DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received on 5/28/2026. Claims 6-10, 17-22, and 24-30 are pending. Claims 6, 18, 20, and 29-30 have been amended. Claims 1-5, 11-16, and 23 have been previously cancelled. All pending claims are currently under examination.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. This Office Action is Final.
Oath/Declaration
The Applicant’s Declaration filed on 5/28/2026 has been considered but is not persuasive to place the claims in condition for allowance. Specific issues and arguments raised in the Declaration are addressed in the “Response to Arguments” section, below. Additionally, a Declaration was also filed 4/29/2026, which appears to be a substantial duplication of the Declaration filed 5/28/2026. Thus, the contents of both Declaration have been reviewed and addressed in this action.
Claim Rejections - 35 USC § 112 – New Matter Rejection Necessitated by Amendment
Claims 6-10, 17-22, and 24-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding independent claims 6 and 20, these claims have been amended to recite that the bacterial cell exhibits at least about 32% increased production of dsRNA in vivo compared with a bacterial cell lacking an exogenous nucleic acid expressing pyrE and a nucleic acid construct encoding a capsid protein. This claim language therefore is drawn to a comparison to the claimed cell comprising components a-c (claim 6) and components a-b (claim 20) with respect to the amount of dsRNA produced between two such cells. However, this claim language is problematic because a cell that is missing both an exogenous pyrE gene encoded on a nucleic acid and a bacteriophage capsid was never compared with the cells claimed in claims 6 and 20 in the specification as filed.
Regarding the comparisons of dsRNA production, the Applicant has tested and compared the cells offered in Examples 1-5 and Tables 1-5. The plasmids used in the methods include APSE10379, APSE10447, APSE10448, APSE10471, and APSE10458 (Tables 1-5). However, each of these strains/plasmid comprises an exogenous pyrE, capsid protein, or both (see description of these plasmids in examples 1-5, pages 10-14). Thus, no comparison between the cell recited in claim 6 was ever made to a cell lacking components “a” and “c” (pyrE, capsid) as presently recited in claim 6. A similar issue exists for the method of claim 20. Thus, the Applicant is claiming new subject matter, as no such relative comparisons between the cells/methods recited were ever performed with cells lacking both exogenous pyrE “and” the capsid protein, which is required by both independent claims 6 and 20.
The dependent claims of independent claims 6 and 20 do not resolve the issue and are also rejected.
Claim Rejections - 35 USC § 103 – Maintained/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).
Furthermore, regarding the claim limitation “the bacterial cell exhibits at least about 32% increased production of the dsRNA in vivo compared to a bacterial cell lacking (a) and (c),” this comparison cell lacking components “a” and “c” (i.e., an exogenous construct encoding the pyrE gene, “a,” and a construct encoding a capsid protein, “c”) are taught by Killmer. For instance, such a comparison cell is taught in Example 1 of Killmer, comprising the plasmid pAPSE10181 which lacks both the capsid protein MS2 (“c”), where the cell does not comprise an exogenous construct encoding pryE “a” (see Table 1, and see Example 1 beginning at paragraph 48). Thus, Killmer teaches that an increase in production of dsRNA in vivo of at least 32% is known when a capsid is co-expressed in comparison with a cell not expression elements “a” and “c” of claim 6.
Example 1 of Killmer teaches a comparison of dsRNA production, where one cell contains plasmid pAPSE10180, which encodes the MS2 capsid protein, and the other cell contains plasmid pAPSE10181, which does not encode a capsid protein (see Table 1 and Example 1). Killmer teaches that the capsid-containing E. coli strain produced 75-90 mg/mL of dsRNA, whereas the strain lacking the capsid produced less than 2 mg/ml (Example 1, and Table 1,rows 1-2). Thus, Killmer teaches that strains comprising a capsid protein have an increased production percentage of at least 75/2 = 37.5 times that of strains which lack both claim elements “a” and “c” (exogenous pyrE and capsid). Killmer therefore teaches bacterial strains with at least 32% increased production of dsRNA in vivo compared with a cell lacking elements “a” and “c.” (Table 1 rows 1-2, and Example 1). Killmer therefore teaches that it si reasonable to predict that a cell encoding a capsid protein will have at least a 32% increase in dsRNA production.
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, paragraphs 7-8). 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). For instance, Blattner teaches “orotate phosphoribosyltransferase activity can be enhanced by a modification that increases the expression of the encoding gene relative to a parent strain such as a wild type strain or an unmodified strain otherwise having the same genetic background,” (paragraph 24). Blattner also clarifies and teaches that “enhanced orotate phosphoribosyltransferase activity” means “an increase in the number of orotate phosphoribosyltransferase molecules per cell compared to that of the wild type,” (paragraph 23). Thus, by teaching orotate phosphoribosyltransferase with enhanced activity, Blattner teaches increasing the number of orotate phosphoribosyltransferase molecules per cell (paragraphs 23-24). Blattner teaches that orotate phosphoribosyltransferase should be enhanced/rescued in strains which have suboptimal expression of the gene (paragraph 22).
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). The practitioner of ordinary skill in the art would understand that one way to overexpress pyrE would be to introduce the gene on a plasmid, as directly taught by Blattner as a method of gene introduction, in light of the motivational teachings provided by Blattner to “enhance” i.e., overexpress, pyrE.
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 the E. coli 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. Furthermore, increased production efficiencies of at least 32% are within increased production levels taught by Killmer where dsRNA production is compared with cells lacking exogenous pyrE and a capsid protein (Killmer Table 1 rows 1-2, Example 1).
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, 17-18, 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 5/28/2026 have been considered and are not persuasive to place the claims in condition for allowance.
Summary of Applicant’s Amendments and their insufficiency to overcome the rejection:
The Applicant has amended claim 6 to now recite that the bacterial cell has an increased dsRNA production in vivo of at least 32% compared with a cell lacking a capsid protein and exogenous pyrE expression. However, Killmer teaches that introducing the capsid protein alone increased dsRNA production by over 32% (Table 1, Example 1). Thus, such an increase in production is already known in the art. The addition of pyrE exogenously would reasonably only increase nucleic acid yield, as was also taught in the art. Thus, both the components (pyrE and capsid) are known to improve nucleic acid production efficiency, where the magnitude of the increase falls within the predictable range given that Killmer teaches even higher production efficiencies using capsid proteins alone.
The Applicant argues that the cited prior art references, either individually or taken together, do not disclose the claimed subject matter. This argument is not persuasive because each of the claim limitations are known and/or obvious in view of the prior art references cited in the 103 rejection above. Specifically, Killmer teaches the introduction of capsid proteins to increase the production of dsRNA by at least 32% compared with a reference cell lacking the capsid protein and exogenous pyrE (Table 1 rows 1-2 of Killmer, Example 1). Furthermore, Blattner teaches increasing the expression of pyrE, by increasing the number of molecules encoded by the pyrE gene, where such a strategy is beneficial to improve the production of molecules such as nucleic acids (Abstract, paragraphs 7-8). Given that Blattner teaches a beneficial motivation of overexpressing pyrE in E. coli, and also teaches such methods as the introduction of exogenous genes on a plasmid, the practitioner of ordinary skill in the art can immediately recognize that pyrE can be expressed on an exogenous plasmid, in order to carry out the suggestion of Blattner to “enhance” pyrE expression by increasing the number of proteins encoded by this gene in a cell (paragraphs 22-24).
Regarding the limitation that the production is increased by 32%, this level of increase in production is taught by Killmer, who teaches at least 37.5 times production increase in dsRNA production when a capsid protein is expressed with the bacterial cell (Table 1, rows 1-2 and Example 1). There is no reason to believe that the additional inclusion of pyrE as taught and suggested by Blattner would decrease this value. To the contrary, Blattner teaches that such pyrE enhancement improves nucleic acid production. Thus, the practitioner of ordinary skill in the art would not find the presently recited subject matter unexpected because even a single component of the enhancement molecules (i.e., capsid proteins) was already known to increase the production efficiency of dsRNA by over 32% alone. The inclusion of an additional beneficial gene such as pyrE, which was already known to improve growth and production of nucleic acids does not yield unexpected results with respect to increasing production of dsRNA in addition to the capsid protein. Such an increase in dsRNA production would be expected given the teachings of Blattner.
Regarding the Applicant’s argument that dsRNA is unpredictable, and scaling dsRNA production is inherently unpredictable, this is an argument from counsel. MPEP 716.01(c) makes clear that arguments of counsel cannot take the place of evidence in the record. Presently, Killmer teaches that increased production by the introduction of a capsid protein alone increases dsRNA output by at least 32% (above). There is no evidence to suggest that the inclusion of pyrE exogenous expression would decrease this increased yield. To the contrary, Blattner teaches that enhanced production/increased production of pyrE is beneficial for nucleic acid production. The invention as claimed is therefore predictable.
The Applicant argues that there is no motivation to combine Blattner with Killmer, and argues that the two are directed to unrelated technical fields. In response to applicant's argument that Killmer and Blattner are nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor' s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, both Killmer and Blattner are concerned with production of nucleic acids in the context of industrial and commercial applications (Abstract of both, paragraph 4 of Killmer). Furthermore, both Killmer and Blattner are using the same cells for production (E. coli) to produce the same class of molecule (nucleic acids). Both Killmer and Blattner are addressing the same problem of trying to improve cell production conditions to increase the efficiency of nucleic acid productions (e.g., Example 1 of Killmer, Example 4 paragraph 62 of Blattner). The two prior art documents are therefore analogous art and are in the same field of endeavor.
Regarding the Declaration, and tThe Applicant’s arguments about unexpected results: this argument is not persuasive. As an initial matter, Killmer teaches that the introduction of the capsid protein alone yields increased dsRNA production well above 32% (Table 1 rows 1-2 and Example 1). Thus, recitation of an increase in dsRNA that is at least 32% is not an unexpected result, as Killmer teaches that such an increase is to be expected when producing dsRNA using the expression of a capsid protein. Furthermore, it is not unexpected that the addition of pyrE further improves nucleic acid yield because Blattner directly says that the inclusion of an increase of functional pyrE improves nucleic acid production:
“Figure 1, demonstrate the presence of the metabolic mutations (correction of the ivlG frameshift mutation and deletion of the rph, iclR and arpA genes) in E. coli K-12 cell lines confers improved growth rates (faster doubling times, higher Mu) resulting in higher cell densities and improved production of nucleic acids and proteins,” (paragraph 62).
Thus, neither the effect nor the magnitude of the increase of nucleic acid production are unpredictable, as the art teaches such effects and outcomes. It is not unexpected that expressing pyrE would enhance nucleic acid production because Blattner teaches that pyrE enhances nucleic acid production by improving cell growth (paragraph 62). Furthermore, Killmer teaches that the presence of capsid proteins alone are sufficient to reach an increased production of dsRNA that is at least 32% (Table 1 rows 1-2, Example 1).
The Applicant argues that the Declaration states that Dr. Kumar would not read Blattner as teaching the introduction of pyrE on an exogenous nucleic acid, but teaches the correction of a frameshift mutation to increase the efficiency of pyrE. This argument is not persuasive because Blattner also teaches that enhanced pyrE gene expression also corresponds with “an increase in the number of orotate phosphoribosyltransferase molecules per cell compared to that of the wild type,” (paragraph 23) which a practitioner could readily envision to suggest the expression of the pyrE gene on a construct using an exogenous nucleic acid, a method of gene expression also taught by Blatter, as the introduction of an exogenous gene to “increase the number” of a gene’s protein in a cell is a widely known method of ‘increasing the number” of a gene’s protein in a cell. Thus, Blattner does not only relate to the activity of the pyrE gene product, but also teaches the increase in production of the gene product. A practitioner could readily envision exogenous expression of pyrE on a plasmid to reach this goal.
Furthermore, in response the Applicant’s argument of unexpected results, even if it were argued that the combination of a capsid protein and pyrE yielded an unexpected result in the sense that the dsRNA yield were higher than expected, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the present case, the practitioner is already sufficiently motivated to include the pyrE gene and its expression in methods of manufacturing nucleic acids because pyrE expression/enhanced expression was already known to be useful in methods of manufacturing nucleic acids. Thus, the presently recited subject matter would flow naturally from the suggestions which already exist in the art, where the bacterial cell is rendered obvious by Killmer and Blattner and the specific production increase is simply an inherent characteristic of the bacterial cell rendered obvious by the combination of the art. Thus, recitation of the percentage by which the dsRNA is increased in the cell can not be the basis of patentability, as this can be characterized as simply another advantage of a cell which was already rendered obvious by the combination of prior art references.
The Applicant argues that a practitioner has no reasonable expectation of success when combining Killmer and Blattner, where no guidance is provided which would give a reasonable prediction of success to asses the recited modifications. This argument is not persuasive. Killmer and Blattner have both reduced their methods to practice, where both methods use the same cells to achieve the same goals of increased nucleic acid production. MPEP 2143.02 teaches that obviousness does not require absolute predictability, but only a reasonable expectation of success is required. In the present case, given the overlapping nature of the two references, and the fact that both have been reduced to practice, there is a reasonable expectation of success when combining the two art references.
The Applicant argues that Baum does not remedy the deficiencies of the combination of Killmer and Blattner. This argument is not persuasive because Killmer and Blattner are sufficient for a prima facie case of obviousness, and are therefore not deficient to make the 103 rejection. Furthermore, Baum teaches that the use of two terminators has beneficial outcomes, and would therefore motivate the practitioner to include the teachings of Baum to arrive at the inventions of claims 19 and 26. Baum teaches the use of multiple terminators and reduces them to practice to improve dsRNA production (Example 14), and therefore motivates a practitioner to include such teachings in methods of dsRNA production.
Regarding the remaining issues with respect to the Declaration: the Declaration states that the magnitude of the difference in dsRNA expression presented in Figure 1 and Table 1 is unexpectedly high. The argument is not persuasive because expression of capsid proteins alone were taught to render such differences in dsRNA, as taught by Table 1, Example 1 of Killmer, who teaches fold-changes compared to non-capsid E. coli cells including 37.5 times higher dsRNA production (Table 1, rows 1-2). Thus, such magnitudes of production when comparing capsid-expressing vs. non-capsid expressing cells such as those discussed in the Declaration were already known and therefore expected.
The Applicant argues in their Declaration filed 5/28/2026 that they have shown comparative data which shows that the pyrE and capsid co-expression has unexpected results with respect to dsRNA production. These arguments are not persuasive. As an initial matter, the data presented do not show a negative control without either pyrE or the capsid protein expressed. Rather, the data in the Declaration, like the specification, compares strains comprising pyrE, capsid, or a combination of both. Therefore, the statement in the Declaration that “overexpression of pyrE alone fails to improve accumulation of dsRNA” can not be relied upon without a negative control strain which expresses dsRNA without both pyrE and the capsid protein. The data do not indicate that pyrE alone does not improve dsRNA production. By way of comparison, Killmer did perform experiments in cells lacking both pyrE and capsid, and found that dsRNA production is less than 2 mg/mL. Although a direct comparison between Killmer and the Declaration can not be made, the finding that the expression of pyrE alone in the Declaration (Figure 1) yields dsRNA that is 5.21 mg/mL could be viewed as an increased production of dsRNA to levels known in the art (i.e., less than 2 mg/mL as thaught by Killmer). In that light, it would not be surprising that the combination of pyrE and capsid yields dsRNA that is 2x that of capsid alone, because evidence in the art appears to suggest that baseline dsRNA production is around 2 mg/mL (Killmer, Table 1) where the addition of pyrE yields ~5 mg/mL, (or 2.5x more dsRNA). Furthermore, Killmer already teaches that the inclusion of a capsid protein can increase dsRNA expression by 38-45 times (Table 1, rows 1-2 of Killmer). Thus, the magnitude of increased expression is already known in the art, per Killmer. The Applicant’s argument that the “magnitude of difference” in the yield is unexpected is not persuasive because it is on the same order of magnitude of what is already known to be expected (Killmer, Table 1, e.g., rows 1-2).
Regarding the data discussing terminator sequences, Baum has taught improved RNA expression was observed from an RNA production vector containing two terminators (column 50, final two paragraphs, Example 14). This teaching alone motivates the practitioner to include multiple terminators. The Declaration states that their post-filing findings conflict with the findings of Baum. This argument is not persuasive because the claims are drawn sequences with at least two terminators, where the practitioner would be motivated based on the teachings of Baum and Buam’s data to include two terminators.
Double Patenting – Maintained/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).
The teachings of Killmer and Blattner a they relate to the 103 rejection above are incorporated here in their entirety.
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. Claim 1 of ‘851 does not recite that the cell exhibits at least 32% increased production of dsRNA.
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, regarding the claim limitation “the bacterial cell exhibits at least about 32% increased production of the dsRNA in vivo compared to a bacterial cell lacking (a) and (c),” this comparison cell lacking components “a” and “c” (i.e., an exogenous construct encoding the pyrE gene, “a,” and a construct encoding a capsid protein, “c”) are taught by Killmer. For instance, such a comparison cell is taught in Example 1 of Killmer, comprising the plasmid pAPSE10181 which lacks both the capsid protein MS2 (“c”), where the cell does not comprise an exogenous construct encoding pryE “a” (see Table 1, and see Example 1 beginning at paragraph 48). Thus, Killmer teaches that an increase in production of dsRNA in vivo of at least 32% is known when a capsid is co-expressed in comparison with a cell not expression elements “a” and “c” of claim 6.
Example 1 of Killmer teaches a comparison of dsRNA production, where one cell contains plasmid pAPSE10180, which encodes the MS2 capsid protein, and the other cell contains plasmid pAPSE10181, which does not encode a capsid protein (see Table 1 and Example 1). Killmer teaches that the capsid-containing E. coli strain produced 75-90 mg/mL of dsRNA, whereas the strain lacking the capsid produced less than 2 mg/ml (Example 1, and Table 1,rows 1-2). Thus, Killmer teaches that strains comprising a capsid protein have an increased production percentage of at least 75/2 = 37.5 times that of strains which lack both claim elements “a” and “c” (exogenous pyrE and capsid). Killmer therefore teaches bacterial strains with at least 32% increased production of dsRNA in vivo compared with a cell lacking elements “a” and “c.” (Table 1 rows 1-2, and Example 1). Killmer therefore teaches that it si reasonable to predict that a cell encoding a capsid protein will have at least a 32% increase in dsRNA production.
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. Furthermoe, the results are predictable because Killmer teaches that 32% production increases of dsRNA are achievable using capsid protein alone.
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 4/29/2026 have been considered but are not persuasive. The Applicant argues that ‘851 in combination with Killmer, Blattner, and Baum do not arrive at the claimed subject matter. The Applicant reiterates arguments presented and addressed in the response to the 103 “Response to Arguments” section, which is incorporated here. As discussed in the 103 rejection above, ‘851 in light of Killmer, Blattner, and Baum renders obvious the claimed subject matter (see “Response to Arguments,” above). The double patenting rejection is therefore maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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 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.
/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
Prosecution Insights