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/Status of Claims
Receipt of Arguments/Remarks filed on 11/12/2025 is acknowledged. Claims 3,4, 6 and 12 were/stand cancelled. Claims 1,2 and 7 were amended. Claims 1,2,5,7-11 and 13-15 are pending.
The following rejections have been amended to reflect the claim amendments.
Patent Prosecution Highway
The examiner notes that the certification statement required by the Patent Prosecution Highway Program, certifying that the amended claims sufficiently correspond to the allowable/patentable claims in the OEE application is omitted. Applicant is advised to follow PPH practice. In the interest of compact prosecution, the examiner is putting on the record that the statement was not provided, but will continue to examine the application, and if the statement is not provided with the next office action, then the amendments may not be entered and may be treated as a non-responsive reply.
Oath/Declaration
A Declaration is due full consideration and weight for all that it discloses.
Declarations are reviewed for the following considerations: 1) whether the Declaration presents a nexus such as a side-by-side or single-variable comparison (In re Huang, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996)), 2) whether the Declaration presents a comparison to the closest art, 3) whether the Declaration is commensurate in scope with the scope of the claims (In re Kulling, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)), 4) whether the Declaration shows the difference in results are in fact unexpected and unobvious and of both statistical and practical significance (Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)), and 5) whether the prima facie case is sufficiently strong that allegedly superior results are insufficient to overcome the case for obviousness (Pfizer Inc. v. Apotex, Inc., 82 USPQ2d 1321, 1339 (Fed. Cir. 2007)).
The Declaration under 37 CFR 1.132 filed 11/12/2025 is insufficient to overcome the 35 U.S.C. 103 rejections of claims 1,6-11 and 13-15 as unpatentable over Daros et al. in view of Guo et al. and Lee et al.; claim 2 as unpatentable over Daros in view of Guo and Lee and further in view of Puttaraju; and claim 5 as unpatentable over Daros in view of Guo and Lee and further in view of Kurger et al. as set forth in the last Office action because:
The claims as amended recite the dsRNA is about 100 bp. The Declaration states that WO 2015177100 is useless to produce longer dsRNA of circa 100 bp and longer (Page 2, fourth point). However, Daros teaches the cDNAs coding for the hairpin RNAs (which are double-stranded) were transferred to the vector containing pELVd, and that the sizes of hairpin RNAs are 100 nt, 434 nt and 482 nt (Example 2.8 page 39). Therefore, Daros teaches that dsRNAs of 100 bp or more can be produced. As seen on pages 3,5 and 6 of the Declaration, a dsRNA of 83 bp was produced by the system disclosed in the instant invention, not a dsRNA of about 100 bp. The specification does not provide a definition for “about 100 bp”. Therefore, as the Declaration shows producing dsRNA of 83 rather than about 100 bp, the results produced by the Declaration are not commensurate in scope with the claims.
The Declaration refer(s) only to the system described in the above referenced application and not to the individual claims of the application. Thus, there is no showing that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Response to Arguments
Applicant’s arguments, see page 6, filed 11/12/2025, with respect to the 35 U.S.C. 112(b) rejection of claims 6 and 7 have been fully considered and are persuasive due to the cancelation of claim 6, and the amendments to claim 7 correcting the antecedent basis issues. The 35 U.S.C. 112(b) rejection of claims 6 and 7 has been withdrawn.
Applicant’s arguments, see pages 6-9, filed 11/12/2025, with respect to the 35 U.S.C. 112(a) Written Description rejection of claims 13-15 have been fully considered and are persuasive due to the amendment to claim 1 limiting the plant Avsunviroidae sequence to an Eggplant latent viroid (ELVd) sequence and placement of element (a) into the ELVd sequence at a specific position in the ELVd sequence. In addition, applicants arguments regarding the structure-function correlation of type I autocatalytic introns and exons provided in paragraph 0028, and the structure-function of tRNA ligases provided in paragraphs 0053-0058 and the arguments that the structures thereof are well known for one skilled in the art were persuasive. The 35 U.S.C. 112(a) rejection of claims 13-15 has been withdrawn.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1,7-11 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2015177100 (‘100), Published 26 Nov 2015, cited on an IDS, Guo et al. (PMC PubMed Central, RNA, 2002, Vol. 8, Issue 5, pages 647-658), cited on an IDS, and Lee et al. (Methods, Vol. 30, Issue 4, August 2003, Pages 322-329).
Claim Interpretation: The instant specification discloses that the term “autocatalytic intron” refers to self-splicing introns which do not need the action of a spliceosome to be removed from the nucleotide sequence (page 7, lines 18-20). Therefore, self-splicing introns also meet the claim limitation of being an autocatalytic intron.
Regarding claim 1, ‘100 teaches an isolated nucleic acid encoding a chimeric RNA molecule comprising a target RNA and plant viroid scaffold, and the nucleotide sequence encoding the target RNA may be inserted within the nucleotide sequence encoding the plant viroid scaffold (page 18, lines 16-23). ‘100 teaches the target RNA can be any RNA molecule of interest, including short hairpin RNA (shRNA), interfering RNA and siRNA (page 13, lines 14-16), and therefore teaches the target may be dsRNA. ‘100 teaches the target RNA is inserted into a viroid scaffold at a position corresponding to position 245-245 of ELVd (page 12, lines 24-26) of Genbank Entry number AJ5436613.1, and that the sequence and structure of ELVd is shown in Figure 1. The Description of Figure 1 on page 3 of ‘100 says Figure 1 shows the sequence and predicted structure of Eggplant latent viroid (ELVd), and the position U245-U246 where recombinant RNAs were inserted as indicated by the arrow. Figure 1 of ‘100 is the exact same figure as shown in instant Figure 4. In addition, the instant specification discloses the ELVd sequence is available as GenBank Entry Number AJ536613.1 and is SEQ ID NO: 7, and the sequence and structure of ELVd is shown in Figure 4 (page 10 lines 29-35, page 11). Therefore, ‘100 teaches the same ELVd sequence and position of the insertion as instant claim 1. ‘100 teaches the cDNAs coding for the hairpin RNAs were transferred to the vector containing pELVd, and that the sizes of hairpin RNAs are 100 nt, 434 nt and 482 nt (Example 2.8 page 39).
Regarding claim 7, ‘100 teaches production of hairpin RNAs with potential insecticide activity, specifically crop protecting activity (Example 2.8 page 39).
Regarding claims 8,9 and 15, ‘100 further teaches in addition to the nucleic acid encoding a chimeric RNA molecule comprising a target RNA and a plant viroid scaffold, a nucleic acid encoding a tRNA ligase (page 23, lines 11-16) and that suitable plant tRNA ligases are well-known in the art and include Solanum melangena (eggplant) tRNA ligase (page 16, lines 29-30).
Regarding claim 10, ‘100 teaches the nucleic acids of the invention may be comprised within an expression vector (page 18, lines 25-34).
Regarding claim 11, ‘100 teaches a recombinant host cell that expresses a chimeric RNA molecule and tRNA ligase, and the host cell may comprise a heterologous nucleic acid encoding tRNA ligase and a heterologous nucleic acid encoding the chimeric RNA molecule (page 21, lines 11-19).
Regarding claim 13, ‘100 teaches production of large amounts of recombinant RNA in host cells through co-expression of a tRNA ligase and a chimeric RNA molecule that comprises a target RNA within a plant viroid scaffold (page 11, lines 15-21 and page 23, lines 18-20). ‘100 teaches the vector may further comprise the nucleic acid encoding the tRNA ligase or the nucleic acid encoding the tRNA ligase may be contained in a separate vector (page 19, lines 25-27). ‘100 teaches co-expression of ELVd RNA and eggplant tRNA ligase in E coli (Example 2.1 page 29).
Regarding claim 14, the host cell may be E. coli (page 12, line 8).
‘100 does not teach the cDNAs of two strands of a dsRNA specific for a target gene separated by a type I autocatalytic intron flanked by exons or exon fragments.
However, before the effective filing date, Guo et al. teach that group I introns, to which the Tetrahymena intron family belongs, catalyze their own splicing in two sequential transesterification reactions to produce accurately ligated exons and a spliced intron with an exogenous guanosine linked at its 5’ end (Intro, page 647). Guo et al. teach selecting for better intron variants that splice at high temperature in thermophilic bacteria, and the placement of the Tetrahymena group I intron inserted into a thermally stable kanamycin nucleotidyltransferase gene by in vivo selection (Results, page 648). The study used the group I intron from T. thermophila and was tested in E. coli (Conclusions, page 655). Guo et al. teach the environment in cells is much more complex and hard to control compared to in vitro selection, and if the goal is to obtain a variant ribozyme with improved activity in cells, in vivo selection is a more direct approach (Conclusion, page 655). Guo et al. teach a construct wherein a 5’ exon and a 3’ exon flank a type I self-splicing intron, used in the transcription of pre-mRNA (Fig 2A).
PNG
media_image1.png
134
560
media_image1.png
Greyscale
Guo et al. teach quantification of the pre-mRNA as well as the ligated exons and the spliced intron bands revealed that the two mutant constructs had increased splicing rates (Page 651 and Fig. 3B).
Additionally, Lee et al. teach dsRNA causes sequence-specific posttranscriptional silencing of a corresponding gene in a variety of organisms, and RNAi is used to inactivated genes of interest and is a powerful tool to study gene function (Intro, page 322). Lee et al. teach methods to express dsRNA stably in transgenic Drosophila, and most of these methods employ transgenes having an inverted-repeat (IR) configuration which are able to produce dsRNA as extended hairpin RNA, however a problem with these methods is it is often difficult to make stable recombinant plasmids containing IRs in Escherichia coli (Intro, page 322). Lee et al. teach that intron-spliced hairpin RNA can induced gene silencing in plants more efficiently than standard hairpin-loop RNA, and the nonpalindromic intron sequence may also provide stability to the DNA construct with inverted repeats in bacteria (page 324, right column). Lee et al. also teach a construct wherein inverted repeats corresponding to the third exon of the white gene are separated by the second intron of the same gene and were placed into a transformation vector, and a fragment containing the white second intron and third exon was ligated to a fragment containing the inverted white exon to generate transgenic RNAi against the Drosphila white gene by intron-spliced hairpin RNA (Figure 2, page 325).
PNG
media_image2.png
409
514
media_image2.png
Greyscale
Lee et al. teach the ligation products including inverted repeats were transformed into E. coli (page 325, left column). Lee et al. teach introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli (Conclusion, page 329), and therefore Lee et al. describes an IR-based transgene designed such that the repeats are separated by a functional intron and thus are defined exons (Intro, page 322).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the isolated nucleic acid encoding a chimeric RNA molecule comprising the cDNAs a target RNA (dsRNA) inserted in the ELVd between positions U245-U-246 of ‘100 and insert the type I self-splicing (autocatalytic) intron flanked by exons of Guo et al. between the cDNAs of two strands of target dsRNA with a reasonable expectation of success. This would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so, because Guo et al. teach that group I introns, to which the Tetrahymena intron family belongs, catalyze their own splicing to produce accurately ligated exons and a spliced intron and that mutant constructs had increased splicing rates, and Lee et al. teach dsRNA for RNAi is used to inactivate genes of interest, but most of these methods employ transgenes having an inverted-repeat (IR) configuration which are able to produce dsRNA as extended hairpin RNA, and the problems are that it is difficult to make stable recombinant plasmids containing IRs in Escherichia coli (Intro, page 322). Lee et al. teach that introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli (Conclusion, page 329).
Accordingly, claims 1 and 7-11 taken as a whole would have been prima facie obvious before the effective filing date.
It would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the chimeric RNA molecule used in the method for producing recombinant RNA in host cells through co-expression of a tRNA ligase and a chimeric RNA molecule that comprises a target RNA within the ELVd sequence of ‘100, by inserting the type I self-splicing (autocatalytic) intron flanked by exons of Guo et al. between the cDNAs of two strands of target dsRNA with a reasonable expectation of success. ‘100, Guo et al., and Lee et al. all teach use in E. coli host cells. This would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so, because ‘100 teaches production of large amounts of recombinant RNA in host cells through co-expression of a tRNA ligase and a chimeric RNA molecule that comprises a target RNA within a plant viroid scaffold (page 11, lines 15-21 and page 23, lines 18-20), and because Guo et al. teach that group I introns, to which the Tetrahymena intron family belongs, catalyze their own splicing to produce accurately ligated exons and a spliced intron and that mutant constructs had increased splicing rates, and Lee et al. teach dsRNA for RNAi is used to inactivate genes of interest and that introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli (Conclusion, page 329).
Accordingly, claims 13-15 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive.
Applicant argues on page 10 that Daros teaches an isolated nucleic acid encoding a chimeric RNA molecule comprising a target RNA and a plant viroid scaffold (see page 18, lines 18-20) and the target RNA might be inserted into the viroid scaffold at positions corresponding to position 245-246 (page 12, lines 28-30) of ELVd (GenBank entry AJ536613.1, page 14, lines 20-22). Daros teaches the system can produce chimeric RNA of 27 and 48 nt-long or 76 and 100 nt long microRNA containing three or four tandem repeats (pages 38-39). Applicant argues that Daros is useless to produce longer dsRNA, e.g., a dsRNA of about 100 bp (See Exhibit A). Applicant argues on page 11 that Daros does not disclose that the cDNAs of two strands of the target RNA are separated by a type I autocatalytic intron flanked by exon or exon fragments, and the technical effect associated with this difference is that the production of large quantities of dsRNAs of about 100 bp is possible, and as can be seen by Figure 1 of the patent application, the “inverted terminal repeats” are the DNA which will be transcribed to produce dsRNA. Applicant states in order to provide the above technical effect in comparison with the system of Daros, further experiments were carried out by the inventors as shown in Exhibit A, and that starting from Daros, the technical problem to be solved by the present invention lies in the provision of nucleotide sequence which allows the production of large quantities of dsRNAs of about 100 bp. The solution is the nucleotide sequence defined in claim 1 inserted at a location corresponding to that shown in Figure 4. Applicant argues that based on the data disclosed in the example of the patent application (see Figures 5,6 and 7 and section Conclusions) it is showed that the problem has been effectively solved.
This is not found persuasive. Applicant states above that Daros teaches producing 100 nt long microRNA. In addition, the 103 rejection above as modified based on the amendments, shows that Daros teaches the cDNAs coding for the hairpin RNAs (which are double-stranded) were transferred to the vector containing pELVd, and that the sizes of hairpin RNAs are 100 nt, 434 nt and 482 nt (Example 2.8 page 39). Therefore, Daros teaches that dsRNAs of 100 bp or more can be produced. Therefore, the Declaration of Exhibit A is not found persuasive. The Declaration states that Daros (‘100) is useless to produce longer dsRNA of circa 100 bp and longer. However, the Declaration shows that the dsRNA produced is 83 bp (See pages 3,5 and 6). The amended claims recite that the dsRNA is about 100 bp. The specification does not provide a definition for “about 100 bp”. Therefore, the examiner is not interpreting 83 bp, which is the length of the dsRNA produced using the inventive system provided in the Declaration, that is intended to be distinguished from Daros, to be about 100 bp. Therefore, the results produced by the Declaration are not commensurate in scope with the claims.
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983). Note: MPEP 716.02(d).
Applicant argues on page 12 that this solution is not obvious in view of the closest prior art since Daros does not disclose or point to the solution in claim 1 and does not disclose or suggest to insert into plant viroid sequence the cDNAs of two strands of a dsRNA specific for a target gene separated by an autocatalytic intron flanked by exons in order to produce large quantities of dsRNAs of about 100 bp.
Applicant describes the teachings of Guo on page 12, and states the that construct of Guo is used to study the splicing velocity and splicing efficiency of Tetrahymena intron in different E. coli mutants, and teaches how to use introns flanked by two exons to increase the splicing rate and how splicing rate is enhanced with temperature, but that Guo is silent as to how to produce large quantities of dsRNA of about 100 bp and does not provide any hint that leads a skilled person to separate the strands of the target RNA by a type I autocatalytic intron flanked by exons in order to produce large quantities of dsRNAs of about 100 bp. Applicant describes the teachings of Lee on page 12, and that spacer sequences are introduced between repeats to help stabilize some recombinant plasmids when the plasmid is replicated in E. coli, but does not teach the spacer sequences between repeats allow the production of large quantities of dsRNA of about 100 bp in E coli. Applicant argues on page 13 the ordinary skilled person wishing to produce large quantities of dsRNAs of about 100 bp in E. coli would not have been motivated to combine the teachings of 100’, Guo et al. and Lee et al. because none of these documents provides any hint that inserting the cDNAs of two strands of the target RNA separated by a type I autocatalytic intron flanked by exon or exon fragments into ELVd sequence results in the production of large quantities of dsRNAs of about 100 bp in E. coli.
This is not found persuasive. Regarding Applicants argument that Daros does not disclose or point to the solution in claim 1 and does not disclose or suggest to insert into plant viroid sequence the cDNAs of two strands of a dsRNA specific for a target gene separated by an autocatalytic intron flanked by exons in order to produce large quantities of dsRNAs of about 100 bp, the reason to combine references does not have to be for the same purpose of that of the inventor. It is well settled that "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." KSR Int 'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). As long as some suggestion to combine the elements is provided by the prior art as a whole, the law does not require that they be combined for the reason or advantage contemplated by the inventor. In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304 (CCPA 1976). MPEP 2143.01 and 2144 (IV).
The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991)
Applicant states in the Declaration on pages 2-3 that “We reasoned that bridging the two inverted repeats by intervening sequence (e.g., a sequence of 433 bp) should be enough to stabilize the resulting plasmid in E coli. In addition, we also reasoned that if the intervening sequence encodes a self-splicing type-I intron, such as the Tetrahymena thermophila 26S rRNA intron, plus short flanking exons (10 bp), the intron would be spliced out from the primary transcript in E. coli, and the two flanking exons would form a hairpin loop joining the two strands of the recombinant RNA of interest”. However, Guo et al. teach a construct wherein a 5’ exon and a 3’ exon flank a type I self-splicing intron, used in the transcription of pre-mRNA (Fig 2A) and quantification of the pre-mRNA as well as the ligated exons and the spliced intron bands revealed that the two mutant constructs had increased splicing rates (Page 651 and Fig. 3B) and Lee et al. teach introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli (Conclusion, page 329) and Lee et al. describes an IR-based transgene designed such that the repeats are separated by a functional intron and thus are defined exons (Intro, page 322). Therefore, Guo et al. and Lee et al. provide motivations such as increased splicing rates and improving stability of the plasmid using the same structure recited in the claims. Applicant even stated in the Declaration: “We reasoned that bridging the two inverted repeats by intervening sequence (e.g., a sequence of 433 bp) should be enough to stabilize the resulting plasmid in E coli” which is what Lee et al. taught (Introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli (Conclusion, page 329)) and Lee et al. also taught that intron-spliced hairpin RNA can induce gene silencing in plants more efficiently than standard hairpin-loop RNA, and the nonpalindromic intron sequence may also provide stability to the DNA construct with inverted repeats in bacteria. For these reasons, the examiner maintains there is sufficient motivation to combine the cited references and the 103 rejection is maintained.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over ‘100, Guo et al. and Lee et al. as applied to claims 1,7-11 and 13-15 above, and further in view of Puttaraju et al. (Nucleic Acids Research, Vol. 20, No. 20, September 1992, pages 5357-5364), cited on an IDS.
The teachings of ‘100, Guo et al. and Lee et al. as applicable to claim 1 are described above.
‘100, Guo et al. and Lee et al. do not teach that the isolated nucleotide sequence further comprises type I permuted autocatalytic intron-exon sequences between the ELVd sequence and the cDNAs sequences.
However, before the effective filing date, Puttaraju et al. teach circularly permuted Group I intron precursor RNAs containing end-to end fused exons which interrupt half-intron sequences, and that an autocatalytic RNA can form when the primary order of essential intron sequence elements, splice sites and exons are permuted in this manner (Abstract). Puttaraju et al. teach because the exons were fused and the order of the splice sites reversed, splicing released the fused-exon as a circle, and that circular RNAs have properties that would make them attractive for certain studies of RNA structure and function (Abstract). Puttaraju et al. teach construction and testing of permuted version of the Tetrahymena intron, and that in each case circular exons were generated under splicing conditions in vitro (Discussion, page 5363). Puttaraju et al. teaches the need for a general method for efficient production of large quantities of circular RNA to use to answer specific questions about circular RNA, and that self-splicing Group I PIE sequences may offer a method for generating circular RNAs in vivo (Page 5364).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to further modify the isolated nucleic acid encoding a chimeric RNA molecule comprising the cDNAs a target RNA (dsRNA) inserted in the ELVd between positions U245-U-246 of ‘100, Guo et al. and Lee et al., by inserting type I permuted autocatalytic intron-exon sequences between the ELVd sequence and the cDNAs sequences according to the teachings of Puttaraju et al. with a reasonable expectation of success, as this would have amounted to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to add type I permuted autocatalytic intron-exon sequences between the ELVd sequence and the cDNA sequences because Puttaraju et al. teach the need for a general method for efficient production of large quantities of circular RNA, which have properties that would make them attractive for certain studies of RNA structure and function, and that circularly permuted Group I intron precursor RNAs containing end-to end fused exons which interrupt half-intron sequences can form autocatalytic RNA when the primary order of essential intron sequence elements, splice sites and exons are permuted in this manner, and splicing released the fused-exon as a circle.
Response to Arguments
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive. Applicant argues on page 13 that Puttaraju fails to address the shortcomings of Daros, Guo and Lee as identified relative to claim 1.
The examiner has responded to the 103 arguments for Claims 1,6-11 and 13-15 above. As the 103 rejection is maintained for claims 1,7-11 and 13-15 and no additional arguments are made regarding the rejection of claim 2 other than that Puttaraju fails to address the shortcomings of Daros, Guo and Lee, the 103 rejection of claim 2 is likewise maintained.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over ‘100, Guo et al. and Lee et al. as applied to claims 1,7-11 and 13-15 above, and further in view of Kruger et al. (Cell, Vol, 31, 147-157, Nov 1982).
The teachings of ‘100, Guo et al. and Lee et al. as applicable to claim 1 are described above.
‘100, Guo et al. and Lee et al. do not teach wherein the type I autocatalytic intron is the type I autocatalytic intron of the rRNA 26S from Tetrahymena thermophila.
However, before the effective filing date, Kruger et al. teach that in the macronuclear rRNA genes of Tetrahymena thermophila, a 413 bp intervening sequence (IVS) interrupts the 26S rRNA-coding region (Abstract). Kruger et al. teach plasmids containing the IVS and adjacent 26S rRNA-coding sequences (Results, page 147), and that several cleavage and ligation reactions involved in splicing of the Tetrahymena rRNA precursor do not involve any enzyme, and had the ability to perform three cleavage reactions and at least two of the ligation reactions that are shown to be involved in Tetrahymena pre-rRNA splicing (Discussion, page 152). In addition, the pre-rRNA transcribed from the plasmid undergoes exon ligation (Discussion, page 152).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to modify the isolated nucleic acid of ‘100 and Guo et al. in view of Lee et al. by replacing the type I autocatalytic intron of Guo et al. with the type I autocatalytic intron of the rRNA 26S from Tetrahymena thermophila with a reasonable expectation of success, as this would have amounted to simple substitution of one known element (type 1 autocatalytic intron of Guo et al.) for another (the self-splicing intron of the rRNA 26S from Tetrahymena thermophila) to obtain predictable results. One of ordinary skill in the art would have been motivated to use a type I autocatalytic intron of the rRNA 26S from Tetrahymena thermophila in the isolated nucleic acid, because Kruger et al. teach a 413 bp intervening sequence (IVS) interrupts the 26S rRNA-coding region Tetrahymena thermophila and that several cleavage and ligation reactions involved in splicing of the Tetrahymena rRNA precursor do not involve any enzyme, and had the ability to perform three cleavage reactions and at least two of the ligation reactions that are shown to be involved in Tetrahymena pre-rRNA splicing (Discussion, page 152).
Response to Arguments
Applicant's arguments filed 11/12/2025 have been fully considered but they are not persuasive. Applicant argues on page 14 that Kruger fails to address the shortcomings of Daros, Guo and Lee as identified relative to claim 1.
The examiner has responded to the 103 arguments for Claims 1,6-11 and 13-15 above. As the 103 rejection is maintained for claims 1,7-11 and 13-15 for the reasons above, the 103 rejection of claim 5 is likewise maintained.
Conclusion
Claims 1,2,5,7-11 and 13-15 are rejected.
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 STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram R 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636