DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/02/2026 has been entered.
Disposition of Claims
Claims 1-20 remain pending. Amendments to claims 1, 15-16, and 18 are acknowledged and entered.
Examiner’s Note
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
All paragraph numbers citing the specification are in reference to the USPGPub of this application, US20220325298A1, Pub. 10/13/2022, unless otherwise noted.
Response to Arguments
Applicant's arguments filed 03/02/2026 regarding the previous Office action dated 12/29/2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Claim Rejections - 35 USC § 112(b); Second Paragraph
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(New rejection.) Claims 1, 8, and 18 and dependent claims 2-7, 9-17, and 19-20 thereof 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.
Claims 1 and 18 are drawn to an HSV vector which comprises elements for CRISPR/Cas delivery to a target cell. Both claims 1 and 18 note that the vector would comprise one or more polynucleotides encoding one or more activators. Further claims dependent upon claim 1 note that there are additional polynucleotides that may encode one or more repressors. The term “activators” in claims 1 and 18 are a relative term which renders the claim indefinite. The term “activators” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Similarly, the term “repressor” in claim 8 is a relative term which renders the claim indefinite. The term “repressor” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Both claims 1 and 18 are broadly drawn to the HSV comprising a “cas nuclease”, with claim 8 depending upon claim 1. However, activators and repressors in the context of CRISPR/Cas9 systems are almost exclusively utilized with “dead” Cas9 (dCas9). While regular (wild-type) Cas9 is an endonuclease designed to cut DNA, dCas9 is a mutated, catalytically inactive version that can only bind to DNA, making it the ideal tool for recruiting effectors without causing permanent DNA damage. Typically, dCas9 or the associated gRNA has activator domains (like VP64) or repressor domains (like KRAB) fused directly to said dCas9/gRNA to allow it to be sensitive to the appropriate activator or repressor. Further, while there is an “activation gRNA scaffold” claimed, said scaffold must comprise two PP7 stem loops and is therefore limited to activation from specific activators. Therefore, as claims 1 and 18 are generically drawn to the use of any cas nuclease and any activator, and claim 8 is drawn generically to any “repressor”, it is unclear how the system would be activated (or repressed) as 1) the term is a relative term and 2) even when the identity of the “activator” or “repressor” is provided, specific structural guidance in the claim is not provided as to how it works in the claimed system. It is unclear if the “activator” encoded by the nucleotide sequence of part (b) in each claim must act directly upon the activation gRNA scaffold or acts in a more generalized “activation” manner in the system. Further dependent claims are drawn to the activators being VP64, p65, Rta, HSF1, and combinations thereof, but none of these proteins bind directly to the PP7 RNA hairpin, and require fusion to another protein, such as PP7 coat protein (PCP). As it is unclear structurally and functionally what is being claimed by the “activators” and “repressors”, and how said proteins can be used with all types of cas nucleases, the instant claims are rejected on the grounds of being indefinite.
Since a skilled artisan would not be reasonably apprised as to the metes and bounds of the claimed invention, instant Claim(s) 1, 8, and 18 are rejected on the grounds of being indefinite. Claim(s) 2-7, 9-17, and 19-20 are also rejected since they depend from claim 1, 8, or 18, but do not remedy these deficiencies of claim 1, 8, or 18.
(New rejection.) Claim 5 is 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.
Claim 5 is drawn to “wherein the target sequence is selected from the group consisting of SCN9A, MyD88, PENK, GAD1, KCNA2, and combinations thereof.” However, this Markush group does not comprise actual target sequences, but instead is drawn to target genes or target proteins in a more generic sense. It is unclear by providing the protein name as to what the target sequence would be (e.g. open reading frame (ORF) of said protein, regulatory elements, etc.) Further, in typical CRISPR/Cas9 systems, the target sequence must immediately precede a 2-6 base pair DNA sequence known as a protospacer adjacent motif (PAM). One suggestion is to amend the claim along the lines of the following:
“The HSV vector of claim 1, wherein the one or more gRNA(s) bind to one or more target sequence(s) within an open reading frame of a protein from the group consisting of SCN9A, MyD88, PENK, GAD1, KCNA2, and combinations thereof.”
For at least these reasons, the metes and bounds of claim 5 are unclear.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a recombinant herpes simplex virus (HSV) vector comprising one or more polynucleotides encoding:
(a) at least one guide RNA (gRNA) comprising:
(i) one or more guide sequences that hybridize to a target sequence, and
(ii) one or more activation gRNA scaffolds comprising an aptamer target site specific for an RNA binding protein, wherein the one or more activation gRNA scaffolds comprise two PP7 stem loops;
(b) one or more polynucleotides encoding one or more activators; and
(c) a Cas nuclease.
NB: “aptamers” are being interpreted as “short, single-stranded DNA or RNA molecules that fold into specific 3D shapes to bind targets like proteins or small molecules with high affinity, acting like synthetic antibodies.
Further limitations on the HSV vector of claim 1 are wherein the HSV vector is HSV-1 (claim 2); wherein the Cas nuclease is Cas9 nuclease (claim 3), wherein the one or more polynucleotides encoding Cas9 protein comprise the nucleotide sequence of SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41 (claim 4); wherein the one or more gRNA(s) bind to one or more target sequence(s) within an open reading frame of a protein from the group consisting of SCN9A, MyD88, PENK, GAD1, KCNA2, and combinations thereof (claim 5); wherein the guide sequence is selected from the group consisting of:(a) one or more of SEQ ID NOs: 1-7; (b) one or more of SEQ ID NOs: 8-12; (c) one or more of SEQ ID NOs: 13-20; (d) one or more of SEQ ID NOs: 21-28; (e) one or more of SEQ ID NOs: 29-35; and (f) combinations thereof (claim 6); wherein HSV vector comprises at least two guide RNAs (gRNAs)(claim 7); further comprising one or more polynucleotides encoding one or more repressors (claim 8), wherein the one or more repressors are selected from the group consisting of Hpla, Krab,MeCP2, and combinations thereof (claim 9), wherein the one or more polynucleotides encoding one or more repressors comprise the nucleotide sequence of SEQ ID NO: 42 or SEQ ID NO: 43 (claim 10), further comprising one or more repression gRNA scaffolds (claim 11); further comprising one or more polynucleotides encoding one or more activators (claim 12), wherein the one or more activators are selected from the group consisting of VP64, p65, Rta, HSF1, and combinations thereof (claim 13), wherein the one or more polynucleotides encoding one or more activators comprises the nucleotide sequence of SEQ ID NO: 44 (claim 14), comprising two or more activation gRNA scaffolds (claim 15); wherein the one or more activation gRNA scaffolds comprise the nucleotide sequence of SEQ ID NO: 37 (claim 16); and a pharmaceutical composition comprising the HSV vector of claim 1 and a pharmaceutically acceptable carrier (claim 17).
Claim 18 is drawn to a multiplexed CRISPR-based circuit comprising: (a) one or more guide RNAs (gRNAs) comprising (i) one or more guide sequences complementary to a portion of target sequence and (ii) one or more activation gRNA scaffolds, wherein the one or more activation gRNA scaffolds comprise two PP7 stem loops; (b) a nucleotide sequence encoding one or more activators; and (c) a nucleotide sequence encoding a Cas nuclease.
Claim 19 is drawn to a pharmaceutical composition comprising the multiplex CRISPR-based circuit of claim 18 and a pharmaceutically acceptable carrier.
Claim 20 is drawn to a method for ameliorating pain in a subject, the method comprising administering to the subject a therapeutically effective amount of the HSV vector of claim 1, thereby ameliorating pain in the subject.
Claim Rejections - 35 USC § 112(a); First Paragraph
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.
(New rejection.) Claims 1-20 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.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice .... reduction to drawings .... or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1-20 are rejected as lacking adequate descriptive support for any herpes simplex virus (HSV) vector comprising any guide RNA (gRNA) that hybridizes to any target sequence and any sequences encoding any activators along with any cas nuclease. The specification fails to reasonably convey applicant was in possession of the claimed genera at the time of the invention.
In support of the claimed genera (any HSV vector, any gRNA that binds to any target sequence, any activators encoded by said HSV vector, any cas nuclease), the application discloses one example regarding aptamer-mediated CRISPR epigenetic modulation in vitro, wherein gRNAs with SEQ ID NOs: 1-35 which hybridize to a portion of target gene involved in nociceptive processing (Scna9, Myd88, Penk, GAD1, or Kcna2) were transfected along with a plasmid encoding dCas9 (a nuclease-dead Cas9 which remains competent for DNA binding but lacks endonuclease activity) and an effector cassette ( MS2-HP1a-KRAB or PCP-VP64-P65AD-BRLF-1AD). The concrete gRNA examples are from specific genes involved in nociception, namely SEQ ID NOs: 1-7 that correspond to SCN9A, SEQ ID NOs: 8-12 that correspond to MyD88, SEQ ID NOs: 13-20 that correspond to PENK, SEQ ID NOs: 21-28 that correspond to GAD1, and SEQ ID NOs: 29-35 that correspond to KCNA2. It is not clear if these sequences target the open reading frame (ORF) of the gene itself or if they target regulatory elements regarding these genes; regardless, these limited examples do not embody the breadth of “any gRNA capable of hybridizing to any target sequence”. The only cas endonuclease tested actually lacks endonuclease activity (dCas9), and no other cas endonucleases aside from Cas9 were disclosed. While Cas9 endonucleases are compatible with PP7 scaffolds, certain other cas endonucleases are not compatible with said scaffolds, such as Cas12a/Cpf1 or dCas12e. Example 1 does not utilize any HSV vector, and Example 2 only prophetically speaks of HSV vectors. While HSV vectors are known in the art, they are modulated to be highly specific for the payload, target cell, and intended purpose. In the instant specification, there is insufficient description as to which HSV vector is best suited for this delivery (e.g. HSV-1 vs. HSV-2, attenuated/non-attenuated vector, if the vector is attenuated, if it can still target appropriate neural cells, where said CRISPR/Cas materials should be inserted into the HSV vector, etc.) With respect to the method, it is unclear as to which genes must be targeted to achieve the claimed function (e.g. “amelioration of pain in a subject”), as claim 1 is not drawn to any specific genes associated with any pain being targeted. Further, said method does not clarify how the HSV vector is to be delivered to achieve the desired functional outcome. Finally, as noted in the 35 USC 112b rejection supra, it is unclear how the “activator” and/or “repressor” are tied to the HSV vector system, and the systems tested in Example 1 utilized MS2-HP1a-KRAB or PCP-VP64-P65AD-BRLF-1AD, wherein the MS2-HP1a-KRAB effector is an enhanced CRISPR interference (CRISPRi) system used for strong transcriptional silencing, wherein MS2 is a bacteriophage coat protein that binds to MS2 hairpin aptamers added to the gRNA (protein that binds to activation gRNA scaffold), HP1a recruits chromatin remodeling factors to promote heterochromatin formation, and KRAB is a potent repressor domain that recruits other co-repressors to aid in silencing gene expression. The PCP-VP64-P65AD-BRLF-1AD effector is a CRISPR activation (CRISPRa) system, wherein PCP (Phage Coat Protein) is a specific RNA-binding protein that binds to a specific PP7 stem-loop on the gRNA to recruit the activator (protein that binds to the PP7 stem loops on activation scaffold), VP64 is a tetramer of the Herpes simplex virus VP16 activator, P65AD is the activation domain of NF-kappa B subunit p65, and BRLF-1AD is a potent transactivator from Epstein-Barr virus (EBV). No other activator or repressor systems appear to have been tested or engineered for Example 1, nor were any of these activator or repressor cassettes inserted into any HSV vector to determine if they retained functionality, as at least the activator system appears to comprise components which are homologous to domains or proteins found naturally within herpesviruses. Thus, the application fails to provide sufficient examples of representative species within the claimed genera.
Further, while the claims provide both a structure and a function, the application fails to draw any correlation between the two. In other words, the claims are drawn to claiming components by their function, rather than by their structure. For instance, the gRNA is claimed by its function (e.g. “hybridize to a target sequence”) rather than by its structure (e.g. sequences). Moreover, no correlation has been made with respect to the method as to which HSV vectors may be used in order to achieve the claimed function of ameliorating pain in a subject, as the data claims to be using those SEQ ID NOs: 1-35, but from the figures it is unclear as to which SEQ ID NO: corresponds to which testing condition, and, even so, certain gRNA clearly have little to no effect on their target proteins, whether they were intended to be activated or repressed (e.g. See Fig. 4). Further, the “activators” and “repressors” which may be encoded by the HSV vector are broadly claimed, and not specified until further dependent claims, and are not clearly structurally defined as set forth supra in the 35 USC 112b rejection, so said elements are being claimed solely by their function, and not by their structure.
Thus, in view of the above, there would have been significant uncertainty as to which HSV vectors to generate with which claimed CRISPR/cas elements and be able confer the claimed functions of hybridizing to targets and treatment of pain. In view of this uncertainty and the lack of sufficient examples of the claimed genera, the claims are rejected for lack of adequate written description support, as the specification fails to reasonably convey to a skilled artisan that the inventors has possession of the claimed invention as a whole.
(New rejection.) Claims 1-20 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.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to any recombinant herpes simplex virus (HSV) vector comprising one or more polynucleotides encoding:
(a) at least one guide RNA (gRNA) comprising:
(i) one or more guide sequences that hybridize to a target sequence, and
(ii) one or more activation gRNA scaffolds comprising an aptamer target site specific for an RNA binding protein, wherein the one or more activation gRNA scaffolds comprise two PP7 stem loops;
(b) one or more polynucleotides encoding one or more activators; and
(c) a Cas nuclease.
“Aptamers” are being interpreted as “short, single-stranded DNA or RNA molecules that fold into specific 3D shapes to bind targets like proteins or small molecules with high affinity, acting like synthetic antibodies.
“Cas nuclease” is any CRISPR-associated nuclease of Class 1 (multi-protein complexes) or Class 2 (single protein) systems. Cas9 nucleases (Class 2, Type II) are the most well-studied and generate double-stranded DNA breaks that produce blunt ends. There are over 65 distinct families of Cas proteins, divided into two classes, six types, and about 33 subtypes.
“Guide RNA” (gRNA) in CRISPR system is a synthetic or engineered RNA molecule that directs the Cas nuclease to a precise nucleic acid sequence for editing, wherein the editing encompasses enabling targeted gene knockouts, insertions, or modifications. It is typically composed of an approximately 20 nucleotide sequence that matches the target nucleic acid (spacer) and a scaffolding sequence that binds to the specific Cas enzyme being used. Types of gRNA include CRISPR RNA (crRNA) and sgRNA (single guide RNA, combining both crRNA and trans-activating RNA (tracrRNA)).
“Activators” is subject to a 35 USC 112b rejection regarding its definition (see supra).
“HSV” is either herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), and includes any variant, mutant, vector, or hybrid thereof. HSV is a large double-stranded DNA virus that can be engineered to carry large amounts of nucleic acid, and can target epithelial cells or cells of the nervous system (engineered forms can be generated to infect a wide variety of cell types.)
State of the prior art/Predictability of the art. Regarding the CRISPR/Cas art at the time of filing, CRISPR-mediated transcriptional activation (CRISPRa) or repression/interference (CRISPRi) systems generally employed a catalytically inactive “dead” cas9 nuclease (dCas9) in order to elicit the regulation desired without cleaving DNA. The dCas9 was directed by a guide RNA (gRNA) typically to regulatory regions of a target gene, such as promoter or enhancer regions, wherein fused or recruited transcriptional activators were able to increase/decrease the expression of the target protein. It was well understood in the CRISPRa/i art that this technology, in order to be effective, required precise targeting of the gRNA to specific genomic locations relative to the transcription start site, with resulting activity highly dependent not only on the position of the target site, but also local chromatin context and the presence of appropriate protospacer adjacent motif (PAM)(Karlson CKS, et. al. Plants (Basel). 2021 Sep 29;10(10):2055.; Synthego. Ch. 2: CRISPRa and CRISPRi: A Comprehensive Guide on CRISPR Methods. https://www.synthego.com/guide/crispr-methods/crispri-crispra/. Accessed 04/16/2026.)
Additionally, the art recognized that identifying functional guide RNA target sites was not straightforward, as transcription start sites may be poorly annotated, regulatory regions may be inaccessible, and activation efficiency varies significantly depending on the target site selection and promoter context (Fontana J, et. al. Nat Commun. 2020 Apr 1;11(1):1618.) The art also taught the use of modified gRNA scaffolds containing RNA aptamers, such as MS2 or PP7 stem loops, to recruit additional transactivator proteins. However, said systems remained sensitive to gRNA design parameters and target site positioning (Sanson KR, et. al. Nat Commun. 2018 Dec 21;9(1):5416.)
With respect to HSV vector systems, successful implementation of CRISPRa/i in any type of viral vector requires careful vector design to achieve targeted delivery and coordinated expression of the CRISPR components from the vector, further complicating the complexity of making and using CRISPRa/i systems. For instance, HSV vectors, namely HSV-1 based systems, are commonly studied vectors for gene delivery that offer unique advantages for expressing CRISPR/Cas9, including a large transgene capacity, strong neural or epithelial cell tropism, and the ability to maintain long-term, non-integrating episomal expression. HSV vectors are increasingly studied for complex genetic engineering in the central nervous system (CNS) and for designing therapeutic, "shock and kill" strategies for chronic infections (Wen Z, et. al. Elife. 2025 Apr 23;13:RP95964.; Verlengia G, et. al. Sci Rep. 2017 May 4;7(1):1507.) However, the art at the time of filing primarily focuses on the use of adeno-associated virus (AAV) and lentivirus-based delivery systems for CRISPR/Cas9 components (Dong W, et. al. Viruses. 2021 Jul 1;13(7):1288.; Yu W, et. al. Methods Mol Biol. 2019;1950:123-139.)
In summation, while CRISPRa/i systems were known, and HSV vectors were known, the art reflected the limitations in both of these systems and the components that required empirical testing to ensure the desired regulation of target genes, and generalized rules for such systems were not yet fully established.
Working examples. No working example is disclosed in the specification that has engineered any HSV vector that expresses any CRISPR system component. Example 1 as outlined above in the 35 USC 112a written description rejection notes the delivery of CRISPR components through transfection to N2a cells in vitro. Example 2 provides prophetic guidance as to HSV vectors that may be developed, but provides little structural guidance as to what vectors to use and where to insert the CRISPR materials into said vector. Example 1 utilizes gRNAs with SEQ ID NOs: 1-35 which hybridize to a portion of target gene involved in nociceptive processing (Scna9, Myd88, Penk, GAD1, or Kcna2) and were transfected along with a plasmid encoding dCas9 (a nuclease-dead Cas9 which remains competent for DNA binding but lacks endonuclease activity) and an effector cassette (MS2-HP1a-KRAB or PCP-VP64-P65AD-BRLF-1AD). The concrete gRNA examples are from specific genes involved in nociception, namely SEQ ID NOs: 1-7 that correspond to SCN9A, SEQ ID NOs: 8-12 that correspond to MyD88, SEQ ID NOs: 13-20 that correspond to PENK, SEQ ID NOs: 21-28 that correspond to GAD1, and SEQ ID NOs: 29-35 that correspond to KCNA2. It is not clear if these sequences target the open reading frame (ORF) of the gene itself or if they target regulatory elements regarding these genes; regardless, these limited examples do not embody the breadth of “any gRNA capable of hybridizing to any target sequence”. The only cas endonuclease tested actually lacks endonuclease activity (dCas9), and no other cas endonucleases aside from Cas9 were disclosed. While Cas9 endonucleases are compatible with PP7 scaffolds, certain other cas endonucleases are not compatible with said scaffolds, such as Cas12a/Cpf1 or dCas12e. Example 1 does not utilize any HSV vector, and Example 2 only prophetically speaks of HSV vectors. Only the effector cassette PCP-VP64-P65AD-BRLF-1AD comprises the material that would bind to a PP7 loop. No examples of treatment of any human or non-human subjects using any HSV vectors encoding any of the materials was provided, nor is it clear how said vectors would be delivered to said subjects.
Guidance in the specification. The specification provides prophetic guidance towards the generation of HSV vectors which encode CRISPRa/i -based materials, and for specifically targeting genes important in nociception.
Amount of experimentation necessary. Additional research is required in order to determine how effective the claimed HSV vectors would be in delivery of the CRISPRi/a materials to a subject in need thereof. The specification does not provide sufficient guidance to enable the skilled artisan to identify and design effective guide sequences across the full scope of the potential target sequences, nor does the specification provide sufficient guidance as towards what HSV vector may be used and where said CRISPRi/a sequences may be inserted into said vector. The specification fails to disclose criteria for selecting target sites within genes (e.g. promoter regions, enhancers, or ORFs) or guidance regarding factors affecting transcriptional activation efficiency, thereby requiring the skilled artisan to engage in extensive empirical testing to determine which gRNAs, vectors, activators, repressors, and nucleases would be able to be functionally expressed, especially in order to use said vectors in the methods claimed.
In light of the Supreme Court decision in Amgen Inc. et al. v. Sanofi et al., 143 S. Ct. 1243 (2023) (hereafter Amgen), updated guidelines were provided regarding the assessment of enablement (Federal Register, pp. 1563-1566; Pub. Jan. 10, 2024.) In Amgen, the Supreme Court unanimously affirmed that a genus of monoclonal antibodies were not enabled because when a range within a genus is claimed, there must be reasonable enablement of the scope of the range. The Court found in Amgen that due to the large number of possible candidates within the scope of the claims and the specification's corresponding lack of structural guidance, it would have required undue experimentation to synthesize and screen each candidate to determine which compounds in the claimed class exhibited the claimed functionality. In the instantly claimed invention, the experimentation that would be required to make the HSV vectors and use them in the methods as claimed would be undue in light of the breadth of the limitations within the instant claims and the unpredictability of CRISPRi/a and HSV vector systems.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed methods.
Claim Rejections - 35 USC § 102
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained and extended – necessitated by amendment.) Claims 1, 3, 5, 7-9, 11-13, 15, and 17-20 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et. al. (US20190359971A1, Pub. 11/28/2019; hereafter “Zhang”.)
The Prior Art
Zhang teaches a CRISPR/Cas9-based treatment of various physical ailments or symptoms resulting from specific diseases or infections, such as chronic pain (entire document; see abstract; ¶[0041][0230][0241][0270][0644][0684][0675][0726-0727][0863-0868].) Zhang teaches that said system would comprise a viral vector encoding the genome editing elements (¶[0034][0163][0708][0734]), such as a recombinant herpes simplex virus (HSV) vector (¶[0759]; reference claims 19, 37, 115, 137), wherein said vector is comprising one or more polynucleotides encoding at least one guide RNA (gRNA) (¶[0338][0519]) comprising (i) one or more guide sequences that hybridize to a target sequence (¶[0152][0711-0712]), and (ii) one or more gRNA scaffolds (¶[0285][0890][1031]) comprising an aptamer target site (¶[0020]) specific for an RNA binding protein, such as M2 (¶[0020]), (b) one or more polynucleotides encoding one or more activators, such as VP64 (¶[0047]); and (c) a Cas nuclease (entire document; see abstract; ¶[0008-0015]; reference claim 1.) Zhang also notes the one or more aptamer sequences may be a PP7 sequence, wherein the PP7 sequence inherently comprises a stem loop structure ¶[0425]), and that the gRNA includes either an activator or a repressor, with the sites for activator or repressor binding found in the gRNA, and wherein the actual activators or repressors may be introduced into the system in the form of fusion proteins (¶[0434][0452-0453]). Zhang therefore teaches every element required by instant claims 1 and 7. While Zhang notes the use of Cas13a is a preferred embodiment, Cas9 nuclease is also disclosed as an alternate embodiment (¶[0950][0989]; instant claim 3). Zhang teaches that for brain or other CNS expression, the targets could be Synapsin I, CaMKII-alpha, GAD67 (aka glutamate decarboxylase 1 or GAD-1), GAD65, or VGAT (¶[0548]), as well as KCNA-B1 (¶[0866]; instant claim 5). Zhang teaches that the system may encode one or more repressors, such as KRAB or SID4X (¶[0800][0816]; instant claims 8-9). Additional activators may be present, and can include VP64 (¶[0047]), p65, MyoD1, HSF1, RTA, SET7/9 or a histone acetyltransferase (¶[0815]; instant claims 12-13). Zhang teaches the vector may be within a pharmaceutical composition comprising a pharmaceutically-acceptable carrier (¶[0517-0520]; instant claim 17). The system may be a single or multiplexed system (¶[0507]). The use of “repression/activation gRNA” and “repression/activation gRNA scaffold” are interchangeable in the instant application (¶[0039-0040]), as the “scaffold” has not been specifically re-defined by the instant specification and is noted in the art as the conserved structural part of the gRNA that physically docks with the cas nuclease; the tracrRNA (trans-activating CRISPR RNA) contains the scaffold. Zhang teaches identifying tracr sequences in genomes of interest (¶[0476]) and that the system would comprise tracrRNA (¶[0151][0173][0500][0505][0720][0748]). As Zhang teaches the system may comprise one or more gRNA, and thus one or more gRNA scaffolds, and teaches that the gRNA may comprise one or more repressors and/or one or more activators, Zhang therefore teaches every aspect of the limitations of instant claims 11, 15, and 18-19. Zhang teaches the use of the pharmaceutical composition in methods of treatment in a subject in need thereof, through the administration of a therapeutically effective amount of the composition, for treatment of diseases, conditions, or symptoms, such as chronic pain (¶[0512-0520][0675][0728]; instant claim 20).
For at least these reasons, Zhang expressly or inherently teaches every aspect of instant claims 1, 3, 5, 7-9, 11-13, 15, and 17-20, and anticipates the invention encompassed by said claims.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive.
Applicant argues that Zhang fails to teach a system as claimed that has the activation gRNA scaffolds comprising two PP7 stem loops. As Zhang teaches the system may comprise one or more activation gRNA scaffolds, and teaches that the scaffold may be PP7, which inherently comprises a stem loop, it remains that Zhang teaches the limitations of newly amended claims 1 and 18.
Therefore, Applicant’s arguments are unpersuasive, and the rejection has been maintained.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(Rejection maintained.) Claim 4 remains rejected under 35 U.S.C. 103 as being unpatentable over Zhang as applied to claims 1, 3, 5, 7-9, 11-13, 15, and 17-20 above, and further in view of Ewaisha et. al. (WO2019018041A1; Pub. 01/24/2019; CITED ART OF RECORD; hereafter “Ewaisha”.)
The rationale behind this rejection was presented in a prior Office action and will not be repeated herein.
(Rejection maintained.) Claim 2 remains rejected under 35 U.S.C. 103 as being unpatentable over Zhang as applied to claims 1, 3, 5, 7-9, 11-13, 15, and 17-20 above, and further in view of Ruan et. al. (US20190022192A1, Pub. 01/24/2019; CITED ART OF RECORD; hereafter “Ruan”.)
The rationale behind this rejection was presented in a prior Office action and will not be repeated herein.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive.
Applicant argues that neither Ruan nor Ewaisha fails to teach the limitations added to amended claims 1 and 18, namely the addition of activator gRNA scaffolds with PP7 stem loops, and thus fail to cure the deficiencies of Zhang. However, Zhang was not determined to be deficient in their teachings of this limitation, so the anticipation rejection regarding Zhang was maintained, as were the rejections utilizing the teachings of Ewaisha and Ruan.
No further arguments regarding Ewaisha or Ruan were presented.
For at least these reasons, Ruan and Ewaisha are still relevant to the obvious nature of the amended claims.
Double Patenting
The text regarding nonstatutory double patenting was presented in a previous Office action.
(Rejection maintained and extended – necessitated by amendment.) Claims 1-15 and 17-20 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 9-11 of U.S. Patent No. 11,884,925 as evidenced by Liu et. al. (Liu F, et. al. J Neuroinflammation. 2017 Mar 31;14(1):70.; CITED ART OF RECORD; hereafter “Liu”) and Zhang (detailed supra).
Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to a synthetic system which encodes a gRNA targeting MyD88 and gRNA engineered to comprise a hairpin aptamer target site specific for an RNA binding protein (MS2 in the ‘925 patent; NB: at least one reasonable interpretation of the ”scaffold” language rejected under 35 USC 112b supra includes hairpin aptamer target sites specific for an RNA binding protein, see instant specification at ¶[0010]; also see discussion of “scaffold” as per the instant specification supra detailed in the Zhang teachings.) While the instant claims are drawn to two PP7 stem loops as the activation scaffold, such a difference would be obvious to try in the claims of ‘925 as 1) both PP7 and MS2 targeting domains are known in the CRISPR art and are equivalents that can be substituted for one another and 2) since they both have different proteins target to their locations, they can also be used together as they can target different effectors (e.g. an activator to one location, a repressor to another) to different areas of the genome simultaneously. Further, the use of both is envisioned by the teachings of Zhang, that notes two or more of the same or different adapters may be used in the system, and notes MS2 and PP7 as common aptamers (¶[0425]).
Reference SEQ ID NO: 55 is 100% identical to instant SEQ ID NO: 43. Both claim the system encodes cas nuclease, both claim the system is delivered via a viral vector. Both claim the system may comprise a repression domain, such as a KRAB domain or HDT1 domain. Both claim the use of cas9 nuclease, and both claim the system may be within a pharmaceutical composition comprising pharmaceutically acceptable carriers. While the instant claims are targeting MyD88 for the alleviation of pain, such a method of using the CRISPR/Cas system of the ‘925 claims would be obvious as MyD88 is known in the art as a protein involved in inflammation, particularly in the development and maintenance of chronic pain conditions like neuropathic and inflammatory pain as evidenced by the teachings of Liu (entire document; see abstract.) Additionally, the ‘925 claims are specifically drawn to systems comprising repression systems (emphasis added), which the instant claims provide for systems comprising activation systems, with repression systems being an additional, dependent limitation. The use of both activation and repression systems in a single CRISPR/Cas9 system would be obvious to a skilled artisan, given the teachings of Zhang, who provides for specific, multiple repression and/or activation systems to be used in a CRISPR/Cas9 system delivered by an HSV vector. The language of the ’925 claims is open-ended, allowing for the inclusion of additional, unrecited elements. The additional elements, such as activation domains, would be obvious given the prior art, as taught by Zhang.
Therefore, the ‘925 claims are an obvious version of the instant claims, and the two sets of claims are not patentably distinct, especially in view of the teachings of Liu and Zhang.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive.
Applicant again argues that the ‘925 claims are drawn to the use of repression domains, and not activation domains as in the instant independent claims. First, dependent instant claims 8-9 and 11 provide for the construct to have repressors encoded within the system. Second, the ‘925 claims are open-ended, allowing for the inclusion of additional, unrecited elements, and such elements would be obvious additions to such a system, given the teachings of Zhang. Therefore, the question as to whether or not the improper timewise extension of patent rights is drawn to whether or not it would be obvious to modify the ‘925 claims to arrive at the instant claims. Again, as the ‘925 claims utilize open-ended claim language (“comprising”), this allows the inclusion of additional, unrecited elements not present in the claims. Further, the teachings of both Liu and Zhang to show the differences between the instant claims and the patented claims would be obvious modifications for a skilled artisan to make. Therefore, such an argument is not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Finally, Applicant argues the amendments to claims 1 and 18 further distinguish the ‘925 claims from those of the instant claims, as Zhang fails to teach PP7 stem loops. As set forth supra with the anticipation argument, said argument was not persuasive, as Zhang clearly teaches one or more activating aptamers and/or repression aptamers may be used in a system, and that PP7 stem loops are an embodiment of said aptamers. Zhang also notes that PP7 and MS2 are equivalents with respect to CRISPR technology, which are used to guide specific effector proteins to the guide RNA, meaning it would be obvious to try and substitute one known element with another, given their known equivalent nature in the art and also their ability to be used simultaneously to target different effector proteins to different genomic locations without interfering with one another.
Therefore, this line of argument is not persuasive.
For at least these reasons, the instant claims remain rejected over those noted ‘925 claims.
(New rejection – necessitated by amendment.) Claims 1-15 and 17-20 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 9-13 of copending U.S. Patent Application 18/535,658 as evidenced by Kuchroo et. al. (US20160377631A1; Pub. 12/29/2016; CITED ART OF RECORD; hereafter “Kuchroo”) and Zhang (detailed supra).
Although the claims at issue are not identical, they are not patentably distinct from each other because both are drawn to methods of using in a therapeutic manner in a patient a synthetic system which encodes a gRNA targeting MyD88 and gRNA engineered to comprise a hairpin aptamer target site specific for an RNA binding protein (MS2 in the ‘658 claims; NB: at least one reasonable interpretation of the ”scaffold” language rejected under 35 USC 112b supra includes hairpin aptamer target sites specific for an RNA binding protein, see instant specification at ¶[0010]). While the instant claims are drawn to two PP7 stem loops as the activation scaffold, such a difference would be obvious to try in the claims of ‘658 as 1) both PP7 and MS2 targeting domains are known in the CRISPR art and are equivalents that can be substituted for one another and 2) since they both have different proteins target to their locations, they can also be used together as they can target different effectors (e.g. an activator to one location, a repressor to another) to different areas of the genome simultaneously. Further, the use of both is envisioned by the teachings of Zhang, that notes two or more of the same or different adapters may be used in the system, and notes MS2 and PP7 as common aptamers (¶[0425]).
Reference SEQ ID NO: 55 is 100% identical to instant SEQ ID NO: 43. Both claim the system encodes cas nuclease, both claim the system is delivered via a viral vector. Both claim the system may comprise a repression domain, such as a KRAB domain or HDT1 domain. Both claim the use of cas9 nuclease, and both claim the system may be within a pharmaceutical composition comprising pharmaceutically acceptable carriers. While the instant claims are targeting MyD88 for the alleviation of pain and the ‘658 claims are treating septicemia, both symptoms are known to be a result of the inflammatory pathways triggered by MyD88, which is known in the art as a protein involved in inflammation, particularly in the development and maintenance of chronic pain conditions like neuropathic and inflammatory pain as evidenced by the teachings of Kuchroo (entire document; see abstract; ¶[0009-0010][0023-0025][0062-0064][0192-0193]; Table 3.) Additionally, the ‘658 claims are specifically drawn to systems comprising repression systems (emphasis added), which the instant claims provide for systems comprising activation systems, with repression systems being an additional, dependent limitation. The use of both activation and repression systems in a single CRISPR/Cas9 system would be obvious to a skilled artisan, given the teachings of Zhang, who provides for specific, multiple repression and/or activation systems to be used in a CRISPR/Cas9 system delivered by an HSV vector. The language of the ‘658 claims is open-ended, allowing for the inclusion of additional, unrecited elements. The additional elements, such as activation domains, would be obvious given the prior art, as taught by Zhang.
Therefore, the ‘658 claims are an obvious version of the instant claims, and the two sets of claims are not patentably distinct, especially in view of the teachings of Liu and Zhang.
Response to Arguments
Applicant's arguments filed 03/02/2026 have been fully considered but they are not persuasive.
Applicant again argues that the ‘658 claims are drawn to the use of repression domains, and not activation domains as in the instant independent claims, and presents similar arguments to those detailed supra with the ‘925 patent claims. First, dependent instant claims 8-9 and 11 provide for the construct to have repressors encoded within the system. Second, the ‘658 claims, like the ‘925 claims, are open-ended, allowing for the inclusion of additional, unrecited elements, and such elements would be obvious additions to such a system, given the teachings of Zhang. Therefore, the question as to whether or not the improper timewise extension of patent rights is drawn to whether or not it would be obvious to modify the ‘658 claims to arrive at the instant claims. Again, as the ‘658 claims utilize open-ended claim language (“comprising”), this allows the inclusion of additional, unrecited elements not present in the claims. Further, the teachings of both Liu and Zhang to show the differences between the instant claims and the patented claims would be obvious modifications for a skilled artisan to make. Therefore, such an argument is not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Finally, Applicant argues the amendments to instant claims 1 and 18 further distinguish the ‘658 claims from those of the instant claims, as Zhang fails to teach PP7 stem loops. As set forth supra with the anticipation argument, said argument was not persuasive, as Zhang clearly teaches one or more activating aptamers and/or repression aptamers may be used in a system, and that PP7 stem loops are an embodiment of said aptamers. Zhang also notes that PP7 and MS2 are equivalents with respect to CRISPR technology, which are used to guide specific effector proteins to the guide RNA, meaning it would be obvious to try and substitute one known element with another, given their known equivalent nature in the art and also their ability to be used simultaneously to target different effector proteins to different genomic locations without interfering with one another.
Therefore, this line of argument is not persuasive.
For at least these reasons, the instant claims remain rejected over those noted ‘658 claims.
Allowable Subject Matter
(Objection maintained.) Claim 16 remains objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: SEQ ID NO: 37 appears to be novel and non-obvious.
Conclusion
No claims are allowed.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671
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