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 06/09/2026 is acknowledged. No claims were amended. Claims 1,2,5,7-11 and 13-15 are pending and under examination.
Withdrawn Objections
Applicant’s arguments, see page 2, filed 06/09/2026, with respect to the objection regarding the PPH Certification Statement have been fully considered and are persuasive as Applicant has stated that the statement regarding correspondence between the claims in the EP application and this application was provided in the Preliminary Amendment filed 05/9/2025 on page 6. The Examiner has reviewed page 6 of the preliminary amendment filed on 05/9/2025 which does state that the attached claim amendments are based off of the allowable claims in the co-pending European application, being submitted for consideration under the PPH. The objection has been withdrawn.
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 06/09/2026 is insufficient to overcome the 35 U.S.C. 103 rejections of claims 1,7-11 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 Kruger et al. as set forth in the last Office action because:
The Declaration does not show that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716. The Declaration does not show the difference in results is in fact unexpected and unobvious and of both statistical and practical significance, and the prima facie case is strong such that the results are insufficient to overcome the case for obviousness.
The Declaration states that WO 2015177100 (Daros) was able to produce short recombinant dsRNA of 40 nt (12 bp), 60 nt (22 bp), 80 nt (32 bp) and 100 nt (42 bp) on pages 2-3 of Declaration. However, when attempting to produce larger dsRNAs (equal to or longer than 100 bp), the technology failed, which encouraged them to develop a new system able to produce large recombinant dsRNA, and this novel technology added completely new elements, specifically self-splicing introns in two different fashions direct and permuted, and was able to produce large recombinant dsRNA as shown in Fig 2. Point 7 in the Declaration on page 4 states that in an experiment to produce dsRNAs of 100 nt, 42 bp (RNA 1), 100 nt, 42 bp (RNA 2), 434 nt, 133 bp (RNA 3) and 482 nt, 157 bp (RNA4) using the technology of ‘100, they failed to observe any substantial amount of these dsRNAs (see Fig. 3), and therefore as seen in Figure 3, the system disclosed in ‘100 is not useful for producing high amounts of large circular dsRNA (100 bp or longer).
This is not found persuasive, because the arguments consistently repeat that Daros does not show production of large or high amounts of circular dsRNA of 100 bp. However, the 103 rejection is not based solely on Daros, but the combination with Guo et al. and Lee et al. which teach all of the recited components. The 103 rejection stated that ‘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 (H1 and H2), 434 nt (H3) and 482 nt (H4) (Example 2.8 page 39). These are the same sizes that Applicant points to in the Declaration at point 7. ‘100 teaches molecules and plasmids containing cDNAs coding for H3 and H4, which are the 434 nt and 482 nt hairpins which correspond to the 133 and 157 bp dsRNA that would be produced as stated in the Declaration. Therefore, the length of the cDNAs of the two strands of dsRNA, wherein the dsRNA is about 100 bp, that is recited in claim 1 is taught by ‘100. The Examiner is basing the rejection on the combination of ‘100, Guo et al. and Lee et al. which would result in the production of dsRNA of about 100 bp.
In addition, regarding claims 1 and 7-11, these claims are directed to a product. “The patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02. There is nothing recited in claims 1 and 7-11 that requires production of circular dsRNA of about 100bp, much less high amounts of circular dsRNA of about 100bp as argued by Applicant, as the claims are a product with a specific structure. What is required is that component a) comprising 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, wherein the dsRNA is about 100 bp. As long as the cDNAs of two strands of a dsRNA, wherein the dsRNA is about 100 bp is taught by the art, and the remaining structural elements are taught, the claim limitations are met. The art does not have to teach that this product results in producing high amounts of circular dsRNA of about 100 bp or more. In addition, 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). Therefore, for the product claims, the Examiner maintains a sufficient case of obviousness was presented.
Regarding the method claims 13-15, these claims also do not recite producing high amounts of circular dsRNA as Applicant argues. There is no requirement recited in the method steps that large quantities of a dsRNA of about 100 bp is produced. The claims merely require some amount of a dsRNA to be produced and do not require a particular amount of dsRNA to be produced, and does not recite that the dsRNA is circular.
The Declaration only focuses on how ‘100 alone cannot produce longer dsRNA of about 100 bp, and does not show that modifying the isolated nucleic acid encoding a chimeric RNA molecule comprising the cDNAs a target RNA (dsRNA) which are hairpin RNAs of 434 nt or 482 nts inserted in the ELVd between positions U245-U246 of ‘100 and inserting the type I self-splicing (autocatalytic) intron flanked by exons of Guo et al. between the cDNAs of two strands of target dsRNA and the teachings of Lee et al. would not arrive at the instant claims with a reasonable expectation of success.
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 argues on page 3 of response, filed 06/09/2026 that the Office asserts that the Declaration filed on 11/12/2025 is insufficient to overcome the 103 rejection over Daros in view of Guo and Lee because the Declaration shows production dsRNA of 83 bp rather than about 100 bp so the results are allegedly not commensurate in scope with the claims. Applicant submits this objection misinterprets the purpose of the Declaration, which is submitted primarily to rebut the Office’s factual assertion that Daros teaches successful production of about 100 bp or more. Applicant argues the Declaration filed 11/12/2025 demonstrated that using the system of Daros with the tested constructs did not produce high amounts of long fragments of dsRNA, as shown in Fig. 1 of the Declaration, which means the system of Daros did not demonstrate production of high amounts of long recombinant dsRNA of about 100 bp or more in E. coli. This evidence is directly responsive to the Office’s reliance on Example 2. 8 of Daros. The Declaration also shows the system of the instant application is capable of producing fragments as long as 83 bp (See Fig 2 and 3 of Declaration), but the capability of the claimed system to produce dsRNA of about 100 bp is evidenced by the examples disclosed in the patent application itself, for example, a circular dsRNA corresponding to a 100-bp fragment of C. capitata beta-actin mRNA shown in Fig. 6 of the instant application which provides using the system disclosed in the instant patent application, it is possible to produce high amounts of long dsRNA of 100 bp in E coli.
This is not found persuasive because both Declarations are focusing on proving that the system of Daros does not produce high amounts of long fragments of dsRNA. However, the obviousness rejection is not based on Daros alone, but Daros in combination with Guo et al. and Lee et al., and does not explain how the combination of references would not result in a reasonable expectation of success of arriving at the instant claimed product, or that the recited method can be carried out. Daros still teaches molecules of hairpin RNAs of 434 nt (H3) and 482 nt (H4) in which cDNAs coding for H3 and H4 are inserted between positions U245 and U246 of ELVd-AJ536613 and therefore teaches sequence with the required length requirement. No explanation has been provided how modifying this construct with the type I autocatalytic intron flanked by exons as taught by Guo et al. and Lee et al. would not result in the production of dsRNA of the recited length.
Regarding Applicants’ arguments pertaining to instant Fig. 6, this shows that the instant invention works as intended. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
Applicant argues on pages 4-5 of response, that Example 2.8 of Daros discloses construction of four plasmids which were transformed in E. coli, and electrophoretic mobility of the plasmids is shown in Figure 22 which does not show the production of large amounts of circular dsRNA of 100 bp. Contrary to the Office’s statement (Daros teaches that dsRNAs of 100 bp or more can be produced), Example 2.8 of Daros does not provide experimental results showing the effective production of high amounts of circular dsRNA of about 100 bp or more following transforming the plasmids in E. coli. Applicant argues as shown in the Declaration 2, when tested, the plasmids corresponding to those in Example 2.8 of Daros did not produce high amounts of the dsRNA of about 100 bp. A new Declaration 2 disclosing the original assays retrieved from the laboratory notebook is submitted, showing that production of large amounts of the dsRNA of 100 bp did not happen and the system of Daros failed to produce the circular dsRNAs of 100 bp.
This is not found persuasive, because the arguments consistently repeat that Daros does not show production of large or high amounts of circular dsRNA of 100 bp. The rejection is not based solely on Daros, but the combination with Guo et al. and Lee et al. As stated above, Daros teaches molecules of hairpin RNAs of 434 nt (H3) and 482 nt (H4) in which cDNAs coding for H3 and H4 are inserted between positions U245 and U246 of ELVd-AJ536613 and therefore teaches sequences with the required length requirement. In addition, regarding claims 1 and 7-11, these claims are directed to a product. “The patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02. There is nothing recited in claims 1 and 7-11 that requires production of high amounts of circular dsRNA of about 100bp as argued by Applicant, as the claims are a product with a specific structure. Therefore, the art does not have to teach that this product results in producing high amounts of circular dsRNA of about 100 bp or more. In addition, 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). Therefore, for the product claims, the Examiner maintains a sufficient case of obviousness was presented.
Regarding the method claims 13-15, these claims also do not recite producing high amounts of circular dsRNA as Applicant argues. The claims also merely require some amount of a dsRNA to be produced and do not require a particular amount to be produced, and does not recite that the dsRNA is circular.
In response to the Office stating that the specification does not provide a definition for “about 100 bp”, Applicant submits that absent an express definition, the term should be given its ordinary and customary meaning in view of the specification and understanding of a person of ordinary skill in the art, and that a person of ordinary skill in this field would understand the scope of “about 100 bp” in the context of the examples in the specification to include dsRNAs that are a little longer and a litter shorter than 100 bp.
This is not found persuasive. If the dsRNA produced in the Declaration were 95 bp in length, then that would seem reasonable to fall within the scope of about 100 bp, however dsRNA of 83 bp seems a bit far from the scope of about 100 bp.
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 (H1 and H2), 434 nt (H3) and 482 nt (H4) (Example 2.8 page 39). Therefore, ‘100 teaches the cDNAs of two strands of a dsRNA (hairpin RNAs) and wherein the dsRNA is about 100 bp (434 or 482 nt for H3 or H4 respectively) are inserted into the ELVd sequence at a location equivalent to that located between positions U245 and U246 of SEQ ID NO: 7.
‘100 does not teach the cDNAs of two strands of a dsRNA specific for a target gene are separated by a type I autocatalytic intron flanked by exons or exon fragments.
However, before the effective filing date, Guo et al. taught 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).
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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 inactivate 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 Drosophila white gene by intron-spliced hairpin RNA (Figure 2, page 325).
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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).
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).
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 coding for hairpin RNAs of 434nt (H3) or 482 nt (H4) which are the dsRNA of about 100 bp, inserted in the ELVd sequence between positions U245-U246 of ‘100 and insert the type I self-splicing (autocatalytic) intron flanked by exons of Guo et al. between the cDNAs coding for the hairpin RNAs based on the teachings of Lee et al. 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 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 and introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli.
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 and the teachings of Lee et al. 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 recombinant RNA in host cells through co-expression of a tRNA ligase and a chimeric RNA molecule that comprises a target RNA, and teaches hybrid molecules within a plant viroid scaffold (page 11, lines 15-21 and page 23, lines 18-20), and specifically teaches hybrid molecules of cDNAs coding for H3 (434 nt) and H4 (482 nt) inserted between positions U245 and U246 of ELVd-AJ536613, 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 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 and introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli.
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 06/09/2026 have been fully considered but they are not persuasive.
Applicant argues on page 7 that the sizes of the hairpin RNAs disclosed in Daros are 100 nt, 434 nt and 482 nt but Daros does not show that circular dsRNA are produced in high amounts using these plasmids. Applicant argues as shown in Declaration 2 filed with this response, the system of Daros does not work to produce high amounts of circular dsRNA of 100 bp. Therefore, Daros does not teach successful production of high amounts of circular dsRNA of about 100 bp or more, and Daros does not teach the cDNA of two strands of a dsRNA specific for a target gene separated by an autocatalytic intron flanked by exons or exon fragments, wherein the dsRNA is about 100 bp. Applicant argues that Guo teaches a construct wherein a 5’ exon and a 3’ exon flank a type I self-slicing intron and how the splicing rate of these autocatalytic introns is increased by introducing mutations in the P1 helix extension (page 651 and Fig 3B), and Guo does not teach or suggest the use of 5’ exon and 3’ exon flanking a type I self-splicing intron to produce high amounts of circular dsRNA of 100 bp or more from an ELVd scaffold, and Guo does not provide any hint to lead the skilled person in the art to think that inserting the cDNAs of two strands of a dsRNA of about 100 bp specific for a target gene separated by an autocatalytic intron flanked by exons between positions U245 and U246 of SEQ ID NO: 7 (structure disclosed in Daros) results in the production of high amounts of circular dsRNA of 100 bp. Applicant states that Lee teaches that nonpalindromic intron sequence may also provide stability to the DNA construct with inverted repeats in bacteria, but does not suggest the use of 5’ exon and 3’ exon flanking a type I self-splicing intron for producing high amounts of circular dsRNA of 100 bp. Guo and Lee provide no teaching or suggestion that inserting element (a) of claim 1 between position U245 and U246 of SEQ ID NO: 7 would achieve the production of high amounts of circular dsRNA of about 100 bp or more.
Applicant argues that as Declaration 2 demonstrates that the system disclosed in Daros on which the Office relies, did not yield substantial production of circular dsRNA of about 100 bp, and neither Guo nor Lee teach the capacity for element (a) for producing high amounts of circular dsRNA of 100 bp when inserted between positions U245 and U246 of SEQ ID NO: 7, the subject matter of claim 1 would not be obvious over Daros in combination with Guo and Lee.
This is not found persuasive. The rejection is not based solely on Daros, but the combination with Guo et al. and Lee et al. As stated above, Daros teaches molecules of hairpin RNAs of 434 nt (H3) and 482 nt (H4) in which cDNAs coding for H3 and H4 are inserted between positions U245 and U246 of ELVd-AJ536613 and therefore teaches sequences with the required length requirement. In addition, regarding claims 1 and 7-11, these claims are directed to a product. “The patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Note: MPEP 2111.02. There is nothing recited in claims 1 and 7-11 that requires production of high amounts of circular dsRNA of about 100bp as argued by Applicant, as the claims are a product with a specific structure. Therefore, the art does not have to teach that this product results in producing high amounts of circular dsRNA of about 100 bp or more. In addition, 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).
Regarding the method claims 13-15, these claims also do not recite producing high amounts of circular dsRNA as Applicant argues. The claims also merely require some amount of a dsRNA to be produced and do not require a particular amount to be produced, and does not recite that the dsRNA is circular. 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 9 that the combination of Guo and Lee does not yield predictable results because neither references suggests that element (a) when inserted between positions U245 and U246 of SEQ ID NO: 7 would enable production of substantial amounts of circular dsRNA of about 100 bp or more and therefore there is no reasonable expectation of success.
This is not found persuasive. Claims 1 and 7-11 are product claims, and as explained above, do not require that substantial amounts of circular dsRNA of about 100 bp or more be produced. Additionally, 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).
However, as explained in the 103 rejection, Guo et al. teach a construct wherein a 5’ exon and a 3’ exon flank a type I self-splicing intron and that 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 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) and taught introduction of intron spacer sequences between the repeats helps stabilize some recombinant plasmids when the plasmid is replicated in E. coli. The instant specification even discloses that to solve the problem of the instability of inverted DNA repeats in E. coli, the repeats were separated with a cDNA corresponding to the group I intron of the 26S ribosomal RNA of Tetrahymena thermophila, and the intron is self-cleaved with extraordinary efficiency and a hairpin of dsRNA is formed (page 3). Therefore, the cited references provide sufficient motivation to arrive at the recited arrangement in the instant claims, and the cited references also teach self-slicing introns and that intron-spliced hairpin RNA has better stability in bacteria which are the same purposes disclosed in the instant specification.
Applicant also argues regarding the statement on page 10 of the office action, that contrary to the teachings by Guo, type I self-splicing intron used in claim 1 of instant application is not mutated, and Lee associates the production of dsRNA with the addition of intron spacers between the repeats for stabilizing recombinant plasmids in E. coli but nothing indicates this strategy is useful for producing high amounts of long circular dsRNA such as those with a size of 100 bp, and that this information is only gleaned from the specification of the instant application.
This is not found persuasive, because instant claim 1 encompasses any type I autocatalytic intron, and does not recite or require that it is not mutated. 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. 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 06/09/2026 have been fully considered but they are not persuasive. Applicant argues on page 10 that since claim 2 depends on claim 1, and as Puttaraju fails to address the shortcomings of Daros, Guo and Lee, claim 2 should be allowed for the same reasons articulated for claim 1.
The examiner has responded to the 103 arguments for Claims 1,7-11 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 06/09/2026 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 1,7-11 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.
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.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
