DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received on 3/19/2024. Claims 1-17 are pending. All pending claims are currently under examination.
Petition Status
The present application was previously abandoned 10/31/2024. The Applicant’s petition to revive the patent for examination was granted 12/18/2024.
Information Disclosure Statement
37 CFR 1.98(a)(1) requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. No Information Disclosure Statement has been filed with the present application, thus, no IDS has been considered.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5, 7, and 10-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to products of nature without significantly more.
Regarding claim 1, claim 1 recites a gene modulator of C9orf72 comprising a DNA-binding domain that binds to a target site of at least 12 bases of the C9orf72 gene and a transcriptional regulatory domain. Claim 1 is therefore drawn to a a composition of matter (Step 1 of Subject Matter Eligibility Test, MPEP 2106). Regarding the composition claimed, Yuva-Aydemir (Yuva-Aydemir Y et al. Nat Commun. 2019 Nov 29;10(1):5466) is a research article which focuses on the AFF2 elongation factor which binds to the C9orf72 gene (Title, Abstract, and throughout). Yuva-Aydemir teaches that:
“AFF2 preferentially regulates the transcription of the C9ORF72 allele containing expanded G4C2 repeats. AFF2 is a subunit of the SEC-like complex SEC-L2, which is required for transcription elongation of only a small subset of genes,” (page 8, right column, second paragraph).
Yuva-Aydemir therefore teaches the AFF2 gene modulator, which binds to the C9orf72 gene preferentially to expanded hexanucleotide repeats (i.e., binds at least 12 nucleotides), where furthermore AFF2 is transcriptional elongation factor (i.e., AFF2 comprises a transcriptional regulatory domain). Thus, claim 1 is drawn to the naturally occurring AAF2 DNA-binding elongation factor/transcriptional regulator (Step 2A, prong I). Regarding Steps 2A, prong II and Step 2B, claim 1 does not recite any additional limitations which would integrate the judicial exception into a practical application (Step 2A, prong II) or transform the claim into significantly more than the judicial exception because claim 1 does not recite markedly different characteristics compared with the naturally occurring AAF2 transcriptional sub-unit (Step 2B). Claim 1 is therefore not subject matter eligible.
Additionally, regarding claim 1, transcription factors which bind to the hexanucleotide repeat motifs of the C9orf72 gene (i.e., DNA-binding domains that target 12 nucleotides in the C9orf72 gene) and regulate transcription via a regulatory domain are naturally occurring products of nature as taught by Goodman (Goodman LD et al. Trends Genet. 2020 Feb;36(2):81-92). Goodman teaches the DNA-binding transcription factor DSIF, and that DSIF binds with the C9orf72 hexanucleotide repeat motif and modulates the expression of expanded C9orf72 (Abstract, page 5 third paragraph). Thus, DSIF is a “gene modulator” that binds to the C9orff72 gene via a DNA-binding domain and regulates the transcription of C9orf72 (Abstract, and page 5). Thus, DSIF reads on the structure of the claim language presently recited. Claim 1 is therefore also not subject matter eligible in view of the teachings of Goodman, as no other claim limitations which would integrate the subject matter into practical application or instill markedly different characteristics are present in the claim.
Regarding claim 2, as evidenced by Wenzel (Wenzel S et al.. Biochem Biophys Res Commun. 2008 Jun 6;370(3):414-8), the DSIF protein taught by Goodman comprises a Zinc Finger Protein (Wenzel Title, Abstract, and throughout). Thus, the limitations recited in claim 2 (“ZFP” ) are simple naturally occurring characteristics of DSIF. Claim 2 is therefore not subject matter eligible.
Regarding claim 3, Yuva-Aydemir teaches that AAF2 is an transcriptional elongation factor subunit and therefore teaches that AAF2 comprises an activation domain (page 8, right column, second paragraph). Thus, the additional features recited in claim 3 are simply characteristics of the naturally occurring AAF2 gene. Similarly, Goodman teaches that DSIF plays a role in the activation of the transcription of C9orf72 (Abstract and page 5). Claim 3 is not subject matter eligible.
Regarding claim 4, Yuva-Aydemir teaches that AAF2 is a gene encoded by the human genome (page 4, right column, fourth paragraph). Thus, AAF2 is encoded by a polynucleotide because it occurs in the human genome. Goodman teaches that DSIF is a canonical transcription factor regulating the human gene C9orf72; DSIF is therefore a gene encoded within the human genome. Claim 4 is therefore not subject matter eligible.
Regarding claims 5, the term “gene delivery vehicle” is not defined specifically in the specification. The instant specification recites “pharmaceutical compositions comprising one or more genetic modulators, one or more polynucleotides (e.g., gene delivery vehicles).” The specification therefore allows for a polynucleotide to be the “gene delivery vehicle,” (paragraph 22). As AAF2 and DSIF are encoded within the human genome, the genome itself which is comprised of polynucleotides can reasonably be interpreted to be a “gene delivery vehicle” in light of the specification (paragraph 22 of specification, page 4, right column, fourth paragraph of Yuva-Aydemir). Thus, the limitations of claim 5 are simply drawn to the naturally occurring AAF2 or DSIF genes encoded within the human genome. Similarly, the mRNA which encodes AAF2 or DSIF could be viewed as a “gene delivery vehicle.” Claim 5 is not subject matter eligible.
Regarding claim 7, the term “pharmaceutical composition” is defined in the specification as “a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals,” (paragraph 92). As such, the pharmaceutical composition can broadly be interpreted as a cell itself, as cells are know delivery compositions for biological compounds. Claim 7 is therefore simply drawn to a naturally occurring human cell expressing AAF2 or DSIF. Claim 7 is therefore not subject matter eligible.
Regarding claims 10-11, AAF2, the gene modulator of C9orf72, is naturally expressed within human cells (Yuva-Aydemir, page 4 right column, fourth paragraph, Goodman Abstract). Thus, claim 101-11 are broadly drawn to naturally occurring human cells. The subject matter of claims 10-11 is not subject matter eligible.
Claim Rejections - 35 USC § 102
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 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.
Claims 1-2, 4-12, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Miller (US 2015/0353917 A1).
Regarding claims 1-2, Miller teaches a gene modulator of C9orf72, where the modulator comprises a DNA-binding domain (“single guide RNA”) that binds to a target site in the C9orf72 gene and a nuclease domain (“Cas protein”) (see paragraphs 21-22). Given that Miller teaches a guide RNA targeting the C9orf72 gene and that Cas proteins are used to target/cleave DNA, a practitioner of ordinary skill in the art would immediately envision that the endogenous gene modifying systems in paragraph 22 comprising a functional domain which associates with the guide RNA is a Cas protein (paragraph 22). Furthermore, Miller teaches that the “spacer” domain, i.e., the targeting domain of the guide RNA, is between 10-30 nucleotides (paragraph 121). Miller therefore teaches that the DNA-binding domain binds to a target of at least 12 nucleotides.
Furthermore, Miller teaches that:
“Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disorder and is fatal for most patients less than three years from when the first symptoms appear. Generally, it appears that the development of ALS in approximately 90-95% of patients is completely random (sporadic ALS, sALS), with only 5-10% of patients displaying any kind of identified genetic risk (familial ALS, fALS). Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe,” (paragraph 91).
The practitioner can therefore immediately envision a gene modulator targeting C9orf72 comprising the components taught by Miller (nuclease domain, DNA-binding domain with at least 12 nucleotides) because 1) Miller teaches such a gene modulator in paragraph 22 and 2) Miller specifically highlights the C9orf72 gene and its role in ALS (paragraph 91).
Regarding claim 4, Miller teaches a polynucleotide encoding the genetic modulator of claim 1 (paragraph 22, “The first and second nucleic acids may be
on the same or different vectors”).
Regarding claims 5-6, Miller teaches that AAV vectors are used as gene delivery vehicles to deliver the genetic modulator (e.g., paragraphs 96-97, 229, 244, 247, and 255).
Regarding claim 7, Miller teaches that the components of their system can be formulated into pharmaceutical compositions for delivery (e.g., paragraphs 254-255, and 257).
Regarding claim 8, Miller teaches that the nuclease domain of the genetic modulator cleaves the target DNA, where the target gene can be C9orf72 (paragraphs 21-22).
Regarding claim 9, Miller teaches that a donor molecule is used to replace (i..e, is integrated) into the endogenous gene, which can be C9orf72 (paragraphs 22 and 34).
Regarding claims 10-11, Miller teaches that the delivery of their gene modulators can be ex vivo, and therefore teaches isolated cells comprising the components of claim 1 (paragraph 234).
Regarding claim 12, Miller teaches:
“a method of modifying an endogenous gene (e.g., modulating expression of the endogenous gene), the method comprising administering to the cell a first nucleic acid molecule comprising a single guide RNA that recognizes a target site in the endogenous gene and a second nucleic acid molecule that encodes a functional
domain, wherein the functional domain associates with the single guide RNA on the target site, thereby modifying the endogenous gene…the endogenous gene is…C9orf72,” (paragraph 22).
Miller therefore anticipates the method of claim 12.
Regarding claim 17, Miller teaches that the components of their methods and systems can be formulated into a kit (paragraph 45).
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.
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 3 and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Miller (US 2015/0353917 A1).
A discussion of Miller as it relates to claims 1-2, 4-12, and 17 as discussed in the 102 rejection is incorporated here.
Regarding claims 3 and 13-16, Miller teaches the system of claim 1 (paragraph 22). Furthermore, Miller also teaches that the Cas protein component of their system can be a catalytically dead Cas which represses/”inhibit” the transcription of the target gene/”gene expression” (paragraph 189). Thus, Miller teaches that their system can comprise a transcriptional regulatory domain which comprises a repression domain (paragraph 189). Furthermore, Miller also teaches that both transcriptional activation domains and repression domains can be incorporated into their system (e.g., paragraphs 27 and 193).
Furthermore, Miller teaches that:
“Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disorder and is fatal for most patients less than three years from when the first symptoms appear. Generally, it appears that the development of ALS in approximately 90-95% of patients is completely random (sporadic ALS, sALS), with only 5-10% of patients displaying any kind of identified genetic risk (familial ALS, fALS). Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe,” (paragraph 91).
Furthermore, Miller teaches that the administration can be intracranial (paragraph 251).
Miller teaches that C9orf72 is a leading cause of familial ALS, and teaches that C9orf72 can be targeted using their gene modulator system (paragraphs 91 and 22, respectively), and further teaches in vivo, intracranial delivery of their vectors, where furthermore Miller teaches that AAV vectors have been successfully delivered to the brain using known methods (paragraph 97). Miller therefore teaches that such gene targeting/gene therapy delivery vehicles are known to be predictable, as they have been reduced to practice in the brain successfully (paragraphs 97, and also “Gene therapy has been attempted for this disease were AAV comprising the AS PA gene was introduced into the brain with some success,” paragraph 96). Application of AAVs in methods to deliver genes to the brain are therefore known to work and have been reduced to practice (paragraphs 96-97).
With specific respect to the C9orf72 gene, Miller does not teach that the system comprises a repression domain, where the system was used to treat ALS.
It would have been obvious to a person of ordinary skill in the art before the filing of the present invention to modify the genetic modulator system taught by Miller to include a repression domain, as such a combination is the simple combination of known prior art elements with predictable success. In the present case, Miller has already taught that such repression domains can be incorporated into their system, either by incorporating such domains directly or by creating dead Cas nuclease variants which act as transcription repressors of gene expression. The combination of repressor domains to the specific context of the C9orf72 embodiment also taught by Miller is therefore both obvious and predictable. Furthermore, the practitioner is motivated to combine such repression domains because Miller teaches that the C9orf72 gene is a pathogenic allele that is known to be associated with the development of the disease ALS. The practitioner is therefore motivated to repress such a pathogenic allele to ameliorate or treat ALS.
Furthermore, regarding the limitation of claim 14, that both the sense and antisense strand are repressed, a practitioner can immediately envision such an embodiment because the mutant C9orf72 gene is known to be a pathogenic allele which causse ALS (Miller, above).
Claim Rejections - 35 USC § 112 – Written Description
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.
Claims 1-17 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.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making 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 Regents of the University of California v. Eli Lilly & Co, 119 F.3d at 1568, 43 USPQ2d at 1406.
Regarding claim 1, claim 1 is broadly drawn to a genus of gene modulator with specific regulatory domains which bind to the C9orf72 gene via a DNA-binding domain. Thus, claim 1 recites a genus of DNA-binding gene modulator, which can broadly be interpreted to be proteins such as transcription factors. Claim 1 is problematic because the art teaches that gene modulators which bind to C9orf72 are highly unpredictable and not fully understood. The specification does not show representative examples of the genus of gene modulator as a whole. The Applicant has therefore not shown possession of the scope of the claimed invention.
Regarding specific guidance in the specification, the specification offers Examples 1-4. Example 1 teaches artificial transcription factors which bind the C9orf72 gene (pages 74-78). Example 2 shows the specificity of C9orf72 repression using artificial transcripts (page 78). Example 3 shows gene modulation using the some of the systems of Example 1 in primary mouse neurons (page 78-79). Example 4 recites an in vivo model using the transcription factor systems in AAV expression constructs (pages 79-80). Although Example 4 alludes to data collected to show the efficacy of using the constructs, the data is not presented (see pages 79-80). Thus, the specification has reduced to practice a few working examples of gene modulators with DNA-binding domains which bind with the C9orf72 gene.
Regarding the state of the art, it is known in the art that gene modulators of the C9orf72 gene are highly unpredictable and furthermore uncharacterized. For instance, Yuva-Aydemir (Yuva-Aydemir Y et al. Nat Commun. 2019 Nov 29;10(1):5466) is a research article that focuses on transcription factors/elongation factors which associate with the C9orf72 gene (Title, Abstract, and throughout). Yuva-Aydemir teaches that it is largely unknown how RNAs comprising expanded G4C2 motifs such as those in the C9orf72 gene are transcribed (Abstract). Thus, gene modulators which bind DNA with regulatory domains (e.g., transcription factors) which interact with C9orf72 are a largely unclassified genus of proteins (Abstract, Yuva-Aydemir). Yuva-Aydemir teaches that the AFF2 protein binds with C9orf72, but teaches that empirical validation and experimental procedures were required to identify such a DNA-binding gene modulator (see Discussion). Thus, DNA-binding gene modulators are not inherently predictable, where Yuva-Aydemir teaches a post-filing teaching of AFF2, previously unknown to act as a DNA-binding gene modulator of C9orf72 (Abstract, Discussion).
Similarly, Goodman (Goodman LD et al. Trends Genet. 2020 Feb;36(2):81-92) teaches post-filing evidence of novel DNA-binding gene modulators which bind to C9orf72. For instance, Goodman teaches that the transcription factors DSIF and PAF1 are transcription factors which bind with C9orf72 (Abstract). Goodman also teaches that such binding to the repeat regions of C9orf72 by DSIF and PAF1 is a “novel role” for these “canonical” transcription factors (e.g., Title). Thus, Goodman teaches that known, canonical transcription factors have been discovered to act as gene modulators of C9orf72, where such factors were not previously known or understood to bind with C9orf72 and act as gene modulators (Title, Abstract). Thus, the evidence in the art, both Yuva-Aydemir and Goodman, teach post-filing discovery of previously unknown gene modulators which bind with C9orf72 using DNA binding domains, which further act as transcriptional regulators (“transcription regulatory domain,” as claimed in claim 1). The Applicant therefore did not show possession of the claimed genus of gene modulator which bind with C9orf72 because the art teaches that such transcription of such genes is largely unknown (Goodman, Abstract), where novel examples were discovered post-filing.
Claims 2-17 depend from claim 1 and do not resolve these 112(a) issues and are therefore also rejected.
Claim Rejections - 35 USC § 112 - Enablement
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.
Claims 12-16 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 of modulating C9orf72 gene expression in a cell in vitro or by direct administration to the brain (e.g., intracranially, claims 12-15) and treating ALS or FTD caused by mutations in C9orf72 by intracranial administration (claim 16), does not reasonably provide enablement for modulating gene expression of C9orf72 by general administration of a gene modulator in vivo (claims 12-15), or preventing ALS or FTD (claim 16), or for treating ALS/FTD caused by sporadic genetic changes not related to the C9orf72 gene (claim 16). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of these in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Nature of Invention/Breadth of Claims
Regarding claim 12, claim 12 is broadly drawn to a method of modulating gene expression of C9orf72 in a cell by administering the gene modulator of claim 1 into a cell. Claim 12 therefore broadly encompasses gene modulation of C9orf72 to a cell by methods such as intravenous administration in vivo, for instance as recited in dependent claim 15. This claim language is problematic because the specification is only enabling for in vitro gene modulation or gene modulation when the modulator of claim 1 is directly administered to the brain. Other in vivo delivery routes of administration (e.g., intracranial, intranasal) are not enabled because such methods of administration are known in the art to be unpredictable, where the practitioner suffers undue experimental burden to practice such a method (see below).
Regarding claim 16, claim 16 is broadly drawn to a method of treating or preventing either ALS or FTD by repressing C9orf72 using the system of claim 1. This claim language is problematic because ALS is known to be a sporadic disease caused by unknown factors which are not related to C9orf72. The method as recited in claim 16 would not reasonably treat ALS which is not caused by mutations in C9orf72. Furthermore, with respect to the limitation of “preventing” ALS/FTD, the specification does not show that even ALS caused by mutations in C9orf72 can be prevented by repressing the expression of C9orf72, as presently recited. The specification at most shows that ALS caused by pathogenic forms of the C9orf72 gene can be treated by administration of C9orf72 repressors such as those recited, but there is no evidence that ALS could be “prevented” by the administration of C9orf72 repressors.
Guidance in the Specification
Regarding specific guidance in the specification, the specification offers Examples 1-4. Example 1 teaches artificial transcription factors which bind the C9orf72 gene (pages 74-78). Example 2 shows the specificity of C9orf72 repression using artificial transcripts (page 78). Example 3 shows gene modulation using the some of the systems of Example 1 in primary mouse neurons (page 78-79). Example 4 recites an in vivo model using the transcription factor systems in AAV expression constructs (pages 79-80). Although Example 4 alludes to data collected to show the efficacy of using the constructs, the data is not presented (see pages 79-80).
Regarding claim 12, the specification does not teach or reduce to practice methods of administration which are not direct intracranial injections of the constructs of claim 1, nor does the specification demonstrate that efficient or effective local delivery of the recited gene modulators could reach the brain/target cells by broad administration methods (e.g., intravenous infusion).
The specification does not teach methods of preventing ALS or FTD, and furthermore does not teach that ALS/FTD which is caused by genes which are not C9orf72 could be treated using the methods of the application, nor does the specification demonstrate that treatment of ALS/FTD could be achieved using general administration methods (e.g., intravenous infusion).
State of the Art
Regarding the state of the art, it is known that generalized methods of administration for gene therapies are unpredictable and often ineffective. For instance, Ye (Ye D et al. Adv Drug Deliv Rev. 2024 Aug;211:115363) is a review article that focuses on the use of AAV vectors for the delivery of therapeutic payloads to the brain (Title, Abstract, and throughout). Ye teaches that “the blood–brain barrier (BBB) poses a significant challenge to successfully delivering AAV vectors to the brain,” (Abstract). Ye further teaches regarding intravenous injections of AAV vectors that:
“only a few of these naturally existing AAVs have demonstrated the capability to cross the BBB effectively and target the CNS. Recognizing these limitations, recent research efforts have been directed toward engineering novel AAV capsids capable of crossing the BBB to enhance brain transduction,” (page 4, right column, second paragraph).
Ye teaches that:
“AAV9 is a naturally exist AAV and was proven to achieve spreaded transduction in the brain. Although the mechanism remains unclear, it is believed that AAV9 crosses the BBB by active-transport mechanisms, such as receptor-mediated vesicular transport…However, although proven the most effective in transducing the brain, the transduction efficiency of IV administered AAV9 is age-dependent. AAV9 transgene is widely distributed in neonatal animals, predominantly in neurons across numerous brain regions (olfactory bulb, striatum, cerebral cortex, hippocampus, and brainstem). In contrast, most transduced cells for adult mice are glial (astrocytes or endothelial cells) with sparse neuronal transduction. For instance, one study found that when administered at birth, AAV9 infected approximately 60 % of motor neurons and 30 % of astrocytes in amyotrophic lateral sclerosis mice; however, when injected into the adult mice, AAV9 more efficiently transduced astrocytes (around 50 %), compared to motor neurons (8 %). Similar trends have also been observed in NHPs [47,64,67,69,74]. The mechanisms underlying these age-related differences in transduction are not fully
understood but could be related to developmental changes in the brain,” (page 4, right column, final paragraph).
Thus, Ye teaches that vector delivery mechanisms to the brain to deliver a gene therapy are known to be unreliable, where furthermore specifically engineered vectors are required in order to access the brain, where furthermore the exact mechanisms of blood-brain barrier crossing are unclear (above). Additionally, Ye teaches that, through an unknown mechanism, the specific cell-types which gene therapies efficiently target changes over time without known cause when using IV administration (above). Thus, Ye teaches a high degree of unpredictability and uncertainty when using generic delivery vectors with respect to functional and effective delivery to the brain using intravenous administration routes.
Similarly, Ye teaches regarding intranasal delivery of gene therapies that:
the mechanisms and distribution patterns of AAV in the brain post-IN delivery still require further exploration to fully leverage this promising delivery route,” (page 5, right column, second paragraph).
Thus, Ye teaches that distribution of gene therapies using intranasal administration (“IN”) relies upon an unknown and unpredictable mechanism. Ye therefore teaches inherent unpredictability when delivering a gene therapy to an intended cellular target in the brain.
Regarding claim 16, it is known that ALS is a complex disease which can be caused by a number of variable underlying factors. For instance, Miller (US 2015/0353917 A1) teaches that:
“Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disorder and is fatal for most patients less than three years from when the first symptoms appear. Generally, it appears that the development of ALS in approximately 90-95% of patients is completely random (sporadic ALS, sALS), with only 5-10% of patients displaying any kind of identified genetic risk (familial ALS, fALS). Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe,” (paragraph 91).
Thus, Miller teaches that 95% of ALS patients have “sporadic” ALS which is completely random and not associated with C9orf72. Thus, Miller teaches that there is a high degree of uncertainty that the present method would have an functional use when treating ALS that is not associated with a mutation in C9orf72 because the present treatment method specifically targets C9orf72 and not the other “random” causes of ALS.
Furthermore, given that most cases of ALS are sporadic and “random,” where the disease is only observed after onset of symptoms, the presently recited method is not enabled because such C9orf72 gene modulators would not ‘prevent” ALS in the vast majority of cases. Furthermore, even ALS cases which have pathogenic C9orf72 as an underlying cause could not be “prevented” by the administration of the recited gene modulators, where such administration would at best “treat” ALS symptoms but would not in fact prevent the onset of the disease, nor is a mechanism proposed in the specification which would ‘prevent” ALS by using a gene modulator which represses the expression of C9orf72. For instance, it is not reasonable to say that administering the gene modulators presently recited would prevent hexanucleotide expansion of the C9orf72.
Claim 16 also suffers from the issues of administration/delivery in methods which do not rely on direct administration to the brain as discussed in the teachings of Ye (above).
Experimental Burden
A practitioner is beset with experimental burden when attempting to practice the presently recited methods of the claims. For instance, the practitioner would be required to develop efficient and reliable administration methods to an in vivo organism to deliver the recited gene therapy gene modulators, where such in vivo delivery to the brain is known to be unpredictable and challenging as taught by Ye (above). The Applicant has not reasonably shown enablement of such a method by solving known issues associated with delivering gene therapies across the blood-brain barrier as taught by Ye. The practitioner would therefore be burdened by having to work out these known mechanistic issues in order to effectively practice the recited methods.
Additionally, there is no evidence that application of a C9orf72 gene modulator would work to treat sporadic ALS which is not caused by mutations in C9orf72. The practitioner could therefore not use the method as recited to generally treat or prevent ALS in sporadic cases.
Furthermore, even if the method as recited is used to “treat” ALS caused by pathogenic C9orf72 alleles, there is no evidence that such a method would “prevent” ALS, as repressing the pathogenic allele would at most treat the symptoms of ALS but not prevent its onset. The practitioner is therefore burdened with developing a method using the recited gene modulators to “prevent” ALS, where the outcome is not likely to produce a method of prevention as presently recited.
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 1-3 and 10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 8 of U.S. Patent No. US 12,139,517 B2 (reference ‘517). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-3, claim 1 of ‘517 recites:
“A fusion protein comprising a zinc finger protein (ZFP) DNA-binding domain and a transcription repressor domain, wherein the ZFP DNA-binding domain binds to a target site in a human C9orf72 gene”
‘517 therefore recites a gene modulator protein that is a ZFP (instant claim 2) comprising a DNA-binding domain and a repressor domain which binds C9orf72 (instant claim 1). Claim 3 of ‘517 recites that the binding protein binds 3 tandem repeats of a hexanucleotide and therefore recites that the complex binds to at least 12 nucleotides (instant claim 1).
Regarding claim 10, claim 8 of ‘517 recites:
“The fusion protein of claim 1, wherein the fusion protein represses both sense transcription and antisense transcription from the mutant C9orf72 allele in a human cell”
Claim 8 of ‘517 therefore recites that the repression occurs in a single cell; the practitioner can therefore envision an “isolated” cell, as recited in instant claim 10.
Claims 4-9 and 11-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 8 of U.S. Patent No. US 12,139,517 B2 (reference ‘517) in view of Miller (US 2015/0353917 A1).
A discussion of ‘517 as it relates to claims 1-3 and 10 is given above and incorporated here.
‘517 does not recite the claim elements of claims 4-9 and 11-17.
Milller is a patent document that teaches gene modulators to target C9orf72 (paragraph 22). Miller therefore directly overlaps with ‘517.
Regarding claim 4, Miller teaches a polynucleotide encoding the genetic modulator of claim 1 (paragraph 22, “The first and second nucleic acids may be
on the same or different vectors”).
Regarding claims 5-6, Miller teaches that AAV vectors are used as gene delivery vehicles to deliver the genetic modulator (e.g., paragraphs 96-97, 229, 244, 247, and 255).
Regarding claim 7, Miller teaches that the components of their system can be formulated into pharmaceutical compositions for delivery (e.g., paragraphs 254-255, and 257).
Regarding claim 8, Miller teaches that the nuclease domain of the genetic modulator cleaves the target DNA, where the target gene can be C9orf72 (paragraphs 21-22).
Regarding claim 9, Miller teaches that a donor molecule is used to replace (i..e, is integrated) into the endogenous gene, which can be C9orf72 (paragraphs 22 and 34).
Regarding claim 11, Miller teaches that the delivery of their gene modulators can be ex vivo, and therefore teaches isolated cells comprising the components of claim 1 (paragraph 234).
Regarding claim 12, Miller teaches:
“a method of modifying an endogenous gene (e.g., modulating expression of the endogenous gene), the method comprising administering to the cell a first nucleic acid molecule comprising a single guide RNA that recognizes a target site in the endogenous gene and a second nucleic acid molecule that encodes a functional
domain, wherein the functional domain associates with the single guide RNA on the target site, thereby modifying the endogenous gene…the endogenous gene is…C9orf72,” (paragraph 22).
Miller therefore teaches the method of claim 12.
Regarding claims 13-16, Miller teaches the system of claim 1 (paragraph 22). Furthermore, Miller also teaches that the Cas protein component of their system can be a catalytically dead Cas which represses/”inhibit” the transcription of the target gene/”gene expression” (paragraph 189). Thus, Miller teaches that their system can comprise a transcriptional regulatory domain which comprises a repression domain (paragraph 189). Furthermore, Miller also teaches that both transcriptional activation domains and repression domains can be incorporated into their system (e.g., paragraphs 27 and 193).
Furthermore, Miller teaches that:
“Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disorder and is fatal for most patients less than three years from when the first symptoms appear. Generally, it appears that the development of ALS in approximately 90-95% of patients is completely random (sporadic ALS, sALS), with only 5-10% of patients displaying any kind of identified genetic risk (familial ALS, fALS). Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe,” (paragraph 91).
Furthermore, Miller teaches that the administration can be intracranial (paragraph 251).
Miller teaches that C9orf72 is a leading cause of familial ALS, and teaches that C9orf72 can be targeted using their gene modulator system (paragraphs 91 and 22, respectively), and further teaches in vivo, intracranial delivery of their vectors, where furthermore Miller teaches that AAV vectors have been successfully delivered to the brain using known methods (paragraph 97). Miller therefore teaches that such gene targeting/gene therapy delivery vehicles are known to be predictable, as they have been reduced to practice in the brain successfully (paragraphs 97, and also “Gene therapy has been attempted for this disease were AAV comprising the AS PA gene was introduced into the brain with some success,” paragraph 96). Application of AAVs in methods to deliver genes to the brain are therefore known to work and have been reduced to practice (paragraphs 96-97).
With specific respect to the C9orf72 gene, Miller does not teach that the system comprises a repression domain, where the system was used to treat ALS.
‘517 teaches that the system comprises a repression domain (claim 1).
It would have been obvious to a person of ordinary skill in the art before the filing of the present invention to modify the genetic modulator system taught by ‘517 to be used in a method to repress gene expression of C9orf72 to treat ALS, as such a combination is the simple combination of known prior art elements with predictable success. In the present case, Miller has already taught that such repression domains can be incorporated into their system, either by incorporating such domains directly or by creating dead Cas nuclease variants which act as transcription repressors of gene expression. The results are therefore predictable. Furthermore, Miller teaches ALS is caused by mutations in C9orf72, which would motivated the practitioner to target this gene for treatment of ALS in a cell. The claim elements of for instance claims 4 and 5, where the components are encoded in a gene delivery vector, are obvious in light of Miller, as such components are simply known art elements to reduce to practice practical embodiments of such systems (i.e., encoding the protein in nucleic acid as in claim 4 or delivering the therapeutic using a vector as in claim 5).
Furthermore, regarding the limitation of claim 14, that both the sense and antisense strand are repressed, claim 8 of ‘517 teaches that both sense and antisense strands of C9orf72 are targeted.
Regarding claim 17, Miller teaches that the components of their methods and systems can be formulated into a kit (paragraph 45).
Claims 1-3 and 10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 8 of copending Application No. 18/943,130 (‘130, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-3, claim 1 of ‘130 recites:
“A fusion protein comprising a zinc finger protein (ZFP) DNA-binding domain and a transcription repressor domain, wherein the ZFP DNA-binding domain binds to a target site in a human C9orf72gene.”
‘130 therefore recites a gene modulator protein that is a ZFP (instant claim 2) comprising a DNA-binding domain and a repressor domain which binds C9orf72 (instant claim 1). Claim 3 of ‘130 recites that the binding protein binds 3 tandem repeats of a hexanucleotide and therefore recites that the complex binds to at least 12 nucleotides (instant claim 1).
Regarding claim 10, claim 8 of ‘130 recites:
“the fusion protein of claim 1, wherein the fusion protein represses both sense transcription and antisense transcription from the mutant C9orf72 allele in a human cell.”
Claim 8 of ‘130 therefore recites that the repression occurs in a single cell; the practitioner can therefore envision an “isolated” cell, as recited in instant claim 10.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 4-9 and 11-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 8 of copending Application No. 18/943,130 (‘130) in view of Miller ((US 2015/0353917 A1).
A discussion of ‘130 as it relates to claims 1-3 and 10 is given above and incorporated here.
‘130 does not recite the claim elements of claims 4-9 and 11-17.
Milller is a patent document that teaches gene modulators to target C9orf72 (paragraph 22). Miller therefore directly overlaps with ‘130.
Regarding claim 4, Miller teaches a polynucleotide encoding the genetic modulator of claim 1 (paragraph 22, “The first and second nucleic acids may be
on the same or different vectors”).
Regarding claims 5-6, Miller teaches that AAV vectors are used as gene delivery vehicles to deliver the genetic modulator (e.g., paragraphs 96-97, 229, 244, 247, and 255).
Regarding claim 7, Miller teaches that the components of their system can be formulated into pharmaceutical compositions for delivery (e.g., paragraphs 254-255, and 257).
Regarding claim 8, Miller teaches that the nuclease domain of the genetic modulator cleaves the target DNA, where the target gene can be C9orf72 (paragraphs 21-22).
Regarding claim 9, Miller teaches that a donor molecule is used to replace (i..e, is integrated) into the endogenous gene, which can be C9orf72 (paragraphs 22 and 34).
Regarding claim 11, Miller teaches that the delivery of their gene modulators can be ex vivo, and therefore teaches isolated cells comprising the components of claim 1 (paragraph 234).
Regarding claim 12, Miller teaches:
“a method of modifying an endogenous gene (e.g., modulating expression of the endogenous gene), the method comprising administering to the cell a first nucleic acid molecule comprising a single guide RNA that recognizes a target site in the endogenous gene and a second nucleic acid molecule that encodes a functional
domain, wherein the functional domain associates with the single guide RNA on the target site, thereby modifying the endogenous gene…the endogenous gene is…C9orf72,” (paragraph 22).
Miller therefore teaches the method of claim 12.
Regarding claims 13-16, Miller teaches the system of claim 1 (paragraph 22). Furthermore, Miller also teaches that the Cas protein component of their system can be a catalytically dead Cas which represses/”inhibit” the transcription of the target gene/”gene expression” (paragraph 189). Thus, Miller teaches that their system can comprise a transcriptional regulatory domain which comprises a repression domain (paragraph 189). Furthermore, Miller also teaches that both transcriptional activation domains and repression domains can be incorporated into their system (e.g., paragraphs 27 and 193).
Furthermore, Miller teaches that:
“Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disorder and is fatal for most patients less than three years from when the first symptoms appear. Generally, it appears that the development of ALS in approximately 90-95% of patients is completely random (sporadic ALS, sALS), with only 5-10% of patients displaying any kind of identified genetic risk (familial ALS, fALS). Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe,” (paragraph 91).
Furthermore, Miller teaches that the administration can be intracranial (paragraph 251).
Miller teaches that C9orf72 is a leading cause of familial ALS, and teaches that C9orf72 can be targeted using their gene modulator system (paragraphs 91 and 22, respectively), and further teaches in vivo, intracranial delivery of their vectors, where furthermore Miller teaches that AAV vectors have been successfully delivered to the brain using known methods (paragraph 97). Miller therefore teaches that such gene targeting/gene therapy delivery vehicles are known to be predictable, as they have been reduced to practice in the brain successfully (paragraphs 97, and also “Gene therapy has been attempted for this disease were AAV comprising the AS PA gene was introduced into the brain with some success,” paragraph 96). Application of AAVs in methods to deliver genes to the brain are therefore known to work and have been reduced to practice (paragraphs 96-97).
With specific respect to the C9orf72 gene, Miller does not teach that the system comprises a repression domain, where the system was used to treat ALS.
‘130 teaches that the system comprises a repression domain (claim 1).
It would have been obvious to a person of ordinary skill in the art before the filing of the present invention to modify the genetic modulator system taught by ‘130 to be used in a method to repress gene expression of C9orf72 to treat ALS, as such a combination is the simple combination of known prior art elements with predictable success. In the present case, Miller has already taught that such repression domains can be incorporated into their system, either by incorporating such domains directly or by creating dead Cas nuclease variants which act as transcription repressors of gene expression. The results are therefore predictable. Furthermore, Miller teaches ALS is caused by mutations in C9orf72, which would motivated the practitioner to target this gene for treatment of ALS in a cell. The claim elements of for instance claims 4 and 5, where the components are encoded in a gene delivery vector, are obvious in light of Miller, as such components are simply known art elements to reduce to practice practical embodiments of such systems (i.e., encoding the protein in nucleic acid as in claim 4 or delivering the therapeutic using a vector as in claim 5).
Furthermore, regarding the limitation of claim 14, that both the sense and antisense strand are repressed, claim 8 of ‘130 teaches that both sense and antisense strands of C9orf72 are targeted.
Regarding claim 17, Miller teaches that the components of their methods and systems can be formulated into a kit (paragraph 45).
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 and 10-17 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8, 17-18, 24-25, 27, and 30 of copending Application No. 18/942,681 (‘681, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-4, claim 1 of ‘681 recites:
“A nucleic acid construct comprising a coding sequence for a fusion protein comprising a zinc finger protein (ZFP) domain and a transcription repressor domain, wherein the coding sequence is linked operably to a transcription regulatory element, wherein the ZFP DNA-binding domain binds to a target site in a human C9orf72 gene”
Thus, the fusion protein encoded by a nucleic acid recited in claim 1 of ‘681 anticipates the presently recited fusion protein, as ‘681 recites a fusion protein (gene modulator) comprising a ZFP (instant claim 2) and transcription repressor domain (instant claim 3) which targets the C9orf72 gene (instant claim 1). Furthermore, claim 3 of ‘681 recites that the fusion protein binds to 3 hexanucleotide repeats, and therefore binds to at least 12 nucleotides as recited in instant claim 1. Furthermore, given that instant claim 1 recites a nucleic acid encoding the fusion protein, the practitioner can immediately envision the fusion protein.
Regarding claim 4, claim 4 of ‘681 recites that the fusion protein is encoded in a nucleic acid.
Regarding claims 5-6, claim 17 of ‘681 recites that the nucleic acid is in an AAV viral construct (i.e., a gene delivery vector).
Regarding claims 7, claim 24 of ‘681 recites that the nucleic acid is in a pharmaceutically acceptable carrier.
Regarding claims 10-11, claim 18 of ‘681 recites that the constructs can be in a host cell (i.e., an isolated cell).
Regarding claims 12-13, claim 25 of ‘681 recites a method of inhibiting/repressing C9orf72 in a cell by introducing the construct of claim 1.
Regarding claim 14, claim 8 of ‘681 recites that both the sense and antisense strand can be repressed.
Regarding claim 15, claim 30 of ‘681 recites that the composition can be administered intracranially.
Regarding claim 16, claim 27 of ‘681 recites that the subject is suffering from ALS; the practitioner can therefore immediately envision that the composition is administered to treat ALS.
Regarding claim 17, as ‘681 recites the components of claim 6, the practitioner can immediately envision the components in a “kit” which is broadly interpreted to simply refer to the recited components.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 8-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 24 of copending Application No. 18/942,681 (‘681, reference application) in view of Miller ((US 2015/0353917 A1).
Regarding claims 1, 4, and 7, a discussion of ‘681 as it relates to these claims is given above.
Regarding claims 8-9, ‘681 does not recite that the composition comprises a nuclease domain that cleaves C9orf72 (claim 8) or that the composition comprises a donor template (claim 9).
Milller is a patent document that teaches gene modulators to target C9orf72 (paragraph 22). Miller therefore directly overlaps with ‘681.
Regarding claim 8, Miller teaches that the nuclease domain of the genetic modulator cleaves the target DNA, where the target gene can be C9orf72 (paragraphs 21-22).
Regarding claim 9, Miller teaches that a donor molecule is used to replace (i..e, is integrated) into the endogenous gene, which can be C9orf72 (paragraphs 22 and 34).
It would have been obvious to a person of ordinary skill in the art before the filing date of ‘681 to modify the pharmaceutical composition of ‘681 to include a nuclease domain that cleaves C9orf72 and also a donor template, as taught by Miller, because such a combination is the simple combination of known prior art elements with predictable success. Furthermore, the practitioner is motivated to adopt the teachings of Miller because Miller teaches that such embodiments are useful for targeting the known C9orf72 pathogenic allele.
This is a provisional nonstatutory double patenting rejection.
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-29 of copending Application No. 18/980,517 (‘517, reference patent) in view of Miller (US 2015/0353917 A1).
Regarding claim 1, claim 13 of ‘517 recites:
“A method of modulating gene expression in a cell, the method comprising: introducing a composition comprising two or more artificial transcription factors into the cell, wherein each artificial transcription factor comprises a DNA-binding domain and functional domain, wherein the artificial transcription factors synergistically modulate gene expression in the cell.”
Claim 19 of ‘517 recites that ALS is targeted/treated using the method and components of claim 13 of ‘517 by targeting the C9orf72 gene, where the gene is targeted for repression.
‘517, while reciting that C9orf72 is repressed, does not specifically recite that the functional domain is a regulatory domain such as a Cas protein or repressor. ‘517 does not recite that the DNA-binding domain binds at least 12 nucleotides.
Milller is a patent document that teaches gene modulators to target C9orf72 (paragraph 22). Miller therefore directly overlaps with ‘517.
Miller teaches a gene modulator of C9orf72, where the modulator comprises a DNA-binding domain (“single guide RNA”) that binds to a target site in the C9orf72 gene and a nuclease domain (“Cas protein”) (see paragraphs 21-22). Given that Miller teaches a guide RNA targeting the C9orf72 gene and that Cas proteins are used to target/cleave DNA, a practitioner of ordinary skill in the art would immediately envision that the endogenous gene modifying systems in paragraph 22 comprising a functional domain which associates with the guide RNA is a Cas protein (paragraph 22). Furthermore, Miller teaches that the “spacer” domain, i.e., the targeting domain of the guide RNA, is between 10-30 nucleotides (paragraph 121). Miller therefore teaches that the DNA-binding domain binds to a target of at least 12 nucleotides.
Furthermore, Miller teaches that:
“Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset motor neuron disorder and is fatal for most patients less than three years from when the first symptoms appear. Generally, it appears that the development of ALS in approximately 90-95% of patients is completely random (sporadic ALS, sALS), with only 5-10% of patients displaying any kind of identified genetic risk (familial ALS, fALS). Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe,” (paragraph 91).
The practitioner can therefore immediately envision a gene modulator targeting C9orf72 comprising the components taught by Miller (nuclease domain, DNA-binding domain with at least 12 nucleotides) because 1) Miller teaches such a gene modulator in paragraph 22 and 2) Miller specifically highlights the C9orf72 gene and its role in ALS (paragraph 91).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the artificial transcription factors of ‘517 to include DNA-binding domains that target at least 12 nucleotides of C9orf72, as taught by Miller, because such a combination is the simple combination of known prior art elements with predictable results. In the present case, Miller teaches that such embodiments using gene modulators that target the C9orf72 gene are useful for treatments of ALS.
Regarding claim 2, as discussed above, Miller teaches that the system comprises single guide RNAs (paragraph 22).
Regarding claim 3, claim 19 of ‘517 recites that C9orf72. Furthermore, Miller teaches that their systems are compatible with repressor domain fusions (paragraph 27). The practitioner can therefore immediately envision that the C9orf72 gene is repressed, as ‘517 recites that the gene is repressed, where furthermore Miller teaches that the recited systems are compatible with repressor domain fusions.
Regarding claim 4, claim 15 of ‘517 recites that the composition is encoded in a polynucleotide.
Regarding claims 5-6, claim 17 of ‘517 recites that the composition is in a gene delivery vehicle such as an AAV.
Regarding claim 7, the composition of claim 7 is rendered obvious by the combination of ‘517 and Miller (claim 1, above). Furthermore, claim 21 of ‘517 recites that the composition is administered to a subject. A practitioner would therefore immediately understand that the composition is administered in a “pharmaceutical composition” as the composition is administered to in the context of diseased subjects (claims 19 and 21 of ‘517).
Regarding claim 8, Miller teaches that the nuclease domain of the genetic modulator cleaves the target DNA, where the target gene can be C9orf72 (paragraphs 21-22).
Regarding claim 9, Miller teaches that a donor molecule is used to replace (i..e, is integrated) into the endogenous gene, which can be C9orf72 (paragraphs 22 and 34).
Regarding claims 8-9, it would be obvious to a person of ordinary skill in the art to modify the artificial transcription factors taught by ‘517 to comprise nuclease domains that cleave the gene and a donor molecue, as taught by Miller, because Miller teaches that such embodiments of gene modulators are useful for targeting a specific target.
Regarding claims 10-11, claim 13 of ‘517 recites that the method occurs in a “cell.” The practitioner can therefore immediately envision one such cell undergoing the method of claim 13 of ‘517.
Regarding claim 12-13, claim 13 of ‘517 is directed to a method of modulating the expression of a gene in a cell, where claim 19 of ‘517 is directed to modulating expression of the C9orf72 gene by repressing the gene within a cell.
Regarding claim 14, a practitioner can immediately envision targeting both the sense and antisense strands because the C9orf72 gene is known to be a pathogenic allele which causse ALS, as taught by Miller. The practitioner is therefore motivated to target both strands of the pathogenic allele.
Regarding claim 15, claim 22 of ‘517 recites intracranial administration.
Regarding claim 16, claim 19 of ‘517 recites that the subject has ALS and that the method is a treatment of ALS.
Regarding claim 17, Miller teaches that the components of their methods and systems can be formulated into a kit (paragraph 45).
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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