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 .
Application Status
This action is written in response to applicant’s correspondence received 16 March 2026. Claims 85-88 and 90-106 are currently pending. Accordingly, claims 85-88 and 90-106 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments 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
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.
Claim(s) 85, 87-88, 92-93, 95-101, and 103-106 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hoge (PG Pub No. WO 2017/062513 A1) in view of Huang (Pg Pub No. US 2021/0206818; filed 20 January 2017), Huang sequence alignment 72 (SEQ ID NO: 72; accessed 15 June 2026), Huang sequence alignment 73 (SEQ ID NO: 73; accessed 15 June 2026), and Von Niessen ("Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening." Molecular Therapy 27.4 (2019): 824-836).
Regarding claims 85 and 106, Hoge is drawn to an invention concerned with the use of a chemically modified mRNA that can be utilized to inhibit an anti-drug antibody response in a subject (Abstract). Hoge teaches the use of an mRNA molecule comprising a coding region that encodes a polypeptide of interest and is flanked by 5’ UTR and 3’ UTR sequences that are heterologous to the coding region (pg. 33). Hoge teaches that the coding region may encode a fusion protein Hoge teaches that the heterologous flanking UTR sequences encompass flanking UTR sequences that are not normally present in a given polynucleotide (i.e., the flanking UTR regions are non-native) (pg. 112). Further, Hoge teaches that the mRNA may comprise Mir binding sites such that, when the mRNA is expressed in an immune cell of interest, microRNA binds to the Mir binding sites such that an anti-drug antibody response is reduced in the immune cell (pg. 8). Hoge teaches that the immune cell may be a splenic myeloid cell (pg. 8). Hoge teaches that the expression level of a polypeptide of interest expressed from the mRNA can be detected at least 72 hours after administration (pg. 77).
Hoge does not teach or suggest that the 3’ UTR comprises a sequence having at least 90% identity to the claimed SEQ ID NO: 52 (Claim 85) or comprises the claimed SEQ ID NO: 52 (Claim 106). Hoge does not teach or suggest that the 5’ UTR comprises a sequence having at least 90% identity to the claimed SEQ ID NO: 46 (Claim 100).
Huang is drawn towards an invention concerned with isolated mRNAs encoding at least one intracellular binding domain (Abstract). Huang teaches the use of multiple anti-MCL1 mmRNA constructs comprising an open reading frame that is flanked by a 5′ UTR having the sequence shown in SEQ ID NO: 72 and a 3′ UTR having the sequence shown in SEQ ID NO: 73 ([1222]). Huang teaches that the 3’ UTR that has 100% identity to the claimed SEQ ID NO: 52 ([1222]; see SEQ ID NO: 73 in attached sequence alignment). Huang further teaches that SEQ ID NOs: 72-73 can flank many different ORFS that encode proteins that are different in both structure and function ([1207]-[1208]).
Von Niessen is drawn towards a study concerned with the stabilization effects that 3’ UTRs have on mRNA (Abstract). Von Niessen teaches that non-native 3’ UTRs were attached to destabilized luciferase reporter genes and that the luciferase activity was measured over 72 hours (pg. 828; see Figure 2). Von Niessen teaches that attaching the non-native 3’ UTRs to the destabilized luciferase reporter genes had a stabilizing effect that increased the luciferase mRNA half-life compared to a control (pg. 828; see Figure 2).
Therefore, the prior art teaches that the addition of a non-native 3’ UTR to an mRNA molecule can have a stabilizing effect on the mRNA’s half-life such that it is increased compared to an mRNA not comprising the 3’ UTR.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the 5’ and 3’ UTRS of Hoge for the 5’ and 3’ UTRs of Huang because it would have merely amounted to simple substitution of one known element for another to obtain predictable results. Because Huang teaches the use of 5’ and 3’ UTRs for the same purpose as Hoge (i.e., the expression of a polypeptide of interest via the flanking of an ORF with the UTRs), then one would have had a reasonable expectation of success in expressing the fusion protein of Hoge within a cell through the use of the 5’ and 3’ UTRs of Huang. Further, because Von Niessen teaches that attaching a non-native 3’ UTR to an mRNA of interest resulted in a greater half-life of the molecule, a person of ordinary skill in the art, upon reading Von Niessen, would have reasonably expected that the addition of the claimed 3’ and 5’ UTRs would have produced a similarly stable mRNA and consequently prolonged detection of the polypeptide.
Reading claims 87-88, Hoge teaches that the 3’ UTR region comprises a spacer between the end of a Mir binding site and polyA tail nucleotides (i.e., the 3’ UTR comprises a poly A sequence) (pg. 58). Hoge teaches the use of a 140 nucleotide polyA tail (i.e., a poly A tail that is about 50-250 nucleotides in length) (pg. 120). Hoge teaches that the modified mRNAs of the disclosure can be produced by IVT enzymatic synthesis methods (i.e., the 3’ UTR comprising a poly A sequence can be added enzymatically (pg. 50).
Regarding claims 92 and 105, Huang teaches that the 5’ UTR is 47 nucleotides in length ([1222]; see SEQ ID NO: 72 in attached sequence alignment).
Regarding claim 93, Hoge teaches that the mRNA molecules of the disclosure can be produced in in vitro processes (i.e., the mRNA of Hoge can be an in vitro transcribed mRNA) (pg. 26).
Regarding claim 95, Hoge teaches that the mRNA may comprise one or more modified nucleobases (i.e., less than 50% of the residues in Hoge can be modified) (pg. 3). Hoge teaches that the modified nucleotide may be a pseudo uridine (pg. 37).
Regarding claim 96, Hoge teaches that any number, including none, of the nucleobases may be modified (pg. 32-33).
Regarding claim 97, Hoge teaches the use of a cationic lipid nanoparticle that can encapsulate the mRNA and be administered intravenously (pg. 6).
Regarding claim 98, Hoge teaches that an in vivo cell can be contacted with the mRNA of the disclosure (pg. 109).
Regarding claim 99, Hoge teaches that the immune cell that the mRNA is expressed within may be a splenic myeloid cell (pg. 8).
Regarding claim 101, Hoge teaches the use of a pharmaceutical composition comprising the mRNA of the disclosure (i.e., an isolated mRNA (pg. 32)) and a pharmaceutically acceptable excipient (pg. 20).
Regarding claim 103, Hoge teaches that the mRNA may be administered to preferentially kill liver cancer cells (i.e., treat a cancer in a subject in need thereof) (pg. 61).
Regarding claim 104, the obviousness of arriving at the claimed composition is discussed above as applied to claim 85. Hoge teaches that the expression level of a polypeptide of interest expressed from the mRNA can be detected at least 72 hours after administration (pg. 77). Hoge teaches that (a) the mRNA molecules of the disclosure can be produced in in vitro processes (i.e., the mRNA of Hoge can be an in vitro transcribed mRNA) (pg. 26). Hoge teaches that (b) that the 3’ UTR region comprises a spacer between the end of a Mir binding site and polyA tail nucleotides (i.e., the 3’ UTR comprises a poly A sequence) (pg. 58) and that the modified mRNAs of the disclosure can be produced by IVT enzymatic synthesis methods (i.e., the 3’ UTR comprising a poly A sequence can be added enzymatically (pg. 50). Hoge teaches that (c) for cells present in vitro, a composition comprising the mRNA may be added to a culture medium (i.e., a microenvironment that endows cell growth and survival) comprising the cell of interest in order to transfect the mRNA into the cell (pg. 109).
Claim(s) 86 and 94 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hoge (PG Pub No. WO 2017/062513 A1) in view of Huang (Pg Pub No. US 2021/0206818; filed 20 January 2017), Huang sequence alignment 72 (SEQ ID NO: 72; accessed 15 June 2026), Huang sequence alignment 73 (SEQ ID NO: 73; accessed 15 June 2026), and Von Niessen ("Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening." Molecular Therapy 27.4 (2019): 824-836) as applied to claims 85, 87-88, 92-93, 95-101, and 103-106 above, and further in view of Tirtha (PG Pub No. US 2017/0202979 A1).
Regarding claims 86, 94, and 100, Hoge in view of Huang and Von Niessen renders obvious claims 85, 87-88, 92-93, 95-101, and 103-106 as described above. Hoge further teaches that the mRNA molecule may comprise a 5’ cap structure (pg. 34).
Hoge in view of Huang and Von Niessen does not teach or suggest the use of a 5’ methyl guanylate cap (Claim 86). Hoge in view of Huang and Von Niessen does not teach or suggest that the +1 nucleotide of the 5’ methyl guanylate cap comprises a ribose methylated at the 2’ O position (Claim 94).
Tirtha is drawn towards an invention concerned with compositions and methods for the manufacture of polynucleotide comprising at least one terminal modification (Abstract). Tirtha teaches the use of an mRNA molecule that can comprise a cap moiety ([0587]). Tirtha teaches the use of a 5’ guanylate cap that can comprise a 5’ terminal 2’-O-methylated ribose (i.e., a +1 ribonucleotide comprises the ribose methylated at the 2’-O position) ([0586]). Tirtha teaches that utilizing a guanylate cap can allow for the targeted degradation of the mRNA molecule ([0586]). Tirtha teaches that the mRNA molecule may be made via an in vitro transcription enzymatic synthesis method ([0052]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the 5’ cap structure and flanking 5’ UT of Hoge for the 5’ guanylate cap of Tirtha. Because Tirtha similarly teaches the use of a 5’ cap structure to express an mRNA of interest within a cell, then one would have had a reasonable expectation of success in using the 5’ cap structure of Tirtha within the mRNA construct of Hoge and Huang. Further, because Tirtha teaches that the specific cap structure is advantageous to utilize due to the ability to control the expression level of the mRNA via targeted degradation, then one would have been motivated to have done so.
Claim(s) 102 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hoge (PG Pub No. WO 2017/062513 A1) in view of Huang (Pg Pub No. US 2021/0206818; filed 20 January 2017), Huang sequence alignment 72 (SEQ ID NO: 72; accessed 15 June 2026), Huang sequence alignment 73 (SEQ ID NO: 73; accessed 15 June 2026), Niessen ("Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening." Molecular Therapy 27.4 (2019): 824-836) as applied to claims 85, 87-88, 92-93, 95-101, and 103-106 above, and further in view of Baeuerle (PG Pub No. WO 2021/050948 A1, filed 11 September 2020).
Regarding claim 102, Hoge in view of Huang and Von Niessen renders obvious claims 85, 87-88, 92-93, 95-101, and 103-106 as described above.
Hoge in view of Huang and Von Niessen does not teach or suggest that the fused polypeptide is a chimeric fusion protein comprising an extracellular domain comprising an anti-HER2 binding domain (Claim 102).
Baeuerle is drawn towards an invention concerned with recombinant nucleic acids encoding T cell receptor fusion proteins (Abstract). Baeuerle teaches the use of a recombinant nucleic acid molecule encoding (i.e., the recombinant nucleic acid molecule is an mRNA) a T cell receptor (TCR) fusion protein (TFP) comprising a TCR subunit comprising at least a portion of a TCR extracellular domain, and a transmembrane domain, and an antibody comprising an antigen binding domain; and a sequence encoding a TCR constant domain(s) ([0008]). Baeuerle teaches that the antigen binding domain may be an anti-HER2 binding domain ([0016]). Baeuerle teaches that the fusion proteins can be utilized to in T cell therapies to act against human malignancies ([0003]-[0005]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the mRNA sequence of Hoge for the mRNA sequence encoding a chimeric fusion protein comprising an extracellular domain comprising an anti-HER2 binding domain, as described by Baeuerle. Because Baeuerle similarly teaches the expression of a recombinant nucleic acid, then one would have had a reasonable expectation of success in using the nucleic acid encoding the chimeric fusion protein within the mRNA construct of Hoge and Huang. Further, because Baeuerle teaches that the specific fusion protein can be utilized to target and treat human malignancies, then one would have been motivated to have done so.
Allowable Subject Matter
Claims 90-91 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claim 90, the closest prior art is Asrani ("Optimization of mRNA untranslated regions for improved expression of therapeutic mRNA." RNA biology 15.6 (2018): 756-762). Asrani is drawn towards a study concerned with optimization of mRNA UTRs for the improved expression of mRNA (Abstract). Asrani teaches that the effect that a specific 5’ or 3’ UTR has on the expression levels of an mRNA is highly sequence specific and that it is unpredictable what effect a specific UTR will have on protein expression 72 hours post transfection (pg. 758; see Figures 1 and 2). Asrani teaches that some UTRs results in a lower expression level when compared to other UTRs 72 hours post transfection (pg. 758; see Figures 1 and 2).
Accordingly, the prior art does not teach or suggest that it would be predictable for an mRNA constructs comprising the claimed 3’ or 5’ UTRS to inherently have a higher expression level than an mRNA construct not comprising the claimed 3’ or 5’ UTRs because the effect that a given UTR may have on a protein’s expression level is highly sequence specific.
Applicant has provided evidence that the addition of the claimed 3’ and 5’ UTRs to the claimed construct resulted in a higher expression level compared to both standard UTRs and mock constructs at 72 hours post transfection ([0024], [0052]-[0053]; see FIG. 3 and 15). Accordingly, Applicant has provided adequate support under 35 USC 112(a) in the instant specification for the claimed composition comprising the claimed unexpected function/result.
Regarding claim 91, the closest prior art is Grier ("pEVL: a linear plasmid for generating mRNA IVT templates with extended encoded poly (A) sequences." Molecular Therapy Nucleic Acids 5 (2016)). Grier is drawn towards a study concerned with a liner plasmid that can be utilized to generate extended encoded polyA sequences (Abstract). Grier teaches that, compared to encoded polyA tails, enzymatically polyadenylated mRNAs are less stable because they have polyA tails varying in length from ≃60 to 500 bases, depending on the amount of EPAP used, the amount of time given for the polyadenylation reaction, and the construct size and composition (pg. 3). Grier teaches that enzymatically added polyA sequences displayed lower expression levels than encoded poly A sequences across time (pg. 5; see Figure 4).
Accordingly, the prior art does not teach or suggest that mRNA constructs comprising enzymatically added polyA tails resulted in an expression level higher than mRNA constructs comprising non-enzymatically added polyA tails.
Applicant has provided evidence that the addition of enzymatically added polyA tails to the claimed construct resulted in a higher expression level compared to both encoded polyA tails and mock constructs ([0026]; see FIG. 5). Accordingly, Applicant has provided adequate support under 35 USC 112(a) in the instant specification for the claimed composition comprising the claimed unexpected function/result.
Response to Arguments
Applicant's arguments filed 16 March 2026 have been fully considered but they are not persuasive.
Applicant alleges that none of the prior art cited in the previously pending rejections teach or suggest the use of a 3’ UTR sequence comprising the claimed SEQ ID NO: 52 (Remarks; pg. 5-6).
This argument is not found persuasive because the newly recited rejections necessitated by amendment teach and render obvious the use of a 3’ UTR sequence that comprises 100% identity to the claimed SEQ ID NO: 52.
Applicant alleges that a person of ordinary skill in the art would not expect that utilizing the claimed SEQ ID NO: 52 results in the prolonged and increased expression of the fused polypeptide in cells (Remarks; g. 6).
This argument is not found persuasive because, as discussed above in the currently outstanding 35 USC rejection of claim 85, Von Niessen provides evidence that the addition of a non-native 3’ UTR to an mRNA molecule can have a stabilizing effect on the mRNA’s half-life such that it is increased compared to an mRNA not comprising the 3’ UTR. Accordingly, one of ordinary skill in the art would have reasonably expected that the addition of the claimed 3’ and 5’ UTRs to the mRNA of Hoge would have similarly produced a stable mRNA and consequently prolonged detection of the polypeptide.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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