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 .
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 .
Note that a Final Office Action had been previously mailed on 12/17/2025. Upon further review it was deemed necessary to include additional 112(b) rejections not included in the Final Action mailed 12/17/2025. The 112(b) rejections are not necessitated by amendment. Finality of the office action of 12/17/2025 is withdrawn. Thus, the following is a NON-FINAL ACTION.
Application Status
This action is written in response to applicant’s correspondence received on 9/16/2025. Claims 6-12 and 17-30 are pending. Claims 6-12 and 17-20 have been amended. Claims 1-5 and 13-16 have been cancelled. Claims 11-12, 20, and 23 are withdrawn from consideration as they are directed to a non-elected invention. Claims 6-10, 17-22, and 24-30 are currently under examination.
Communication with Applicant
Examiner Ryan conducted a telephonic conversation with Applicant representative Poornima Sukumar (Reg. No 71,844) on 1/14/2026 to inform the Applicant of the mailing of this NON-FINAL office action. Examiner Ryan informed representative Sukumar that new 112(b) rejections are contained within this non-final office action.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 18 and 29-30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 18, claim 18 recites registered trademark names. Specifically, claim 18 recites the trademark registered names “ATCC No. 47076” and “ATCC No. 27325.” Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe E. coli strains and, accordingly, the identification/description is indefinite.
Regarding claims 29-30, claims 29-30 are recited to depend from claim 16. Claim 16 has been canceled. Thus, claims 29-30 depend from a canceled claim. The metes and bounds of claims 29-30 are therefore unclear owing to this dependency issue, as it is unclear as to what limitations claims 29-30 would be further limiting, or what the limitations of claims 29-30 are meant to be.
Claim Interpretation
Note that claims 29-30 have been rejected under 112(b) for depending from a canceled claim (claim 16). For the purposes of the 103 rejection (below), claims 29-30 are being interpreted to depend from claim 6. This interpretation appears to be consistent with the application, as the limitations of claim 16 appear to be incorporated into independent claim 6.
Claim Rejections - 35 USC § 103 – Updated in Response to Amendment
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.
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 6-10, 17-18, 20-22, 24-25, and 27-30 are rejected under 35 U.S.C. 103 as being unpatentable over Killmer (WO 2017/160600 A1, provided in IDS filed 11/30/2021) in view of Blattner (WO 2015/073720 A1, provided in IDS filed 11/30/2021).
Regarding claim 6, Killmer teaches a modified bacterial cell for producing dsRNA in vivo, the modified bacterial cell comprising a nucleic acid construct comprising a nucleic acid sequence encoding a double-stranded RNA (dsRNA) linked to an expression control sequence and a nucleic acid construct comprising a nucleic acid sequence encoding a capsid protein linked to an expression control sequence (see claims 1-8 Killmer). Furthermore, Killmer teaches the introduction of such genes on exogenous nucleic acid constructs expressed from a promoter where the outcome is overexpression (paragraphs 13-14).
Killmer, while teaching exogenous nucleic acid constructs with promoters to express genes, does not teach that pyrE is expressed from such a construct.
Blattner is a patent document that focuses on modified bacterial cells for the improved production of protein and nucleic acids (Abstract). Killmer and Blattner therefore overlap in subject matter and field of endeavor because both teach modified bacterial cells, the design of which are to improve the production of nucleic acids (see Abstracts of both). Blattner teaches modified bacterial strains designed to enhance orotate phosphoribisyltransferase activity (i.e., the gene encoded by pyrE per the present specification paragraph 6). Specifically, Blattner teaches that that orotate phosphoribosyltransferase activity can be enhanced by a modification that increases the expression of the encoding gene (i.e., increasing expression of pyrE, paragraph 24). Blattner therefore teaches that modification of pyrE to increase its expression is already a known technique to improve the production of nucleic acids (i.e., RNA).
Furthermore, Blattner teaches the overexpression of pyrE in modified cells (paragraph 24). Blattner also teaches the technique of using heterologous nucleic acid encoding proteins (i.e., “exogenous nucleic acid construct encoding a gene”) in the form of a plasmid, where the plasmid is operatively linked to a promoter and/or additional regulatory sequences (paragraph 41). Given that Blattner also teaches overexpression of pyrE for beneficial purposes (paragraph 24) and that pyre should be overexpressed, Blattner teaches both the means and the motivation to overexpress pyrE using an exogenous plasmid with promoter, also taught by Blattner (paragraph 41).
Blattner teaches that their method and products are useful for producing nucleic acids by improving yield (Example 3 and paragraph 62).
It would have been obvious to a person of ordinary skill in the art before the time of the filing date of the claimed invention to modify the bacterial cells taught by Killmer to include an exogenous nucleic acid expression construct with promoter to express pyrE on, for instance, a plasmid with a promoter (an “exogenous” nucleic acid construct with a promoter) as taught by Blattner because such a combination is the simple combination of known prior art elements with a predictable expectation of success. Furthermore, a practitioner would be motivated to incorporate the teachings of Blattner because Blattner teaches the motivational teaching that increasing the expression of pyrE is a known strategy with the beneficial outcome of improving nucleic acid production in modified cells (paragraphs 7-8 and 24, Blattner). Furthermore the results are predictable because both Killmer and Blattner reduce their methods to practice, and each of the recited claim limitations would be used in the same manner taught by Killmer and Blattner. For instance, both Killmer and Blattner teach the introduction of exogenous nucleic acid constructs with promoters, where furthermore Blattner directly states that pyrE should be overexpressed; Blattner therefore teaches both the means and the motivation to overexpress pyrE using an exogenous plasmid with promoter, also taught by Blattner (paragraphs 24 and 41).
Regarding claim 7, Killmer teaches the production of siRNA (paragraph 82).
Regarding clam 8, Killmer teaches the capsid protein is encoded by a levivirdae coat protein gene (claim 2 of Killmer).
Regarding claim 9, Killmer teaches that the capsid protein is encoded by the coat protein gene of bacteriophage MS2 (claim 3 of Killmer).
Regarding claim 10, Killmer teaches the capsid protein is encoded by the coat protein gene of bacteriophage Q-beta (claim 4 of Killmer).
Regarding claim 17, Killmer teaches that the cells express dsRNA, and therefore teaches cells which comprise the dsRNA that is encoded in the nucleic acid that encodes the dsRNA (e.g., paragraph 22). Furthermore, claim 17 does not add structural or functional limitations to the claim and merely describe an inherent characteristic of the cell. Given that the combination of Killmer and Blattner renders obvious the creation of such a cell, its inherent properties follow naturally.
Regarding claim 18, Blattner teaches that strain MG1655 can be used in their methods (paragraph 22).
Regarding claim 20, Killmer teaches methods for producing dsRNA in vivo (e.g., paragraph 22). Furthermore, the claim limitations of dsRNA, capsid protein, and overexpression of pyrE are rendered obvious by the combination of Killmer/Blattner for the reasons outlined in claim 1, above.
Regarding claim 21, Killmer teaches siRNA (paragraph 82).
Regarding claim 22, Killmer teaches that the capsid protein is a capsid protein of MS2, or Q-beta (claims 3-4 of Killmer).
Regarding claim 24, Killmer teaches expressing the dsRNA and capsid protein from a nucleic acid expression construct, where the expression of each is operably linked with an expression control sequence (e.g., paragraphs 13-14).
Regarding claim 25, Killmer teaches expressing proteins using exogenous nucleic acid sequences operably linked to a promoter (paragraphs 13-14). As discussed in the rejection of claim 1, the combination of Killmer/Blattner renders obvious the overexpression of pyrE to produce dsRNA, and therefore the introduction of an exogenous nucleic acid encoding pyrE linked to a promoter is obvious (see rejection of claim 1).
Regarding claim 27, Killmer teaches lysing cells to produce a lysate and purifying the dsRNA from the cell within the lysate prior to processing the purified dsRNA for application (paragraph 15).
Regarding claim 28, Killmer teaches that the dsRNA is not further purified from cell lysates but is processed directly for application (paragraph 15).
Regarding claim 29, Killmer teaches that the promoters can be constitutive or inducible (paragraph 45).
Regarding claim 30, Killmer teaches that the exogenous nucleic acid construct is incorporated in a plasmid (paragraph 14).
Claims 19 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Killmer (WO 2017/160600 A1, provided in IDS filed 11/30/2021) in view of Blattner (WO 2015/073720 A1, provided in IDS filed 11/30/2021), as applied to claims 6-10, 16-18, 20-22, 24-25, and 27-30 above, and further in view of Baum (US 9,814,243 B2, published 11/14/2017).
Regarding claims 6-10, 16-18, 20-22, 24-25, and 27-30, a discussion of the teachings of Killmer and Blattner are provided above. The combination of Killmer/Blattner renders obvious cells expressing dsRNA, capsid proteins, and pyrE, where such modifications are expressed from plasmid constructs (see the rejection of claim 1 and paragraphs 13-14 of Killmer). Killmer/Blattner therefore render obvious plasmid constructs expressing dsRNA, capsid proteins, and the pyrE gene under control of promoters.
Regarding claims 19 and 26, as an initial matter, these claims recite the plasmid pAPSE10448 (SEQ ID NO 3). As discussed in the present specification, plasmid pAPSE10448 was constructed by modifying the production plasmid pAPSE10379 (paragraph 33 of instant specification). Production plasmid pAPSE10379 was modified by cloning two terminator sites T1-T2 using restriction cloning and encoding the pyrE gene coupled with a ribosome binding site into the production plasmid downstream of a T7 promoter in order to create pAPSE10448 (paragraph 33). Thus, plasmid pAPSE10448 was created using standard restriction site cloning techniques, where two terminators were included in the construct, where the pyrE gene was cloned downstream of a known promoter.
Killmer teaches the production plasmid pAPSE10379, the plasmid which was modified to produce the instantly recited pAPSE10448 (paragraph 72). Furthermore, Killmer teaches plasmid construction methods using restriction fragments/cloning strategies, and also teaches that the T7 promoter is a well-known promoter used for such purposes, which can be used to drive expression of MS2 in the same manner as pAPSE10448 (paragraph 29 of Killmer, paragraph 33 of instant specification).
Killmer does not teach dual terminator T1-T2 rrn B terminators of pAPSE10448.
Baum is a patent document that specifically focuses on the improved production of dsRNA (Abstract). Baum teaches rrn BT1 and rrn BT2 dual terminators to be used in dsRNA expression constructs (Table 4). Baum teaches that improved RNA expression was observed from an RNA production vector containing two terminators (column 50, final two paragraphs, Example 14). Thus, Baum teaches the vector construction strategy of including dual terminators is known to improve RNA expression, specifically in the context of creating vectors to enhance/improve dsRNA yield (Example 14, Table 4).
It would have been obvious to a person of ordinary skill in the art before the time of the effective filing date of the claimed invention to modify the pAPSE10379 production plasmid with the terminators taught by Baum because such a combination is the simple combination of known prior art elements to yield predictable results. Furthermore, a practitioner would be motivated to include the teachings of Baum because Baum teaches that dual terminators are known to offer improved yield of dsRNA (above). Furthermore, the results are predictable because the present constructs were created using standard molecular cloning techniques (e.g., restriction fragment cloning, T7 expression promoters, etc.). The results are therefore not only obvious but also predictable, as these are known components to work in the context of dsRNA production.
Response to Arguments
The Applicant’s arguments filed 9/16/2025 have been considered but are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The Applicant argues that the references, either alone or in combination, to do not teach an exogenous nucleic acid construct encoding the pyrE gene operably linked with a promoter. This argument is a piecemeal argument and does not consider the totality of the what the prior art references teach. For instance, both Blattner and Killmer teach the introduction of exogenous nucleic acid constructs comprising promoters to express genes (e.g., plasmids and vectors, see above, and Methods throughout). Furthermore, Blattner provides a direct motivation to overexpress pyrE, as such overexpression relative to wildtype is shown to have increased nucleic acid production (paragraph 24, Example 3, paragraph 62). Thus, both the method of introducing a gene for overexpression on an exogenous plasmid with a promoter and the motivation to overexpress pyrE are present within the prior art. Therefore, given the motivational and methodological teachings of Blattner, a practitioner would be motivated to and could immediately envision expressing pyrE from such an exogenous construct, as Blattner also teaches such a method of introducing exogenous genes (as does Killmer). Thus, the totality of the teachings of Blattner and Killmer render obvious claim 6.
The Applicant argues that Blattner fails to teach that increased production of pyrE gene product orotate phosphoribosyltransferase alone can lead to increased nucleic acid production, where furthermore Blattner teaches that single modifications have no effect. This argument is not persuasive because claim 6 is not restricted to what modifications exist in the cell, only that the recited modifications are present (“comprising”). Thus, the cells of Blattner, comprising all of the modifications that they teach, still read on claim 6, which does not strictly prohibit or preclude the presence of additional modifications such as those taught by Blattner.
The Applicant argues that Blattner does not teach introducing pyrE on an exogenous nucleic acid construct, but concedes that Blattner does teach increasing the activity of pyrE. The Applicant argues that Blattner does not enable one to arrive at the present claim 6. These arguments are not persuasive because Blattner does teach the method of introducing exogenous nucleic acid constructs with promoters, as does Killmer, where furthermore such methods are readily known in the art (i.e., not only do Killmer and Blattner teach exogenous nucleic acid construct with promoters to express proteins, a practitioner of ordinary skill is certainly enabled to introduce a plasmid with a desired gene into a cell). Furthermore, Blattner teaches that:
“Enhanced orotate phosphoribosyltransferase activity in the modified E. coli
K-12 strain of the invention corresponds to an increase in the number of orotate phosphoribosyltransferase molecules per cell compared to that of the wild type (e.g.MG 1655) or unmodified strain, or to an increase in the orotate
phosphoribosyltransferase activity within a cell compared to that of cells of the wildtype or unmodified strain,” (emphasis added, paragraph 23).
Thus, Blattner does teach increasing the expression of pyrE, and not simply to increase the activity by frameshift mutation. Given the teachings of both Killmer and Blattner, it is obvious to a practitioner of ordinary skill that pyrE gene products can be increased by introducing a plasmid that expresses the pyrE gene, the method to do so being taught by both Killmer and Blattner. The practitioner would readily understand that introducing such pyrE constructs on a plasmid would accomplish an “increase in the number of orotate phosphoribosyltransferase molecules per cell compared to that of wildype,” as directly taught and suggested by Blattner. The practitioner is further enabled to do so, as Blattner teaches the use of plasmids with genes operably linked to promoters (paragraph 41).
The Applicant argues that a practitioner would understand that dsRNA production may not be increased in the methods of Blattner, who only reduces to practice dsDNA. This argument is not persuasive. Firstly, the argument is not supported by any evidence, and is therefore only an argument of counsel. MPEP 716.01(c) makes clear that arguments of counsel cannot take the place of evidence in the record. Furthermore, Blattner teaches that the method improves nucleic acid production (e.g. Example 3 and paragraph 62). Given that Blattner has reduced to practice embodiments where nucleic acid production is improved, and teaches motivational teachings to that effect, the evidence of record leans in favor of predictability concerning the teachings of Blattner with respect to dsRNA. There is no clear reason why the improved production of nucleic acids observed by Blattner would not also apply to dsRNA, as presently recited, and inherently encompassed by Blattner’s teaching of “nucleic acids.” Furthermore, a practitioner of ordinary skill in the art, given the teachings of Blattner who teaches ‘nucleic acids” could immediately contemplate RNA as such a nucleic acid and would therefore be motivated to apply the teachings to dsRNA with a reasonably expectation of success.
The Applicant argues that Blatner does not teach combining pyrE gene expression with the capsid construct of Killmer. However, it is Blattner that is modifying Killmer and not the other way round: Blattner supplies motivational teachings to modify Killmer with a reasonable expectation of success, which is sufficient to combine Blattner with Killmer to modify to teachings of Killmer.
The Applicant argues that a 50 to 100% increase in production of dsRNA was observed, and that such a result is an unexpected result. This argument is not found to be persuasive given the teachings of Blattner, who teaches that the increased expression of pyrE gene products is known to be associated with increased nucleic acid production (Example 3 and paragraph 62). The observation that an increase in nucleic acid production was seen is therefore not an unpredictable result, as Blattner has already taught this phenomenon.
The Applicant argues that Baum does not cure the deficiencies of Killmer and Blattner. This argument is not found to be persuasive because, for the reasons given above, Killmer and Blattner do not appear to be deficient with respect to rendering obvious the present invention.
Double Patenting – Updated in Response to Amendment
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 6-10, 17-18, 20-22, 24-25, and 27-30 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. US 11,718,851 B2 (‘851) in view of Killmer (WO 2017/160600 A1, provided in IDS filed 11/30/2021) and Blattner (WO 2015/073720 A1, provided in IDS filed 11/30/2021).
Note that claims 29-30 have been rejected under 112(b) for depending from a canceled claim (claim 16). For the purposes of this double patenting rejection, claims 29-30 are being interpreted to depend from claim 6. This interpretation appears to be consistent with the application, as the limitations of claim 16 appear to be incorporated into independent claim 6.
Regarding claim 6, claim 1 of ‘851 recites:
“A method for producing unencapsidated dsRNA in a microbial cell, comprising the step of co-expressing in the microbial cell the dsRNA, and a leviviridae coat protein gene encoding a capsid protein or an amino-terminal fragment of the capsid protein, wherein the unencapsidated dsRNA is directly recoverable from a cell lysate; and wherein the unencapsidated dsRNA comprises a length exceeding the interior diameter of the leviviridae coat protein.”
‘851 recites that the elements are expressed from a promoter (claim 3) and that the elements can be on a plasmid (claim 6, i.e., an exogenous nucleic acid construct with a promoter).
Claim 1 of ‘851 does not recite a genetic modification for increasing expression of a pyrE gene.
Killmer teaches a modified bacterial cell for producing dsRNA in vivo, the modified bacterial cell comprising a nucleic acid construct comprising a nucleic acid sequence encoding a double-stranded RNA (dsRNA) linked to an expression control sequence and a nucleic acid construct comprising a nucleic acid sequence encoding a capsid protein linked to an expression control sequence (see claims 1-8 Killmer).
Blattner is a patent document that focuses on modified bacterial cells for the improved production of protein and nucleic acids (Abstract). Killmer and Blattner therefore overlap in subject matter and field of endeavor because both teach modified bacterial cells, the design of which are to improve the production of nucleic acids (see Abstracts of both). Blattner teaches modified bacterial strains designed to enhance orotate phosphoribisyltransferase activity (i.e., the gene encoded by pyrE per the present specification paragraph 6). Specifically, Blattner teaches that that orotate phosphoribosyltransferase activity can be enhanced by a modification that increases the expression of the encoding gene (i.e., increasing expression of pyrE, paragraph 24). Blattner therefore teaches that modification of pyrE to increase its expression is already a known technique to improve the production of nucleic acids (i.e., RNA).
It would have been obvious to a person of ordinary skill in the art before the time of the filing date of the claimed invention to modify the bacterial cells taught by ‘851 to increase the expression/activity of pyrE as taught by Blattner because such a combination is the simple combination of known prior art elements with a predictable expectation of success. Furthermore, a practitioner would be motivated to incorporate the teachings of Blattner because Blattner teaches the motivational teaching that increasing the expression of pyrE is a known strategy with the beneficial outcome of improving nucleic acid production in modified cells (paragraphs 7-8 and 24, Blattner). Furthermore the results are predictable because both ‘851 and Blattner reduce their methods to practice, and each of the recited claim limitations would be used in the same manner taught by ‘851 and Blattner.
Regarding claim 7, Killmer teaches the production of siRNA (paragraph 82).
Regarding claim 8, ‘851 recites levivirdae coat proteins (claim 1 of ‘851).
Regarding claims 9 and 10, ‘851 recites MS2 coat proteins and Q-beta coat proteins (claim 2).
Regarding claim 17, ‘851 recites producing dsRNA in a cell comprising dsRNA and capsid proteins (claim 1). Killmer teaches that the cells express dsRNA, and therefore teaches cells which comprise the dsRNA that is encoded in the nucleic acid that encodes the dsRNA (e.g., paragraph 22). Furthermore, claim 17 does not add structural or functional limitations to the claim and merely describe an inherent characteristic of the cell. Given that the combination of Killmer and Blattner renders obvious the creation of such a cell, its inherent properties follow naturally.
Regarding claim 18, Blattner teaches that strain MG1655 can be used in their methods (paragraph 22).
Regarding claim 20, claim 1 of ‘851 recites:
“A method for producing unencapsidated dsRNA in a microbial cell, comprising the step of co-expressing in the microbial cell the dsRNA, and a leviviridae coat protein gene encoding a capsid protein or an amino-terminal fragment of the capsid protein, wherein the unencapsidated dsRNA is directly recoverable from a cell lysate; and wherein the unencapsidated dsRNA comprises a length exceeding the interior diameter of the leviviridae coat protein.”
851 recites that the elements are expressed from a promoter (claim 3) and that the elements can be on a plasmid (claim 6, i.e., an exogenous nucleic acid construct with a promoter).
‘851 does not recite that the exogenous nucleic acid construct expresses pyrE in the cell. This limitation is discussed above in the combination of ‘851/Killmer/Blattner.
Regarding claim 21, Killmer teaches the production of siRNA (paragraph 82).
Regarding claim 22, ‘851 recites MS2 and/or Q-beta capsid proteins (claim 2).
Regarding claim 24, Killmer teaches expressing the dsRNA and capsid protein from a nucleic acid expression construct, where the expression of each is operably linked with an expression control sequence (e.g., paragraphs 13-14).
Regarding claim 25, Killmer teaches expressing proteins using exogenous nucleic acid sequences operably linked to a promoter (paragraphs 13-14). As discussed in the rejection of claim 1, the combination of Killmer/Blattner renders obvious the overexpression of pyrE to produce dsRNA, and therefore the introduction of an exogenous nucleic acid encoding pyrE linked to a promoter is obvious (see rejection of claim 1).
Regarding claim 27, Killmer teaches lysing cells to produce a lysate and purifying the dsRNA from the cell within the lysate prior to processing the purified dsRNA for application (paragraph 15).
Regarding claim 28, Killmer teaches that the dsRNA is not further purified from cell lysates but is processed directly for application (paragraph 15).
Regarding claim 29, Killmer teaches that the promoters can be constitutive or inducible (paragraph 45).
Regarding claim 30, Killmer teaches that the exogenous nucleic acid construct is incorporated in a plasmid (paragraph 14).
Claims 19 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. US 11,718,851 B2 (‘851) in view of Killmer (WO 2017/160600 A1, provided in IDS filed 11/30/2021) and Blattner (WO 2015/073720 A1, provided in IDS filed 11/30/2021), as applied to claims 6-10, 16-18, 20-22, 24-25, and 27-30 above and further in view of Baum (US 9,814,243 B2, published 11/14/2017).
Regarding claims 19 and 26, ‘851 recites plasmids (claim 6).
‘851 does not recite the pAPSE10448 plasmid.
Regarding claims 19 and 26, as an initial matter, these claims recite the plasmid pAPSE10448 (SEQ ID NO 3). As discussed in the present specification, plasmid pAPSE10448 was constructed by modifying the production plasmid pAPSE10379 (paragraph 33 of instant specification). Production plasmid pAPSE10379 was modified by cloning two terminator sites T1-T2 using restriction cloning and encoding the pyrE gene coupled with a ribosome binding site into the production plasmid downstream of a T7 promoter in order to create pAPSE10448 (paragraph 33). Thus, plasmid pAPSE10448 was created using standard restriction site cloning techniques, where two terminators were included in the construct, where the pyrE gene was cloned downstream of a known promoter.
Killmer teaches the production plasmid pAPSE10379, the plasmid which was modified to produce the instantly recited pAPSE10448 (paragraph 72). Furthermore, Killmer teaches plasmid construction methods using restriction fragments/cloning strategies, and also teaches that the T7 promoter is a well-known promoter used for such purposes, which can be used to drive expression of MS2 in the same manner as pAPSE10448 (paragraph 29 of Killmer, paragraph 33 of instant specification).
Baum is a patent document that specifically focuses on the improved production of dsRNA (Abstract). Baum teaches rrn BT1 and rrn BT2 dual terminators to be used in dsRNA expression constructs (Table 4). Baum teaches that improved RNA expression was observed from an RNA production vector containing two terminators (column 50, final two paragraphs, Example 14). Thus, Baum teaches the vector construction strategy of including dual terminators is known to improve RNA expression, specifically in the context of creating vectors to enhance/improve dsRNA yield (Example 14, Table 4).
It would have been obvious to a person of ordinary skill in the art before the time of the effective filing date of the claimed invention to modify the plasmids recited in ‘851 with the known production plasmid of Killmer and the terminators taught by Baum because such a combination is the simple combination of known prior art elements to yield predictable results. Furthermore, a practitioner would be motivated to include the teachings of Baum because Baum teaches that dual terminators are known to offer improved yield of dsRNA (above). Furthermore, the results are predictable because the present constructs were created using standard molecular cloning techniques (e.g., restriction fragment cloning, T7 expression promoters, etc.). The results are therefore not only obvious but also predictable, as these are known components to work in the context of dsRNA production.
Response to Arguments
The Applicant’s arguments filed 9/16/2025 have been considered but are not persuasive. The Applicant has made similar arguments with regards to the 103 rejection, where such arguments are addressed in the response to arguments for the 103 rejection (above). Briefly, 851 recites that the elements are expressed from a promoter (claim 3) and that the elements can be on a plasmid (claim 6, i.e., an exogenous nucleic acid construct with a promoter). Furthermore, Blattner and Killmer render obvious the elements to express (i.e., dsRNA and bacteriophage capsid from ‘851 and Killmer and pyrE from Blattner). Furthermore, as discussed above, the results are not unpredictable because the methods have been reduced to practice and Blattner has already taught that increased expression of pyrE increases nucleic acid production.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635