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 .
Response to Amendment & Election/Restrictions
Receipt of the claim amendment(s) and remarks filed on 07/21/2026 is acknowledged.
Applicant’s election without traverse of Group I, claims 54-69, 71, and 73-79 drawn to a method, a prokaryotic system, a prokaryotic cell, and formulations thereof for producing a circular RNA, and the species of i: Hammerhead ribozyme as the single self-cleaving ribozyme species for the 5' end and a hepatitis delta virus (HDV) ribozyme as the single self-cleaving ribozyme species for the 3' end, ii: an RtcB ligase as the single tRNA ligase species, and iii: an at least partially double-stranded RNA as the single non-coding RNA cargo sequence in the reply filed on 07/21/2026 is acknowledged.
Applicant has canceled claims 70 and 72 of group II drawn to a method of providing a circular RNA to a subject and a method of treating a disorder in a subject in need thereof. Applicant reserves their right to pursue the Group II claims in a divisional application.
Status of claims
Claims 1-53, 70, and 72 are canceled.
Claims 54-69,71 and 73-79 are pending and under examination.
Priority
This application is a 371 of PCT/US2022/021865, filed 03/25/2022 which claims benefit of 63/189,610, filed 05/17/2021 and claims benefit of 63/166,467, filed 03/26/2021.
Provisional App. No. ‘467 provides support for the all limitations of the instant claims; therefore, the instant claims receive the priority date of 03/26/2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 05/08/2024, 12/02/2025, and 02/20/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See paragraphs 0132-0150 and 0260 reciting http://.
Claim Interpretation
Regarding claims 71 and 79, the preamble recites “a formulation”, while the body of the claim recites “comprising the prokaryotic cell of claim 67” or “comprising the prokaryotic system of claim 73”, respectively, followed by optional “wherein statements”. Therefore, as the body of the claim sets forth all of the required structure, art the teaches the eukaryotic cell of claim 67 or the eukaryotic system of claim 73 also teaches the limitations of claims 71 and 79.
Claim 77 is being considered a product by process claim, as the preamble is to the prokaryotic system of claim 73 (a product), followed by wherein the linear polynucleotide is provided to the prokaryotic cell by: (a); (b); or (c). See MPEP 2173.05(p). See also MPEP 2113: “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). The MPEP also indicates that “the structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979). “In determining validity of a product-by-process claim, the focus is on the product and not the process of making it.” Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1369 (Fed.Cir.2009). The process of making is only relevant “if the process by which a product is made imparts ‘structural and functional differences’ distinguishing the claimed product from the prior art” Greenliant Systems, Inc. v. XicorLLC, 692 F.3d 1261, 1268 (Fed. Cir. 2012).
Claims 54-55, 57, 60-61, 63, 65, 70-71, 74, and 77-79 recite limitations followed by the term, “optionally,” and are therefore considered as not required for the respective claim when regarding prior art.
Claims 54, 56-58, 61-62, 67-68, 73-75 recite limitations separated by the term “and/or.” In such instances, the limitations are being considered in the alternative, and thus only one of the limitations in the list is considered required by the claim when regarding prior art.
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 54-63, 66-69, and 73-77 are rejected under 35 U.S.C. 103 as being unpatentable over Jaffrey et. al., (WO2018237372A1) in view of Carmona (“Circular RNA: Design Criteria for Optimal Therapeutic Utility”, Harvard University, Jan 2019, 130 pages) both cited on an IDS.
Regarding claims 54, 67, and 73, Jaffrey teaches a method of producing a circular RNA molecule comprising providing one or more vectors comprising a nucleic acid sequence encoding a 5’ polymerase promoter, a first ribozyme, an effector sequence, a second ribozyme, and a 3’ polymerase terminator; transcribing the one or more vectors to produce a linear RNA molecule; and contacting the linear RNA molecule with an RNA ligase to circularize it, thereby producing a circular RNA molecule (¶[0012]; claim 30). Jaffrey teaches said transcribing may be carried out by introducing the vector into a cell (claim 31), and that the RNA ligase may be contained in the cell, optionally wherein the cell is engineered to express or overexpress the RNA ligase (¶[0083]; claim 32).
Regarding the requirement that the contacting occur “in a prokaryotic cell,” Jaffrey expressly teaches that the prior art was limited to circular RNA expression in vitro or in bacteria and yeast using group I intron-derived ribozymes, and states that “new systems for generating circular RNAs are needed that can be expressed in virtually any metazoan or bacterial cell” (¶[0009]). Jaffrey states the invention provides “a novel system for generating circular RNAs in virtually any metazoan or bacterial cell,” which “takes advantage of the nearly ubiquitous endogenous RNA ligase, RtcB” (¶[0016]). Jaffrey further teaches that circularization “is dependent on the RNA ligase RtcB, which is expressed in many organisms, including all bacteria, archaea, and multicellular eukaryotes,” that the ribozyme-mediated processing occurs “in all cell types because the ribozyme undergoes cleavage spontaneously, without cellular cofactors,” and that “circularization could be achieved in potentially any cell type” (¶[0166]). Jaffrey also teaches transformation techniques for introducing the vector into bacterial cells and prokaryotic promoters (T7, T3, SP6, T7lac, araBAD, trp, lac, Ptac, pL) suitable for driving transcription of the construct (¶[0070]; ¶[0081]). Therefore, Jaffrey teaches performing the claimed contacting step in a prokaryotic (bacterial) cell.
Regarding formula components (A) and (E), Jaffrey teaches the RNA molecule comprises a first (5’) ribozyme and second (3’) ribozyme, each independently selected from a group including Hammerhead, Hairpin, Hepatitis Delta Virus (“HDV”), Varkud Satellite (“VS”), glmS, Twister, Twister Sister, Hatchet, and Pistol ribozymes (¶[0032]), which is the same group of self-cleaving ribozymes disclosed in the instant specification. Jaffrey teaches that all known ribozymes of this type undergo self-cleavage leaving a 5’-hydroxyl and a 2’,3’-cyclic phosphate end (¶[0129]), i.e., that cleavage of the first ribozyme produces a free 5’-hydroxyl group and cleavage of the second ribozyme produces a free 2’,3’-cyclic phosphate group, resulting in a ligase-compatible linear polyribonucleotide, as claimed.
Regarding formula components (B) and (D), Jaffrey teaches the RNA molecule may further comprise a first ligation sequence positioned upstream of the effector molecule and a second ligation sequence positioned downstream of the effector molecule (claims 35-36), wherein “ligation sequence” refers to a sequence complementary to another sequence that enables Watson-Crick base pairing to form suitable substrates for ligation by an RNA ligase, and that the ligation sequences help draw the 5’ and 3’ ends of the RNA molecule closer together to assist circularization (¶[0042]-[0044]). This reads on the claimed 5’ annealing region comprising a 5’ complementary region and 3’ annealing region comprising a 3’ complementary region, and teaches the limitation of claims 59 and 76, “wherein the 3’ annealing region and the 5’ annealing region promote association of the 3’ and 5’ ends of the linear polyribonucleotide.”
Regarding formula component (C), Jaffrey teaches an “effector” molecule is an RNA sequence selected based on a desired function (¶[0050]), including an RNA aptamer (¶[0051]), and teaches that this effector sequence becomes part of the circular RNA once ligated by RtcB (¶[0018]). This reads on the claimed polyribonucleotide cargo.
Regarding claim 55 and 77, Jaffrey teaches providing an exogenous polyribonucleotide comprising the linear polyribonucleotide is not required, as Jaffrey teaches transcribing the vector after it is introduced into the cell (¶[0081]; claim 31); Jaffrey’s teaching of introducing a vector encoding the linear RNA into the cell by transformation, using bacterial transformation techniques such as calcium chloride transformation, electroporation, and bacteriophage-mediated transfection, and using prokaryotic promoters (¶[0070], ¶[0081]), teaches transcribing in the prokaryotic cell an exogenous recombinant DNA molecule as recited in claim 55(b)/77(b).
Regarding claims 61-63, Jaffrey teaches the effector molecule may encode a peptide sequence, in which case the RNA molecule may further comprise an IRES operably linked to the coding sequence (¶[0060]), satisfying claim 61(a). Jaffrey teaches the effector molecule may be an RNA aptamer (¶[0051]) or, per ¶[0045], a microRNA, siRNA, guide RNA, ribozyme, or other regulatory RNA, satisfying claims 62 and 63. Regarding the elected non-coding cargo species (i.e., at least partially double-stranded RNA) Jaffrey expressly teaches that its RNA aptamer effector molecules “may be single-stranded, partially single-stranded, partially double-stranded, or double-stranded nucleotide sequences” (¶[0051]), directly teaching an “at least partially double-stranded RNA” cargo as claimed.
Regarding claims 64, 65, and 78, Jaffrey’s teaching that the system operates “in virtually any metazoan or bacterial cell” (¶[0016]) and that RtcB “is expressed in many organisms, including all bacteria, archaea” (¶[0166]) teaches a bacterial or archaeal cell. Jaffrey’s further teaches that suitable bacterial cells for use in the methods are well known in the art, ¶[0082].
Regarding part (b) of claims 67 and 73, and claim 60, Jaffrey expressly claims that the RNA ligase is RtcB (claims 9, 19, 29, 34), and teaches that once the RNA is ligated by RtcB it becomes circular (¶[0018]). RtcB is a tRNA ligase, satisfying claim 60.
Regarding claim 66, Jaffrey’s teaching that suitable cells include yeast, insect, fungal, plant, and animal cells including human, non-human primate, and other mammalian cells (¶[0096]) teaches subjects that are human, non-human vertebrate animal (mammalian examples), invertebrate animal (insect), and plant.
Regarding claim 69, Jaffrey teaches that once ligated by RtcB, the RNA becomes circular within the cell (¶[0018], ¶[0166]), i.e., the prokaryotic cell further comprises the circular RNA, as claimed.
Jaffrey does not expressly teach wherein the 5’ complementary region and the 3’ complementary region have a free energy of binding of less than -5 kcal/mol, or the specific length/percent-complementarity limitations of the complementary and non-complementary regions.
Carmona taught design criteria of circular RNA for optimal therapeutic activity. Carmona taught in order for T4 RNA ligase 1 to function well, the 5’ and 3’ end of the RNA molecule must be in close proximity to each other and a certain level of freedom at the 5’ and 3’ terminal nucleotides, and therefore aimed to design a motif that could be appended to either end of RNA that would promote optimal positioning well-suited for single-stranded RNA ligation. This motif would require a stretch of complementary nucleotides with a melting temperature above physiological levels to ensure the two ends are efficiently annealed when inside cells. Secondly, the terminal ends would need to be free of base-pairing to prevent any steric hindrance that could block the ligase from its function. If this motif functions well it would provide advantages over the existing method of RNA ligation as sequence-specific splint optimization and secondary structure considerations would not cause hindrances to workflow (pages 11-12). Carmona taught the design of this sequence named a complement-reverse complement (CRC) motif, contained a 20-nucleotide length of complementary nucleotides at the 5’ and 3’ ends of molecule (called the “complementary regions”) followed by 10 free and random nucleotides at either end of the molecules (called the “non-complementary regions”) (Figure 2A).
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Figure 2: CRC motif enhances single-stranded RNA ligation efficiency. (A) A diagram of the complement-reverse complement (CRC) motif. It is comprised of 2 parts: the complementary region responsible for bringing the two ends of the RNA molecule together and the non-complementary region that provides the single-stranded, free ends necessary for ssRNA T4 Ligase functionality. Above the diagram is a linear representation of an mRNA containing the CRC motif, with the black boxes representing the non-complementary region and the blue boxes representing the complementary regions of the CRC motif.
Carmona taught designing nanoluciferase-encoded RNAs with different CRC motifs, and the CRC motifs contained “complementary regions” that were 10, 20, or 30 NT in length and “non-complementary regions” that were 10, 15, or 20 NT in length. The non-complementary regions were comprised either fully of adenosines (denoted by an “A” in figures) or a random assortment of non-base paired nucleotides (Figure 3A). Head-to-head comparison of ligation efficiencies showed that a 20 nucleotide long “complementary region” provided maximal contributions to ligation efficiency as constructs with 30 NT complementary regions showed no added benefit to ligation efficiency (Figure 3B). With regards to the non-complementary region, the RNAs comprised of a random assortment of free ends showed a reduction in ligation efficiency as the length of these regions increased. This same trend was not observed from the constructs containing adenosine stretches in their non-complementary region.
Figure 3A:
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Carmona taught there was a particular portion of the panel that enhanced translation efficiency, specifically the RNAs containing a 10 NT long complementary region, a non-complementary region containing only adenosines. These same constructs showed very little induction of IFNb in HeLa cells compared to constructs containing longer CRC motifs (Figure 3E). We concluded that a shorter CRC motif comprised of an adenosine non-complementary region was best suited for use in our circRNA constructs as these characteristics enhanced ligation without negatively effecting translation or immunity.
Therefore, regarding the limitation in claims 67 and 73, “wherein the 5’ complementary region and the 3’ complementary region have a free energy of binding of less than -5 kcal/mol”, the instant specification discloses in paragraph 0019 that the 5’ annealing region and the 3’ annealing region each include a complementary region, and the 5’ complementary region is between 2 and 50 ribonucleotide and the 3’ annealing region includes a 3’ complementary region having between 2 and 50 ribonucleotides. Therefore, as Carmona taught CRC motifs contained “complementary regions” that were 10, 20, or 30 NT in length which fall within the range disclosed in the instant specification cited above, the 5’ complementary region and 3’ complementary region of Carmona would have the same property of having a free energy of binding of less than -5 kcal/mol.
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify the ligation-sequence arrangement of Jaffrey by employing Carmona’s complement-reverse complement (CRC) motif (i.e., complementary regions at the respective RNA ends, together with unpaired/non-complementary terminal regions) having the disclosed complementary region and non-complementary region lengths, thereby producing Jaffrey’s ligase-compatible linear RNA with complementary regions capable of stable association, including a binding free energy of less than -5 kcal/mol, and with the claimed complementary/non-complementary region arrangements.
A PHOSITA would have been motivated because applying Carmona’s CRC design to Jaffrey’s ligation sequences would have predictably optimized circularization by increasing productive end proximity while reducing steric or base-pairing interference at the ligation junction, thereby improving ligation efficiency and circular-RNA yield. Jaffrey’s disclosure identified ligation sequences as complementary sequences that form ligase substrates and facilitate circularization, making Carmona’s terminal architecture optimization directly pertinent to Jaffrey’s system and methods.
A PHOSITA would have had a reasonable expectation of success because both references use complementary RNA sequences to promote physical association of the RNA termini before ligation, and Carmona specifically tested CRC motifs having 10-, 20-, and 30-nucleotide non-complementary regions. Those experimentally evaluated ranges overlap the presently claimed ranges, and the claimed free-energy limitation an inherent predictable thermodynamic property of sufficiently complementary RNA regions of the disclosed lengths under conventional ligation conditions. Furthermore, Jaffrey expressly teaches that its ligation sequences may be complementary and serve as substrates for RNA ligase, including RtcB, so substituting a known complementary-end architecture for Jaffrey’s ligation sequences would have involved no change in the basic circularization pathway or intended function of Jaffrey’s RNA molecule and methods.
Claims 64-65, 71, and 78-79 are rejected under 35 U.S.C. 103 as being unpatentable over Jaffrey et. al., (WO2018237372A1) in view of Carmona (“Circular RNA: Design Criteria for Optimal Therapeutic Utility”, Harvard University, Jan 2019, 130 pages) both cited on an IDS as applied to claims 54-63, 66-69, and 73-78 above, and further in view of Thompson B, et al., (WO2014145883A1).
The teachings if Jaffrey and Carmona are incorporated herein by reference to the 103 rejection above.
Jaffrey and Carmona do not teach either that the prokaryotic cell is a bacterial cell or an archaeal cell that is: (a) grown in a culture medium or contained in a bioreactor; or (b) a member of a natural bacterial population; or (c) a member of a microbiome associated with a eukaryotic organism, or that the prokaryotic cell is: (a) a bacterial cell that is associated with the rhizosphere of an angiosperm or gymnosperm plant, or with the microbial community of the soil or growth medium in which the plant grows, or with above-ground tissue of the plant, optionally wherein the association is a symbiosis; or (b) a bacterial cell that is associated with a cell, tissue, or organ of a human, a non-human vertebrate animal, or an invertebrate animal, optionally wherein the association is a symbiosis. Furthermore, Jaffrey and Carmona do not teach a formulation comprising the prokaryotic cell.
Thompson teaches useful bacteria that help plants grow better, see abstract. Thompson isolated many bacterial strains from plant root zones and field soils, then tested them on crops and seedlings. The bacteria are packaged as purified cultures, mixtures, seed coatings, or inoculums that can be applied to plants, seeds, or soil. Some versions also include helpful additives such as carriers, fertilizers, fungicides, or rhizobacteria [0002], [0008]-[0012]. Thompson says these strains can improve plant height, leaf size, root growth, and yield-related traits [0017], [0060]. Thompson also discloses mutant versions of the strains that keep plant-growth-promoting ability but gain added tolerance, such as salt tolerance, thiram resistance, or glyphosate tolerance to enable use in treated or harsh soils, [0025], [0079]-[0081]. Thompson further teaches the bacteria are formulated with agriculturally acceptable carriers and may be combined with rhizobacteria or other agricultural additives to improve delivery and performance, [0016], [0031]-[0034], [0043]-[0050]. The formulations can be liquid, solid, powder, granular, or seed-coating types [0039]-[0042]. Thompson teaches that the methods are intended for many crops, including corn, soybean, lettuce, alfalfa, cucumber, squash, and ryegrass to make agriculture more productive using beneficial microbes instead of relying only on chemical inputs, [0054]-[0059], [0066]-[0083].
It would have been obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date to modify a plant-associated bacterial cell of Thompson to comprise the circular-RNA production system of Jaffrey, as modified by Carmona, and to grow, formulate, and administer the resulting engineered bacterial cell as a bacterial inoculum to a plant, seed, plant growth medium, soil, or rhizosphere. The resulting modified bacterial cell would produce a circular RNA cargo, wherein the cargo may comprise a coding sequence encoding a polypeptide or a regulatory RNA, and would be provided in an agricultural formulation.
A PHOSITA would have been motivated to incorporate Jaffrey’s circular-RNA production system into Thompson’s plant-growth-promoting bacteria because Jaffrey provided a bacterial expression system capable of producing circular RNAs comprising regulatory effector sequences, whereas Thompson identifies plant-associated bacteria as useful agricultural agents that can be cultured, formulated, and delivered to plants, seeds, soils, and the rhizosphere to improve plant growth and yield. The combination would have provided a predictable means to equip Thompson’s deployable beneficial bacteria with an additional selected circular-RNA mediated activity, while preserving the bacteria’s established capacity to plant-associated delivery and agricultural use.
A PHOSITA would have had a reasonable expectation of success because Jaffrey expressly teaches that its self-cleaving-ribozyme/RtcB circularization system can be introduced and transcribed in bacterial cells and can produce circular RNAs containing an effector sequence, including coding and regulatory RNA sequences. Thompson, in turn, teaches that beneficial bacterial cultures can be grown, formulated as inoculum, and delivered to seeds, plants, soil, and plant growth media. Thus, the combination applies Jaffrey’s known bacterial circular-RNA expression system to a known class of agriculturally deployable bacteria using conventional culture, inoculum, and application techniques, with no indication that those techniques would interfere with the bacterial expression of the circular RNA or the bacteria’s delivery to the intended agricultural environment.
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 54-63, 66-69, 71, 73-77, and 79 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54-68, 70-73, and 75-79 copending Application No. 18/283,242 in view of Jaffrey et. al., (WO2018237372A1, in IDS).
The claims of copending Application No. 18/283,242 recite a method, eukaryotic cell, eukaryotic system, and formulation(s) for producing a circular RNA via a linear polyribonucleotide having the formula 5’-(A)-(B)-(C)-(D)-€-3’, wherein (A) and € are 5’ and 3’ self-cleaving ribozymes, (B) and (D) are annealing regions comprising complementary regions with a free energy of binding of less than -5 kcal/mol, (C) is a polyribonucleotide cargo, and an RNA ligase circularizes the ligase-compatible linear polyribonucleotide produced by ribozyme cleavage — substantially the same method, cell, system, and formulation recited in instant claims 54-69, 71, and 73-79. The instant claims differ from the copending claims only in that the instant claims recite that the linear polyribonucleotide is contacted, expressed, and circularized in a prokaryotic cell (instant claims 54, 64, 65, 67, 73, 78), whereas the copending claims recite a eukaryotic cell (copending claims 54, 64, 65, 67, 73, 78).
The copending claims do not claim or teach a prokaryotic, bacterial, or archaeal host cell.
Jaffrey (WO2018237372A1), cited and discussed above, is incorporated herein by reference. As set forth above, Jaffrey teaches that this same ribozyme/RNA-ligase circularization system is expressly designed to function “in virtually any metazoan or bacterial cell” (¶[0016]), and that circularization “could be achieved in potentially any cell type” because RtcB “is expressed in many organisms, including all bacteria, archaea, and multicellular eukaryotes” and ribozyme self-cleavage occurs “without cellular cofactors” (¶[0166]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to perform the method, and make the cell, system, and formulation, of copending claims 54-68, 70-73, and 75-79 in a prokaryotic host cell rather than a eukaryotic host cell, because Jaffrey establishes that the two host-cell types are art-recognized, interchangeable platforms for this identical circularization chemistry, such that substituting one known host cell for the other would have yielded predictable results with a reasonable expectation of success. The instant claims are therefore not patentably distinct from the copending claims.
Claims 64-65 and 78 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54-68, 70-73, and 75-79 of copending Application No. 18/283,242 in view of Jaffrey et al. (WO2018237372A1, in IDS) as applied to claims 54-63, 66-69, 71, 73-77, and 79 above and in further view of Thompson et al. (WO2014145883A1).
The teachings of the copending claims and Jaffrey are incorporated herein by reference to the rejection above. The copending claims do not claim or teach that the eukaryotic cell — or, as modified above, the resulting prokaryotic cell — is a bacterial or archaeal cell that is grown in a culture medium or contained in a bioreactor, a member of a natural bacterial population, or a member of a microbiome associated with a eukaryotic organism (instant claim 64), nor that the bacterial cell is associated with the rhizosphere of a plant, or with the microbial community of the soil or growth medium in which a plant grows, or with above-ground plant tissue, or associated with a cell, tissue, or organ of a human, non-human vertebrate animal, or invertebrate animal (instant claim 65). Copending claims 64-65 instead recite that the cell is a eukaryotic cell not a prokaryotic cell. Jaffrey likewise does not teach these specific bacterial-population or host-association limitations.
Thompson, cited and discussed above, is incorporated herein by reference. As set forth above, Thompson teaches plant-associated bacterial strains isolated from plant root zones and field soils, cultured and formulated as purified cultures, mixtures, seed coatings, or inoculum, optionally combined with rhizobacteria or other agricultural additives, for delivery to plants, seeds, or soil to improve growth and yield (¶[0002], ¶[0008]-[0012], ¶[0016], ¶[0031]-[0050]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to perform the method, and make the cell, of copending claims 54-68, 70-73, and 75-79, as modified to be performed in a prokaryotic cell per the rejection above, using a plant-associated bacterial cell of the type taught by Thompson — i.e., a bacterial cell grown in culture, drawn from a natural rhizosphere population or plant-associated microbiome — for the same reasons of predictability and reasonable expectation of success set forth in the 103 rejection of claims 64-65, 71, and 79 above, which is incorporated herein by reference. The instant claims are therefore not patentably distinct from the copending claims.
Claims 54-63, 66-69, and 73-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-10, 15, 17-19, 21, 23, 24, 28, 30, and 32-35 copending Application No. 18/283,257 in view of Jaffrey et. al., (WO2018237372A1, in IDS).
The claims of copending Application No. ‘257 recite a method, linear polyribonucleotide, DNA molecule, and cell-free system for producing a circular polyribonucleotide via a linear polyribonucleotide comprising, operably linked 5’ to 3’, a 5’ self-cleaving ribozyme, a 5’ annealing region comprising a 5’ complementary region, a polyribonucleotide cargo, a 3’ annealing region comprising a 3’ complementary region, and a 3’ self-cleaving ribozyme, wherein the complementary regions have a free energy of binding of less than -5 kcal/mol and/or a Tm of at least 10°C, and wherein cleavage of the ribozymes produces a ligase-compatible linear polyribonucleotide that is ligated by a ligase to produce the circular polyribonucleotide, which is substantially the same method and structural elements recited in instant claims 54-63, 66-69, and 73-77. Copending claim 15 recites the ligase is a tRNA ligase, optionally an RtcB ligase, corresponding to instant claim 60. Copending claims 6, 8, 21, 23, 33, and 34 recite complementary/non-complementary region length and percent-complementarity limitations falling within, or overlapping, the ranges of instant claims 57 and 58/75 (e.g., copending’s 20-100% complementarity range and instant’s 50-100% range overlap at 50-100%). Copending claims 10 and 24 recite cargo limitations corresponding to instant claims 61-63. Copending claim 17 recites the circular polyribonucleotide product, corresponding to instant claim 69. Copending claims 2, 3, 28, and 32 recite providing the linear polyribonucleotide by transcription of an encoding DNA molecule, corresponding to instant claims 55(b) and 77(b).
The instant claims differ from the copending claims in that the instant claims recite performing the contacting/ligation/circularization steps in a prokaryotic cell (instant claims 54, 67, 73), whereas the copending claims recite performing these same steps in a cell-free system
The copending claims do not recite performing the reaction inside a prokaryotic, or any, cell.
Jaffrey (WO2018237372A1), cited and discussed above, is incorporated herein by reference. As set forth above, Jaffrey teaches that this same ribozyme/RNA-ligase circularization chemistry may be carried out either as an isolated, in vitro/cell-free reaction — “the RNA molecule of the present invention may be isolated or present in in vitro conditions for extracellular expression and/or processing… contacted by an RNA ligase (e.g., RtcB) in vitro, purified, circularized” (¶[0099]) — or inside a cell, including “virtually any metazoan or bacterial cell” (¶[0016]), with circularization achievable “in potentially any cell type” because ribozyme cleavage occurs “without cellular cofactors” (¶[0166]). Jaffrey thus establishes that the cell-free and intracellular (including prokaryotic) modes of performing this identical ribozyme/ligase circularization chemistry are art-recognized, interchangeable alternatives for practicing the same reaction.
It would have been obvious to one of ordinary skill in the art before the effective filing date to perform the method, and make the linear polyribonucleotide/system, of copending claims 1-4, 6, 8-10, 15, 17-19, 21, 23, 24, 28, 30, and 32-35 inside a prokaryotic host cell rather than in a cell-free system, because Jaffrey teaches both modes as predictable, interchangeable means of carrying out the same ribozyme-cleavage/ligase-circularization reaction, such that moving the reaction into a bacterial cell would have yielded predictable results with a reasonable expectation of success. The instant claims are therefore not patentably distinct from the copending claims.
Claims 64-65, 71, and 78- 79 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8-10, 15, 17-19, 21, 23, 24, 28, 30, and 32-35 of copending Application No. 18/283,257 in view of Jaffrey et al. (WO2018237372A1, in IDS) as applied to claims 54-63, 66-69, and 73-77 above and in further view of Thompson et al. (WO2014145883A1),
The teachings of the copending claims and Jaffrey are incorporated herein by reference to the rejection above.
The copending claims do not claim or teach that the prokaryotic cell is a bacterial or archaeal cell that is grown in a culture medium or bioreactor, a member of a natural bacterial population, a member of a microbiome, associated with a plant rhizosphere, or associated with a human/animal cell, tissue, or organ (instant claims 64, 65, 78), nor a formulation comprising the prokaryotic cell/system (instant claims 71, 79). Jaffrey likewise does not teach these specific cell-population, host-association, or formulation limitations.
Thompson, cited and discussed above, is incorporated herein by reference. As set forth above, Thompson teaches plant-associated bacterial strains isolated from plant root zones and field soils (i.e., a natural bacterial population/rhizosphere-associated microbiome member), cultured and formulated as purified cultures, mixtures, seed coatings, or inoculum with agriculturally acceptable carriers for delivery to plants, seeds, or soil (¶[0002], ¶[0008]-[0012], ¶[0016], ¶[0031]-[0050]).
It would have been obvious to one of ordinary skill in the art before the effective filing date to perform the cell-free method/system of the copending claims, as modified to be performed in a prokaryotic cell per the rejection above, using a plant-associated bacterial cell of the type taught by Thompson (i.e., a bacterial cell grown in culture, drawn from a natural rhizosphere population, and formulated with an agriculturally acceptable carrier as an inoculum) for the same reasons of predictability and reasonable expectation of success set forth in the 103 rejection of claims 64-65, 71, and 78-79 above, which is incorporated herein by reference. The instant claims are therefore not patentably distinct from the copending claims.
Conclusion
No claims are allowed.
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/COREY LANE BRETZ/Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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