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 and Election
The amendments and remarks filed 1/30/26 in response to the office action of 10/31/25 are acknowledge and have been entered.
Claims 1, 2, and 4-36 are pending. Claim 3 has been canceled. Claims 1, 2, and 4-10 have been amended.
Applicant’s election of Group I (claims 1-10) in the reply filed 8/27/25 remains acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 11-36 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Amendments to the claims necessitate a new 35 USC § 103 rejection.
Examination on the merits commences on claims 1, 2, and 4-10.
Applicants are informed that the rejections and/or objections of the previous Office action not stated below have been withdrawn from consideration in view of the Applicant' s arguments and/or amendments. Applicant’s 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 – NEW
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.
Claims 1, 2, and 4-10 are rejected under 35 U.S.C. 103 as being unpatentable over Litke of record (Jaffrey, S., and Litke, J., WO2018237372A1), in view of Hasegawa (Hasegawa, Sumitaka, and Jianghong Rao. "Modulating the splicing activity of Tetrahymena ribozyme via RNA self-assembly." FEBS letters 580.6 (2006): 1592-1596.) and Breaker (Breaker, Ronald R. "Riboswitches and translation control." Cold Spring Harbor perspectives in biology 10.11 (2018): a032797.), claim 10 as evidenced by Zamel of record (Zamel, Ricardo, and Richard A. Collins. "Rearrangement of substrate secondary structure facilitates binding to the Neurospora VS ribozyme." Journal of molecular biology 324.5 (2002): 903-915.)
Amendments to claims 1, 2, and 4-10 which further limit the claimed RNA composition as comprising two separate nucleic acid molecules each comprising different structural elements necessitates this new 35 USC § 103 rejection. Regarding claim 1, Litke teaches an RNA molecule comprising: a first ribozyme; a first ligation sequence; an effector molecule; a second ligation sequence; and a second ribozyme (claim 1). Litke teaches wherein the RNA molecule comprises a non-natural or modified nucleotide (claim 2). Litke teaches the RNA molecule of the invention encodes a therapeutic protein or peptide sequence [0098], i.e. encoding a protein of interest. See Figures 2 and 4A below for construct design and self-cleavage.
Regarding the amendments to claim 1 with a first and second RNA molecule, Litke does not specifically describe the coding region and ribozymes split into separate RNA molecules, however, Litke does describe the method as involving more than one vector component. For example, Litke further teaches the method of producing a circular RNA molecule by providing one or more vectors comprising: a nucleic acid sequence encoding a 5' polymerase promoter sequence; a nucleic acid sequence encoding a first ribozyme; a nucleic acid sequence encoding an effector sequence; a nucleic acid sequence encoding a second ribozyme; and a nucleic acid sequence encoding a 3' polymerase terminator sequence; transcribing the one or more vectors to produce one or more linear RNA molecules; and contacting the linear RNA molecules with an RNA ligase to circularize the linear RNA molecule thereby producing a circular RNA molecule which comprises an effector molecule (claim 20) [0012]. Litke teaches when the effector molecule is an RNA molecule encoding a peptide sequence, the RNA molecule may further comprise an internal ribosomal entry site (IRES) wherein the IRES is operatively coupled to the RNA molecule encoding the peptide sequence [0060].
Regarding split ribozyme strategy, Hasegawa teaches a fractured ribozyme coding strategy for self-assembly where the Tetrahymena ribozyme is split into two inactive fragments and flanked with guide sequences that bound to a target mRNA. Only when both pieces interacted with the target RNA template are they brought together, permitting the ribozyme to assemble, self-splice, and translate a reporter protein (abstract, scheme 1). This strategy suggests the application of logic gates for targeted, translation-dependent gene expression.
Further regarding riboswitches for translational control, Breaker teaches common riboswitch expression platform arrangements with mechanisms including ligand-gated presentation or occlusion of ribosome-binding sites, control of alternative splicing of mRNAs, and the regulation of mRNA stability (abstract). Breaker teaches schematic representation (Figure 1) of a riboswitch that permits translation in the absence of ligand (left), but inhibits translation when bound to ligand (right). In the model depicted, ligand binding sequesters the ribosome-binding site (RBS) and prevents ribosome binding to the messenger RNA (mRNA). Breaker further teaches some riboswitch RNAs liberate the RBS on ligand binding to promote ribosome binding and translation (Figure 1). Breaker further teaches tandem arrangement between a riboswitch aptamer and a self-splicing ribozyme which exploits the typical activities of each RNA device to create a far more sophisticated gene-control apparatus and where the riboswitch aptamer can form two distinct structures that are important for indirectly regulating mRNA translation (pg 6 col 2 para 1).
Although Litke does not specifically describe the coding region and ribozymes split into separate RNA molecules, Litke does disclose the method as involving more than one vector component. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention that Litke would have incorporated the claimed separate coding regions and ribozymes on more than one separate RNA molecule as motivated by the advantages described by Breaker and Hasegawa of split ribozymes and logic gate strategies for enhanced and varied translational control.
Regarding claims 2 and 4, Litke teaches wherein each of the first ribozyme and the second ribozyme comprises a sequence that may be cleaved to produce a 5'-OH end and a 2',3'- cyclic phosphate end (2’3’ cP end) (claim 3). Litke teaches FIG. 2 as an illustration showing an example of the sequences of a transcribed RNA prior to cleavage by 5' and 3' ribozymes. This construct contains sequences of a 5' P3 Twister U7A ribozyme (bases 2-57) and a 3' PI Twister ribozyme (bases 154-208) that flank two ligation sequences (bases 58-78 and 126-153) with an internal effector sequence (bases 79-125). Following cleavage by both ribozymes (at positions marked in black), the ligation sequences contain 5'-OH and 2', 3 '-cyclic phosphate modifications and form a stem that is a substrate for RtcB. Once the RNA has been ligated by RtcB, the RNA becomes circular and contains the effector sequence of RNA [0018].
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Litke teaches FIG. 4A (below) as an illustration showing a construct design for autocatalytically processed circRNA expression. Self-cleaving ribozymes flank the ends of the circularized insert that contains an RNA aptamer sequence. The ligation sequences, which remain on either side after cleavage, contain a phosphorylation state and RNA termini modification state that is recognized by an endogenous RNA ligase and circularized. Circular RNAs resist endogenous exoribonucleases, allowing the RNA aptamer to reach exceptionally high concentrations.
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Regarding claims 5 and 6, Litke teaches the RNA molecule wherein each of the first and the second ribozyme is independently selected from the group consisting of Hammerhead (HH), Hairpin, Hepatitis Delta Virus ("HDV"), Varkud Satellite ("VS"), Vgl, glucosamine-6-phosphate synthase ("glmS"), Twister, Twister Sister, Hatchet, Pistol ribozymes, engineered synthetic ribozymes, or derivatives thereof (claim 4).
Regarding claims 7, Litke teaches the above applied to claim 1. Briefly, Litke teaches a method of producing a circular RNA molecule, said method comprising: providing one or more vectors comprising: a nucleic acid sequence encoding a 5' polymerase promoter sequence; a nucleic acid sequence encoding a first ribozyme; a nucleic acid sequence encoding an effector sequence; a nucleic acid sequence encoding a second ribozyme; and a nucleic acid sequence encoding a 3' polymerase terminator sequence; transcribing the one or more vectors to produce one or more linear RNA molecules; and contacting the linear RNA molecules with an RNA ligase to circularize the linear RNA molecule thereby producing a circular RNA molecule (claim 30).
Regarding claim 8, Litke teaches the above applied to claim 1. Litke teaches the above applied to claim 7, i.e. multiple vectors comprising the nucleic acid construct. Litke further teaches an RNA molecule comprising: a first ribozyme; a first ligation sequence; an effector molecule; a second ligation sequence; and a second ribozyme (claim 1). Litke also teaches the RNA molecule wherein each of the first ligation sequence and the second ligation sequence are substrates for an RNA ligase (claim 7). Examiner is interpreting a ligation sequence in a ribozyme as a recognition sequence because it directs the ribozyme to a specific substrate through base-pairing.
Regarding claim 9, Litke teaches the above applied to claims 1, 7, and 8. Litke further teaches the ligation recognition sequences are cleaved by the ribozymes [0018].
Regarding claim 10, Examiner notes that claim 14 recites, “VS-S” and “VS-RZ”. Given guidance from the Specification (pg 10 and Figure 14A), Examiner is interpreting VS-S as a stem loop portion of the VS ribozyme and the VS-RZ is a VS type Ribozyme without the stem loop portion (pg 28). Litke teaches the RNA molecule wherein each of the first and the second ribozyme is Varkud Satellite ("VS").
Litke teaches the ribozymes of the invention contain structural elements (e.g., a loop or stem), lengthening or shortening of an existing stem or loop, changes in the composition or structure of a loop(s) or a stem(s), or any combination of these. [0040]. Further regarding VS stem loops, Zamel et. al., teaches the VS ribozyme differs from other small, naturally occurring ribozymes in that it recognizes for trans cleavage or ligation a substrate that consists largely of a stem-loop structure (abstract). Zamel teaches that cleavage or ligation by the VS ribozyme requires substantial rearrangement of the secondary structure of stem-loop I, which contains the cleavage/ligation site. This rearrangement includes breaking the top base-pair of stem-loop I, allowing formation of a kissing interaction with loop V, and changing the partners of at least three other base-pairs within stem-loop I to adopt a conformation termed shifted (abstract) i.e. the VS ribozyme inherently contains stem-loop and non-stem loop structures.
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 1,2, and 4-10 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1 and 2 of co-pending Application No. 19158634 (reference application) in view of Litke of record (Jaffrey, S., and Litke, J., WO2018237372A1), in view of Hasegawa (Hasegawa, Sumitaka, and Jianghong Rao. "Modulating the splicing activity of Tetrahymena ribozyme via RNA self-assembly." FEBS letters 580.6 (2006): 1592-1596.) and Breaker (Breaker, Ronald R. "Riboswitches and translation control." Cold Spring Harbor perspectives in biology 10.11 (2018): a032797.) as applied to claim 1, claim 10 as evidenced by Zamel of record (Zamel, Ricardo, and Richard A. Collins. "Rearrangement of substrate secondary structure facilitates binding to the Neurospora VS ribozyme." Journal of molecular biology 324.5 (2002): 903-915.).
Regarding instant claims 1, 2, and 4-10, the teachings of Litke, Hasegawa, Breaker, and Zamel are incorporated here. Although the claims at issue are not identical, they are not patentably distinct from the reference claims because the reference claims teach:
Co-pending claim 1 teaches a method of treating a disease or disorder in a subject caused by a mutation in a protein of interest comprising: administering to said subject a first nucleic acid molecule comprising a coding region encoding a first portion of the protein of interest directly linked at the 3' end to a nucleotide sequence of a ribozyme (3'ribozyme); and administering to said subject a second nucleic acid molecule comprising a coding region encoding a second portion of the protein of interest directly linked on the 5' end to a nucleotide sequence of a ribozyme (5'ribozyme); wherein self-cleavage of the 3'ribozyme generates a 3' phosphate at the 3' end of the first portion of the protein of interest and self-cleavage of the 5'ribozyme generates a 5' hydroxy group at the 5' end of the second portion of the protein of interest, allowing for scarless ligation of the protein of interest. Claim 2 recites, the method of claim 1, wherein at least one of the 3'ribozyme and the 5'ribozyme is selected from the group consisting of SEQ ID NO:131, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, SEQ ID NO:142, SEQ ID NO:143, SEQ ID NO:144, SEQ ID NO:145, SEQ ID NO:166, SEQ ID NO:167, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:170, SEQ ID NO:171, SEQ ID NO:172, SEQ ID NO:173, SEQ ID NO:174, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:192, SEQ ID NO:193, SEQ ID NO:194, SEQ ID NO:195, SEQ ID NO:196, SEQ ID NO:197, SEQ ID NO:198, SEQ ID NO:199, SEQ ID NO:200, SEQ ID NO:202, SEQ ID NO:203, SEQ ID NO:204, SEQ ID NO:205, SEQ ID NO:206, SEQ ID NO:207, SEQ ID NO:217, SEQ ID NO:218 or SEQ ID NO:219.
It would have been obvious to combine the patented claims into a single embodiment of the instant claims, given the teachings of Litke of record (Jaffrey, S., and Litke, J., WO2018237372A1), in view of Hasegawa (Hasegawa, Sumitaka, and Jianghong Rao. "Modulating the splicing activity of Tetrahymena ribozyme via RNA self-assembly." FEBS letters 580.6 (2006): 1592-1596.) and Breaker (Breaker, Ronald R. "Riboswitches and translation control." Cold Spring Harbor perspectives in biology 10.11 (2018): a032797.) as applied to claim 1, claim 10 as evidenced by Zamel of record, given the obviousness rational provided above applied to claims 1, 2, and 4-10.
This is a provisional rejection because the copending claims have not yet been patented.
Response to Arguments
Applicant’s arguments are directed to the withdrawn §§101, 112b, and 102 (Remarks pgs 9-11, included in the amended claimset filed 1/30/26). Therefore, the arguments are moot.
Conclusion
No claims are allowable.
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 extension fee 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 date of this final action.
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/JOHN CHARLES MCKILLOP/Examiner, Art Unit 1637
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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