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 Group I (claims 1, 4-17, 19, and 35-36) drawn to polynucleotides and Species C: a polynucleotide comprising both a non-naturally occurring 5'-UTR and 3'-UTR, wherein the 5'-UTR is the nucleotide sequence of SEQ ID NO: 1, and the 3'-UTR is the nucleotide sequence of SEQ ID NO: 20 in the reply filed on 07/22/2026 is acknowledged.
Claims 18, 34, and 37-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/22/2026.
Status of Claims
Claims 2-3 and 20-33 are canceled.
Claims 1, 4-19, and 34-38 are pending.
Claim 18, 34, and 37-38 are withdrawn.
Claims 1, 4-19, and 35-36 are under examination.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copies have been filed in parent Application No. PCT/KR2022/009020, filed on 06/24/2022.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 02/15/2024, 04/03/2024, 06/04/2025, and 07/06/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because FIG 2A-C each contain an x-axis label not in English. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 35-36 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 35-36 depend from canceled claims 2-3. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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, 4-19, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Asrani KH, et al., (RNA Biol. 2018;15(6):756-762, in IDS) in view of Bancel S, et al., (US20140147432A1), Barna M, et al., (US20220064631A1, effective filing date 08/31/2020) and Sample PJ, et al., (Nat Biotechnol. 2019 Jul;37(7):803-809, in IDS).
Since claims 35-36 are dependent on canceled claims 2-3, claims 35-36 are being examined as being dependent from claim 1 for prior art purposes and customer service.
Regarding claims 1 and 19, Asrani teaches “optimization of mRNA untranslated regions for improved expression of therapeutic mRNA,” see title. Asrani “evaluated the role of the 5′ and 3′ UTRs independently by generating a combinatorial UTR library whereby each 5′UTR was paired with all combinations of 3′UTR from the selected genes,” see table 2. One combination in table 2 comprises the C3 5’ UTR paired with the CYP2E1 3’ UTR, which is the same combination as claimed. Asrani reports that “the 5′ UTR appears to be the key driver in protein expression for exogenously delivered mRNA,” and that “the 5′UTR for complement factor 3 (C3) and cytochrome p4502E1 (CYP2E1) showed the largest and most consistent increase in protein expression relative to a reference UTR,” see abstract and introduction.
Regarding claims 6, Asrani further teaches a T7 promoter driving expression the mRNA comprising the C3 5’ UTR paired with the CYP2E1 3’ UTR, see methods vector design and mRNA synthesis.
Regarding claim 7 Asrani further teaches a transcribable nucleotide sequence operably linked and downstream of the 5’UTR, see abstract, methods vector design and table 2.
Regarding claim 8-9, Asrani further teaches the transcribable nucleotide sequence encodes a polypeptide, Arginase 1 (ARG1), which “ARG1 deficiency represents a rare genetic disease whereby loss of the ARG1 gene leads to disease pathology and replacement of the ARG1 protein may have clinical benefit,” see pg. 756 column 2.
Regarding claims 7, 10, 17, and 35-36, Asrani further teaches the mRNA constructs were cloned “into a … T7 containing vector,” see methods vector design and pg. 757 column 1.
Regarding claims 11-13, Asrani teaches a transcribable nucleotide sequence operably linked upstream to the 3’ UTR and a 100NT poly A repeat was added to the end of the 3′UTR (which is the same poly A sequence represented by SEQ ID NO: 41 in claim 12 of the instant application), see methods vector design and mRNA synthesis.
Regarding claim 14 Asrani further teaches a transcribable nucleotide sequence operably linked upstream to the 3’ UTR, see methods vector design and table 2.
Regarding claims 15-16, Asrani teaches that the transcribable nucleotide sequence encoding ARG1 is flanked by comprises the C3 5’ UTR paired with the CYP2E1 3’ UTR.
Asrani does not teach the underlying nucleotide sequences of the C3 5’ UTR (SEQ ID NOs: 1 & 22) or CYP2E1 3’ UTR (SEQ ID NOs: 20 & 40) per se, or to modify the C3 5’ UTR with a single base pair substitution.
Bancel teaches the same architecture of the cDNA and/or mRNA as claimed, see FIG. 1, [0040], and Claims 13-14. Table 6. For example, Bancel teaches a cDNA and/or mRNA that encodes Factor IX “(cDNA with the T7 promoter, 5′ UTR and 3′UTR used in in vitro transcription is given in SEQ ID NO: 251440. mRNA sequence shown in SEQ ID NO: 251437; polyA tail of approximately 160 nucleotides not shown in sequence; 5′cap, Cap 1; fully modified with 5-methylcytosine and pseudouridine),” see [1223].
Bancel further teaches the sequence for the CYP2E1 3’ UTR (SEQ ID NOs: 20 & 40) with 100 % identity, see alignment below:
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Barna teaches a modified C3 5’-UTR with 98.4% sequence identity to C3 5’-UTR claimed (SEQ ID NOs: 1 & 22), see alignment below.
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Sample teaches a deep learning model trained on polysome profiling data from a library of 280,000 randomized human 5’ UTRs, which accurately predicts the effect of 5’ UTR sequence on ribosome loading (a direct measure of translation efficiency), see abstract. Sample further teaches combining this model with a genetic algorithm to iteratively introduce nucleotide-level edits into a 5’ UTR sequence in order to engineer new 5’ UTR variants that direct specified, increased levels of ribosome loading, thereby tuning the sequence for optimal protein expression, see abstract. Sample further teaches applying the trained model to predict the ribosome-loading effect of single nucleotide variants (SNVs) present in 3,577 naturally-occurring human 5’ UTR sequences, and confirms that the model accurately predicts the resulting change in ribosome loading for these natural sequence variants, see abstract. Sample additionally identifies 45 disease-associated SNVs in natural human 5’ UTRs that substantially change ribosome loading relative to the reference/wild-type sequence, demonstrating that a single nucleotide substitution within an otherwise-natural, known 5’ UTR sequence can produce a significant, predictable change in translation efficiency, see abstract. Sample thus teaches that, before the effective filing date, it was well known in the art to introduce single nucleotide substitutions into a known, natural 5’ UTR sequence in order to identify and select variants exhibiting altered (including increased) ribosome loading and translation efficiency relative to the parent sequence.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to substitute the second nucleotide (a cytosine) of the C3 5’ UTR sequence taught by Asrani as evidenced by Barna with a guanine, thereby arriving at the claimed 5’ UTR of SEQ ID NO: 1/22 in combination with the CYP 4502E1 3’ UTR taught by Asrani as evidenced by Bancel. A PHOSITA would have been motivated to do so because Sample teaches that single nucleotide substitutions within a known, natural human 5’ UTR sequence provide a recognized, effective, and predictable means of increasing ribosome loading and, correspondingly, translation efficiency of an mRNA construct. A PHOSITA seeking to improve the therapeutic efficacy of the therapeutic protein-encoding mRNA construct of Asrani would therefore looked to apply Sample’s model to the C3 5’ UTR. A PHOSITA would have had a reasonable expectation of success because Sample’s deep learning model, combined with its genetic algorithm, was already as capable of accurately predicting the ribosome-loading effect of single nucleotide substitutions in natural human 5’ UTR sequences, explaining up to 93% of the observed variance and validated against 3,577 tested natural 5’ UTR variants. Thus, a PHOSITA could reliably predict, generate, and confirm via routine screening which single base substitution(s), including the specific cytosine to guanine substitution would yield a functional 5’ UTR variant with increased translation efficiency without undue experimentation.
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.
Claim 1, 4-19, and 35-36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-5, 12, 14, 16-19, and 26 of copending Application No. 18/722,534 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite a DNA polynucleotide comprising the same 5′-UTR/3′-UTR/promoter/transcribable-sequence/poly(A) architecture as claim 1 of the reference application, including the same 5′-UTR sequence (SEQ ID NO:1, or variants thereof at SEQ ID NOS: 22 to 33, which are identically numbered between the two applications) and the same 3′-UTR sequence (SEQ ID NO:20, or variants thereof at SEQ ID NOS: 34-40, likewise identically numbered), differing only in that the instant claims recite the transcribable nucleotide sequence generically, whereas claim 1 of the reference application narrows the transcribable nucleotide sequence to one specifically encoding a SARS-CoV-2 spike protein or variant thereof having 80% or more sequence identity to SEQ ID NO:42, a species already encompassed by the instant claims’ broader genus (see instant claim 9, reciting the transcribable sequence may encode an “antigenic…polypeptide”). Broadening the specifically-claimed SARS-CoV-2 spike-protein-encoding transcribable sequence of the reference claim to the generic transcribable nucleotide sequence of the instant claims, absent any showing of criticality or unexpected result attributable to that breadth, would have been an obvious variant to a person of ordinary skill in the art.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4-19, and 35-36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 19/523,888 in view of Asrani KH, et al., (RNA Biol. 2018;15(6):756-762, in IDS), Bancel S, et al., (US20140147432A1), and Barna M, et al., (US20220064631A1, effective filing date 08/31/2020).
Claim 8 of the copending application recites a DNA molecule encoding the mRNA of any of claims 1 to 7, which encompasses combining claim 3’s non-natural 5′-UTR (SEQ ID NO:1) with claim 5’s polypeptide-encoding sequence and 3′-UTR, i.e., a DNA molecule comprising the identical 5′-UTR (SEQ ID NO:1), a transcribable/polypeptide-encoding sequence, and a 3′-UTR, differing from the instant claims only in that (a) the copending claims do not tie the 3′-UTR to a specific sequence, and (b) the copending claims do not recite an upstream promoter operably linked to the 5′-UTR. Asrani and Bancel, as previously discussed and incorporated herein by reference, teach this same structure: a 5′-UTR paired with a 3′-UTR in an analogous DNA/mRNA construct operably linked to a T7 promoter driving expression of the intervening transcribable sequence. It would have been obvious to a person of ordinary skill in the art before the effective filing date to select the CYP2E1-derived 3′-UTR of SEQ ID NO:20 taught by Asrani as evidenced by Barna for the generically-recited 3′-UTR of copending claim 8’s mRNA, and to further include an upstream promoter (such as the T7 promoter) operably linked to the 5′-UTR, since Bancel and Asrani each establish that this specific 3′-UTR and this promoter architecture were known components for use with the SEQ ID NO:1 5′-UTR in a DNA construct intended for mRNA expression. A person of ordinary skill would have had a reasonable expectation of success given Asrani’s express teachings of this specific architecture and pairing.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to COREY LANE BRETZ whose telephone number is (571)272-7299. The examiner can normally be reached M-F 7:30am - 6:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
Prosecution Insights