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 .
Applicant’s response filed 12/29/2025 has been received and considered entered. This is a response to amendments and arguments filed 12/29/2025.
Claims Status
Claims 2-53, 65 is/are cancelled and claims 86-94 is/are newly added. Claims 1, 54-64, 66-94 is/are currently pending. Claims 1, 54-64, 66-94 is/are under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Enablement:
Claims 59-64, 66-67, 81, 84, 86-94 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This rejection is maintained.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims:
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that it encompasses methods of treating, preventing, suppressing, or alleviating any disease merely associated with any enterovirus species, using a CRISPR system comprising gRNAs at least 85% identical to SEQ ID NOs:1-6 (SEQ ID NOs:1-6 are designed to target the 3D polymerase gene of EV71). Claim 66 recites diseases which the claimed method is claimed to treat, including diseases which are not associated with the virus EV71; Claim 67 recites that the RNA virus is not required to be EV71. A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification.
The amount of direction provided by the inventor and the level of predictability in the art:
The specification teaches that hand, foot and mouth disease (HFMD) is often caused by EV71 infection (paragraphs [0039], [0042], [0071]). The specification further discloses that viruses of the Picornaviridae family, which EV71 belongs to, are associated with a broad range of diseases (paragraph [0092]). Additionally, the specification defines the term “treatment” as encompassing any remedy of a disease state or any symptom, prevention of a disease, or prevention or slowing of disease progression or of any symptom (paragraph [0081]). However, the disclosure does not describe evidence of or support for the use of RNA-guided RNA-targeting CRISPR systems to treat, prevent, slow, or ameliorate RNA virus-associated diseases of any nature. The art at the time of filing teaches that, while Cas13 CRISPR systems—RNA-guided RNA-targeting gene editing systems—showed promise for the treatment of infections caused by RNA viruses, and in vitro such Cas13 systems were shown to reduce viral titers of targeted viruses, much more research and work were needed in order to determine and facilitate effective and safe use of Cas13-CRISPR systems to treat viral infections in animal models in vivo and in human subjects (see Freije, 2019).
Furthermore, the art at the time of filing teaches that CRISPR systems are intolerant of mismatches between a guide RNA and a target sequence; Anderson teaches that two or more mismatches between a gRNA and a target sequence significantly reduce or render negligible the hybridization of the gRNA to the target sequence. gRNAs less than 100% complementary to a target sequence could not reasonably be assumed to effectively hybridize to the target sequence, as required by the recited methods. Additionally, the recited gRNAs specifically target the 3D polymerase protein of enterovirus 71 (EV71). A person of ordinary skill in the art would not be able to reasonably assume that these guide RNAs would be capable of hybridizing to a 3D polymerase protein-coding sequence of every enterovirus whose genome encodes a 3D polymerase protein, nor that these guide RNAs would be capable of hybridizing to any protein-coding sequence of any enterovirus whose genome does not encode a 3D polymerase protein.
The specification as filed thus does not provide guidance that overcomes this unpredictability within the art.
The existence of working examples:
What is enabled by the working examples is different to the breadth of the claims: The specification discloses in vitro assays and applications (paragraphs [00105]-[00109]; Figs. 2, 5-8). Of these working examples, only inhibition of EV71 is tested—no other RNA virus is tested for inhibition by the molecular systems and methods claimed (see of the working examples and figures, for example, Fig. 8). The specification does not disclose in vivo methods or results, either in animal models or in human subjects, nor does the specification disclose any method of inhibiting in vitro a virus that is not EV71.
The quantity of experimentation needed to make or use the invention:
The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention is the treatment, prevention, amelioration, or slowing of any disease merely associated with infection by an RNA virus, a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials, or in animal models that are predictive of treatment in a representative number of diseases associated with RNA virus infection, including HFMD, in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, Claims 59-64, 66-67, 81, 84, 86-94 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive.
Applicant argues that “a person skilled in the art would understand that the guide RNAs used to target the 3D polymerase gene in enterovirus 71 (EV71) can also be used to target the 3D polymerase gene in other viruses in the Enterovirus genus having the same conserved sequences, and thereby treat diseases associated with or caused by infection, propagation and/or replication of viruses of the Enterovirus genus” (page 18). Applicant also provides alignment of SEQ ID NOs:2, 3, and 5 to the 3D polymerase gene from coxsackievirus A2, having 1-3 mismatches to the gene, which, based on what was known in the art, would reasonably be expected to be sufficiently few mismatches to enable targeting of that gene by those gRNA (see pages 18-19 of arguments).
What is argued in the rejection above, in part, is that the claimed gRNA sequences of SEQ ID NOs:1-6 cannot reasonably be assumed by an artisan to target a gene in any enterovirus species, and thus cannot reasonably be assumed to have antiviral effects in any enterovirus species. While Applicant shows convincing evidence that coxsackievirus A2 3D polymerase gene can be targeted in vitro by at least some of the claimed gRNA sequences, and thus an artisan could reasonably expect the claimed compositions to have an antiviral effect against coxsackievirus A2 in vitro, EV71 and coxsackievirus A2 are not representative of the entire enterovirus genus. For example, the enterovirus genus comprises polioviruses. A BLAST search of SEQ ID NOs:1-6, limited to the human poliovirus genus, does not produce any results for SEQ ID NOs:2-3, and produces alignments of 28-39% identity to SEQ ID NOs:1 and 4-6 in the human poliovirus genome (see alignments below).
SEQ ID NO:1:
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101
1362
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Greyscale
SEQ ID NO:4:
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99
1364
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Greyscale
SEQ ID NO:5:
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100
1360
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Greyscale
SEQ ID NO:6:
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164
1356
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Greyscale
The claimed gRNA sequences can only be reasonably assumed to have an antiviral effect against enteroviruses comprising a 3D polymerase gene in their genome which comprises sequences having at most 2-3 mismatches with the claimed gRNA sequences; however, as exemplified by the alignment of SEQ ID NOs:1-6 to the human poliovirus genome, not all enteroviruses can be reasonably assumed to have the necessary genome sequences to enable targeting by the claimed gRNAs. While EV71 has been shown in the Applicant’s Drawings to be effectively targeted in vitro by the claimed gRNAs, and the degree of complementarity between the claimed gRNAs and the coxsackievirus A2 3D polymerase gene would reasonably indicate that coxsackievirus A2 could also be targeted in vitro by the claimed molecular system, Applicant has not shown that any enterovirus species could be targeted in vitro by the claimed molecular system, and known genome sequences of other enteroviruses, including human poliovirus, indicate that the claimed molecular system would not be effective in targeting any enterovirus species.
Furthermore, Applicant has not provided evidence that the in vitro results provided can be assumed to translate to in vivo efficacy. In order to reasonably assume that the claimed molecular systems were enabled to treat any disease, an artisan would need to be able to reasonably assume that the molecular systems, when administered in vivo, would exhibit antiviral activity. However, Applicant has only provided in vitro assays showing reduction in EV71 viral plaques and viral titers. As discussed in the rejection above, the art at the time of filing taught that it was yet uncertain whether antiviral CRISPR systems could be effectively used in vivo to treat viral diseases. Based on the prior art and the results shown by Applicant, an artisan would not be able to reasonably assume that the in vitro antiviral efficacy of the claimed molecular system would translate to sufficient in vivo antiviral efficacy to enable treatment of a disease associated with an enterovirus species.
For the reasons described above, the enablement rejection of the pending claims, under 35 USC 112(a), is maintained.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 54-58, 68-79, 80, 82-83, 85 is/are rejected under 35 U.S.C. 103 as being unpatentable over Guo (CN110548134A), in view of Konermann (2018). This is an amendment of the previously-presented, maintained rejection of claims under 35 USC 103 over Guo in view of Konermann, necessitated by claim amendments.
Regarding claims 1 and 54, Guo teaches a molecular system comprising an RNA-guided RNA-targeting effector protein (Cas13a) and one guide RNA (crRNA), wherein the gRNA targets the EV71 3D protein (paragraphs [0057]-[0060]). The specific gRNA sequence taught by Guo which targets the EV71 3D protein (see paragraph [0060]) is not at least 70% identical to SEQ ID NOs:1-6. However, Guo explicitly teaches that the protein 3D is a structural gene of the EV71 virus and thus a reasonable target for the CRISPR system of Guo (paragraph [0058]). gRNAs can be designed to target any known genomic sequence. It would have been obvious to a person of ordinary skill in the art at the time of filing that gRNAs could be designed to target other sequences within the 3D protein-coding sequence in order to achieve the targeting of the 3D protein-coding sequence by the CRISPR system of Guo. As such, gRNAs of SEQ ID NOs:1-6 would have been obvious to synthesize and try in the system of Guo.
Regarding claim 55, Guo teaches that the RNA-guided RNA-targeting effector protein is an RNA-guided RNA-targeting Cas protein (Cas13a) (paragraphs [0057]-[0058]).
Regarding claim 56, Guo teaches that the Cas protein is Cas13a (paragraphs [0057]-[0058]).
Regarding claim 58, Guo teaches gRNAs which target the same protein as SEQ ID NOs:1-6 (Enterovirus EV71 3D protein) (paragraphs [0057]-[0060]). It would have been obvious to a person of ordinary skill in the art at the time of filing that gRNAs could be designed to target any sequence within the coding sequence of the EV71 3D protein in order to target a CRISPR system to the EV71 3D protein. It therefore would have been obvious, based on the crRNA taught by Guo, to synthesize and try crRNA sequences of SEQ ID NOs:1-6 to target the same protein as Guo with the molecular system of Guo.
Regarding claim 69, Guo teaches gRNAs which target the same protein as SEQ ID NOs:1-6 (Enterovirus EV71 3D protein) (paragraphs [0057]-[0060]). It would have been obvious to a person of ordinary skill in the art at the time of filing that gRNAs could be designed to target any sequence within the coding sequence of the EV71 3D protein in order to target a CRISPR system to the EV71 3D protein. It therefore would have been obvious, based on the crRNA taught by Guo, to synthesize and try crRNA sequences of SEQ ID NOs:1-6 to target the same protein as Guo.
Regarding claim 77, Guo teaches a composition comprising a polynucleotide (a crRNA) (paragraphs [0057]-[0060]).
Regarding claim 78, Guo teaches that the composition further comprises an RNA-guided RNA-targeting effector protein (paragraphs [0057]-[0058]).
Regarding claim 79, Guo teaches that the RNA-guided RNA-targeting effector protein is Cas13a (paragraphs [0057]-[0058]).
Regarding claims 82-83, Guo teaches gRNAs which target the same protein as SEQ ID NOs:1-6 (Enterovirus EV71 3D protein) (paragraphs [0057]-[0060]). It would have been obvious to a person of ordinary skill in the art at the time of filing that gRNAs could be designed to target any sequence within the coding sequence of the EV71 3D protein in order to target a CRISPR system to the EV71 3D protein. It therefore would have been obvious, based on the crRNA taught by Guo, to synthesize and try crRNA sequences of SEQ ID NOs:1-6 to target the same protein as Guo.
However, Guo does not teach that the Cas protein is CasRx, nor does Guo teach vectors comprising the gRNAs or the molecular systems.
Konermann teaches that CasRx is a Cas13 variant that is preferable for use in human cells, and teaches that CRISPR systems and components of CRISPR systems can be comprised in vectors for delivery to cells.
Regarding claims 57-58 and 80, Konermann teaches the Cas13 variant CasRx (Abstract; pages 669-672; Fig. 4D; Fig. S5).
Konermann teaches that the CasRx variant exhibits greater targeting and gene knockdown efficiency than Cas13a (Guo utilizes Cas13a). Because of this increased efficacy, it would have been obvious to a person of ordinary skill in the art at the time of filing that the Cas13a of Guo should be replaced with the CasRx of Konermann in the molecular system of Guo, in order to increase the rate of gene knockdown by the system of Guo.
Regarding claims 1, 54, 58, 60, and 71, Konemann teaches that the introduction of multiple gRNAs targeting a single protein-coding sequence results in greater targeting efficiency than the introduction of a single gRNA targeting this protein-coding sequence (Fig. 6B). Konemann also teaches that the AAV vector has an inherent limit of the length of a polynucleotide sequence the AAV vector can encapsulate (page 672; limit of 4.7kb). The 3-gRNA-comprising cargo sequence depicted in Fig 6C is under 4.3kb long, at least 400bp shorter than the maximum possible length. Each gRNA is, at most, 66 nucleotides long (Figs. S4A, S2D)—in other words, the AAV donor sequence of Fig. 6C can accommodate at least three more gRNA sequences. It would have been obvious to a person of ordinary skill in the art that the targeting efficiency of the CasRx system could be improved by the use of multiple different gRNAs targeting the same target sequence, and that the efficiency of the 4-gRNA system of Konermann (Fig. 6B) could be further improved by the addition of more gRNA sequences to the CasRx system, including 6 gRNAs.
Regarding claim 68, Konermann teaches a polynucleotide encoding a molecular system comprising one or more gRNAs and a CasRx-encoding polynucleotide sequence (Fig. 6C).
Regarding claim 69, Konermann teaches a vector encoding one or more gRNAs (Fig. 6C).
Regarding claim 70, Konermann teaches a vector encoding four different gRNAs (Fig. 6B-C).
Regarding claims 72-76, Konermann teaches that the CasRx-gRNA molecular system is encoded in an AAV1 vector (pages 672-673; Fig. 6).
Regarding claim 85, Konermann teaches a composition comprising the vector (page e6).
As discussed above, the teachings of Konermann would have rendered obvious to a person of ordinary skill in the art at the time of filing that the Cas13a of Guo should be replaced with the CasRx of Konermann, imparting increased targeting efficiency. It would have been further obvious that an additional benefit imparted by using CasRx instead of Cas13a would be the smaller size of CasRx (Konermann page 672), allowing for the encapsulation of a CasRx-gRNA system in a AAV vector, which vector has a small packaging capacity, but is a preferable delivery vehicle, as AAV vectors are available in a “broad range of capsid serotypes” and exhibit “low levels of insertional mutagenesis” and lack apparent pathogenicity (page 672), allowing great versatility when used to introduce a CasRx-gRNA system into different cell populations. The teachings of Konermann thus render obvious an AAV1 vector comprising the molecular system of Guo and Konermann.
Furthermore, Konermann teaches that a multi-gRNA system, wherein multiple gRNAs targeting the same target polynucleotide are introduced together to the target polynucleotide or a target cell, exhibits greater targeting efficiency than a single-gRNA system. It therefore would have been obvious to a person of ordinary skill in the art that the efficiency of the single g3D gRNA-Cas13a system of Guo (see Guo Fig. 17) could be further improved by the addition to the molecular system of one or more additional, different gRNAs targeting the 3D protein-coding sequence. Additionally, as discussed above, the small size of the CasRx protein-coding sequence allows for the insertion of six or more gRNA-encoding sequences in the AAV-encapsulated donor sequence, based on the teachings of Konermann. It would have been further obvious to a person of ordinary skill in the art at the time of filing that the targeting efficiency of a four-gRNA system, as in Konermann, could be further improved by the inclusion of additional gRNA sequences (see Konermann Fig. 6B, the targeting efficiency is below 100%).
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive.
Applicant has argued that a collection of at least four different gRNAs at least 85% identical to SEQ ID NOs:1-6 are not rendered obvious by the combined teachings of Guo and Konermann for the following reasons: the individual recited gRNAs “did not show any antiviral activity when used individually” but the collection of at least four different recited gRNAs did show antiviral activity; “the specific guide RNA sequences, as recited in the claims, provide a special technical effect, i.e., or unexpected results, an effect or results that could not have been expected from reading Guo” (page 21); the individual gRNAs of Konermann alone show effectiveness in exon skipping, enhanced by the combination of multiple gRNAs, while the instant guide RNAs “did not show any antiviral activity when used individually”.
While Applicant asserts that gRNAs of SEQ ID NOs:1-6, when used individually, did not exhibit antiviral activity, and Applicant indicates Fig. 7 as evidence of such, subsequent Fig. 8 indicates that AAV vectors encoding single gRNAs of SEQ ID NOs:1-6 (AAV-CasRx-EV71-3Dg1, AAV-CasRx-EV71-3Dg2, AAV-CasRx-EV71-3Dg3, AAV-CasRx-EV71-3Dg4, AAV-CasRx-EV71-3Dg5, AAV-CasRx-EV71-3Dg6) result in significant reduction in EV71 virus plaque counts in vitro, and AAV vectors encoding multiple different gRNAs result in greater reduction in virus plaque counts in vitro. As such, an artisan testing individual gRNAs targeting the 3D protein gene of EV71, based on the results of Guo targeting a gRNA to EV71 3D protein gene and on the teachings of Konermann regarding the increased efficacy of using multiple different gRNAs targeting the same gene compared to using a single gRNA, would not conclude, based on the results of any individual gRNA at least 85% identical to instant SEQ ID NOs:1-6, that any one of SEQ ID NOs:1-6 were ineffective. Furthermore, the 3D protein-targeting gRNA of Guo was shown to be effective in reducing EV71 plaque counts (see Guo Drawings). An artisan would reasonably conclude, based on the teachings of Guo, that any gRNAs targeting EV71 3D protein could reduce EV71 plaque counts in vitro, and thus that any feasible gRNA target sequence within the EV71 3D protein gene should be tested. And, furthermore, based on the teachings of Konermann regarding the increased efficacy of targeting multiple gRNAs to different sequences within the same gene compared to targeting a single gRNA to the gene, an artisan would reasonably expect that a greater reduction in EV71 plaque count could be achieved by targeting multiple gRNAs to different sequences within the EV71 3D protein gene, including and in addition to the 3D protein gene-targeting gRNA taught by Guo, and thus, gRNA sequences targeting the EV71 3D protein gene should be tested in combination.
Additionally, while Applicant asserts that gRNAs of SEQ ID NOs:1-6 individually produce unexpected results that could not have been predicted by the teachings of Guo, the Applicant does not indicate specific evidence of the unexpected results of gRNAs of SEQ ID NOs:1-6. The teachings of Konermann, as discussed in the rejection and rebuttal above, would suggest to an artisan at the time of filing that combinations of four different gRNAs targeting one gene would exhibit enhanced effects compared to the use of single gRNAs targeting the same gene, rendering obvious the combination of four different gRNAs targeting EV71 3D protein gene to enhance the antiviral effects of the CRISPR system of Guo. Furthermore, an artisan would reasonably expect, based on the teachings of Guo, that gRNAs targeting the EV71 3D protein gene would result in decreased EV71 viral plaques. Applicants have not provided evidence that an artisan would not be able to reasonably expect that any gRNA targeting the EV71 3D protein gene would have an antiviral effect.
As a result, Applicant’s arguments are not considered persuasive, and the rejection of pending claims under 35 USC 103 is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 54-64, 66-94 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 16-27 of copending Application No. 18838911, in view of Konermann (2018). This rejection is maintained.
The methods of the copending application recite all required limitations of the instant claims except for the use of the CasRx protein, reading on both the compositions and the methods recited by the instant claims. The copending claims recite methods of treating RNA viral infections, the methods comprising administering an AAV vector comprising a Cas13 nuclease and one or more gRNAs. The copending claims further recite the same RNA viruses, Cas13 nucleases (Cas13a, Cas13b, Cas13c, Cas13d), AAV vector serotypes, and gRNAs at least 70% identical to instant SEQ ID NOs:1-6.
However, as noted above, the copending application does not recite the specific Cas13d orthologue CasRx.
Konermann teaches the CasRx orthologue.
Regarding claims 57-58 and 80, Konermann teaches the Cas13 orthologue CasRx (Abstract; pages 669-672; Fig. 4D; Fig. S5).
Konermann teaches that the CasRx variant exhibits greater targeting and gene knockdown efficiency than other Cas13d orthologues. Because of this increased efficacy, it would have been obvious to a person of ordinary skill in the art at the time of filing that the Cas13d of the copending application should be replaced with the CasRx of Konermann in the molecular system and methods of the copending application, in order to increase the rate of gene knockdown by the copending methods.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 12/29/2025 have been fully considered but they are not persuasive.
Applicant has argued that the copending claims do not require the “specific feature of at least four different gRNAs selected from sequences having at least 85% identity to any one of SEQ ID NOs: 1 to 4”, which “confers an unexpected synergistic effect” (page 22). The copending claims recite the use of one or more gRNAs of SEQ ID NOs:1-20 (see claims 1, 22, for example). Copending SEQ ID NOs:1-6 are identical to instant SEQ ID NOs:1-6, and “one or more gRNAs” encompasses any number of gRNAs greater than or equal to one, including four. Furthermore, the copending specification renders obvious that the one or more gRNAs of SEQ ID NOs:1-20 recited in the claims encompass four or more gRNAs (see page 10, “The method as defined herein may comprise administering 1, 2, 3, 4, 5, 6 or more different guide RNAs to a subject. The method may comprise administering 6 different guide RNAs, wherein each of the guide RNAs comprise i) a first nucleic acid sequence having at least 70% sequence identity to a nucleic acid sequence encoded by one of the nucleic acid sequences set forth in SEQ ID NO:1-6”). As such, the copending claims are considered to encompass the limitations of the instant claims, and the rejection for nonstatutory double patenting is 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 AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached on (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
For those applications where applicant wishes to communicate with the examiner via Internet communications, e.g., email or video conferencing tools, the following is a sample authorization form which may be used by applicant:
"Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file."
To facilitate processing of the internet communication authorization or withdraw of authorization, the Office strongly encourages use of Form PTO/SB/439, available at www.uspto.gov/patent/patents-forms. The form may be filed via EFS-Web using the document description Internet Communications Authorized or Internet Communications Authorization Withdrawn to facilitate processing. See MPEP 502.03(II).
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.
/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/RAM R SHUKLA/ Supervisory Patent Examiner, Art Unit 1635