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 .
Election/Restrictions
Applicant’s election without traverse of Group I, Claims 1, 3, 5-6, 16, 18-23, 25, 26, 29, 45-46, and 49, drawn to a method of treatment of a neurological disorder associated with neuronal hyperexcitability and the species c-Fos, KCAN1 gene, seizure disorder and AAV in the reply filed on 05 June 2026 is acknowledged. Claims 21-22, 53, 59, and 62 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 3, 5-6, 16, 18-20, 23, 25, 26, 29, 45-46, and 49 are being examined on the merits.
Information Disclosure Statement
The information disclosure statements filed 06/09/2023 and 05/21/2025 have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 29 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.
Claims 29 recites “first nucleotide sequence comprising a neuronal activity-dependent
promoter” and depends from claim 1. The expression vector of claim 2 already comprises a neuronal activity-dependent promoter that drives the expression the gene product or the intermediate gene product. It is unclear if the expression vector comprises one neuronal activity-dependent promoter that drives the expression of both the gene product/intermediate gene product and the first nucleotide sequence or an additional promoter that drive the expression of the first nucleotide sequence.
Claims 1, 3, 5-6, 16, 18-20, 23, 25, 26, 29, 45-46, and 49 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.
For claims drawn to a genus, MPEP § 2163 states 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.
The claims encompass methods for treating a broad genus of neurological disorders associated with neuronal hyperexcitability using expression of a therapeutic gene of intermediate regulatory gene under the control of an activity-dependent promoter.
The specification, however, primarily describes and exemplifies treatment of epilepsy using expression of KCNA1/Kv1.1 or KCNJ2 constructs in hyperactive neurons. The specification does not provide representative species, or sufficient structural or functional guidance demonstrating possession of neurological disorders using the full scope of claimed therapeutic genes or intermediate regulatory genes. Furthermore, the specification encompasses any therapeutic gene product capable of ameliorating the disorder and any intermediate gene product capable of altering expression of such therapeutic gene products. The specification does not provide representative species spanning the breadth of these genera nor provide structural features common to members of the genera sufficient to demonstrate possession of the full scope of the claimed subject matter.
The art, as evidenced by Kawashima (Kawashima et al. Frontiers in neural circuits 8 (2014): 37) recognized that different activity promoters exhbit different cell-type specificity, expression patterns vary substantially between brain regions, selection of the appropriate promoter depends on the target neuronal subtype and brain region, and no universal activity-dependent promoter exists for all neuronal population [pg. 3, col. 1, para 2; abstract]. Therefore, substantial experimentation would be required to identify suitable promoter, payload, target neuron, delivery location, and expression characteristics for each other numerous claimed neurological disorders.
Accordingly, in view of the limited amount of guidance provided by the specification and the art, one of ordinary skill in the art would conclude that Applicant was not in possession of the claimed invention.
Claims 1, 3, 5-6, 16, 18-20, 23, 25, 26, 29, 45-46, and 49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method to treat epilepsy comprising administering a vector comprising KCNA1/Kv1.1 or KCNJ2 operably linked to a c-Fos, Arc, ESARE, NRAM, or Erg1 promoter, does not reasonably provide enablement for the full breadth of the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Nature of the Invention
The claims encompass methods for treating a broad genus of neurological disorders associated with neuronal hyperexcitability using expression of a therapeutic gene of intermediate regulatory gene under the control of an activity-dependent promoter.
State of the Art
The art, as evidenced by Kawashima (Kawashima et al. Frontiers in neural circuits 8 (2014): 37) recognized that different activity promoters exhbit different cell-type specificity, expression patterns vary substantially between brain regions, selection of the appropriate promoter depends on the target neuronal subtype and brain region, and no universal activity-dependent promoter exists for all neuronal population [pg. 3, col. 1, para 2; abstract]. Therefore, substantial experimentation would be required to identify suitable promoter, payload, target neuron, delivery location, and expression characteristics for each other numerous claimed neurological disorders.
Breadth of the claims
The claims encompass treatment of numerous neurological disorders having substantially different disease mechanisms, target neuronal populations, numerous promoters, anatomical targets, therapeutic requirements, and molecular pathways,
Guidance of the Specification
The specification primarily describes and exemplifies treatment of epilepsy using expression of KCNA1/Kv1.1 or KCNJ2 constructs in hyperactive neurons. The specification does not provide representative species, or sufficient structural or functional guidance demonstrating possession of neurological disorders using the full scope of claimed therapeutic genes or intermediate regulatory genes. Furthermore, the specification encompasses any therapeutic gene product capable of ameliorating the disorder and any intermediate gene product capable of altering expression of such therapeutic gene products.
Experimentation Required
Accordingly, a person of ordinary skill in the art seeking to practice the full scope of the claimed invention would be required test every gene/promoter combination for their ability to treat all neurological disorders associated with neuronal hyperexcitability. The amount of experimentation required is substantial because the specification provides insufficient guidance for predicting which combinations will preserve the disclosed biological functions throughout the full scope of the claimed genus. The Supreme Court has further explained that a specification must enable the full scope of the claimed genus. See Amgen Inc. v. Sanofi. Because the present disclosure requires substantial screening to identify operative members of the claimed genus that retain the disclosed function, the specification does not enable the full scope of claim 1.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 16, 18-19, 46 and 49 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schorge (US 20210000977 A1).
Regarding claims 1, 3, 16, 18-19, and 46 Schorge teaches methods of treatment involving vector particles comprising an engineered KCNA1 gene encoding an edited Kvl.1 potassium ion channel, as well as methods of confirming the presence of engineered KCNA1 mRNA in a cell for the treatment of epilepsy and similar neurological disorders [abstract]. Schorge teaches that the gene can be linked to a promoter such as the CAMK2A promoter which is specific for excitatory neurons [0024, 0053].
Regarding claim 49, Schorge teaches the use of viral vectors including AAV for the delivery of therapeutic gene to neurons [0056].
Claim Rejections - 35 USC § 103
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.
Claims 1, 3, 5-6, 16, 18-20, 23, 46, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Schorge (US 20210000977 A1) in view of by Kawashima (Kawashima et al. Frontiers in neural circuits 8 (2014): 37), Morgan (Morgan et al. Science 237.4811 (1987): 192-197), GenBank: AF332140.1 (GenBank: AF332140.1. 2001. Mus musculus c-Fos (Fos) gene, 5' flanking and promoter regions), NP_000208.2 (NP_000208.2. potassium voltage-gated channel subfamily A member 1 [Homo sapiens] 2019), and Bhalla (Bhalla et al. Nature structural & molecular biology 11.10 (2004): 950-956. (Year: 2004)) and Guild et al (US 10,463,751 B2).
Regarding claims 1, 16, 18-19, and 46 Schorge teaches methods of treatment involving vector particles comprising an engineered KCNA1 gene encoding an edited Kvl.1 potassium ion channel, as well as methods of confirming the presence of engineered KCNA1 mRNA in a cell for the treatment of epilepsy and similar neurological disorders [abstract]. Schorge teaches that the gene can be linked to a promoter such as the CAMK2A promoter which is specific for excitatory neurons [0024, 0053]. NP_000208.2 teaches the amino acid sequence of human Kv1.1 potassium channel as a sequence which is 99.8% identical to the amino acid sequence shown in instant SEQ ID NO: 2; and SEQ ID NO: 1 encodes a KCNA1 gene that comprises a sequence that is 99.9% identical to SEQ ID NO: 2. Guild teaches a cDNA sequence of KCNA1 in Guild’s SEQ ID NO: 9261, which is 92% identical to the instant SEQ ID NO: 1. Thus Guild teaches an engineered KCNA1 gene with a nucleotide sequence having at least 90% sequence identity to the instant SEQ ID NO: 1.
Regarding claim 23, Schorge teaches that KCNA1 is an endogenous gene [01112, 0194].
Regarding claim 49, Schorge teaches the use of viral vectors including AAV for the delivery of therapeutic gene to neurons [0056].
Schorge does not expressly teach expression of the therapeutic gene under the control of an activity-dependent promoter, such as c-Fos. Schorge does not teach that the promoter has nucleotide sequence having at least 80% identity to SEQ ID NO: 3. Schorge does not teach where the Kv1.1 comprises a valine amino acid residue at a position corresponding to amino acid residue 400 shown in SEQ ID NO: 2.
Regarding claims 3 and 5, Kawashima teaches that neuronal immediate early promoters including, c-Fos, Arc/Arg3.1, Erg1m, and the synthetic E-SARE promoter area activity-dependent promoters activated by neuronal activity, synaptic activation and neuronal firing [pg. 1, col. 2, para 2; pg. 4, col. 2, para 2; . Kawashima further teaches that the promoters may be incorporated into viral vectors, including AAV, to selectively express genes in activated neuronal populations [pg. 4, col. 1, para 1].
Morgan teaches that seizure activity induces c-Fos expression within activated neuronal populations and demonstrate that c-Fos regulatory sequences respond to seizure activity [abstract].
Regarding claim 6, GenBank: AF332140.1 teaches a sequence, nucleotides 1410-1984, that is at least 80% identical to SEQ ID NO: 3.
Regarding claim 20, Bhalla teaches an RNA-editing-modified human Kv1.1 where the isoleucine at position 400 in wild type Kv1.1 is recoded to a valine (I400 to V400 mutation) (Fig. 1), thus teaches the amino acid sequence shown in instant SEQ ID NO: 2. Bhalla teaches that this I400V single amino acid mutation results in a 20-fold increase in the recovery rate (fig. 3C, page 952, col 1, line 1) and may be useful in neurological disorders associated with neuronal hyperexcitability (page 954, last para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the constitutive or cell-specific promoter employed by Schorge with one of the activity-dependent promoters taught by Kawashima such as c-Fos (or SEQ ID NO: 3), Arc/Arg3.1, Erg1m, and E-SARE, as further supported by Morgan’s demonstration that seizure activity activates c-Fos expression. One of ordinary skill would be motivated to make the modification for the advantage of selectively express the KCNA1 in pathologically active neurons. One of ordinary skill would have a reasonable expectations of success since Schorge, Kawashima, and Morgan all teach neuronal promoter gene expression.
Regarding claim 20, it would have been further been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the wild type Kv1.1 potassium channel for the mutated V400 channel disclosed by Bhalla, and a KCNA1 gene that is 90% identical to SEQ ID NO: 1, to improve the method of gene therapy with a reasonable expectation of success. Since Bhalla teaches the I400V mutation results in a 20-fold increase in the recovery rate and may be useful in neurological disorders associated with neuronal hyperexcitability, one of ordinary skill in the art would have been motivated to make these modifications in order to provide more active Kv1.1 potassium channel protein in treating epilepsy.
Claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Schorge (US 20210000977 A1) in view of by Kawashima (Kawashima et al. Frontiers in neural circuits 8 (2014): 37), Morgan (Morgan et al. Science 237.4811 (1987): 192-197), GenBank: AF332140.1 (GenBank: AF332140.1. 2001. Mus musculus c-Fos (Fos) gene, 5' flanking and promoter regions), NP_000208.2 (NP_000208.2. potassium voltage-gated channel subfamily A member 1 [Homo sapiens] 2019), and Bhalla (Bhalla et al. Nature structural & molecular biology 11.10 (2004): 950-956. (Year: 2004)) and Guild et al (US 10,463,751 B2) as applied to claim 1, and further in view of Hay (US 20200140885A1, filed 11/04/2019).
The teachings of Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla are discussed above as applied to claim 1 and similarly apply to claims 25-26.
Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla do not teach where intermediate gene is dCas9 or where the vector comprises a U6 polymerase III and a sgRNA ("single guide RNA") that targets the further gene.
Hay teaches a system of transcriptional regulation of a gene by use of a dCas9, which can be driven by the promoter of the essential gene, and a gRNA driven by U6 promoter control.
It would have been further been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include a dCas9 as an immediate gene and further include a U6 polymerase and a sgRNA targeting KCNA1 that in under the control of a U6 promoter as described by Hay in the method as taught by suggested by Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla for the advantage of transcriptional modulation of the KCNA1 gene and to allow for activity-dependent modulation of endogenous genes associated with neuronal excitability while retaining the selective expression in hyperactive neurons provided by the activity-dependent promoter system of Kawashima.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Schorge (US 20210000977 A1) in view of by Kawashima (Kawashima et al. Frontiers in neural circuits 8 (2014): 37), Morgan (Morgan et al. Science 237.4811 (1987): 192-197), GenBank: AF332140.1 (GenBank: AF332140.1. 2001. Mus musculus c-Fos (Fos) gene, 5' flanking and promoter regions), NP_000208.2 (NP_000208.2. potassium voltage-gated channel subfamily A member 1 [Homo sapiens] 2019), and Bhalla (Bhalla et al. Nature structural & molecular biology 11.10 (2004): 950-956. (Year: 2004)) and Guild et al (US 10,463,751 B2) as applied to claim 1, and further in view of Reijmers (Reijmers et al. Science 317.5842 (2007): 1230-1233) and Mansuy (Mansuy et al. Neuron 21.2 (1998): 257-265).
The teachings of Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla are discussed above as applied to claim 1 and similarly apply to claims 29.
Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla do not teach a first nucleotide sequence comprising a neuronal activity-dependent promoter suitable to drive expression of reverse tetracycline-controlled transactivator ("rtTA") in the subject's neural cells; and (b) a second nucleotide sequence comprising a Tet-On promoter suitable to drive expression of [[an]]the intermediate gene or the further gene where the expression system further comprises doxycycline.
Reijmers teaches an activity-dependent tetracycline responsive neuronal expression system in which the c-Fos promoter drive expression of a tetracycline transactivator in activated neurons, while a tetracycline-responsive promoter controls expression of a downstream reporter or effector gene [pg. 1230; Fig. 1]. Reijmers further teaches that this arrangement permits selective labeling and manipulation of activated neuronal populations and provides temporal control through tetracycline administration [abstract; pg. 1230; Fig. 1].
Mansuy teaches that to to obtain rapidly inducible and reversible expression of transgenes in the forebrain of the mouse, we have combined the reverse tetracycline-controlled trans activator (rtTA) system with the CaMKII promoter [abstract], thereby teaching the specific use of rtTA system in neurons and combining rtTA with neuronal promoters to achieve inducible and reversible gene expression in brain tissue. Mansuy teaches that doxycycline induces maximal gene expression in neurons of the forebrain and that this expression can be reversed by removal of doxycycline; and teaches a first nucleotide sequence comprising a neuronal activity-dependent driving rtTA expression and a second nucleotide sequence comprising a Tet-On promoter suitable driving the expression a downstream gene in the presence of doxycycline [Fig. 1].
It would have been further been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the first and second nucleotide sequence of Mansuy in the expression vector and substitute the neuronal CaMKIIa promoter driving rtTa/reporter gene in Mansuy with the neuronal activity-dependent promoters/ KCNA1, respectively, as taught and suggested by Schorge, Kawashima, Morgan and Reijmers; and additionally include a doxycycline construct in the expression vector in order to restrict induction of the Tet-On system to activated neuronal populations while retaining the temporal control afforded by doxycycline administration to control the expression of KCNA1. One of ordinary skill would have reasonable expectation of success because both Reijmers and Mansuy employ neuronal expression systems utilizing tetracycline-responsive regulation which could be utilized in the neuronal expression system of Schorge.
Claim 45 is rejected under 35 U.S.C. 103 as being unpatentable over Schorge (US 20210000977 A1) in view of by Kawashima (Kawashima et al. Frontiers in neural circuits 8 (2014): 37), Morgan (Morgan et al. Science 237.4811 (1987): 192-197), GenBank: AF332140.1 (GenBank: AF332140.1. 2001. Mus musculus c-Fos (Fos) gene, 5' flanking and promoter regions), NP_000208.2 (NP_000208.2. potassium voltage-gated channel subfamily A member 1 [Homo sapiens] 2019), and Bhalla (Bhalla et al. Nature structural & molecular biology 11.10 (2004): 950-956. (Year: 2004)) and Guild et al (US 10,463,751 B2) as applied to claim 1, and further in view of Krook-Magnuson (Krook-Magnuson et al. Nature communications 4.1 (2013): 1376).
The teachings of Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla are discussed above as applied to claim 1 and similarly apply to claims 45.
Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla do not teach a wherein the method of treatment is close-loop therapy.
Accordingly, the combined teaching of Schorge, Kawashima, Morgan results in a system in which increased neuronal activity activates the activity-dependent promoter, resulting in increased expression of therapeutic gene, subsequently suppresses neuronal activity and thereby reduces further promoter activation. Thus, the combined system inherently operates as a negative feedback or closed loop therapeutic system.
Krook-Magnuson further teaches that closed-loop therapeutic intervention in epilepsy provides advantages including limiting treatment to periods of pathological activity while minimizing effects on normal neuronal function. [abstract; pg. 2, col. 1, para 4; pg. 5, see discussion].
It would have been further been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the activity-dependent promoter system as taught and suggested by Schorge, Kawashima, Morgan, GenBank: AF332140.1, NP_000208.2, and Bhalla as a closed-loop therapeutic system as taught by Krook-Magnuson because the activity-dependent promoter would activate therapeutic gene expression only in response to pathological neuronal activity and thereby provide the same advantages of temporally restricted intervention taught by Krook-Magnuson.
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.
Claim 1, 3, 5-6, 16, 18-20, 23, 25, 26, 29, 45-46, and 49 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. US11779658B2 in view of Schorge (US 20210000977 A1), Kawashima (Kawashima et al. Frontiers in neural circuits 8 (2014): 37), Morgan (Morgan et al. Science 237.4811 (1987): 192-197), GenBank: AF332140.1 (GenBank: AF332140.1. 2001. Mus musculus c-Fos (Fos) gene, 5' flanking and promoter regions), NP_000208.2 (NP_000208.2. potassium voltage-gated channel subfamily A member 1 [Homo sapiens] 2019), and Bhalla (Bhalla et al. Nature structural & molecular biology 11.10 (2004): 950-956. (Year: 2004)) and Guild et al (US 10,463,751 B2) Hay (US 20200140885A1, filed 11/04/2019), Reijmers (Reijmers et al. Science 317.5842 (2007): 1230-1233) and Mansuy (Mansuy et al. Neuron 21.2 (1998): 257-265), and Krook-Magnuson (Krook-Magnuson et al. Nature communications 4.1 (2013): 1376). Claim 1 of the patent claims an expression vector comprising an engineered KCNA1 gene encoding an edited Kv1.1 potassium channel operably linked to a promoter suitable to drive expression of the edited Kv1.1 potassium channel in human cells, wherein the engineered KCNA1 gene has a nucleotide sequence comprising or consisting of the nucleotide sequence of SEQ ID NO: 1.
The patent does not teach the use of this system for in a method of treating epilepsy in a subject, where the promoter is a immediate early gene (IEG) promoter of C-Fos (SEQ ID NO: 3), Arc, ERG1, or E-SARE; wherein the edited K v 1.1 potassium channel has an amino acid sequence having at least 90% sequence identity to the amino acid sequence shown in SEQ ID NO: 2 and comprises a valine amino acid residue at a position corresponding to amino acid residue 400 shown in SEQ ID NO: 2; wherein the intermediate gene is dCAs9; the expression vector comprises a U6 polymerase, sgRNA, a first nucleotide sequence comprising a neuronal activity-dependent promoter suitable to drive expression of reverse tetracycline-controlled transacti vator ("rtT A") in the subject's neural cells, a second nucleotide sequence comprising a Tet-On promoter suitable to drive expression of the intermediate gene or the further gene, and doxycycline, the method of treatment is close-loop therapy
Regarding claims 1, 2, and 5, the teachings of Schorge, Kawashima and Morgan are discussed above. It would have been obvious to place the KCNA1 gene under the expression control of C-Fos (SEQ ID NO: 3), Arc, ERG1, or E-SARE and use it in a method of treating epilepsy as taught by Schorge and Kawashima. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since all references teach neuronal gene expression.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of all other references are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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, Jennifer Dunston can be reached at 571-272-2916. 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.
/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
Prosecution Insights