 1. There is insufficient antecedent basis for this limitation in the claim, making it unclear whether the claim(s) require a transcription step to synthesize mRNA.
Claim 22 recites “the mRNA”, “the DNA template” and “the SP6 RNA polymerase” in claim 1. There is insufficient antecedent basis for this limitation in the claim, making it unclear whether the claim(s) require a transcription step to synthesize mRNA and how such step limits the method of claim 1.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 4, 8, 10, 20, 22 and 26 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over US8278036 to Kariko et al. (cited in IDS of 17 Mar 2026), as evidenced by GenBank: BC143225.1 (2009) and PT7TS datasheet.
Regarding claims 1 and 8, Kariko teaches a method of preparing a DNA sequence encoding a protein as a template for in vitro transcription, said method comprising: providing a DNA sequence that comprises a protein coding sequence (human EPO); inserting the DNA sequence into an expression vector; and in vitro transcribing the DNA to produce mRNA (Examples 16-17). Regarding the step in claim 1 of “determining the presence of a termination signal in the DNA sequence”, Kariko teaches a step of obtaining and cloning a known DNA sequence and the knowledge of such sequence inherently comprises determining any sequence elements that are and/or are not present therein. Alternatively, it would have been obvious in view of Kariko to sequence the expressed DNA construct (e.g., to ensure proper cloning/expression) and such sequencing would comprise determining the presence of any sequence elements comprising the sequence.
Regarding step c. of modifying the DNA in claim 1, such step is a contingent step that is carried out only if the termination signal is present. The transcribed DNA of Kariko comprises a PT7TS vector with the human EPO sequence inserted therein (Example 17), and a search of both sequences for the elected species of termination signal (TATCTGTC) reveals such signal is absent (see attached alignments; EPO sequence from GenBank: BC143225.1 and PT7TS sequence from https://www.novoprolabs.com/vector/Vguzdemy). As such, step c. is not required by the claimed method. The instant rejection can be overcome by amending claim 1 to recite that the method comprises detecting the sequence and then modifying the sequence, without the contingent limitation “if one or more termination signal is present”.
Regarding the recitation in the preamble of “preparing an optimized DNA sequence”, the method of Kariko meets all the limitations of the claims and the DNA sequence can thus be considered optimized. Alternatively, Kariko teaches insertion of the DNA into a plasmid comprising sequence elements that facilitate expression of the DNA (e.g., UTRs, polyA tail, etc.), and preparation of the cloned DNA can be considered “optimization”.
Regarding claim 3, Kariko teaches that the transcribed EPO DNA has both 5’- and 3’-UTRs (Example 17).
Regarding claim 4, the DNA of Kariko does not include the termination signal (see above re step c.), and thus the limitation of claim 4 is moot.
Regarding claim 10, the PT7TS vector used by Kariko has a T7 promoter operably linked to the EPO sequence (Example 17; PT7TS datasheet).
Regarding claim 20, Kariko teaches capping and tailing the mRNA (Example 17).
Regarding claim 22, Kariko exemplifies in vitro transcription with T7 RNA polymerase with 7.5 mM dNTPs (Example 17). Kariko further teaches that transcription can be carried out with either T7 or SP6 RNA polymerase (col. 7, lines 19-22; Example 2), and the PT7TS vector contains promoters/cloning sties for both T7 and SP6 (PT7TS datasheet). Thus, it would have been obvious to carry out the in vitro transcription of Kariko with SP6 RNA polymerase with a reasonable expectation of success. Regarding the concentration of SP6 RNA polymerase and the temperature range, differences in concentration or temperature generally do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (see MPEP 2144.05, II., A.). It would have been obvious in view of Kariko to use routine experimentation/optimization to discover the optimal and/or workable concentration/temperature ranges.
Regarding claim 26, Kariko teaches use of the modified NTP pseudouridine (Example 17).
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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Kariko, as applied to claims 1, 3, 4, 8, 10, 20, 22 and 26 above, in view of WO2018157153 to Dias et al.
Claim 5 differs from Kariko, as applied to claims 1, 3, 4, 8, 10, 20, 22 and 26 above, in that: the method further comprises a step of modifying the DNA sequence relative to a wildtype DNA sequence encoding the same protein sequence to optimize: a. elements relevant to mRNA processing and stability, wherein the elements relevant to mRNA processing or stability include cryptic splice sites, mRNA secondary structure, stable free energy of mRNA, repetitive sequences, and RNA instability motifs; and/or b. elements relevant to translation or protein folding, wherein the elements relevant to translation or protein folding include codon usage bias, codon adaptability, internal chi sites, ribosomal binding sites, premature polyA sites, Shine-Dalgarno sequences, codon context, codon-anticodon interactions, and translational pause sites; wherein the modifications are made before the optimized DNA sequence is generated.
Dias teaches methods of preparing mRNA by in vitro translation by T7 or SP6 RNA polymerase (i.e. similar to the method of Kariko), wherein the methods can comprise a step of optimizing the DNA sequence to facilitate efficient transcription and/or translation ([0094]-[0100]). Dias teaches “the DNA sequence may be optimized regarding cryptic splice sites, mRNA secondary structure, stable free energy of mRNA, repetitive sequences, RNA instability motif” or “codon usage bias, codon adaptability, internal chi sites, ribosomal binding sites (e.g., IRES), premature polyA sites, Shine-Dalgarno (SD) sequences, … codon context, codon-anticodon interaction, translational pause sites” ([0097]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the method of Kariko to prepare EPO mRNA via in vitro transcription wherein the DNA transcript is further optimized as taught by Dias because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to optimize the DNA transcript of Kariko to facilitate efficient transcription and/or translation, as taught by Dias. Optimizing the DNA transcript of Kariko to facilitate efficient transcription and/or translation as taught by Dias would have led to predictable results with a reasonable expectation of success because the method of Dias is substantially similar to that of Kariko and Dias further exemplifies the transcription of human EPO (e.g., Dias Example 1).
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 1, 3-5, 8, 10, 20, 22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 18580463 in view of Kariko and Dias (cited in 103 rejection above).
The claims of the ‘463 app teach a method of preparing a DNA sequence encoding a protein to be transcribed in vitro, wherein the DNA sequence is optimized for the production of full-length transcripts by screening for the absence of a termination signal comprising the same consensus sequence recited in the instant claims (which encompasses the elected species TATCTGTC) (‘463, claims 1, 9). Since step c. of instant claim 1 is contingent on the presence of a termination signal, the method of the ‘463 app in which the termination signal is absent would anticipate instant claims 1 and 4. Regarding claim 3, the ‘463 teaches that the DNA includes 5’ and 3’ UTRs (‘463, claim 3). Regarding claim 5, Dias teaches optimizing the recited factors to facilitate efficient transcription and/or translation (see 103 rejection, above), and it would be obvious to further optimize the DNA of the ‘463 method for the same purpose (‘463 claim 6 teaches optimizing for codon usage/bias). Regarding claims 8, 10, 20, 22 and 26, Kariko teaches the claimed steps/features in the context of in vitro transcription (see 103 rejection, above) and it would have been obvious to include such steps in the routine course of in vitro transcription.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-5, 8, 10, 20, 22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-11 and 14-17 of copending Application No. 17923844 in view of Kariko and Dias (cited in 103 rejection above).
The claims of the ‘844 app teach a method of preparing a DNA sequence encoding a protein to be transcribed in vitro, wherein the DNA sequence is optimized for codon usage/bias and by screening for the absence of a termination signal comprising the same consensus sequence recited in the instant claims (which encompasses the elected species TATCTGTC) (‘844, claims 1, 9, 15, 16). Since step c. of instant claim 1 is contingent on the presence of a termination signal, the method of the ‘844 app in which the termination signal is absent would anticipate instant claims 1 and 4. Regarding claims 3, 8, 10, 20, 22 and 26, Kariko teaches the claimed steps/features in the context of in vitro transcription (see 103 rejection, above) and it would have been obvious to include such steps in the routine course of in vitro transcription. Regarding claim 5, Dias teaches optimizing the recited factors to facilitate efficient transcription and/or translation (see 103 rejection, above), and it would be obvious to further optimize the DNA of the ‘844 method for the same purpose.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
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